Conference Coverage

Eribulin seems to be an equally effective chemotherapy to pair with a dual HER2 blockade as taxane as first-line treatment for women with HER2-positive, locally advanced or metastatic breast cancer.

The results of this multicenter, randomized, open-label, parallel-group, phase 3 Japanese trial suggest that patients who cannot tolerate the standard taxane-based regimen have a new option for treatment.

“Our study is the first to show the non-inferiority of eribulin to a taxane, when used in combination with dual HER2 blockade as first-line treatment for this population,” lead author Toshinari Yamashita, MD, PhD, from the Kanagawa Cancer Center, in Kanagawa, Japan, said at the annual meeting of the American Society of Clinical Oncology.

“To our knowledge, noninferiority of eribulin to a taxane when used in combination with dual HER2 blockade has not been investigated,” Dr. Yamashita said.

“The combination of trastuzumab, pertuzumab, and taxane is a current standard first-line therapy for recurrent or metastatic HER2-positive breast cancer,” explained Dr. Yamashita. “However, because of taxane-induced toxicity, the development of less toxic but equally effective alternatives are needed.

“Because its efficacy is comparable to that of the current standard regimen, the combination of eribulin, trastuzumab, and pertuzumab is one of the options for first-line treatment of how to fight locally advanced or metastatic breast cancer,” he continued.
 

Study Results and Methods

The trial enrolled 446 patients, mean age 56 years, all of whom had locally advanced or metastatic breast cancer and no prior use of chemotherapy, excluding T-DM1. Patients who had received hormonal or HER2 therapy alone or the combination, as treatment for recurrence, were also eligible.

They were randomized 1:1 to receive a 21-day chemotherapy cycle of either (i) eribulin (1.4 mg/m² on days 1 and 8), or (ii) a taxane (docetaxel 75 mg/m² on day 1 or paclitaxel 80 mg/m² on days 1, 8 and 15), each being administered in combination with a dual HER2 blockade of trastuzumab plus pertuzumab.

Baseline characteristics of both groups were well balanced, with 257 (57.6%) having ER-positive disease, 292 (65.5%) visceral metastasis, and 263 (59%) with de novo stage 4 disease, explained Dr. Yamashita.

For the primary endpoint, the median progression-free survival (PFS) was 14 versus 12.9 months in the eribulin and taxane group, respectively (hazard ratio [HR] 0.95, P = .6817), confirming non-inferiority of the study regimen, he reported.

The clinical benefit rate was similar between the two groups, with an objective response rate of 76.8% in the eribulin group and 75.2% in the taxane group.

Median OS was 65.3 months in the taxane group, but has not been reached in the study group (HR 1.09).

In terms of side-effects, the incidence of treatment-emergent adverse events was similar between the eribulin and taxane groups (58.9% vs 59.2%, respectively, for grade 3 or higher).

“Skin-related adverse events (62.4% vs 40.6%), diarrhea (54.1% vs 36.6%), and edema (42.2% vs 8.5%) tend to be more common with taxane, whereas neutropenia (61.6% vs 30.7%) and peripheral neuropathy (61.2% vs 52.8%) tend to be more common with eribulin use,” he said.

Overall, “these results suggest that eribulin is less toxic chemotherapeutic partner for dual HER2 blockade and can be used for a longer,” he said.
 

Findings Are a ‘Clinical Pearl’

Harold Burstein, MD, PhD, a breast cancer expert at Dana-Farber Cancer Institute and professor at Harvard Medical School in Boston, described the findings as “a nice clinical pearl,” because some patients do not tolerate taxane therapy. “In such cases, you can substitute eribulin, which is usually tolerated without allergic hypersensitivity issues,” he said in an interview.

Eribulin has specific properties that “could make it a perfect candidate” as an adjunct to standard treatment regimens across different breast cancer subtypes, observed Wynne Wijaya, MD an oncology researcher at the University of Oxford, England, and Universitas Gadjah Mada, in Yogyakarta, Indonesia, in a recent review (World J Exp Med. 2024;14[2]:92558).

Dr. Wijaya, who was not involved in this study, said in an interview that the findings have important implications.

“This encouraging result adds eribulin as another option in the first line treatment regimen for patients with HER2-positive, locally advanced or metastatic breast cancer, especially in terms of side effects/toxicities,” she said. “As clinicians, we can offer to tailor the choice of therapy between eribulin versus taxane in the regimen based on [which side effects patients are better able to tolerate]. It would also be interesting and worthwhile to conduct similar trials in different types of populations to provide more robust evidence.”

Eisai Co. funded the research. Dr. Yamashita disclosed ties with AstraZeneca, Chugai Pharma, Daiichi Sankyo, Eisai, Kyowa Hakko Kiri, Lilly, MSD, Pfizer, Taiho, Gilead Sciences, Nihonkayaku, Ono Yakuhin, and Seagen. Dr. Burstein disclosed a research grant from National Cancer Institute. Dr. Wijaya had no relevant disclosures.

Eribulin seems to be an equally effective chemotherapy to pair with a dual HER2 blockade as taxane as first-line treatment for women with HER2-positive, locally advanced or metastatic breast cancer.

The results of this multicenter, randomized, open-label, parallel-group, phase 3 Japanese trial suggest that patients who cannot tolerate the standard taxane-based regimen have a new option for treatment.

“Our study is the first to show the non-inferiority of eribulin to a taxane, when used in combination with dual HER2 blockade as first-line treatment for this population,” lead author Toshinari Yamashita, MD, PhD, from the Kanagawa Cancer Center, in Kanagawa, Japan, said at the annual meeting of the American Society of Clinical Oncology.

“To our knowledge, noninferiority of eribulin to a taxane when used in combination with dual HER2 blockade has not been investigated,” Dr. Yamashita said.

“The combination of trastuzumab, pertuzumab, and taxane is a current standard first-line therapy for recurrent or metastatic HER2-positive breast cancer,” explained Dr. Yamashita. “However, because of taxane-induced toxicity, the development of less toxic but equally effective alternatives are needed.

“Because its efficacy is comparable to that of the current standard regimen, the combination of eribulin, trastuzumab, and pertuzumab is one of the options for first-line treatment of how to fight locally advanced or metastatic breast cancer,” he continued.
 

Study Results and Methods

The trial enrolled 446 patients, mean age 56 years, all of whom had locally advanced or metastatic breast cancer and no prior use of chemotherapy, excluding T-DM1. Patients who had received hormonal or HER2 therapy alone or the combination, as treatment for recurrence, were also eligible.

They were randomized 1:1 to receive a 21-day chemotherapy cycle of either (i) eribulin (1.4 mg/m² on days 1 and 8), or (ii) a taxane (docetaxel 75 mg/m² on day 1 or paclitaxel 80 mg/m² on days 1, 8 and 15), each being administered in combination with a dual HER2 blockade of trastuzumab plus pertuzumab.

Baseline characteristics of both groups were well balanced, with 257 (57.6%) having ER-positive disease, 292 (65.5%) visceral metastasis, and 263 (59%) with de novo stage 4 disease, explained Dr. Yamashita.

For the primary endpoint, the median progression-free survival (PFS) was 14 versus 12.9 months in the eribulin and taxane group, respectively (hazard ratio [HR] 0.95, P = .6817), confirming non-inferiority of the study regimen, he reported.

The clinical benefit rate was similar between the two groups, with an objective response rate of 76.8% in the eribulin group and 75.2% in the taxane group.

Median OS was 65.3 months in the taxane group, but has not been reached in the study group (HR 1.09).

In terms of side-effects, the incidence of treatment-emergent adverse events was similar between the eribulin and taxane groups (58.9% vs 59.2%, respectively, for grade 3 or higher).

“Skin-related adverse events (62.4% vs 40.6%), diarrhea (54.1% vs 36.6%), and edema (42.2% vs 8.5%) tend to be more common with taxane, whereas neutropenia (61.6% vs 30.7%) and peripheral neuropathy (61.2% vs 52.8%) tend to be more common with eribulin use,” he said.

Overall, “these results suggest that eribulin is less toxic chemotherapeutic partner for dual HER2 blockade and can be used for a longer,” he said.
 

Findings Are a ‘Clinical Pearl’

Harold Burstein, MD, PhD, a breast cancer expert at Dana-Farber Cancer Institute and professor at Harvard Medical School in Boston, described the findings as “a nice clinical pearl,” because some patients do not tolerate taxane therapy. “In such cases, you can substitute eribulin, which is usually tolerated without allergic hypersensitivity issues,” he said in an interview.

Eribulin has specific properties that “could make it a perfect candidate” as an adjunct to standard treatment regimens across different breast cancer subtypes, observed Wynne Wijaya, MD an oncology researcher at the University of Oxford, England, and Universitas Gadjah Mada, in Yogyakarta, Indonesia, in a recent review (World J Exp Med. 2024;14[2]:92558).

Dr. Wijaya, who was not involved in this study, said in an interview that the findings have important implications.

“This encouraging result adds eribulin as another option in the first line treatment regimen for patients with HER2-positive, locally advanced or metastatic breast cancer, especially in terms of side effects/toxicities,” she said. “As clinicians, we can offer to tailor the choice of therapy between eribulin versus taxane in the regimen based on [which side effects patients are better able to tolerate]. It would also be interesting and worthwhile to conduct similar trials in different types of populations to provide more robust evidence.”

Eisai Co. funded the research. Dr. Yamashita disclosed ties with AstraZeneca, Chugai Pharma, Daiichi Sankyo, Eisai, Kyowa Hakko Kiri, Lilly, MSD, Pfizer, Taiho, Gilead Sciences, Nihonkayaku, Ono Yakuhin, and Seagen. Dr. Burstein disclosed a research grant from National Cancer Institute. Dr. Wijaya had no relevant disclosures.

Eribulin seems to be an equally effective chemotherapy to pair with a dual HER2 blockade as taxane as first-line treatment for women with HER2-positive, locally advanced or metastatic breast cancer.

The results of this multicenter, randomized, open-label, parallel-group, phase 3 Japanese trial suggest that patients who cannot tolerate the standard taxane-based regimen have a new option for treatment.

“Our study is the first to show the non-inferiority of eribulin to a taxane, when used in combination with dual HER2 blockade as first-line treatment for this population,” lead author Toshinari Yamashita, MD, PhD, from the Kanagawa Cancer Center, in Kanagawa, Japan, said at the annual meeting of the American Society of Clinical Oncology.

“To our knowledge, noninferiority of eribulin to a taxane when used in combination with dual HER2 blockade has not been investigated,” Dr. Yamashita said.

“The combination of trastuzumab, pertuzumab, and taxane is a current standard first-line therapy for recurrent or metastatic HER2-positive breast cancer,” explained Dr. Yamashita. “However, because of taxane-induced toxicity, the development of less toxic but equally effective alternatives are needed.

“Because its efficacy is comparable to that of the current standard regimen, the combination of eribulin, trastuzumab, and pertuzumab is one of the options for first-line treatment of how to fight locally advanced or metastatic breast cancer,” he continued.
 

Study Results and Methods

The trial enrolled 446 patients, mean age 56 years, all of whom had locally advanced or metastatic breast cancer and no prior use of chemotherapy, excluding T-DM1. Patients who had received hormonal or HER2 therapy alone or the combination, as treatment for recurrence, were also eligible.

They were randomized 1:1 to receive a 21-day chemotherapy cycle of either (i) eribulin (1.4 mg/m² on days 1 and 8), or (ii) a taxane (docetaxel 75 mg/m² on day 1 or paclitaxel 80 mg/m² on days 1, 8 and 15), each being administered in combination with a dual HER2 blockade of trastuzumab plus pertuzumab.

Baseline characteristics of both groups were well balanced, with 257 (57.6%) having ER-positive disease, 292 (65.5%) visceral metastasis, and 263 (59%) with de novo stage 4 disease, explained Dr. Yamashita.

For the primary endpoint, the median progression-free survival (PFS) was 14 versus 12.9 months in the eribulin and taxane group, respectively (hazard ratio [HR] 0.95, P = .6817), confirming non-inferiority of the study regimen, he reported.

The clinical benefit rate was similar between the two groups, with an objective response rate of 76.8% in the eribulin group and 75.2% in the taxane group.

Median OS was 65.3 months in the taxane group, but has not been reached in the study group (HR 1.09).

In terms of side-effects, the incidence of treatment-emergent adverse events was similar between the eribulin and taxane groups (58.9% vs 59.2%, respectively, for grade 3 or higher).

“Skin-related adverse events (62.4% vs 40.6%), diarrhea (54.1% vs 36.6%), and edema (42.2% vs 8.5%) tend to be more common with taxane, whereas neutropenia (61.6% vs 30.7%) and peripheral neuropathy (61.2% vs 52.8%) tend to be more common with eribulin use,” he said.

Overall, “these results suggest that eribulin is less toxic chemotherapeutic partner for dual HER2 blockade and can be used for a longer,” he said.
 

Findings Are a ‘Clinical Pearl’

Harold Burstein, MD, PhD, a breast cancer expert at Dana-Farber Cancer Institute and professor at Harvard Medical School in Boston, described the findings as “a nice clinical pearl,” because some patients do not tolerate taxane therapy. “In such cases, you can substitute eribulin, which is usually tolerated without allergic hypersensitivity issues,” he said in an interview.

Eribulin has specific properties that “could make it a perfect candidate” as an adjunct to standard treatment regimens across different breast cancer subtypes, observed Wynne Wijaya, MD an oncology researcher at the University of Oxford, England, and Universitas Gadjah Mada, in Yogyakarta, Indonesia, in a recent review (World J Exp Med. 2024;14[2]:92558).

Dr. Wijaya, who was not involved in this study, said in an interview that the findings have important implications.

“This encouraging result adds eribulin as another option in the first line treatment regimen for patients with HER2-positive, locally advanced or metastatic breast cancer, especially in terms of side effects/toxicities,” she said. “As clinicians, we can offer to tailor the choice of therapy between eribulin versus taxane in the regimen based on [which side effects patients are better able to tolerate]. It would also be interesting and worthwhile to conduct similar trials in different types of populations to provide more robust evidence.”

Eisai Co. funded the research. Dr. Yamashita disclosed ties with AstraZeneca, Chugai Pharma, Daiichi Sankyo, Eisai, Kyowa Hakko Kiri, Lilly, MSD, Pfizer, Taiho, Gilead Sciences, Nihonkayaku, Ono Yakuhin, and Seagen. Dr. Burstein disclosed a research grant from National Cancer Institute. Dr. Wijaya had no relevant disclosures.

Premenopausal patients with hormone receptor positive, HER2 negative (HR+/HER2-) metastatic breast cancer (mBC) continued to show consistent benefit when treated with CDK4/6 inhibition plus endocrine therapy compared with chemotherapy, according to updated survival outcomes of the Young-PEARL study.

“The combination of palbociclib plus exemestane plus leuprolide showed a consistent significant improvement in PFS [progression-free survival] compared to the capecitabine arm,” Yeon Hee Park, MD, PhD, from Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea, reported at the annual meeting of the American Society of Clinical Oncology.
 

Study Methods and Results

Young-PEARL, a prospective, multicenter, open-label, randomized phase 2 study, included 184 patients, median age 44 years, who had relapsed or progressed during previous tamoxifen therapy, with one line of previous chemotherapy for mBC allowed. Patients were randomized to palbociclib plus endocrine therapy (oral palbociclib 125 mg per day for 21 days every 4 weeks, oral exemestane 25 mg per day for 28 days, plus leuprolide 3.75 mg subcutaneously every 4 weeks) or chemotherapy (oral capecitabine 1250 mg/m^2, twice daily for 2 weeks every 3 weeks).

Previously published initial results (Lancet Oncol. 2019 Dec;20[12]:1750-1759) for the primary endpoint showed a median PFS of 20.1 months in the palbociclib group versus 14.4 months in the capecitabine group, (hazard ratio [HR] 0.659, P = .0235) after median follow-up of 17 months.

Updated results showed this benefit was maintained after a median of 54 months, with a PFS of 19.5 months in the palbociclib arm, versus 14 months in capecitabine arm (HR 0.744, P = .0357), Dr. Park reported. However, this PFS benefit did not lead to an overall survival (OS) benefit, with median OS being similar: 54.8 versus 57.8 months in the palbociclib and capecitabine groups, respectively (HR = 1.02, P = .92).

To explore why PFS — but not OS — was better in the palbociclib arm, the researchers conducted a multivariate analysis which showed that going on to an additional CDK4/6 inhibitor treatment after the end of the study was as an independent variable favoring OS. Because more patients in the capecitabine arm received a post-study CDK4/6 inhibitor (49.3%) compared with in the palbociclib group (15%), this weighted the OS to the capecitabine arm, Dr. Park explained in an interview.

“In the capecitabine arm, excluding post-study CDK4/6 inhibitor use, the median OS was 38.8 months.” This was inferior to the 49 months OS seen in the palbociclib arm (P = .065), she said.

“As expected, hematologic toxicity was more common in the palbociclib arm compared with in the capecitabine arm,” Dr. Park said (92% vs 86%), with neutropenia topping the list [of all adverse events] (65.2% vs 27.9%, all grades). However, “most [adverse events] were not that serious,” Dr. Park said. Arthralgia was more common in the palbociclib arm (25% vs 7%), and diarrhea and hand-foot syndrome were more common in the capecitabine arm (15.2% vs 39.5% and 79.1% vs 2.2%).
 

Study Validates Endocrine Therapy + CDK4/6 Inhibitor as First Line

Commenting on Young-PEARL in an interview, Harold Burstein, MD, PhD, said, “The point of this study was to compare whether upfront chemotherapy would be better than upfront hormonal therapy for patients who had metastatic ER positive breast cancer.”

“This is the first study in probably 20 years that has compared these two approaches, and it validated that for the vast majority of patients with ER positive metastatic breast cancer, the appropriate first treatment is endocrine therapy with a CDK4/6 inhibitor,” continued Dr. Burstein, a breast cancer expert at Dana-Farber Cancer Institute, and professor at Harvard Medical School in Boston.

Dr. Park disclosed honoraria from AstraZeneca, Daiichi Sankyo, Eisai, Lilly, MSD, Novartis, Pfizer, and Roche; consulting or advisory roles for AstraZeneca, Boryung, Daiichi Sankyo, Eisai, Gilead Sciences, Lilly, Menarini, MSD, Novartis, Pfizer, and Roche; research funding from AstraZeneca, Gencurix, Genome Insight, NGeneBio, Pfizer; and Roche; and travel/accommodations/expenses from Gilead. Dr. Burstein disclosed a research grant from the National Cancer Institute.

Premenopausal patients with hormone receptor positive, HER2 negative (HR+/HER2-) metastatic breast cancer (mBC) continued to show consistent benefit when treated with CDK4/6 inhibition plus endocrine therapy compared with chemotherapy, according to updated survival outcomes of the Young-PEARL study.

“The combination of palbociclib plus exemestane plus leuprolide showed a consistent significant improvement in PFS [progression-free survival] compared to the capecitabine arm,” Yeon Hee Park, MD, PhD, from Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea, reported at the annual meeting of the American Society of Clinical Oncology.
 

Study Methods and Results

Young-PEARL, a prospective, multicenter, open-label, randomized phase 2 study, included 184 patients, median age 44 years, who had relapsed or progressed during previous tamoxifen therapy, with one line of previous chemotherapy for mBC allowed. Patients were randomized to palbociclib plus endocrine therapy (oral palbociclib 125 mg per day for 21 days every 4 weeks, oral exemestane 25 mg per day for 28 days, plus leuprolide 3.75 mg subcutaneously every 4 weeks) or chemotherapy (oral capecitabine 1250 mg/m^2, twice daily for 2 weeks every 3 weeks).

Previously published initial results (Lancet Oncol. 2019 Dec;20[12]:1750-1759) for the primary endpoint showed a median PFS of 20.1 months in the palbociclib group versus 14.4 months in the capecitabine group, (hazard ratio [HR] 0.659, P = .0235) after median follow-up of 17 months.

Updated results showed this benefit was maintained after a median of 54 months, with a PFS of 19.5 months in the palbociclib arm, versus 14 months in capecitabine arm (HR 0.744, P = .0357), Dr. Park reported. However, this PFS benefit did not lead to an overall survival (OS) benefit, with median OS being similar: 54.8 versus 57.8 months in the palbociclib and capecitabine groups, respectively (HR = 1.02, P = .92).

To explore why PFS — but not OS — was better in the palbociclib arm, the researchers conducted a multivariate analysis which showed that going on to an additional CDK4/6 inhibitor treatment after the end of the study was as an independent variable favoring OS. Because more patients in the capecitabine arm received a post-study CDK4/6 inhibitor (49.3%) compared with in the palbociclib group (15%), this weighted the OS to the capecitabine arm, Dr. Park explained in an interview.

“In the capecitabine arm, excluding post-study CDK4/6 inhibitor use, the median OS was 38.8 months.” This was inferior to the 49 months OS seen in the palbociclib arm (P = .065), she said.

“As expected, hematologic toxicity was more common in the palbociclib arm compared with in the capecitabine arm,” Dr. Park said (92% vs 86%), with neutropenia topping the list [of all adverse events] (65.2% vs 27.9%, all grades). However, “most [adverse events] were not that serious,” Dr. Park said. Arthralgia was more common in the palbociclib arm (25% vs 7%), and diarrhea and hand-foot syndrome were more common in the capecitabine arm (15.2% vs 39.5% and 79.1% vs 2.2%).
 

Study Validates Endocrine Therapy + CDK4/6 Inhibitor as First Line

Commenting on Young-PEARL in an interview, Harold Burstein, MD, PhD, said, “The point of this study was to compare whether upfront chemotherapy would be better than upfront hormonal therapy for patients who had metastatic ER positive breast cancer.”

“This is the first study in probably 20 years that has compared these two approaches, and it validated that for the vast majority of patients with ER positive metastatic breast cancer, the appropriate first treatment is endocrine therapy with a CDK4/6 inhibitor,” continued Dr. Burstein, a breast cancer expert at Dana-Farber Cancer Institute, and professor at Harvard Medical School in Boston.

Dr. Park disclosed honoraria from AstraZeneca, Daiichi Sankyo, Eisai, Lilly, MSD, Novartis, Pfizer, and Roche; consulting or advisory roles for AstraZeneca, Boryung, Daiichi Sankyo, Eisai, Gilead Sciences, Lilly, Menarini, MSD, Novartis, Pfizer, and Roche; research funding from AstraZeneca, Gencurix, Genome Insight, NGeneBio, Pfizer; and Roche; and travel/accommodations/expenses from Gilead. Dr. Burstein disclosed a research grant from the National Cancer Institute.

Premenopausal patients with hormone receptor positive, HER2 negative (HR+/HER2-) metastatic breast cancer (mBC) continued to show consistent benefit when treated with CDK4/6 inhibition plus endocrine therapy compared with chemotherapy, according to updated survival outcomes of the Young-PEARL study.

“The combination of palbociclib plus exemestane plus leuprolide showed a consistent significant improvement in PFS [progression-free survival] compared to the capecitabine arm,” Yeon Hee Park, MD, PhD, from Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea, reported at the annual meeting of the American Society of Clinical Oncology.
 

Study Methods and Results

Young-PEARL, a prospective, multicenter, open-label, randomized phase 2 study, included 184 patients, median age 44 years, who had relapsed or progressed during previous tamoxifen therapy, with one line of previous chemotherapy for mBC allowed. Patients were randomized to palbociclib plus endocrine therapy (oral palbociclib 125 mg per day for 21 days every 4 weeks, oral exemestane 25 mg per day for 28 days, plus leuprolide 3.75 mg subcutaneously every 4 weeks) or chemotherapy (oral capecitabine 1250 mg/m^2, twice daily for 2 weeks every 3 weeks).

Previously published initial results (Lancet Oncol. 2019 Dec;20[12]:1750-1759) for the primary endpoint showed a median PFS of 20.1 months in the palbociclib group versus 14.4 months in the capecitabine group, (hazard ratio [HR] 0.659, P = .0235) after median follow-up of 17 months.

Updated results showed this benefit was maintained after a median of 54 months, with a PFS of 19.5 months in the palbociclib arm, versus 14 months in capecitabine arm (HR 0.744, P = .0357), Dr. Park reported. However, this PFS benefit did not lead to an overall survival (OS) benefit, with median OS being similar: 54.8 versus 57.8 months in the palbociclib and capecitabine groups, respectively (HR = 1.02, P = .92).

To explore why PFS — but not OS — was better in the palbociclib arm, the researchers conducted a multivariate analysis which showed that going on to an additional CDK4/6 inhibitor treatment after the end of the study was as an independent variable favoring OS. Because more patients in the capecitabine arm received a post-study CDK4/6 inhibitor (49.3%) compared with in the palbociclib group (15%), this weighted the OS to the capecitabine arm, Dr. Park explained in an interview.

“In the capecitabine arm, excluding post-study CDK4/6 inhibitor use, the median OS was 38.8 months.” This was inferior to the 49 months OS seen in the palbociclib arm (P = .065), she said.

“As expected, hematologic toxicity was more common in the palbociclib arm compared with in the capecitabine arm,” Dr. Park said (92% vs 86%), with neutropenia topping the list [of all adverse events] (65.2% vs 27.9%, all grades). However, “most [adverse events] were not that serious,” Dr. Park said. Arthralgia was more common in the palbociclib arm (25% vs 7%), and diarrhea and hand-foot syndrome were more common in the capecitabine arm (15.2% vs 39.5% and 79.1% vs 2.2%).
 

Study Validates Endocrine Therapy + CDK4/6 Inhibitor as First Line

Commenting on Young-PEARL in an interview, Harold Burstein, MD, PhD, said, “The point of this study was to compare whether upfront chemotherapy would be better than upfront hormonal therapy for patients who had metastatic ER positive breast cancer.”

“This is the first study in probably 20 years that has compared these two approaches, and it validated that for the vast majority of patients with ER positive metastatic breast cancer, the appropriate first treatment is endocrine therapy with a CDK4/6 inhibitor,” continued Dr. Burstein, a breast cancer expert at Dana-Farber Cancer Institute, and professor at Harvard Medical School in Boston.

Dr. Park disclosed honoraria from AstraZeneca, Daiichi Sankyo, Eisai, Lilly, MSD, Novartis, Pfizer, and Roche; consulting or advisory roles for AstraZeneca, Boryung, Daiichi Sankyo, Eisai, Gilead Sciences, Lilly, Menarini, MSD, Novartis, Pfizer, and Roche; research funding from AstraZeneca, Gencurix, Genome Insight, NGeneBio, Pfizer; and Roche; and travel/accommodations/expenses from Gilead. Dr. Burstein disclosed a research grant from the National Cancer Institute.

MILAN — Seladelpar, an investigational selective peroxisome proliferator-activated receptor delta agonist, achieves both biochemical and clinically meaningful improvements in pruritus and liver injury in patients with primary biliary cholangitis (PBC), both with and without compensated liver cirrhosis, according to two interim analyses of the ASSURE long-term extension study.

The first analysis of 337 patients with PBC, with and without cirrhosis, showed that treatment with seladelpar had a durable effect up to 2 years on cholestasis and markers of liver injury, as well as a sustained reduction in pruritus, Palak Trivedi, MD, associate professor at the National Institute for Health Research Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, England, reported in a poster presented at the European Association for the Study of the Liver (EASL) Congress 2024.

The 2-year analysis also showed that seladelpar, a first-in-class, orally active agent, was safe and well tolerated in this patient population, he added.

These “results are consistent with the pivotal phase 3 RESPONSE study,” Dr. Trivedi noted. The RESPONSE study showed that seladelpar significantly improved liver biomarkers of disease activity and symptoms of pruritus at 12 months in patients with PBC who had an inadequate response or intolerance to ursodeoxycholic acid (UDCA), the standard of care, and had no history of hepatic decompensation. Patients with cirrhosis were allowed to enroll.

A total of 158 patients from the RESPONSE trial, both from the placebo and from the active treatment arm, were rolled over into the ASSURE trial. Another subset of 179 patients were drawn from prior seladelpar placebo-controlled studies (referred to as “legacy studies”), including the ENHANCE study. All participants in the current analysis received 10 mg of seladelpar, once daily, for up to 155 weeks.

Of the participants from the legacy studies, 99 completed 24 months of treatment with seladelpar, and 164 completed 12 months of treatment. In the 24-month treatment group, 70% met the composite response endpoint, which included alkaline phosphatase (ALP) levels below 1.67 times the upper limit of normal, a decrease in ALP levels of at least 15%, and total bilirubin levels at or below the upper limit of normal, according to a press release of the study findings. In addition, 42% of these participants achieved ALP normalization at 24 months, a marker of liver disease progression. In the 12-month treatment group, 73% achieved the clinically meaningful composite response endpoint, with 42% experiencing ALP normalization.

For patients rolled over from RESPONSE, 102 received 18 months of treatment with seladelpar, and 29 received 24 months of treatment. A total of 62% of patients in the 18-month group achieved the composite endpoint, and 33% achieved ALP normalization, while 72% of the 24-month group reached the composite endpoint, and 17% had ALP normalization.

Of patients who had received a placebo in the RESPONSE trial and went on to receive treatment with seladelpar, 75% achieved the composite endpoint, 27% had ALP normalization at 6 months, and 94% achieved the composite endpoint and 50% reached ALP normalization at 12 months.

Key secondary endpoints included ALP normalization and changes in liver enzymes (ALP, total bilirubin, gamma-glutamyl transferase [GGT], alanine transaminase [ALT], and aspartate aminotransferase [AST]).
 

Pruritus Relief Important for Quality of Life

Among study participants who reported a four or more at baseline on the numerical rating scale (NRS) for pruritus, legacy patients at 12 months and 24 months of treatment reported a mean reduction of 3.8 and 3.1, respectively. Participants from RESPONSE also reported a mean reduction of 3.8.

This level of reduction in NRS is “considered clinically significant” and takes patients from a level of moderate to severe itching down to mild, said Carrie Frenette, MD, executive director, Global Medical Affairs, Liver Diseases, Gilead Sciences, Foster City, California, and a former hepatologist of 20 years with a special interest in liver transplantation.

This “is a huge benefit in quality of life for these patients,” Dr. Frenette said in an interview.

Dr. Frenette also noted that UDCA, the current first-line treatment for PBC, is inadequate in up to 40% of patients, and second-line treatments, notably obeticholic acid, can cause itching.

European Society for Organ Transplantation

Eleonora De Martin, MD, transplant hepatologist at Centre Hépato-Biliaire, Paul Brousse Hospital, Paris, France, who comoderated the session, pointed out that PBC is a complex disease.

“We need both disease control and symptom control, and they’re not always compatible,” she said. “Sometimes you can control the disease but not the symptoms, and symptomatic control is so important,” especially with pruritus.
 

Patients With PBC and Cirrhosis

A separate analysis from ASSURE looked at a subset of 17 patients with PBC and cirrhosis who completed 24 months of treatment. The findings were presented by Stuart Gordon, MD, professor of medicine, Wayne State University School of Medicine, and hepatologist at Henry Ford Hospital, both in Detroit.

In this analysis, the mean patient age was 60.8 years, 91.4% were female, 88.6% were Child-Pugh A, and 22.9% had portal hypertension, while the mean baseline liver stiffness by FibroScan was 19.9 kPa.

Baseline biochemical measures were mean ALP of 245.4 U/L, mean total bilirubin of 0.995 mg/dL, mean GGT of 216.1 U/L, and mean ALT of 36.6 U/L.

A total of 11 participants (65%) met the composite endpoint at 24 months, with ALP normalization in 4 patients (24%). The overall mean percent change from baseline in ALP was approximately −30% and in total bilirubin was around −14%. Other changes in biochemical markers included reductions from baseline in GGT and ALT of approximately −30% and −10%, respectively. No change was observed in AST.

While 80% of patients with cirrhosis “had an adverse event of some form,” there were no treatment-related serious adverse events.

“It’s interesting to see results in these patients who have advanced disease and are cirrhotic because it might stabilize disease or even provide improvement,” Dr. De Martin commented. “However, the numbers in the study are very small, so it’s hard to draw firm conclusions yet, but it is a first step in showing that this drug is safe.”

Seladelpar is an “important step forward in PBC because we’ve been stuck with ursodeoxycholic acid for so many years,” Dr. De Martin added. “We’ve seen in liver disease with other etiologies that sometimes just one drug can make a difference, and you can change the natural history of the disease.”

Dr. Frenette is an employee and stockholder of Gilead Sciences. Dr. Gordon declared grants and support from AbbVie, Arbutus, CymaBay, Cour Pharmaceuticals, GlaxoSmithKline (GSK), Ipsen, and Mirum Pharmaceuticals; and advisory board activity from CymaBay, GSK, and Ipsen Pharmaceuticals. Dr. De Martin had no disclosures of relevance to seladelpar but has received speaker fees from other companies, including GSK, Ipsen, and Astellas. Dr. Trivedi reports institutional funding support from National Institute for Health Research Birmingham (UK); lecture fees from Advanz Pharma/Intercept Pharmaceuticals, Albireo/Ipsen, and Dr. Falk Pharma; advisory board/consulting fees from Advanz Pharma/Intercept Pharmaceuticals, Albireo/Ipsen, Chemomab Therapeutics, CymaBay, Dr. Falk Pharma, Gilead Sciences, Perspectum, and Pliant Therapeutics; and grant support from Advanz Pharma/Intercept Pharmaceuticals, Albireo/Ipsen, Bristol-Myers Squibb, Core (Guts UK), EASL, Gilead Sciences, GSK, LifeArc, NIHR, Mirum Pharma, PSC Support, The Wellcome Trust, The Medical Research Foundation (UK), and Regeneron.

A version of this article first appeared on Medscape.com.

MILAN — Seladelpar, an investigational selective peroxisome proliferator-activated receptor delta agonist, achieves both biochemical and clinically meaningful improvements in pruritus and liver injury in patients with primary biliary cholangitis (PBC), both with and without compensated liver cirrhosis, according to two interim analyses of the ASSURE long-term extension study.

The first analysis of 337 patients with PBC, with and without cirrhosis, showed that treatment with seladelpar had a durable effect up to 2 years on cholestasis and markers of liver injury, as well as a sustained reduction in pruritus, Palak Trivedi, MD, associate professor at the National Institute for Health Research Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, England, reported in a poster presented at the European Association for the Study of the Liver (EASL) Congress 2024.

The 2-year analysis also showed that seladelpar, a first-in-class, orally active agent, was safe and well tolerated in this patient population, he added.

These “results are consistent with the pivotal phase 3 RESPONSE study,” Dr. Trivedi noted. The RESPONSE study showed that seladelpar significantly improved liver biomarkers of disease activity and symptoms of pruritus at 12 months in patients with PBC who had an inadequate response or intolerance to ursodeoxycholic acid (UDCA), the standard of care, and had no history of hepatic decompensation. Patients with cirrhosis were allowed to enroll.

A total of 158 patients from the RESPONSE trial, both from the placebo and from the active treatment arm, were rolled over into the ASSURE trial. Another subset of 179 patients were drawn from prior seladelpar placebo-controlled studies (referred to as “legacy studies”), including the ENHANCE study. All participants in the current analysis received 10 mg of seladelpar, once daily, for up to 155 weeks.

Of the participants from the legacy studies, 99 completed 24 months of treatment with seladelpar, and 164 completed 12 months of treatment. In the 24-month treatment group, 70% met the composite response endpoint, which included alkaline phosphatase (ALP) levels below 1.67 times the upper limit of normal, a decrease in ALP levels of at least 15%, and total bilirubin levels at or below the upper limit of normal, according to a press release of the study findings. In addition, 42% of these participants achieved ALP normalization at 24 months, a marker of liver disease progression. In the 12-month treatment group, 73% achieved the clinically meaningful composite response endpoint, with 42% experiencing ALP normalization.

For patients rolled over from RESPONSE, 102 received 18 months of treatment with seladelpar, and 29 received 24 months of treatment. A total of 62% of patients in the 18-month group achieved the composite endpoint, and 33% achieved ALP normalization, while 72% of the 24-month group reached the composite endpoint, and 17% had ALP normalization.

Of patients who had received a placebo in the RESPONSE trial and went on to receive treatment with seladelpar, 75% achieved the composite endpoint, 27% had ALP normalization at 6 months, and 94% achieved the composite endpoint and 50% reached ALP normalization at 12 months.

Key secondary endpoints included ALP normalization and changes in liver enzymes (ALP, total bilirubin, gamma-glutamyl transferase [GGT], alanine transaminase [ALT], and aspartate aminotransferase [AST]).
 

Pruritus Relief Important for Quality of Life

Among study participants who reported a four or more at baseline on the numerical rating scale (NRS) for pruritus, legacy patients at 12 months and 24 months of treatment reported a mean reduction of 3.8 and 3.1, respectively. Participants from RESPONSE also reported a mean reduction of 3.8.

This level of reduction in NRS is “considered clinically significant” and takes patients from a level of moderate to severe itching down to mild, said Carrie Frenette, MD, executive director, Global Medical Affairs, Liver Diseases, Gilead Sciences, Foster City, California, and a former hepatologist of 20 years with a special interest in liver transplantation.

This “is a huge benefit in quality of life for these patients,” Dr. Frenette said in an interview.

Dr. Frenette also noted that UDCA, the current first-line treatment for PBC, is inadequate in up to 40% of patients, and second-line treatments, notably obeticholic acid, can cause itching.

European Society for Organ Transplantation

Eleonora De Martin, MD, transplant hepatologist at Centre Hépato-Biliaire, Paul Brousse Hospital, Paris, France, who comoderated the session, pointed out that PBC is a complex disease.

“We need both disease control and symptom control, and they’re not always compatible,” she said. “Sometimes you can control the disease but not the symptoms, and symptomatic control is so important,” especially with pruritus.
 

Patients With PBC and Cirrhosis

A separate analysis from ASSURE looked at a subset of 17 patients with PBC and cirrhosis who completed 24 months of treatment. The findings were presented by Stuart Gordon, MD, professor of medicine, Wayne State University School of Medicine, and hepatologist at Henry Ford Hospital, both in Detroit.

In this analysis, the mean patient age was 60.8 years, 91.4% were female, 88.6% were Child-Pugh A, and 22.9% had portal hypertension, while the mean baseline liver stiffness by FibroScan was 19.9 kPa.

Baseline biochemical measures were mean ALP of 245.4 U/L, mean total bilirubin of 0.995 mg/dL, mean GGT of 216.1 U/L, and mean ALT of 36.6 U/L.

A total of 11 participants (65%) met the composite endpoint at 24 months, with ALP normalization in 4 patients (24%). The overall mean percent change from baseline in ALP was approximately −30% and in total bilirubin was around −14%. Other changes in biochemical markers included reductions from baseline in GGT and ALT of approximately −30% and −10%, respectively. No change was observed in AST.

While 80% of patients with cirrhosis “had an adverse event of some form,” there were no treatment-related serious adverse events.

“It’s interesting to see results in these patients who have advanced disease and are cirrhotic because it might stabilize disease or even provide improvement,” Dr. De Martin commented. “However, the numbers in the study are very small, so it’s hard to draw firm conclusions yet, but it is a first step in showing that this drug is safe.”

Seladelpar is an “important step forward in PBC because we’ve been stuck with ursodeoxycholic acid for so many years,” Dr. De Martin added. “We’ve seen in liver disease with other etiologies that sometimes just one drug can make a difference, and you can change the natural history of the disease.”

Dr. Frenette is an employee and stockholder of Gilead Sciences. Dr. Gordon declared grants and support from AbbVie, Arbutus, CymaBay, Cour Pharmaceuticals, GlaxoSmithKline (GSK), Ipsen, and Mirum Pharmaceuticals; and advisory board activity from CymaBay, GSK, and Ipsen Pharmaceuticals. Dr. De Martin had no disclosures of relevance to seladelpar but has received speaker fees from other companies, including GSK, Ipsen, and Astellas. Dr. Trivedi reports institutional funding support from National Institute for Health Research Birmingham (UK); lecture fees from Advanz Pharma/Intercept Pharmaceuticals, Albireo/Ipsen, and Dr. Falk Pharma; advisory board/consulting fees from Advanz Pharma/Intercept Pharmaceuticals, Albireo/Ipsen, Chemomab Therapeutics, CymaBay, Dr. Falk Pharma, Gilead Sciences, Perspectum, and Pliant Therapeutics; and grant support from Advanz Pharma/Intercept Pharmaceuticals, Albireo/Ipsen, Bristol-Myers Squibb, Core (Guts UK), EASL, Gilead Sciences, GSK, LifeArc, NIHR, Mirum Pharma, PSC Support, The Wellcome Trust, The Medical Research Foundation (UK), and Regeneron.

A version of this article first appeared on Medscape.com.

MILAN — Seladelpar, an investigational selective peroxisome proliferator-activated receptor delta agonist, achieves both biochemical and clinically meaningful improvements in pruritus and liver injury in patients with primary biliary cholangitis (PBC), both with and without compensated liver cirrhosis, according to two interim analyses of the ASSURE long-term extension study.

The first analysis of 337 patients with PBC, with and without cirrhosis, showed that treatment with seladelpar had a durable effect up to 2 years on cholestasis and markers of liver injury, as well as a sustained reduction in pruritus, Palak Trivedi, MD, associate professor at the National Institute for Health Research Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, England, reported in a poster presented at the European Association for the Study of the Liver (EASL) Congress 2024.

The 2-year analysis also showed that seladelpar, a first-in-class, orally active agent, was safe and well tolerated in this patient population, he added.

These “results are consistent with the pivotal phase 3 RESPONSE study,” Dr. Trivedi noted. The RESPONSE study showed that seladelpar significantly improved liver biomarkers of disease activity and symptoms of pruritus at 12 months in patients with PBC who had an inadequate response or intolerance to ursodeoxycholic acid (UDCA), the standard of care, and had no history of hepatic decompensation. Patients with cirrhosis were allowed to enroll.

A total of 158 patients from the RESPONSE trial, both from the placebo and from the active treatment arm, were rolled over into the ASSURE trial. Another subset of 179 patients were drawn from prior seladelpar placebo-controlled studies (referred to as “legacy studies”), including the ENHANCE study. All participants in the current analysis received 10 mg of seladelpar, once daily, for up to 155 weeks.

Of the participants from the legacy studies, 99 completed 24 months of treatment with seladelpar, and 164 completed 12 months of treatment. In the 24-month treatment group, 70% met the composite response endpoint, which included alkaline phosphatase (ALP) levels below 1.67 times the upper limit of normal, a decrease in ALP levels of at least 15%, and total bilirubin levels at or below the upper limit of normal, according to a press release of the study findings. In addition, 42% of these participants achieved ALP normalization at 24 months, a marker of liver disease progression. In the 12-month treatment group, 73% achieved the clinically meaningful composite response endpoint, with 42% experiencing ALP normalization.

For patients rolled over from RESPONSE, 102 received 18 months of treatment with seladelpar, and 29 received 24 months of treatment. A total of 62% of patients in the 18-month group achieved the composite endpoint, and 33% achieved ALP normalization, while 72% of the 24-month group reached the composite endpoint, and 17% had ALP normalization.

Of patients who had received a placebo in the RESPONSE trial and went on to receive treatment with seladelpar, 75% achieved the composite endpoint, 27% had ALP normalization at 6 months, and 94% achieved the composite endpoint and 50% reached ALP normalization at 12 months.

Key secondary endpoints included ALP normalization and changes in liver enzymes (ALP, total bilirubin, gamma-glutamyl transferase [GGT], alanine transaminase [ALT], and aspartate aminotransferase [AST]).
 

Pruritus Relief Important for Quality of Life

Among study participants who reported a four or more at baseline on the numerical rating scale (NRS) for pruritus, legacy patients at 12 months and 24 months of treatment reported a mean reduction of 3.8 and 3.1, respectively. Participants from RESPONSE also reported a mean reduction of 3.8.

This level of reduction in NRS is “considered clinically significant” and takes patients from a level of moderate to severe itching down to mild, said Carrie Frenette, MD, executive director, Global Medical Affairs, Liver Diseases, Gilead Sciences, Foster City, California, and a former hepatologist of 20 years with a special interest in liver transplantation.

This “is a huge benefit in quality of life for these patients,” Dr. Frenette said in an interview.

Dr. Frenette also noted that UDCA, the current first-line treatment for PBC, is inadequate in up to 40% of patients, and second-line treatments, notably obeticholic acid, can cause itching.

European Society for Organ Transplantation

Eleonora De Martin, MD, transplant hepatologist at Centre Hépato-Biliaire, Paul Brousse Hospital, Paris, France, who comoderated the session, pointed out that PBC is a complex disease.

“We need both disease control and symptom control, and they’re not always compatible,” she said. “Sometimes you can control the disease but not the symptoms, and symptomatic control is so important,” especially with pruritus.
 

Patients With PBC and Cirrhosis

A separate analysis from ASSURE looked at a subset of 17 patients with PBC and cirrhosis who completed 24 months of treatment. The findings were presented by Stuart Gordon, MD, professor of medicine, Wayne State University School of Medicine, and hepatologist at Henry Ford Hospital, both in Detroit.

In this analysis, the mean patient age was 60.8 years, 91.4% were female, 88.6% were Child-Pugh A, and 22.9% had portal hypertension, while the mean baseline liver stiffness by FibroScan was 19.9 kPa.

Baseline biochemical measures were mean ALP of 245.4 U/L, mean total bilirubin of 0.995 mg/dL, mean GGT of 216.1 U/L, and mean ALT of 36.6 U/L.

A total of 11 participants (65%) met the composite endpoint at 24 months, with ALP normalization in 4 patients (24%). The overall mean percent change from baseline in ALP was approximately −30% and in total bilirubin was around −14%. Other changes in biochemical markers included reductions from baseline in GGT and ALT of approximately −30% and −10%, respectively. No change was observed in AST.

While 80% of patients with cirrhosis “had an adverse event of some form,” there were no treatment-related serious adverse events.

“It’s interesting to see results in these patients who have advanced disease and are cirrhotic because it might stabilize disease or even provide improvement,” Dr. De Martin commented. “However, the numbers in the study are very small, so it’s hard to draw firm conclusions yet, but it is a first step in showing that this drug is safe.”

Seladelpar is an “important step forward in PBC because we’ve been stuck with ursodeoxycholic acid for so many years,” Dr. De Martin added. “We’ve seen in liver disease with other etiologies that sometimes just one drug can make a difference, and you can change the natural history of the disease.”

Dr. Frenette is an employee and stockholder of Gilead Sciences. Dr. Gordon declared grants and support from AbbVie, Arbutus, CymaBay, Cour Pharmaceuticals, GlaxoSmithKline (GSK), Ipsen, and Mirum Pharmaceuticals; and advisory board activity from CymaBay, GSK, and Ipsen Pharmaceuticals. Dr. De Martin had no disclosures of relevance to seladelpar but has received speaker fees from other companies, including GSK, Ipsen, and Astellas. Dr. Trivedi reports institutional funding support from National Institute for Health Research Birmingham (UK); lecture fees from Advanz Pharma/Intercept Pharmaceuticals, Albireo/Ipsen, and Dr. Falk Pharma; advisory board/consulting fees from Advanz Pharma/Intercept Pharmaceuticals, Albireo/Ipsen, Chemomab Therapeutics, CymaBay, Dr. Falk Pharma, Gilead Sciences, Perspectum, and Pliant Therapeutics; and grant support from Advanz Pharma/Intercept Pharmaceuticals, Albireo/Ipsen, Bristol-Myers Squibb, Core (Guts UK), EASL, Gilead Sciences, GSK, LifeArc, NIHR, Mirum Pharma, PSC Support, The Wellcome Trust, The Medical Research Foundation (UK), and Regeneron.

A version of this article first appeared on Medscape.com.

The newly updated US Department of Veterans Affairs (VA) prostate cancer clinical pathway looks like a set of guidelines, but it’s really something unique. As attendees learned at an Association of VA Hematology/Oncology (AVAHO) regional meeting in Detroit in June, the clinical pathways are designed to point the way toward a standard ideal treatment for the majority of cases, not just to suggest a number of possible options.

“Pathways will always offer one scenario. They try to get oncologists to practice in a similar fashion so things can be managed more uniformly,” Michael M. Goodman, MD, told Federal Practitioner prior to the AVAHO meeting that was focused on prostate cancer care. Goodman is an associate professor of medicine with Atrium Health Wake Forest Baptist Medical Center and helped develop the VA genitourinary oncology pathways.

“The overall goal is not just to standardize care as much as possible but also to synthesize the best and most cost-effective practices,” Goodman said. For example, “If you have 5 different therapies, and they all have about the same efficacy and safety, and 1 is less costly than the other 4, then it would make sense to choose that.”

The VA has offered pathways for multiple types of cancer since 2021, and the pathway for prostate cancer is among the most comprehensive. The VA system updated the pathway in March 2024, is available online both via SharePoint and externally.

“It goes through the entire gamut from screening, diagnosis, and management to end of life,” Goodman explained. Multiple disciplines, from primary care and surgery to genetics and imaging, can rely on the pathway to assist decision-making.

In terms of screening, the pathway offers a flow map guiding the screening choices. In patients aged ≤ 54 years, only certain high-risk groups, such as African Americans and those with a family history of prostate cancer, should be screened. From ages 54 to 69 years, patients should be consulted as part of a shared decision making process, while screening is not recommended for patients aged ≥ 70 years.

Pathway flow maps also provide information about diagnostic standards, evaluation of the newly diagnosed, risk stratification, molecular testing, and end-of-life care.

Goodman says the pathway is now integrated into the VA electronic health record system via a template so clinicians can easily document pathway use. This allows the VA to track the use of the pathways locally, regionally, and nationally track the use of the pathways.

Clinicians are not mandated to follow every step in the pathway, but Goodman said the goal is > 80% adherence. If clinicians follow the standards, he said, “you’re considering efficacy, safety, and cost for that veteran.”

Prospective data suggests that adherence to the pathway eliminates certain disparities. African American veterans, for example, are as well-represented or even better represented than White veterans in prostate cancer care when pathways are followed.

Why might clinicians veer from the pathway? “If you’re seeing a patient who was treated in the community with drug X, but drug Y is chosen by the pathway, you can carry on with the previous care.” Alternatively, in some cases, patients may not tolerate the pathway standard, Goodman noted.

Goodman reports that he consults the pathway every day. “It’s helped standardize the care I provide to ensure there’s no gaps in how I’m treating patients.”

The newly updated US Department of Veterans Affairs (VA) prostate cancer clinical pathway looks like a set of guidelines, but it’s really something unique. As attendees learned at an Association of VA Hematology/Oncology (AVAHO) regional meeting in Detroit in June, the clinical pathways are designed to point the way toward a standard ideal treatment for the majority of cases, not just to suggest a number of possible options.

“Pathways will always offer one scenario. They try to get oncologists to practice in a similar fashion so things can be managed more uniformly,” Michael M. Goodman, MD, told Federal Practitioner prior to the AVAHO meeting that was focused on prostate cancer care. Goodman is an associate professor of medicine with Atrium Health Wake Forest Baptist Medical Center and helped develop the VA genitourinary oncology pathways.

“The overall goal is not just to standardize care as much as possible but also to synthesize the best and most cost-effective practices,” Goodman said. For example, “If you have 5 different therapies, and they all have about the same efficacy and safety, and 1 is less costly than the other 4, then it would make sense to choose that.”

The VA has offered pathways for multiple types of cancer since 2021, and the pathway for prostate cancer is among the most comprehensive. The VA system updated the pathway in March 2024, is available online both via SharePoint and externally.

“It goes through the entire gamut from screening, diagnosis, and management to end of life,” Goodman explained. Multiple disciplines, from primary care and surgery to genetics and imaging, can rely on the pathway to assist decision-making.

In terms of screening, the pathway offers a flow map guiding the screening choices. In patients aged ≤ 54 years, only certain high-risk groups, such as African Americans and those with a family history of prostate cancer, should be screened. From ages 54 to 69 years, patients should be consulted as part of a shared decision making process, while screening is not recommended for patients aged ≥ 70 years.

Pathway flow maps also provide information about diagnostic standards, evaluation of the newly diagnosed, risk stratification, molecular testing, and end-of-life care.

Goodman says the pathway is now integrated into the VA electronic health record system via a template so clinicians can easily document pathway use. This allows the VA to track the use of the pathways locally, regionally, and nationally track the use of the pathways.

Clinicians are not mandated to follow every step in the pathway, but Goodman said the goal is > 80% adherence. If clinicians follow the standards, he said, “you’re considering efficacy, safety, and cost for that veteran.”

Prospective data suggests that adherence to the pathway eliminates certain disparities. African American veterans, for example, are as well-represented or even better represented than White veterans in prostate cancer care when pathways are followed.

Why might clinicians veer from the pathway? “If you’re seeing a patient who was treated in the community with drug X, but drug Y is chosen by the pathway, you can carry on with the previous care.” Alternatively, in some cases, patients may not tolerate the pathway standard, Goodman noted.

Goodman reports that he consults the pathway every day. “It’s helped standardize the care I provide to ensure there’s no gaps in how I’m treating patients.”

The newly updated US Department of Veterans Affairs (VA) prostate cancer clinical pathway looks like a set of guidelines, but it’s really something unique. As attendees learned at an Association of VA Hematology/Oncology (AVAHO) regional meeting in Detroit in June, the clinical pathways are designed to point the way toward a standard ideal treatment for the majority of cases, not just to suggest a number of possible options.

“Pathways will always offer one scenario. They try to get oncologists to practice in a similar fashion so things can be managed more uniformly,” Michael M. Goodman, MD, told Federal Practitioner prior to the AVAHO meeting that was focused on prostate cancer care. Goodman is an associate professor of medicine with Atrium Health Wake Forest Baptist Medical Center and helped develop the VA genitourinary oncology pathways.

“The overall goal is not just to standardize care as much as possible but also to synthesize the best and most cost-effective practices,” Goodman said. For example, “If you have 5 different therapies, and they all have about the same efficacy and safety, and 1 is less costly than the other 4, then it would make sense to choose that.”

The VA has offered pathways for multiple types of cancer since 2021, and the pathway for prostate cancer is among the most comprehensive. The VA system updated the pathway in March 2024, is available online both via SharePoint and externally.

“It goes through the entire gamut from screening, diagnosis, and management to end of life,” Goodman explained. Multiple disciplines, from primary care and surgery to genetics and imaging, can rely on the pathway to assist decision-making.

In terms of screening, the pathway offers a flow map guiding the screening choices. In patients aged ≤ 54 years, only certain high-risk groups, such as African Americans and those with a family history of prostate cancer, should be screened. From ages 54 to 69 years, patients should be consulted as part of a shared decision making process, while screening is not recommended for patients aged ≥ 70 years.

Pathway flow maps also provide information about diagnostic standards, evaluation of the newly diagnosed, risk stratification, molecular testing, and end-of-life care.

Goodman says the pathway is now integrated into the VA electronic health record system via a template so clinicians can easily document pathway use. This allows the VA to track the use of the pathways locally, regionally, and nationally track the use of the pathways.

Clinicians are not mandated to follow every step in the pathway, but Goodman said the goal is > 80% adherence. If clinicians follow the standards, he said, “you’re considering efficacy, safety, and cost for that veteran.”

Prospective data suggests that adherence to the pathway eliminates certain disparities. African American veterans, for example, are as well-represented or even better represented than White veterans in prostate cancer care when pathways are followed.

Why might clinicians veer from the pathway? “If you’re seeing a patient who was treated in the community with drug X, but drug Y is chosen by the pathway, you can carry on with the previous care.” Alternatively, in some cases, patients may not tolerate the pathway standard, Goodman noted.

Goodman reports that he consults the pathway every day. “It’s helped standardize the care I provide to ensure there’s no gaps in how I’m treating patients.”

MILAN — Tirzepatide, a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptor agonist, was more effective than was placebo in the resolution of metabolic dysfunction–associated steatohepatitis (MASH) and in the improvement of fibrosis, according to the results of the phase 2 SYNERGY-NASH trial.

Specifically, 44%-62% of participants with MASH and moderate or severe fibrosis treated with 5-15 mg of tirzepatide achieved MASH resolution without worsening of fibrosis compared with 10% on placebo; 51%-55% of those on tirzepatide achieved at least one stage of fibrosis improvement without worsening of MASH compared with 30% on placebo. Tirzepatide also led to weight loss.

The study (Abstract LBO-001) was presented at the European Association for the Study of the Liver (EASL) Congress 2024 by Rohit Loomba, MD, professor of medicine, NAFLD Research Center, University of California at San Diego in La Jolla, and published simultaneously in The New England Journal of Medicine. 

“The results are clinically meaningful,” Dr. Loomba said in an interview. 

University of California, San Diego

Both of the endpoints — improvements in MASH resolution and fibrosis — are considered approvable endpoints for MASH therapeutic development, and therefore, increase the likelihood of success of using such a strategy in a phase 3 setting, Dr. Loomba said.
 

MASH Resolution, No Worsening of Fibrosis

The dose-finding, multicenter, double-blind, placebo-controlled trial randomly assigned a total of 190 participants to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. Participants had biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. 

Overall, approximately 42% of participants had F2 fibrosis and over 57% had F3 fibrosis. The proportion of F3 fibrosis was numerically higher in the placebo (64.6%) and 5-mg tirzepatide (63.8%) groups. 

The mean age of the study cohort was 54 years; 57% were female, 86% were White, and 36% were Hispanic; the mean body mass index was 36; 58% had type 2 diabetes; and A1c was 6.5. NAFLD activity score (NAS) was 5.3. Baseline noninvasive test results were consistent with the study population of MASH with F2/F3 fibrosis and NAS ≥ 4. 

The primary endpoint was resolution of MASH without worsening of fibrosis at 52 weeks, and the key secondary endpoint was an improvement (decrease) of at least one fibrosis stage without worsening of MASH. Other secondary endpoints included a ≥ 2-point decrease in NAS with ≤ 1-point decrease in two or more NAS components.

A total of 157 participants (83%) underwent liver biopsies at week 52, providing results for the current analysis. 

Among tirzepatide-treated patients, 43.6% in the 5-mg group, 55.5% in the 10-mg group, and 62.4% in the 15-mg group met the criteria for resolution of MASH without worsening of fibrosis compared with  10% in the placebo group (P < .001 for all three comparisons). 

Fibrosis improved by at least one stage without worsening of MASH in 54.9% of participants in the 5-mg tirzepatide group, 51.3% in the 10-mg tirzepatide group, and 51.0% in the 15-mg tirzepatide group compared with 29.7% in the placebo group (P < .001 for all risk differences with placebo). 

Changes in NAS and subscores for the individual components of NAS, including steatosis, lobular inflammation, and hepatocellular ballooning, were also seen in participants on tirzepatide. 

The researchers used a composite endpoint of a ≥ 2-point decrease in NAS with a ≥ 1-point decrease in at least two NAS components. Of the tirzepatide-treated groups, 71.7%,78.3%, and 76.6% in the 5-mg, 10-mg, and 15-mg groups, respectively, met this endpoint compared with 36.7% in placebo. 

Imaging of liver fat with MRI-based proton density fat fraction (MRI-PDFF) showed reductions from baseline of -45.7, -41.3, -57.0 in participants on 5-mg, 10-mg, and 15-mg tirzepatide, respectively. Differences from placebo were all statistically significant. 

Percentage of body weight change from baseline was -10.7%, -13.3%, and -15.6% in the 5-mg, 10-mg, and 15-mg tirzepatide groups, respectively, compared with weight loss of -0.8% in the placebo group. 

“Tirzepatide led to significant weight loss in both patients with diabetes and those without diabetes,” reported Dr. Loomba. 

There were more adverse events in patients on tirzepatide (92.3%) compared with patients on placebo (83.3%). 

“The most common adverse events were gastrointestinal in nature, with 96% of them mild to moderate in severity,” said Dr. Loomba. “Discontinuations occurred in 4.2% of participants, which was similar between patients on tirzepatide and those on placebo.”

He pointed out that the safety profile of tirzepatide in a MASH population “was generally similar to that observed in the phase 3 trials of type 2 diabetes and obesity.”

Incidence of serious adverse events was also similar at 6.3% for participants on tirzepatide vs 6.2% for those on placebo; 2.8% on tirzepatide and 4.2% on placebo progressed to cirrhosis. There was no evidence of drug-induced liver injury. 
 

‘Convincing Results’

Commenting on the study, co-moderator Sven Francque, MD, hepatologist and head of department at the University Hospital of Antwerp, Belgium, said that the study was in a relatively “severe” patient population, which was one of its strengths. 

“These are convincing results in terms of MASH resolution, showing a strong response and dose-dependence,” he said. 

Dr. Francque

MILAN — Tirzepatide, a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptor agonist, was more effective than was placebo in the resolution of metabolic dysfunction–associated steatohepatitis (MASH) and in the improvement of fibrosis, according to the results of the phase 2 SYNERGY-NASH trial.

Specifically, 44%-62% of participants with MASH and moderate or severe fibrosis treated with 5-15 mg of tirzepatide achieved MASH resolution without worsening of fibrosis compared with 10% on placebo; 51%-55% of those on tirzepatide achieved at least one stage of fibrosis improvement without worsening of MASH compared with 30% on placebo. Tirzepatide also led to weight loss.

The study (Abstract LBO-001) was presented at the European Association for the Study of the Liver (EASL) Congress 2024 by Rohit Loomba, MD, professor of medicine, NAFLD Research Center, University of California at San Diego in La Jolla, and published simultaneously in The New England Journal of Medicine. 

“The results are clinically meaningful,” Dr. Loomba said in an interview. 

University of California, San Diego

Both of the endpoints — improvements in MASH resolution and fibrosis — are considered approvable endpoints for MASH therapeutic development, and therefore, increase the likelihood of success of using such a strategy in a phase 3 setting, Dr. Loomba said.
 

MASH Resolution, No Worsening of Fibrosis

The dose-finding, multicenter, double-blind, placebo-controlled trial randomly assigned a total of 190 participants to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. Participants had biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. 

Overall, approximately 42% of participants had F2 fibrosis and over 57% had F3 fibrosis. The proportion of F3 fibrosis was numerically higher in the placebo (64.6%) and 5-mg tirzepatide (63.8%) groups. 

The mean age of the study cohort was 54 years; 57% were female, 86% were White, and 36% were Hispanic; the mean body mass index was 36; 58% had type 2 diabetes; and A1c was 6.5. NAFLD activity score (NAS) was 5.3. Baseline noninvasive test results were consistent with the study population of MASH with F2/F3 fibrosis and NAS ≥ 4. 

The primary endpoint was resolution of MASH without worsening of fibrosis at 52 weeks, and the key secondary endpoint was an improvement (decrease) of at least one fibrosis stage without worsening of MASH. Other secondary endpoints included a ≥ 2-point decrease in NAS with ≤ 1-point decrease in two or more NAS components.

A total of 157 participants (83%) underwent liver biopsies at week 52, providing results for the current analysis. 

Among tirzepatide-treated patients, 43.6% in the 5-mg group, 55.5% in the 10-mg group, and 62.4% in the 15-mg group met the criteria for resolution of MASH without worsening of fibrosis compared with  10% in the placebo group (P < .001 for all three comparisons). 

Fibrosis improved by at least one stage without worsening of MASH in 54.9% of participants in the 5-mg tirzepatide group, 51.3% in the 10-mg tirzepatide group, and 51.0% in the 15-mg tirzepatide group compared with 29.7% in the placebo group (P < .001 for all risk differences with placebo). 

Changes in NAS and subscores for the individual components of NAS, including steatosis, lobular inflammation, and hepatocellular ballooning, were also seen in participants on tirzepatide. 

The researchers used a composite endpoint of a ≥ 2-point decrease in NAS with a ≥ 1-point decrease in at least two NAS components. Of the tirzepatide-treated groups, 71.7%,78.3%, and 76.6% in the 5-mg, 10-mg, and 15-mg groups, respectively, met this endpoint compared with 36.7% in placebo. 

Imaging of liver fat with MRI-based proton density fat fraction (MRI-PDFF) showed reductions from baseline of -45.7, -41.3, -57.0 in participants on 5-mg, 10-mg, and 15-mg tirzepatide, respectively. Differences from placebo were all statistically significant. 

Percentage of body weight change from baseline was -10.7%, -13.3%, and -15.6% in the 5-mg, 10-mg, and 15-mg tirzepatide groups, respectively, compared with weight loss of -0.8% in the placebo group. 

“Tirzepatide led to significant weight loss in both patients with diabetes and those without diabetes,” reported Dr. Loomba. 

There were more adverse events in patients on tirzepatide (92.3%) compared with patients on placebo (83.3%). 

“The most common adverse events were gastrointestinal in nature, with 96% of them mild to moderate in severity,” said Dr. Loomba. “Discontinuations occurred in 4.2% of participants, which was similar between patients on tirzepatide and those on placebo.”

He pointed out that the safety profile of tirzepatide in a MASH population “was generally similar to that observed in the phase 3 trials of type 2 diabetes and obesity.”

Incidence of serious adverse events was also similar at 6.3% for participants on tirzepatide vs 6.2% for those on placebo; 2.8% on tirzepatide and 4.2% on placebo progressed to cirrhosis. There was no evidence of drug-induced liver injury. 
 

‘Convincing Results’

Commenting on the study, co-moderator Sven Francque, MD, hepatologist and head of department at the University Hospital of Antwerp, Belgium, said that the study was in a relatively “severe” patient population, which was one of its strengths. 

“These are convincing results in terms of MASH resolution, showing a strong response and dose-dependence,” he said. 

Dr. Francque

MILAN — Tirzepatide, a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptor agonist, was more effective than was placebo in the resolution of metabolic dysfunction–associated steatohepatitis (MASH) and in the improvement of fibrosis, according to the results of the phase 2 SYNERGY-NASH trial.

Specifically, 44%-62% of participants with MASH and moderate or severe fibrosis treated with 5-15 mg of tirzepatide achieved MASH resolution without worsening of fibrosis compared with 10% on placebo; 51%-55% of those on tirzepatide achieved at least one stage of fibrosis improvement without worsening of MASH compared with 30% on placebo. Tirzepatide also led to weight loss.

The study (Abstract LBO-001) was presented at the European Association for the Study of the Liver (EASL) Congress 2024 by Rohit Loomba, MD, professor of medicine, NAFLD Research Center, University of California at San Diego in La Jolla, and published simultaneously in The New England Journal of Medicine. 

“The results are clinically meaningful,” Dr. Loomba said in an interview. 

University of California, San Diego

Both of the endpoints — improvements in MASH resolution and fibrosis — are considered approvable endpoints for MASH therapeutic development, and therefore, increase the likelihood of success of using such a strategy in a phase 3 setting, Dr. Loomba said.
 

MASH Resolution, No Worsening of Fibrosis

The dose-finding, multicenter, double-blind, placebo-controlled trial randomly assigned a total of 190 participants to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. Participants had biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. 

Overall, approximately 42% of participants had F2 fibrosis and over 57% had F3 fibrosis. The proportion of F3 fibrosis was numerically higher in the placebo (64.6%) and 5-mg tirzepatide (63.8%) groups. 

The mean age of the study cohort was 54 years; 57% were female, 86% were White, and 36% were Hispanic; the mean body mass index was 36; 58% had type 2 diabetes; and A1c was 6.5. NAFLD activity score (NAS) was 5.3. Baseline noninvasive test results were consistent with the study population of MASH with F2/F3 fibrosis and NAS ≥ 4. 

The primary endpoint was resolution of MASH without worsening of fibrosis at 52 weeks, and the key secondary endpoint was an improvement (decrease) of at least one fibrosis stage without worsening of MASH. Other secondary endpoints included a ≥ 2-point decrease in NAS with ≤ 1-point decrease in two or more NAS components.

A total of 157 participants (83%) underwent liver biopsies at week 52, providing results for the current analysis. 

Among tirzepatide-treated patients, 43.6% in the 5-mg group, 55.5% in the 10-mg group, and 62.4% in the 15-mg group met the criteria for resolution of MASH without worsening of fibrosis compared with  10% in the placebo group (P < .001 for all three comparisons). 

Fibrosis improved by at least one stage without worsening of MASH in 54.9% of participants in the 5-mg tirzepatide group, 51.3% in the 10-mg tirzepatide group, and 51.0% in the 15-mg tirzepatide group compared with 29.7% in the placebo group (P < .001 for all risk differences with placebo). 

Changes in NAS and subscores for the individual components of NAS, including steatosis, lobular inflammation, and hepatocellular ballooning, were also seen in participants on tirzepatide. 

The researchers used a composite endpoint of a ≥ 2-point decrease in NAS with a ≥ 1-point decrease in at least two NAS components. Of the tirzepatide-treated groups, 71.7%,78.3%, and 76.6% in the 5-mg, 10-mg, and 15-mg groups, respectively, met this endpoint compared with 36.7% in placebo. 

Imaging of liver fat with MRI-based proton density fat fraction (MRI-PDFF) showed reductions from baseline of -45.7, -41.3, -57.0 in participants on 5-mg, 10-mg, and 15-mg tirzepatide, respectively. Differences from placebo were all statistically significant. 

Percentage of body weight change from baseline was -10.7%, -13.3%, and -15.6% in the 5-mg, 10-mg, and 15-mg tirzepatide groups, respectively, compared with weight loss of -0.8% in the placebo group. 

“Tirzepatide led to significant weight loss in both patients with diabetes and those without diabetes,” reported Dr. Loomba. 

There were more adverse events in patients on tirzepatide (92.3%) compared with patients on placebo (83.3%). 

“The most common adverse events were gastrointestinal in nature, with 96% of them mild to moderate in severity,” said Dr. Loomba. “Discontinuations occurred in 4.2% of participants, which was similar between patients on tirzepatide and those on placebo.”

He pointed out that the safety profile of tirzepatide in a MASH population “was generally similar to that observed in the phase 3 trials of type 2 diabetes and obesity.”

Incidence of serious adverse events was also similar at 6.3% for participants on tirzepatide vs 6.2% for those on placebo; 2.8% on tirzepatide and 4.2% on placebo progressed to cirrhosis. There was no evidence of drug-induced liver injury. 
 

‘Convincing Results’

Commenting on the study, co-moderator Sven Francque, MD, hepatologist and head of department at the University Hospital of Antwerp, Belgium, said that the study was in a relatively “severe” patient population, which was one of its strengths. 

“These are convincing results in terms of MASH resolution, showing a strong response and dose-dependence,” he said. 

Dr. Francque

CHICAGO — The landscape of antibody-drug conjugates, or ADCs, continues to grow more crowded in metastatic breast cancer. Indications are expanding, new agents are emerging, combinations with other drug classes are being tested, and many patients with this disease are now receiving more than one ADC.

ADCs use antibodies to bind to the surface proteins of cancer cells to deliver a potent payload of cytotoxic chemotherapy. Three are approved for use in pretreated patients with metastatic breast cancer: sacituzumab govitecan, or SG, for patients with triple-negative disease; trastuzumab deruxtecan, or T-DXd, for patients with HER2-positive and HER2-low disease; and trastuzumab emtansine, or T-DM1, for patients with HER2-positive disease. A fourth agent, datopotamab deruxtecan, or Dato-DXd, is being assessed by the US Food and Drug Administration (FDA) for use in pretreated HR-positive, HER2-negative patients, and others, including sacituzumab tirumotecan, are being tested in clinical trials.At the annual meeting of the American Society of Clinical Oncology, T-DXd (Enhertu, AstraZeneca) showed better progression free survival than chemotherapy in people with HR-positive, HER 2-low metastatic breast cancers. These findings, from the DESTINY Breast-06 trial, were among the most talked-about at ASCO, and are likely to change clinical practice (J Clin Oncol. 2024;42[suppl 17; abstr LBA1000]).

But other ADC results presented at ASCO showed that there is still much to be worked out about the timing and sequencing of these agents, as well as their synergy with other drug classes, in metastatic breast cancer.
 

An ADC gets its first test, and falls short

Antonio Giordano, MD, PhD, of the Dana-Farber Cancer Institute in Boston, presented findings from an open-label phase 2 study of the ADC enfortumab vedotin (EV), an agent currently approved for use in advanced or metastatic urothelial cancer, at ASCO. This study included two cohorts of previously treated metastatic breast cancer patients: one with triple-negative disease (n = 42) and the other with HR-positive HER2-negative (n = 45).

Dr. Giordano and his colleagues’ study is the first to look at this ADC in breast cancer. EV’s antibody targets the cell adhesion molecule Nectin-4.

The researchers found that though EV demonstrated anti-tumor activity in both cohorts — with 19% of the triple-negative patients and 15.6% of the HR-positive/HER2-negative patients responding — the results did not meet the prespecified response thresholds for either cohort. (J Clin Oncol. 2024;42[suppl 16; abstr 1005]).

In an interview, Dr. Giordano said that studies in urothelial cancer had shown better response to EV associated with more expression of Nectin-4, but this study did not see such clear associations between expression and response. While there is no question that Nectin-4 is highly expressed in breast cancer and therefore a viable target, he said, “it may need to be looked at a little more deeply.”

It could also be the case, Dr. Giordano said, that the effect of EV’s payload may have been less robust in participants who had been previously treated with taxane chemotherapy, as nearly all patients in the two cohorts were.

“Taxanes are microtubule disruptors. And with this drug we had a payload with pretty much the same mechanism of action,” Dr. Giordano said. Ideally, he said, he would like to test the agent in a first-line setting, possibly in combination with an immunotherapy agent.

The timing of ADCs is as important as their targets and their payloads — and something that investigators are still struggling to figure out, he said.

A third of the patients in the triple-negative cohort of his study had been previously treated with SG, and a handful of individuals with T-Dxd, he noted.

“We’re in the middle of an ADC revolution,” he said. “It’s really key to figure out the best sequencing for a patient and if it’s actually worth it to do it. Very often we see patients respond best to the first ADC. But sometimes we see patients that do not respond to the first ADC and then they respond to the second one. It’s not very frequent, but it happens.”
 

Hint of Benefit from Adding Immunotherapy to SG

In a separate presentation at ASCO, Ana C. Garrido-Castro, MD, also of the Dana-Farber Cancer Institute, presented results from the SACI-IO HR+ trial, a randomized phase 2 study of SG (Trodelvy, Gilead) with and without pembrolizumab (Keytruda, Merck) in 104 patients with metastatic HR-positive/HER2-negative breast cancer who received prior endocrine therapy and up to one chemotherapy regimen for advanced disease. SACI-IO HR+ is the first randomized trial to report the efficacy of a topoisomerase I-inhibitor ADC with an immune checkpoint inhibitor for the treatment of breast cancer.

The addition of the immune checkpoint inhibitor did not result in a significant improvement in median progression-free survival in the overall population, Dr. Garrido-Castro reported. Median PFS was 8.1 vs 6.2 months with the combination of SG plus pembrolizumab or sacituzumab govitecan alone, respectively. At a median follow-up of 12.5 months, there was also no significant difference seen in median overall survival (OS): 18.5 vs 18.0 months.

About 40% of participants were found to have PD-L1-positive tumors and, among this subgroup, there was a 4.4-month increase in median PFS and 6.0-month increase in median OS with the addition of pembrolizumab to SG, although this did not reach statistical significance. (J Clin Oncol. 2024;42[suppl 17; abstr LBA1004]).

“While the study did not demonstrate a statistically significant benefit with the addition of the immune checkpoint inhibitor to the ADC, there is an interesting signal for potential synergistic activity between the two agents, particularly in those patients with PD-L1 positive tumors,” Dr. Garrido-Castro said in an interview. She noted that the sample sizes for the PD-L1 subgroup were relatively small, and overall survival data are not yet mature.

A separate phase 3 study is looking at the experimental ADC called sacituzumab tirumotecan with and without pembrolizumab compared with chemotherapy in patients with metastatic HR-positive, HER2-negative breast cancer who have received prior endocrine therapy and no prior chemotherapy for metastatic disease, she said.

Similar to SG, sacituzumab tirumotecan is a TROP2-directed ADC with a topoisomerase I-inhibitor payload. With an estimated enrollment of 1,200 patients, this trial may help shed light on whether adding the immune checkpoint inhibitor to the topoisomerase I-inhibitor TROP2-directed ADC improves outcomes in the subgroup of patients with PD-L1 positive tumors, Dr. Garrido-Castro said.
 

Unlocking the Order and Timing of ADCs

Dr. Garrido-Castro is also leading a study that will evaluate the sequential use of ADCs in metastatic breast cancer. That trial, to be called TRADE-DXd, will enroll patients with HER2-low metastatic breast cancer who have received up to one prior line of chemotherapy and no previous topoisomerase I-inhibitors. Participants will receive either T-DXd or Dato-DXd as the first ADC, and then switch to the other ADC (Dato-DXd or T-DXd, respectively) at the time of progression, thus switching the target of the ADC from HER2 to TROP2 or vice versa.

“In real-world practice now, there are patients who receive sequential ADCs, because they are candidates for both,” Dr. Garrido-Castro explained. However, more robust data are needed to refine the selection of the initial antibody drug conjugate and to determine who is more likely to benefit from a second — or maybe even third — ADC.

“One potential mechanism of resistance to antibody drug conjugates is the downregulation of the target of the antibody drug conjugate,” Dr. Garrido-Castro said. “Thus, an important question is, if you modify the target of the ADC, is it possible to overcome that mechanism of resistance?” Another possible mechanism of resistance is to the chemotherapy payload of the ADCs, she said.

Dr. Garrido-Castro’s study will collect tumor samples and blood samples for the purposes of planned correlative analyses to try to better understand the mechanisms that drive response and resistance to these agents.

Dr. Giordano commented that Dr. Garrido-Castro’s study was likely to result in a much better understanding of ADCs and how to use them strategically.

At Dana-Farber, “we collect a lot of samples of patients receiving ADCs. And we are trying to do all kinds of work on circulating tumor DNA, immunohistochemistry expression, and protein expression,” he said. “We are trying to figure out how ADCs really work, and why they stop working.”

Dr. Giordano and colleagues’ study was funded by Astellas Pharma and by Seagen, which was bought by Pfizer in 2023. Dr. Giordano disclosed receiving consulting fees from Pfizer, and several of his coauthors reported relationships with this and other companies. Two were Astellas employees.

Dr. Garrido-Castro and colleagues’ study was funded by Merck and Gilead Sciences. Dr. Garrido-Castro disclosed receiving research support from Gilead Sciences, AstraZeneca, Daiichi Sankyo, Merck, Zenith Epigenetics, Bristol-Myers Squibb, Novartis, Biovica, Foundation Medicine, 4D Path, Precede Biosciences; scientific advisory board/consulting fees from AstraZeneca, Novartis, Daiichi Sankyo; speaker honoraria from AstraZeneca, Daiichi Sankyo; and other support from Roche/Genentech, Gilead Sciences, AstraZeneca, Daiichi Sankyo, Novartis, and Merck, while her coauthors reported similar relationships.

CHICAGO — The landscape of antibody-drug conjugates, or ADCs, continues to grow more crowded in metastatic breast cancer. Indications are expanding, new agents are emerging, combinations with other drug classes are being tested, and many patients with this disease are now receiving more than one ADC.

ADCs use antibodies to bind to the surface proteins of cancer cells to deliver a potent payload of cytotoxic chemotherapy. Three are approved for use in pretreated patients with metastatic breast cancer: sacituzumab govitecan, or SG, for patients with triple-negative disease; trastuzumab deruxtecan, or T-DXd, for patients with HER2-positive and HER2-low disease; and trastuzumab emtansine, or T-DM1, for patients with HER2-positive disease. A fourth agent, datopotamab deruxtecan, or Dato-DXd, is being assessed by the US Food and Drug Administration (FDA) for use in pretreated HR-positive, HER2-negative patients, and others, including sacituzumab tirumotecan, are being tested in clinical trials.At the annual meeting of the American Society of Clinical Oncology, T-DXd (Enhertu, AstraZeneca) showed better progression free survival than chemotherapy in people with HR-positive, HER 2-low metastatic breast cancers. These findings, from the DESTINY Breast-06 trial, were among the most talked-about at ASCO, and are likely to change clinical practice (J Clin Oncol. 2024;42[suppl 17; abstr LBA1000]).

But other ADC results presented at ASCO showed that there is still much to be worked out about the timing and sequencing of these agents, as well as their synergy with other drug classes, in metastatic breast cancer.
 

An ADC gets its first test, and falls short

Antonio Giordano, MD, PhD, of the Dana-Farber Cancer Institute in Boston, presented findings from an open-label phase 2 study of the ADC enfortumab vedotin (EV), an agent currently approved for use in advanced or metastatic urothelial cancer, at ASCO. This study included two cohorts of previously treated metastatic breast cancer patients: one with triple-negative disease (n = 42) and the other with HR-positive HER2-negative (n = 45).

Dr. Giordano and his colleagues’ study is the first to look at this ADC in breast cancer. EV’s antibody targets the cell adhesion molecule Nectin-4.

The researchers found that though EV demonstrated anti-tumor activity in both cohorts — with 19% of the triple-negative patients and 15.6% of the HR-positive/HER2-negative patients responding — the results did not meet the prespecified response thresholds for either cohort. (J Clin Oncol. 2024;42[suppl 16; abstr 1005]).

In an interview, Dr. Giordano said that studies in urothelial cancer had shown better response to EV associated with more expression of Nectin-4, but this study did not see such clear associations between expression and response. While there is no question that Nectin-4 is highly expressed in breast cancer and therefore a viable target, he said, “it may need to be looked at a little more deeply.”

It could also be the case, Dr. Giordano said, that the effect of EV’s payload may have been less robust in participants who had been previously treated with taxane chemotherapy, as nearly all patients in the two cohorts were.

“Taxanes are microtubule disruptors. And with this drug we had a payload with pretty much the same mechanism of action,” Dr. Giordano said. Ideally, he said, he would like to test the agent in a first-line setting, possibly in combination with an immunotherapy agent.

The timing of ADCs is as important as their targets and their payloads — and something that investigators are still struggling to figure out, he said.

A third of the patients in the triple-negative cohort of his study had been previously treated with SG, and a handful of individuals with T-Dxd, he noted.

“We’re in the middle of an ADC revolution,” he said. “It’s really key to figure out the best sequencing for a patient and if it’s actually worth it to do it. Very often we see patients respond best to the first ADC. But sometimes we see patients that do not respond to the first ADC and then they respond to the second one. It’s not very frequent, but it happens.”
 

Hint of Benefit from Adding Immunotherapy to SG

In a separate presentation at ASCO, Ana C. Garrido-Castro, MD, also of the Dana-Farber Cancer Institute, presented results from the SACI-IO HR+ trial, a randomized phase 2 study of SG (Trodelvy, Gilead) with and without pembrolizumab (Keytruda, Merck) in 104 patients with metastatic HR-positive/HER2-negative breast cancer who received prior endocrine therapy and up to one chemotherapy regimen for advanced disease. SACI-IO HR+ is the first randomized trial to report the efficacy of a topoisomerase I-inhibitor ADC with an immune checkpoint inhibitor for the treatment of breast cancer.

The addition of the immune checkpoint inhibitor did not result in a significant improvement in median progression-free survival in the overall population, Dr. Garrido-Castro reported. Median PFS was 8.1 vs 6.2 months with the combination of SG plus pembrolizumab or sacituzumab govitecan alone, respectively. At a median follow-up of 12.5 months, there was also no significant difference seen in median overall survival (OS): 18.5 vs 18.0 months.

About 40% of participants were found to have PD-L1-positive tumors and, among this subgroup, there was a 4.4-month increase in median PFS and 6.0-month increase in median OS with the addition of pembrolizumab to SG, although this did not reach statistical significance. (J Clin Oncol. 2024;42[suppl 17; abstr LBA1004]).

“While the study did not demonstrate a statistically significant benefit with the addition of the immune checkpoint inhibitor to the ADC, there is an interesting signal for potential synergistic activity between the two agents, particularly in those patients with PD-L1 positive tumors,” Dr. Garrido-Castro said in an interview. She noted that the sample sizes for the PD-L1 subgroup were relatively small, and overall survival data are not yet mature.

A separate phase 3 study is looking at the experimental ADC called sacituzumab tirumotecan with and without pembrolizumab compared with chemotherapy in patients with metastatic HR-positive, HER2-negative breast cancer who have received prior endocrine therapy and no prior chemotherapy for metastatic disease, she said.

Similar to SG, sacituzumab tirumotecan is a TROP2-directed ADC with a topoisomerase I-inhibitor payload. With an estimated enrollment of 1,200 patients, this trial may help shed light on whether adding the immune checkpoint inhibitor to the topoisomerase I-inhibitor TROP2-directed ADC improves outcomes in the subgroup of patients with PD-L1 positive tumors, Dr. Garrido-Castro said.
 

Unlocking the Order and Timing of ADCs

Dr. Garrido-Castro is also leading a study that will evaluate the sequential use of ADCs in metastatic breast cancer. That trial, to be called TRADE-DXd, will enroll patients with HER2-low metastatic breast cancer who have received up to one prior line of chemotherapy and no previous topoisomerase I-inhibitors. Participants will receive either T-DXd or Dato-DXd as the first ADC, and then switch to the other ADC (Dato-DXd or T-DXd, respectively) at the time of progression, thus switching the target of the ADC from HER2 to TROP2 or vice versa.

“In real-world practice now, there are patients who receive sequential ADCs, because they are candidates for both,” Dr. Garrido-Castro explained. However, more robust data are needed to refine the selection of the initial antibody drug conjugate and to determine who is more likely to benefit from a second — or maybe even third — ADC.

“One potential mechanism of resistance to antibody drug conjugates is the downregulation of the target of the antibody drug conjugate,” Dr. Garrido-Castro said. “Thus, an important question is, if you modify the target of the ADC, is it possible to overcome that mechanism of resistance?” Another possible mechanism of resistance is to the chemotherapy payload of the ADCs, she said.

Dr. Garrido-Castro’s study will collect tumor samples and blood samples for the purposes of planned correlative analyses to try to better understand the mechanisms that drive response and resistance to these agents.

Dr. Giordano commented that Dr. Garrido-Castro’s study was likely to result in a much better understanding of ADCs and how to use them strategically.

At Dana-Farber, “we collect a lot of samples of patients receiving ADCs. And we are trying to do all kinds of work on circulating tumor DNA, immunohistochemistry expression, and protein expression,” he said. “We are trying to figure out how ADCs really work, and why they stop working.”

Dr. Giordano and colleagues’ study was funded by Astellas Pharma and by Seagen, which was bought by Pfizer in 2023. Dr. Giordano disclosed receiving consulting fees from Pfizer, and several of his coauthors reported relationships with this and other companies. Two were Astellas employees.

Dr. Garrido-Castro and colleagues’ study was funded by Merck and Gilead Sciences. Dr. Garrido-Castro disclosed receiving research support from Gilead Sciences, AstraZeneca, Daiichi Sankyo, Merck, Zenith Epigenetics, Bristol-Myers Squibb, Novartis, Biovica, Foundation Medicine, 4D Path, Precede Biosciences; scientific advisory board/consulting fees from AstraZeneca, Novartis, Daiichi Sankyo; speaker honoraria from AstraZeneca, Daiichi Sankyo; and other support from Roche/Genentech, Gilead Sciences, AstraZeneca, Daiichi Sankyo, Novartis, and Merck, while her coauthors reported similar relationships.

CHICAGO — The landscape of antibody-drug conjugates, or ADCs, continues to grow more crowded in metastatic breast cancer. Indications are expanding, new agents are emerging, combinations with other drug classes are being tested, and many patients with this disease are now receiving more than one ADC.

ADCs use antibodies to bind to the surface proteins of cancer cells to deliver a potent payload of cytotoxic chemotherapy. Three are approved for use in pretreated patients with metastatic breast cancer: sacituzumab govitecan, or SG, for patients with triple-negative disease; trastuzumab deruxtecan, or T-DXd, for patients with HER2-positive and HER2-low disease; and trastuzumab emtansine, or T-DM1, for patients with HER2-positive disease. A fourth agent, datopotamab deruxtecan, or Dato-DXd, is being assessed by the US Food and Drug Administration (FDA) for use in pretreated HR-positive, HER2-negative patients, and others, including sacituzumab tirumotecan, are being tested in clinical trials.At the annual meeting of the American Society of Clinical Oncology, T-DXd (Enhertu, AstraZeneca) showed better progression free survival than chemotherapy in people with HR-positive, HER 2-low metastatic breast cancers. These findings, from the DESTINY Breast-06 trial, were among the most talked-about at ASCO, and are likely to change clinical practice (J Clin Oncol. 2024;42[suppl 17; abstr LBA1000]).

But other ADC results presented at ASCO showed that there is still much to be worked out about the timing and sequencing of these agents, as well as their synergy with other drug classes, in metastatic breast cancer.
 

An ADC gets its first test, and falls short

Antonio Giordano, MD, PhD, of the Dana-Farber Cancer Institute in Boston, presented findings from an open-label phase 2 study of the ADC enfortumab vedotin (EV), an agent currently approved for use in advanced or metastatic urothelial cancer, at ASCO. This study included two cohorts of previously treated metastatic breast cancer patients: one with triple-negative disease (n = 42) and the other with HR-positive HER2-negative (n = 45).

Dr. Giordano and his colleagues’ study is the first to look at this ADC in breast cancer. EV’s antibody targets the cell adhesion molecule Nectin-4.

The researchers found that though EV demonstrated anti-tumor activity in both cohorts — with 19% of the triple-negative patients and 15.6% of the HR-positive/HER2-negative patients responding — the results did not meet the prespecified response thresholds for either cohort. (J Clin Oncol. 2024;42[suppl 16; abstr 1005]).

In an interview, Dr. Giordano said that studies in urothelial cancer had shown better response to EV associated with more expression of Nectin-4, but this study did not see such clear associations between expression and response. While there is no question that Nectin-4 is highly expressed in breast cancer and therefore a viable target, he said, “it may need to be looked at a little more deeply.”

It could also be the case, Dr. Giordano said, that the effect of EV’s payload may have been less robust in participants who had been previously treated with taxane chemotherapy, as nearly all patients in the two cohorts were.

“Taxanes are microtubule disruptors. And with this drug we had a payload with pretty much the same mechanism of action,” Dr. Giordano said. Ideally, he said, he would like to test the agent in a first-line setting, possibly in combination with an immunotherapy agent.

The timing of ADCs is as important as their targets and their payloads — and something that investigators are still struggling to figure out, he said.

A third of the patients in the triple-negative cohort of his study had been previously treated with SG, and a handful of individuals with T-Dxd, he noted.

“We’re in the middle of an ADC revolution,” he said. “It’s really key to figure out the best sequencing for a patient and if it’s actually worth it to do it. Very often we see patients respond best to the first ADC. But sometimes we see patients that do not respond to the first ADC and then they respond to the second one. It’s not very frequent, but it happens.”
 

Hint of Benefit from Adding Immunotherapy to SG

In a separate presentation at ASCO, Ana C. Garrido-Castro, MD, also of the Dana-Farber Cancer Institute, presented results from the SACI-IO HR+ trial, a randomized phase 2 study of SG (Trodelvy, Gilead) with and without pembrolizumab (Keytruda, Merck) in 104 patients with metastatic HR-positive/HER2-negative breast cancer who received prior endocrine therapy and up to one chemotherapy regimen for advanced disease. SACI-IO HR+ is the first randomized trial to report the efficacy of a topoisomerase I-inhibitor ADC with an immune checkpoint inhibitor for the treatment of breast cancer.

The addition of the immune checkpoint inhibitor did not result in a significant improvement in median progression-free survival in the overall population, Dr. Garrido-Castro reported. Median PFS was 8.1 vs 6.2 months with the combination of SG plus pembrolizumab or sacituzumab govitecan alone, respectively. At a median follow-up of 12.5 months, there was also no significant difference seen in median overall survival (OS): 18.5 vs 18.0 months.

About 40% of participants were found to have PD-L1-positive tumors and, among this subgroup, there was a 4.4-month increase in median PFS and 6.0-month increase in median OS with the addition of pembrolizumab to SG, although this did not reach statistical significance. (J Clin Oncol. 2024;42[suppl 17; abstr LBA1004]).

“While the study did not demonstrate a statistically significant benefit with the addition of the immune checkpoint inhibitor to the ADC, there is an interesting signal for potential synergistic activity between the two agents, particularly in those patients with PD-L1 positive tumors,” Dr. Garrido-Castro said in an interview. She noted that the sample sizes for the PD-L1 subgroup were relatively small, and overall survival data are not yet mature.

A separate phase 3 study is looking at the experimental ADC called sacituzumab tirumotecan with and without pembrolizumab compared with chemotherapy in patients with metastatic HR-positive, HER2-negative breast cancer who have received prior endocrine therapy and no prior chemotherapy for metastatic disease, she said.

Similar to SG, sacituzumab tirumotecan is a TROP2-directed ADC with a topoisomerase I-inhibitor payload. With an estimated enrollment of 1,200 patients, this trial may help shed light on whether adding the immune checkpoint inhibitor to the topoisomerase I-inhibitor TROP2-directed ADC improves outcomes in the subgroup of patients with PD-L1 positive tumors, Dr. Garrido-Castro said.
 

Unlocking the Order and Timing of ADCs

Dr. Garrido-Castro is also leading a study that will evaluate the sequential use of ADCs in metastatic breast cancer. That trial, to be called TRADE-DXd, will enroll patients with HER2-low metastatic breast cancer who have received up to one prior line of chemotherapy and no previous topoisomerase I-inhibitors. Participants will receive either T-DXd or Dato-DXd as the first ADC, and then switch to the other ADC (Dato-DXd or T-DXd, respectively) at the time of progression, thus switching the target of the ADC from HER2 to TROP2 or vice versa.

“In real-world practice now, there are patients who receive sequential ADCs, because they are candidates for both,” Dr. Garrido-Castro explained. However, more robust data are needed to refine the selection of the initial antibody drug conjugate and to determine who is more likely to benefit from a second — or maybe even third — ADC.

“One potential mechanism of resistance to antibody drug conjugates is the downregulation of the target of the antibody drug conjugate,” Dr. Garrido-Castro said. “Thus, an important question is, if you modify the target of the ADC, is it possible to overcome that mechanism of resistance?” Another possible mechanism of resistance is to the chemotherapy payload of the ADCs, she said.

Dr. Garrido-Castro’s study will collect tumor samples and blood samples for the purposes of planned correlative analyses to try to better understand the mechanisms that drive response and resistance to these agents.

Dr. Giordano commented that Dr. Garrido-Castro’s study was likely to result in a much better understanding of ADCs and how to use them strategically.

At Dana-Farber, “we collect a lot of samples of patients receiving ADCs. And we are trying to do all kinds of work on circulating tumor DNA, immunohistochemistry expression, and protein expression,” he said. “We are trying to figure out how ADCs really work, and why they stop working.”

Dr. Giordano and colleagues’ study was funded by Astellas Pharma and by Seagen, which was bought by Pfizer in 2023. Dr. Giordano disclosed receiving consulting fees from Pfizer, and several of his coauthors reported relationships with this and other companies. Two were Astellas employees.

Dr. Garrido-Castro and colleagues’ study was funded by Merck and Gilead Sciences. Dr. Garrido-Castro disclosed receiving research support from Gilead Sciences, AstraZeneca, Daiichi Sankyo, Merck, Zenith Epigenetics, Bristol-Myers Squibb, Novartis, Biovica, Foundation Medicine, 4D Path, Precede Biosciences; scientific advisory board/consulting fees from AstraZeneca, Novartis, Daiichi Sankyo; speaker honoraria from AstraZeneca, Daiichi Sankyo; and other support from Roche/Genentech, Gilead Sciences, AstraZeneca, Daiichi Sankyo, Novartis, and Merck, while her coauthors reported similar relationships.

VIENNA — From a dozen or so studies and sessions devoted to the role of chimeric antigen receptor (CAR) T cells in rheumatic diseases at the annual European Congress of Rheumatology, the message was uniformly positive, supporting growing evidence that drugs in this class are heading toward a paradigm shift in refractory rheumatic diseases.

Of the reports, an update from a 15-patient case series with at least 1 year of follow-up provides “the first long-term evidence of safety and efficacy in multiple rheumatic diseases,” according to Georg Schett, MD, PhD, director of rheumatology and immunology, University of Erlangen-Nürnberg, Erlangen, Germany.

Ted Bosworth/Medscape Medical News

The report of high rates of activity and low relative risk of serious adverse events from the same series was published earlier this year in The New England Journal of Medicine when the median follow-up was 15 months. Almost all of the patients have now completed at least 1 year of follow-up and about a third have completed more than 2 years.
 

SLE Is Frequently Targeted in CAR T-Cell Studies

The three rheumatic diseases represented in this series of patients, all of whom had failed multiple previous immune suppressive treatments, were systemic lupus erythematosus (SLE), idiopathic inflammatory myositis (IIM), and systemic sclerosis (SSc). After the autologous T cells were harvested, they were expanded and transfected with the CD19 CAR. The proprietary investigational product, called MB-CART19.1 (Miltenyi Biotec), was administered in a single dose of one million cells per kg bodyweight.

The response rates have been, and continue to be, impressive. For the eight patients with SLE, all achieved the definition of remission in SLE criteria after one dose of treatment. Complete resolution of all major symptom types was achieved after 6 months of follow-up. So far, no patient has relapsed.

For the three patients with IIM, all reached the American College of Rheumatology–EULAR criteria for a major response. All creatine kinase levels had normalized by 3 months. In this group, there was one relapse, which occurred after 18 months of follow-up.

All four patients with SSc achieved a major response on the European Scleroderma Trials and Research (EUSTAR) group activity index. The median reduction from baseline in the EUSTAR score was 4.2 points, and this has been maintained in follow-up to date.
 

Remissions Have Persisted Off All Therapies

These remissions were achieved and maintained after a single dose of CAR T-cell therapy despite discontinuation of all immunosuppressive therapies. With the exception of the single relapse, all remissions have persisted through follow-up to date.

These responses were achieved with manageable side effects, according to Dr. Schett. The most serious adverse event was a grade 4 neutropenia that developed 4 months after receiving CAR T cells. It resolved with granulocyte colony-stimulating factor treatment. Cytokine release syndrome (CRS) has occurred in 10 patients, but it was grade 1 in eight patients and grade 2 in the others. There has been no neurotoxicity.

Almost all patients have experienced an infection during follow-up, but there has been no discernible pattern in relationship to the timing or types of infections. The most common have involved the upper respiratory tract and have been of mild severity, with cases disseminated similarly over early vs late follow-up. There was one case of pneumonia involving antibiotic treatment and a hospital stay, but it resolved.

Dr. Schett acknowledged that safety is a bigger concern in autoimmune diseases, which are often serious but rarely fatal, than in the hematologic malignancies for which CAR T cells were initially tested, but the low rates of serious adverse events in his and other early studies have supported the premise that the risks are not the same.

Asked specifically if CAR T cells can be considered a game changer in autoimmune rheumatic diseases, Dr. Schett was cautious. One reason is the CAR T cells are a complex therapy relative to biologic disease-modifying antirheumatic drugs. He thinks, therefore, that much more data are needed to confirm safety and efficacy. In addition, they are expensive, so it is not yet clear how they will be integrated with other options.

Yet, he thinks the evidence so far suggests a profound effect on the fundamental drivers of autoimmune disease. Their specific mechanism of benefit is still being evaluated, but he considers the clinical responses consistent with a “reset” hypothesis.

After a response, “we are seeing drug-free remissions in some patients as long as they have been followed,” Dr. Schett said. Based on the fact that disease control is being observed off all other therapies, “this only makes sense to me if there is some sort of immunologic reset.”
 

CAR T-Cell Studies in Autoimmune Diseases Are Proliferating

At last count, there were about 40 studies being performed with CAR T cells in various autoimmune diseases, most of which were rheumatologic disorders, according to Dr. Schett. He noted that funding is coming from multinational drug companies, small biotech startups, and investigator-initiated studies at academic centers.

At EULAR, beyond case studies and anecdotal reports, all of the clinical studies were still at the level of phase 1 or 1/2. Consistent with the data presented by Dr. Schett, the drugs have been nearly uniformly effective, with major responses persisting in patients off other therapies. Adverse events have been manageable.

Examples include a phase 1/2 multinational study with the investigational CAR T-cell therapy YTB323 (Novartis), which demonstrated acceptable safety and a strong signal of benefit in six patients with SLE. In this report, CRS was also common, but no case of CRS was more severe than grade 2. There was no neurotoxicity. Infections did occur but were of relatively mild grades and resolved with treatment.

For efficacy in the ongoing follow-up, SLE symptoms as measured with the SLE Disease Activity Index began to abate at about 14 days after the single-infusion treatment. Improvement on the Physician Global Assessment was also observed between 14 and 28 days. C3 and C4 complement levels started to rise at about 28 days. While the responses have correlated with the observed changes in biomarkers of immune function, they have endured through a median follow-up that now exceeds 6 months.
 

Complete B-Cell Depletion Is Followed by Full Recovery

“Pharmacokinetic and pharmacodynamic studies revealed peak expansion of CAR T cells approximately 13-21 days post infusion, which was accompanied by deep B-cell depletion followed by subsequent B-cell recovery,” reported Josefina Cortés-Hernández, MD, PhD, a senior lecturer at Vall d’Hebron Research Institute, Barcelona, Spain.

Dr. Schett had reported the same pattern of expansion followed by a rapid elimination of detectable CAR T cells despite the sustained clinical benefit.

Dr. Cortés-Hernández said that the signal of efficacy in the context of acceptable safety supports an expansion of clinical studies with this CAR T-cell product in SLE and perhaps other autoimmune disorders.

In another early-stage study, patients with SLE who had failed multiple prior lines of therapy have been enrolled in an ongoing study with a compound CAR (cCAR) T cell. This experimental proprietary product (iCAR Bio Therapeutics, Zhongshan, China) targets both the B-cell maturation antigen and CD19, according to Greg Deener, the chief executive officer of iCell Gene Therapeutics, New York City.

Ted Bosworth/Medscape Medical News

cCAR T-Cell Construct Targets Immune Reset

With this construct, the goal is to deplete long-lived plasma cells as well as B cells in order to achieve a more complete humoral reset. While preliminary data from the phase 1 trial were published earlier this year in Annals of the Rheumatic Diseases, Mr. Deener focused his presentation at EULAR 2024 on 12 patients with SLE and lupus nephritis, a severe form of SLE that threatens glomerular structures and can lead to end-stage liver disease.

B cells in the peripheral blood could not be detected within 10 days of the cCAR infusion, and the immunoglobulins IgM and IgA were undetectable by day 42.

However, after B-cell recovery by day 150, “flow cytometry and B-cell receptor sequencing confirmed full humoral reset was achieved,” Mr. Deener said.

The remission has been durable in 11 of the 12 patients after a mean follow-up of 458 days, Mr. Deener reported. He noted that an improvement in renal function has been observed in the majority of patients.

Like others, he reported that treatment has been relatively well tolerated. In this series of patients, there have been no cases of CRS more severe than grade 1.

Overall, the cCAR data in lupus nephritis support the hypothesis that CAR T cells are reprogramming the immune system, according to Mr. Deener.

Combined with a reasonable safety profile, the consistency of benefit from CAR T cells in autoimmune rheumatic diseases is good news, but all of the investigators who spoke at EULAR agreed that there are still many unanswered questions. Not least, it is unclear whether patients can be effectively and safely retreated when and if relapses occur. Even though Dr. Schett did report a response with retreatment following a relapse, he said that there is no conclusion to draw from a single patient.

Yet, the high rates of remissions in patients with disease refractory to other therapeutic options is highly encouraging, particularly with the manageable side effects now reported by multiple investigators using different CAR T-cell products.

“Roughly 100 patients with rheumatic diseases have been treated with CAR T-cells, and we have not seen a high-grade CRS or neurotoxicity,” he said.

Long-term efficacy is less clear. With the first clinical studies in autoimmune diseases initiated in 2021, few patients have been followed for more than 2 years. Even with the high rates of response that will certainly fuel efforts to rapidly bring these treatments forward, long-term data are now the missing piece.
 

Other Case Series Presented at EULAR

Several other abstracts reported on patients with SSc who were treated with CD19-targeting CAR T cells:

Three patients for whom autologous hematopoietic stem cell transplantation was contraindicated or unsuccessful were successfully and safely treated.

Six patients with diffuse and progressive disease achieved stable disease activity without additional immunosuppression for up to 1 year after treatment.

Dr. Schett reported no potential conflicts of interest, and the study he presented was not funded by industry. Dr. Cortés-Hernández reported a financial relationship with Novartis, which funded the study of the CAR T-cell therapy YTB323, as well as with GlaxoSmithKline, which was not involved in the study she presented.  Mr. Deener is an employee of iCell Gene Therapeutics, which provided funding for the trial he presented.

August 7, 2024 — Editor's note: This article was updated with additional disclosure information for Dr. Josefina Cortés-Hernández.

A version of this article appeared on Medscape.com.

VIENNA — From a dozen or so studies and sessions devoted to the role of chimeric antigen receptor (CAR) T cells in rheumatic diseases at the annual European Congress of Rheumatology, the message was uniformly positive, supporting growing evidence that drugs in this class are heading toward a paradigm shift in refractory rheumatic diseases.

Of the reports, an update from a 15-patient case series with at least 1 year of follow-up provides “the first long-term evidence of safety and efficacy in multiple rheumatic diseases,” according to Georg Schett, MD, PhD, director of rheumatology and immunology, University of Erlangen-Nürnberg, Erlangen, Germany.

Ted Bosworth/Medscape Medical News

The report of high rates of activity and low relative risk of serious adverse events from the same series was published earlier this year in The New England Journal of Medicine when the median follow-up was 15 months. Almost all of the patients have now completed at least 1 year of follow-up and about a third have completed more than 2 years.
 

SLE Is Frequently Targeted in CAR T-Cell Studies

The three rheumatic diseases represented in this series of patients, all of whom had failed multiple previous immune suppressive treatments, were systemic lupus erythematosus (SLE), idiopathic inflammatory myositis (IIM), and systemic sclerosis (SSc). After the autologous T cells were harvested, they were expanded and transfected with the CD19 CAR. The proprietary investigational product, called MB-CART19.1 (Miltenyi Biotec), was administered in a single dose of one million cells per kg bodyweight.

The response rates have been, and continue to be, impressive. For the eight patients with SLE, all achieved the definition of remission in SLE criteria after one dose of treatment. Complete resolution of all major symptom types was achieved after 6 months of follow-up. So far, no patient has relapsed.

For the three patients with IIM, all reached the American College of Rheumatology–EULAR criteria for a major response. All creatine kinase levels had normalized by 3 months. In this group, there was one relapse, which occurred after 18 months of follow-up.

All four patients with SSc achieved a major response on the European Scleroderma Trials and Research (EUSTAR) group activity index. The median reduction from baseline in the EUSTAR score was 4.2 points, and this has been maintained in follow-up to date.
 

Remissions Have Persisted Off All Therapies

These remissions were achieved and maintained after a single dose of CAR T-cell therapy despite discontinuation of all immunosuppressive therapies. With the exception of the single relapse, all remissions have persisted through follow-up to date.

These responses were achieved with manageable side effects, according to Dr. Schett. The most serious adverse event was a grade 4 neutropenia that developed 4 months after receiving CAR T cells. It resolved with granulocyte colony-stimulating factor treatment. Cytokine release syndrome (CRS) has occurred in 10 patients, but it was grade 1 in eight patients and grade 2 in the others. There has been no neurotoxicity.

Almost all patients have experienced an infection during follow-up, but there has been no discernible pattern in relationship to the timing or types of infections. The most common have involved the upper respiratory tract and have been of mild severity, with cases disseminated similarly over early vs late follow-up. There was one case of pneumonia involving antibiotic treatment and a hospital stay, but it resolved.

Dr. Schett acknowledged that safety is a bigger concern in autoimmune diseases, which are often serious but rarely fatal, than in the hematologic malignancies for which CAR T cells were initially tested, but the low rates of serious adverse events in his and other early studies have supported the premise that the risks are not the same.

Asked specifically if CAR T cells can be considered a game changer in autoimmune rheumatic diseases, Dr. Schett was cautious. One reason is the CAR T cells are a complex therapy relative to biologic disease-modifying antirheumatic drugs. He thinks, therefore, that much more data are needed to confirm safety and efficacy. In addition, they are expensive, so it is not yet clear how they will be integrated with other options.

Yet, he thinks the evidence so far suggests a profound effect on the fundamental drivers of autoimmune disease. Their specific mechanism of benefit is still being evaluated, but he considers the clinical responses consistent with a “reset” hypothesis.

After a response, “we are seeing drug-free remissions in some patients as long as they have been followed,” Dr. Schett said. Based on the fact that disease control is being observed off all other therapies, “this only makes sense to me if there is some sort of immunologic reset.”
 

CAR T-Cell Studies in Autoimmune Diseases Are Proliferating

At last count, there were about 40 studies being performed with CAR T cells in various autoimmune diseases, most of which were rheumatologic disorders, according to Dr. Schett. He noted that funding is coming from multinational drug companies, small biotech startups, and investigator-initiated studies at academic centers.

At EULAR, beyond case studies and anecdotal reports, all of the clinical studies were still at the level of phase 1 or 1/2. Consistent with the data presented by Dr. Schett, the drugs have been nearly uniformly effective, with major responses persisting in patients off other therapies. Adverse events have been manageable.

Examples include a phase 1/2 multinational study with the investigational CAR T-cell therapy YTB323 (Novartis), which demonstrated acceptable safety and a strong signal of benefit in six patients with SLE. In this report, CRS was also common, but no case of CRS was more severe than grade 2. There was no neurotoxicity. Infections did occur but were of relatively mild grades and resolved with treatment.

For efficacy in the ongoing follow-up, SLE symptoms as measured with the SLE Disease Activity Index began to abate at about 14 days after the single-infusion treatment. Improvement on the Physician Global Assessment was also observed between 14 and 28 days. C3 and C4 complement levels started to rise at about 28 days. While the responses have correlated with the observed changes in biomarkers of immune function, they have endured through a median follow-up that now exceeds 6 months.
 

Complete B-Cell Depletion Is Followed by Full Recovery

“Pharmacokinetic and pharmacodynamic studies revealed peak expansion of CAR T cells approximately 13-21 days post infusion, which was accompanied by deep B-cell depletion followed by subsequent B-cell recovery,” reported Josefina Cortés-Hernández, MD, PhD, a senior lecturer at Vall d’Hebron Research Institute, Barcelona, Spain.

Dr. Schett had reported the same pattern of expansion followed by a rapid elimination of detectable CAR T cells despite the sustained clinical benefit.

Dr. Cortés-Hernández said that the signal of efficacy in the context of acceptable safety supports an expansion of clinical studies with this CAR T-cell product in SLE and perhaps other autoimmune disorders.

In another early-stage study, patients with SLE who had failed multiple prior lines of therapy have been enrolled in an ongoing study with a compound CAR (cCAR) T cell. This experimental proprietary product (iCAR Bio Therapeutics, Zhongshan, China) targets both the B-cell maturation antigen and CD19, according to Greg Deener, the chief executive officer of iCell Gene Therapeutics, New York City.

Ted Bosworth/Medscape Medical News

cCAR T-Cell Construct Targets Immune Reset

With this construct, the goal is to deplete long-lived plasma cells as well as B cells in order to achieve a more complete humoral reset. While preliminary data from the phase 1 trial were published earlier this year in Annals of the Rheumatic Diseases, Mr. Deener focused his presentation at EULAR 2024 on 12 patients with SLE and lupus nephritis, a severe form of SLE that threatens glomerular structures and can lead to end-stage liver disease.

B cells in the peripheral blood could not be detected within 10 days of the cCAR infusion, and the immunoglobulins IgM and IgA were undetectable by day 42.

However, after B-cell recovery by day 150, “flow cytometry and B-cell receptor sequencing confirmed full humoral reset was achieved,” Mr. Deener said.

The remission has been durable in 11 of the 12 patients after a mean follow-up of 458 days, Mr. Deener reported. He noted that an improvement in renal function has been observed in the majority of patients.

Like others, he reported that treatment has been relatively well tolerated. In this series of patients, there have been no cases of CRS more severe than grade 1.

Overall, the cCAR data in lupus nephritis support the hypothesis that CAR T cells are reprogramming the immune system, according to Mr. Deener.

Combined with a reasonable safety profile, the consistency of benefit from CAR T cells in autoimmune rheumatic diseases is good news, but all of the investigators who spoke at EULAR agreed that there are still many unanswered questions. Not least, it is unclear whether patients can be effectively and safely retreated when and if relapses occur. Even though Dr. Schett did report a response with retreatment following a relapse, he said that there is no conclusion to draw from a single patient.

Yet, the high rates of remissions in patients with disease refractory to other therapeutic options is highly encouraging, particularly with the manageable side effects now reported by multiple investigators using different CAR T-cell products.

“Roughly 100 patients with rheumatic diseases have been treated with CAR T-cells, and we have not seen a high-grade CRS or neurotoxicity,” he said.

Long-term efficacy is less clear. With the first clinical studies in autoimmune diseases initiated in 2021, few patients have been followed for more than 2 years. Even with the high rates of response that will certainly fuel efforts to rapidly bring these treatments forward, long-term data are now the missing piece.
 

Other Case Series Presented at EULAR

Several other abstracts reported on patients with SSc who were treated with CD19-targeting CAR T cells:

Three patients for whom autologous hematopoietic stem cell transplantation was contraindicated or unsuccessful were successfully and safely treated.

Six patients with diffuse and progressive disease achieved stable disease activity without additional immunosuppression for up to 1 year after treatment.

Dr. Schett reported no potential conflicts of interest, and the study he presented was not funded by industry. Dr. Cortés-Hernández reported a financial relationship with Novartis, which funded the study of the CAR T-cell therapy YTB323, as well as with GlaxoSmithKline, which was not involved in the study she presented.  Mr. Deener is an employee of iCell Gene Therapeutics, which provided funding for the trial he presented.

August 7, 2024 — Editor's note: This article was updated with additional disclosure information for Dr. Josefina Cortés-Hernández.

A version of this article appeared on Medscape.com.

VIENNA — From a dozen or so studies and sessions devoted to the role of chimeric antigen receptor (CAR) T cells in rheumatic diseases at the annual European Congress of Rheumatology, the message was uniformly positive, supporting growing evidence that drugs in this class are heading toward a paradigm shift in refractory rheumatic diseases.

Of the reports, an update from a 15-patient case series with at least 1 year of follow-up provides “the first long-term evidence of safety and efficacy in multiple rheumatic diseases,” according to Georg Schett, MD, PhD, director of rheumatology and immunology, University of Erlangen-Nürnberg, Erlangen, Germany.

Ted Bosworth/Medscape Medical News

The report of high rates of activity and low relative risk of serious adverse events from the same series was published earlier this year in The New England Journal of Medicine when the median follow-up was 15 months. Almost all of the patients have now completed at least 1 year of follow-up and about a third have completed more than 2 years.
 

SLE Is Frequently Targeted in CAR T-Cell Studies

The three rheumatic diseases represented in this series of patients, all of whom had failed multiple previous immune suppressive treatments, were systemic lupus erythematosus (SLE), idiopathic inflammatory myositis (IIM), and systemic sclerosis (SSc). After the autologous T cells were harvested, they were expanded and transfected with the CD19 CAR. The proprietary investigational product, called MB-CART19.1 (Miltenyi Biotec), was administered in a single dose of one million cells per kg bodyweight.

The response rates have been, and continue to be, impressive. For the eight patients with SLE, all achieved the definition of remission in SLE criteria after one dose of treatment. Complete resolution of all major symptom types was achieved after 6 months of follow-up. So far, no patient has relapsed.

For the three patients with IIM, all reached the American College of Rheumatology–EULAR criteria for a major response. All creatine kinase levels had normalized by 3 months. In this group, there was one relapse, which occurred after 18 months of follow-up.

All four patients with SSc achieved a major response on the European Scleroderma Trials and Research (EUSTAR) group activity index. The median reduction from baseline in the EUSTAR score was 4.2 points, and this has been maintained in follow-up to date.
 

Remissions Have Persisted Off All Therapies

These remissions were achieved and maintained after a single dose of CAR T-cell therapy despite discontinuation of all immunosuppressive therapies. With the exception of the single relapse, all remissions have persisted through follow-up to date.

These responses were achieved with manageable side effects, according to Dr. Schett. The most serious adverse event was a grade 4 neutropenia that developed 4 months after receiving CAR T cells. It resolved with granulocyte colony-stimulating factor treatment. Cytokine release syndrome (CRS) has occurred in 10 patients, but it was grade 1 in eight patients and grade 2 in the others. There has been no neurotoxicity.

Almost all patients have experienced an infection during follow-up, but there has been no discernible pattern in relationship to the timing or types of infections. The most common have involved the upper respiratory tract and have been of mild severity, with cases disseminated similarly over early vs late follow-up. There was one case of pneumonia involving antibiotic treatment and a hospital stay, but it resolved.

Dr. Schett acknowledged that safety is a bigger concern in autoimmune diseases, which are often serious but rarely fatal, than in the hematologic malignancies for which CAR T cells were initially tested, but the low rates of serious adverse events in his and other early studies have supported the premise that the risks are not the same.

Asked specifically if CAR T cells can be considered a game changer in autoimmune rheumatic diseases, Dr. Schett was cautious. One reason is the CAR T cells are a complex therapy relative to biologic disease-modifying antirheumatic drugs. He thinks, therefore, that much more data are needed to confirm safety and efficacy. In addition, they are expensive, so it is not yet clear how they will be integrated with other options.

Yet, he thinks the evidence so far suggests a profound effect on the fundamental drivers of autoimmune disease. Their specific mechanism of benefit is still being evaluated, but he considers the clinical responses consistent with a “reset” hypothesis.

After a response, “we are seeing drug-free remissions in some patients as long as they have been followed,” Dr. Schett said. Based on the fact that disease control is being observed off all other therapies, “this only makes sense to me if there is some sort of immunologic reset.”
 

CAR T-Cell Studies in Autoimmune Diseases Are Proliferating

At last count, there were about 40 studies being performed with CAR T cells in various autoimmune diseases, most of which were rheumatologic disorders, according to Dr. Schett. He noted that funding is coming from multinational drug companies, small biotech startups, and investigator-initiated studies at academic centers.

At EULAR, beyond case studies and anecdotal reports, all of the clinical studies were still at the level of phase 1 or 1/2. Consistent with the data presented by Dr. Schett, the drugs have been nearly uniformly effective, with major responses persisting in patients off other therapies. Adverse events have been manageable.

Examples include a phase 1/2 multinational study with the investigational CAR T-cell therapy YTB323 (Novartis), which demonstrated acceptable safety and a strong signal of benefit in six patients with SLE. In this report, CRS was also common, but no case of CRS was more severe than grade 2. There was no neurotoxicity. Infections did occur but were of relatively mild grades and resolved with treatment.

For efficacy in the ongoing follow-up, SLE symptoms as measured with the SLE Disease Activity Index began to abate at about 14 days after the single-infusion treatment. Improvement on the Physician Global Assessment was also observed between 14 and 28 days. C3 and C4 complement levels started to rise at about 28 days. While the responses have correlated with the observed changes in biomarkers of immune function, they have endured through a median follow-up that now exceeds 6 months.
 

Complete B-Cell Depletion Is Followed by Full Recovery

“Pharmacokinetic and pharmacodynamic studies revealed peak expansion of CAR T cells approximately 13-21 days post infusion, which was accompanied by deep B-cell depletion followed by subsequent B-cell recovery,” reported Josefina Cortés-Hernández, MD, PhD, a senior lecturer at Vall d’Hebron Research Institute, Barcelona, Spain.

Dr. Schett had reported the same pattern of expansion followed by a rapid elimination of detectable CAR T cells despite the sustained clinical benefit.

Dr. Cortés-Hernández said that the signal of efficacy in the context of acceptable safety supports an expansion of clinical studies with this CAR T-cell product in SLE and perhaps other autoimmune disorders.

In another early-stage study, patients with SLE who had failed multiple prior lines of therapy have been enrolled in an ongoing study with a compound CAR (cCAR) T cell. This experimental proprietary product (iCAR Bio Therapeutics, Zhongshan, China) targets both the B-cell maturation antigen and CD19, according to Greg Deener, the chief executive officer of iCell Gene Therapeutics, New York City.

Ted Bosworth/Medscape Medical News

cCAR T-Cell Construct Targets Immune Reset

With this construct, the goal is to deplete long-lived plasma cells as well as B cells in order to achieve a more complete humoral reset. While preliminary data from the phase 1 trial were published earlier this year in Annals of the Rheumatic Diseases, Mr. Deener focused his presentation at EULAR 2024 on 12 patients with SLE and lupus nephritis, a severe form of SLE that threatens glomerular structures and can lead to end-stage liver disease.

B cells in the peripheral blood could not be detected within 10 days of the cCAR infusion, and the immunoglobulins IgM and IgA were undetectable by day 42.

However, after B-cell recovery by day 150, “flow cytometry and B-cell receptor sequencing confirmed full humoral reset was achieved,” Mr. Deener said.

The remission has been durable in 11 of the 12 patients after a mean follow-up of 458 days, Mr. Deener reported. He noted that an improvement in renal function has been observed in the majority of patients.

Like others, he reported that treatment has been relatively well tolerated. In this series of patients, there have been no cases of CRS more severe than grade 1.

Overall, the cCAR data in lupus nephritis support the hypothesis that CAR T cells are reprogramming the immune system, according to Mr. Deener.

Combined with a reasonable safety profile, the consistency of benefit from CAR T cells in autoimmune rheumatic diseases is good news, but all of the investigators who spoke at EULAR agreed that there are still many unanswered questions. Not least, it is unclear whether patients can be effectively and safely retreated when and if relapses occur. Even though Dr. Schett did report a response with retreatment following a relapse, he said that there is no conclusion to draw from a single patient.

Yet, the high rates of remissions in patients with disease refractory to other therapeutic options is highly encouraging, particularly with the manageable side effects now reported by multiple investigators using different CAR T-cell products.

“Roughly 100 patients with rheumatic diseases have been treated with CAR T-cells, and we have not seen a high-grade CRS or neurotoxicity,” he said.

Long-term efficacy is less clear. With the first clinical studies in autoimmune diseases initiated in 2021, few patients have been followed for more than 2 years. Even with the high rates of response that will certainly fuel efforts to rapidly bring these treatments forward, long-term data are now the missing piece.
 

Other Case Series Presented at EULAR

Several other abstracts reported on patients with SSc who were treated with CD19-targeting CAR T cells:

Three patients for whom autologous hematopoietic stem cell transplantation was contraindicated or unsuccessful were successfully and safely treated.

Six patients with diffuse and progressive disease achieved stable disease activity without additional immunosuppression for up to 1 year after treatment.

Dr. Schett reported no potential conflicts of interest, and the study he presented was not funded by industry. Dr. Cortés-Hernández reported a financial relationship with Novartis, which funded the study of the CAR T-cell therapy YTB323, as well as with GlaxoSmithKline, which was not involved in the study she presented.  Mr. Deener is an employee of iCell Gene Therapeutics, which provided funding for the trial he presented.

August 7, 2024 — Editor's note: This article was updated with additional disclosure information for Dr. Josefina Cortés-Hernández.

A version of this article appeared on Medscape.com.

Patients with early, triple negative breast cancer (TNBC) and high risk of recurrence after initial therapy had significantly better 3-year overall survival (OS) when given adjuvant avelumab compared with those who were observed without further treatment, in the A-BRAVE trial.

“The 30% reduction in the risk of distant metastasis, and 34% reduction in the risk of death suggests that avelumab may have a role in early triple negative breast cancer patients at high risk of relapse after primary surgery or with invasive residual disease after neoadjuvant chemotherapy,” Pierfranco Conte, MD, from the department of surgery, oncology, and gastroenterology at the University of Padua, Italy, reported at the annual meeting of the American Society of Clinical Oncology.

A-BRAVE is the first randomized phase 3 trial patients with TNBC, treated with adjuvant avelumab, explained Dr. Conte. “Neoadjuvant chemotherapy is recommended for stage cT1c or larger, or cN+ disease. However, in case of invasive residual disease at surgery, prognosis is still very poor.”

TNBC is more immunogenic compared with other breast cancer subtypes, suggesting a role for immune checkpoint inhibitors such as avelumab in this setting, he said.
 

A-BRAVE Methods and Results

The trial enrolled 477 patients, median age 51 years, between June 2016 and October 2020, after their disease had progressed following initial treatment. There were two strata of patients: those who had received upfront surgery and then adjuvant chemotherapy before disease progression (stratum A, 18%); and those who received neoadjuvant chemotherapy, surgery, and then adjuvant chemo, but still had residual disease (stratum B, 82%).

Patients were randomized to either observation (n = 239) or treatment with avelumab (n = 238), at a dose of 10 mg/kg every 2 weeks for one year.

At a median follow-up of 52.1 months, avelumab did not show an advantage for the primary endpoint of 3-year disease-free survival (DFS), with 68.3% of treated patients meeting this endpoint, compared to 63.2% of observed patients (hazard ratio [HR 0.81, P = .172].

However, the treatment did show statistically significant benefits for the secondary 3-year OS endpoint (84.8% vs 76.3%, HR 0.66, P = .035).

“Trying to understand why we did observe a greater benefit with avelumab in overall survival compared to disease-free survival, we also made a post-hoc exploratory analysis on distant disease-free survival,” explained Dr. Conte.

There was a statistically significant 3-year distant disease-free survival (DDFS) benefit for treated patients compared with controls (75.4% vs 67.9%, HR 0.7, P = .0277), translating to a 30% reduction in the risk of distant metastasis, he noted.
 

Findings Are ‘Hypothesis-Generating’

The results are “hypothesis-generating at this point,” Alexandra Thomas, MD, a breast medical oncologist who was not involved in the research, said in an interview. “These results suggest that the story on how to best utilize checkpoint blockade as adjuvant therapy in triple negative breast cancer may not yet be fully written.”

She emphasized the study did not meet its primary endpoint, “though the results for secondary endpoints OS and the exploratory endpoint DDFS are intriguing.

“A-BRAVE is a smaller study, especially relative to Impassion030 (ALEXANDRA), which enrolled over 2,000 patients,” she explained. “It is notable that avelumab has slightly different properties than atezolizumab, which was used in Impassion030.”

“Avelumab is also a weak PD-L2 inhibitor. Could this be important? Notably, today most patients with clinical stage II-III triple negative breast cancer will receive pembrolizumab as per KEYNOTE-522, so the potential for clinical impact is greatly reduced,” added Dr. Thomas, professor and assistant director in the department of internal medicine at Duke Cancer Institute, in Durham, North Carolina.

SWOG1814, which has not been reported yet, “also looks at pembrolizumab in patients with residual disease post neoadjuvant chemotherapy and will provide further important information on in this space,” she said.

Merck KGaA funded the study.

Dr. Conte disclosed consulting or advisory roles with Daiichi Sankyo/Lilly, Gilead Sciences, Reveal Genomics; a HER2Dx patient; and providing expert testimony for AstraZeneca.

Dr. Thomas disclosed research grants from Sanofi and Merck.

Patients with early, triple negative breast cancer (TNBC) and high risk of recurrence after initial therapy had significantly better 3-year overall survival (OS) when given adjuvant avelumab compared with those who were observed without further treatment, in the A-BRAVE trial.

“The 30% reduction in the risk of distant metastasis, and 34% reduction in the risk of death suggests that avelumab may have a role in early triple negative breast cancer patients at high risk of relapse after primary surgery or with invasive residual disease after neoadjuvant chemotherapy,” Pierfranco Conte, MD, from the department of surgery, oncology, and gastroenterology at the University of Padua, Italy, reported at the annual meeting of the American Society of Clinical Oncology.

A-BRAVE is the first randomized phase 3 trial patients with TNBC, treated with adjuvant avelumab, explained Dr. Conte. “Neoadjuvant chemotherapy is recommended for stage cT1c or larger, or cN+ disease. However, in case of invasive residual disease at surgery, prognosis is still very poor.”

TNBC is more immunogenic compared with other breast cancer subtypes, suggesting a role for immune checkpoint inhibitors such as avelumab in this setting, he said.
 

A-BRAVE Methods and Results

The trial enrolled 477 patients, median age 51 years, between June 2016 and October 2020, after their disease had progressed following initial treatment. There were two strata of patients: those who had received upfront surgery and then adjuvant chemotherapy before disease progression (stratum A, 18%); and those who received neoadjuvant chemotherapy, surgery, and then adjuvant chemo, but still had residual disease (stratum B, 82%).

Patients were randomized to either observation (n = 239) or treatment with avelumab (n = 238), at a dose of 10 mg/kg every 2 weeks for one year.

At a median follow-up of 52.1 months, avelumab did not show an advantage for the primary endpoint of 3-year disease-free survival (DFS), with 68.3% of treated patients meeting this endpoint, compared to 63.2% of observed patients (hazard ratio [HR 0.81, P = .172].

However, the treatment did show statistically significant benefits for the secondary 3-year OS endpoint (84.8% vs 76.3%, HR 0.66, P = .035).

“Trying to understand why we did observe a greater benefit with avelumab in overall survival compared to disease-free survival, we also made a post-hoc exploratory analysis on distant disease-free survival,” explained Dr. Conte.

There was a statistically significant 3-year distant disease-free survival (DDFS) benefit for treated patients compared with controls (75.4% vs 67.9%, HR 0.7, P = .0277), translating to a 30% reduction in the risk of distant metastasis, he noted.
 

Findings Are ‘Hypothesis-Generating’

The results are “hypothesis-generating at this point,” Alexandra Thomas, MD, a breast medical oncologist who was not involved in the research, said in an interview. “These results suggest that the story on how to best utilize checkpoint blockade as adjuvant therapy in triple negative breast cancer may not yet be fully written.”

She emphasized the study did not meet its primary endpoint, “though the results for secondary endpoints OS and the exploratory endpoint DDFS are intriguing.

“A-BRAVE is a smaller study, especially relative to Impassion030 (ALEXANDRA), which enrolled over 2,000 patients,” she explained. “It is notable that avelumab has slightly different properties than atezolizumab, which was used in Impassion030.”

“Avelumab is also a weak PD-L2 inhibitor. Could this be important? Notably, today most patients with clinical stage II-III triple negative breast cancer will receive pembrolizumab as per KEYNOTE-522, so the potential for clinical impact is greatly reduced,” added Dr. Thomas, professor and assistant director in the department of internal medicine at Duke Cancer Institute, in Durham, North Carolina.

SWOG1814, which has not been reported yet, “also looks at pembrolizumab in patients with residual disease post neoadjuvant chemotherapy and will provide further important information on in this space,” she said.

Merck KGaA funded the study.

Dr. Conte disclosed consulting or advisory roles with Daiichi Sankyo/Lilly, Gilead Sciences, Reveal Genomics; a HER2Dx patient; and providing expert testimony for AstraZeneca.

Dr. Thomas disclosed research grants from Sanofi and Merck.

Patients with early, triple negative breast cancer (TNBC) and high risk of recurrence after initial therapy had significantly better 3-year overall survival (OS) when given adjuvant avelumab compared with those who were observed without further treatment, in the A-BRAVE trial.

“The 30% reduction in the risk of distant metastasis, and 34% reduction in the risk of death suggests that avelumab may have a role in early triple negative breast cancer patients at high risk of relapse after primary surgery or with invasive residual disease after neoadjuvant chemotherapy,” Pierfranco Conte, MD, from the department of surgery, oncology, and gastroenterology at the University of Padua, Italy, reported at the annual meeting of the American Society of Clinical Oncology.

A-BRAVE is the first randomized phase 3 trial patients with TNBC, treated with adjuvant avelumab, explained Dr. Conte. “Neoadjuvant chemotherapy is recommended for stage cT1c or larger, or cN+ disease. However, in case of invasive residual disease at surgery, prognosis is still very poor.”

TNBC is more immunogenic compared with other breast cancer subtypes, suggesting a role for immune checkpoint inhibitors such as avelumab in this setting, he said.
 

A-BRAVE Methods and Results

The trial enrolled 477 patients, median age 51 years, between June 2016 and October 2020, after their disease had progressed following initial treatment. There were two strata of patients: those who had received upfront surgery and then adjuvant chemotherapy before disease progression (stratum A, 18%); and those who received neoadjuvant chemotherapy, surgery, and then adjuvant chemo, but still had residual disease (stratum B, 82%).

Patients were randomized to either observation (n = 239) or treatment with avelumab (n = 238), at a dose of 10 mg/kg every 2 weeks for one year.

At a median follow-up of 52.1 months, avelumab did not show an advantage for the primary endpoint of 3-year disease-free survival (DFS), with 68.3% of treated patients meeting this endpoint, compared to 63.2% of observed patients (hazard ratio [HR 0.81, P = .172].

However, the treatment did show statistically significant benefits for the secondary 3-year OS endpoint (84.8% vs 76.3%, HR 0.66, P = .035).

“Trying to understand why we did observe a greater benefit with avelumab in overall survival compared to disease-free survival, we also made a post-hoc exploratory analysis on distant disease-free survival,” explained Dr. Conte.

There was a statistically significant 3-year distant disease-free survival (DDFS) benefit for treated patients compared with controls (75.4% vs 67.9%, HR 0.7, P = .0277), translating to a 30% reduction in the risk of distant metastasis, he noted.
 

Findings Are ‘Hypothesis-Generating’

The results are “hypothesis-generating at this point,” Alexandra Thomas, MD, a breast medical oncologist who was not involved in the research, said in an interview. “These results suggest that the story on how to best utilize checkpoint blockade as adjuvant therapy in triple negative breast cancer may not yet be fully written.”

She emphasized the study did not meet its primary endpoint, “though the results for secondary endpoints OS and the exploratory endpoint DDFS are intriguing.

“A-BRAVE is a smaller study, especially relative to Impassion030 (ALEXANDRA), which enrolled over 2,000 patients,” she explained. “It is notable that avelumab has slightly different properties than atezolizumab, which was used in Impassion030.”

“Avelumab is also a weak PD-L2 inhibitor. Could this be important? Notably, today most patients with clinical stage II-III triple negative breast cancer will receive pembrolizumab as per KEYNOTE-522, so the potential for clinical impact is greatly reduced,” added Dr. Thomas, professor and assistant director in the department of internal medicine at Duke Cancer Institute, in Durham, North Carolina.

SWOG1814, which has not been reported yet, “also looks at pembrolizumab in patients with residual disease post neoadjuvant chemotherapy and will provide further important information on in this space,” she said.

Merck KGaA funded the study.

Dr. Conte disclosed consulting or advisory roles with Daiichi Sankyo/Lilly, Gilead Sciences, Reveal Genomics; a HER2Dx patient; and providing expert testimony for AstraZeneca.

Dr. Thomas disclosed research grants from Sanofi and Merck.

Should 5 mg of tamoxifen — known as “baby TAM” — or the usual 20 mg dose be standard of care for breast cancer prevention in high-risk women?

Research to date clearly shows that tamoxifen can reduce the risk for breast cancer in high-risk individuals by 30%-50%. Recent evidence also indicates that this chemoprevention approach can reduce the risk of dying from breast cancer by as much as 57%.

In 2019, the US Preventive Services Task Force issued updated recommendations that clinicians offer risk-reducing medications, such as tamoxifen, raloxifene, or aromatase inhibitors, to women at an increased risk for breast cancer and a low risk for adverse medication effects.

However, this prophylactic strategy remains underused.

A major roadblock: The drugs’ side effects, which include venous thromboembolic events and endometrial cancer as well as symptoms of menopause, such as hot flashes and sexual issues, have made uptake and adherence a challenge.

Offering women a lower dose of tamoxifen could allay fears about toxicities and improve uptake as well as reduce side effects and boost long-term adherence among those receiving baby TAM.

However, experts remain uncertain about whether patients need the standard dose to experience the full prevention benefit.
 

The Debate

Years ago, Andrea De Censi, MD, a breast cancer researcher at the Galliera Hospital in Genova, Italy, and his colleagues reasoned that, because tamoxifen is a competitive estrogen receptor inhibitor, it may indeed have a minimal effective dose below 20 mg/d.

The fruits of that line of thought were presented to the world in the TAM-01 trial, first published in 2019, which pitted tamoxifen 5 mg/d for 3 years against placebo in 500 women with high-risk lesions, including lobular and ductal carcinoma in situ.

Dr. De Censi and colleagues found that baby TAM reduced the risk for invasive breast cancer by 52% and the risk for contralateral breast cancer by 75%.

Treatment adherence was slightly higher in the baby TAM group at 65% vs 61% in the placebo group.

A recent 10-year follow-up showed ongoing benefits associated with baby TAM vs placebo — a 42% reduction in breast cancer and a 64% drop in contralateral lesions.

The baby TAM group vs placebo experienced a slight increase in hot flashes but no significant increase in other common side effects.

Regarding serious adverse events, the baby TAM arm had one case of stage 1 endometrial cancer (0.4% of patients) and 20 cases of endometrial polyps (5%) vs 13 cases of endometrial polyps in the placebo arm. But there were no significant differences in thrombosis, cataracts, bone fractures, and other serious events.

Dr. De Censi said he’s surprised the baby TAM vs tamoxifen topic is still being debated. “Baby TAM, in my opinion, is a new standard of care for endocrine prevention of breast cancer in high-risk [women],” and baby TAM over 3 years is enough, said Dr. De Censi during a debate on the topic at the 2024 European Society for Medical Oncology Breast Cancer Congress in Berlin.

Gareth Evans, MD, a cancer genetics and prevention specialist at the University of Manchester, Manchester, England, however, isn’t convinced.

During the debate, Dr. Evans explained that  his main concern was that the baby TAM trial was limited to women with high-risk lesions, not other common reasons for tamoxifen prophylaxis, such as a positive family history or BRCA mutations.

“In Manchester, we have put over a thousand women on tamoxifen who have a family history or other risk factors, not high-risk lesions,” and there simply isn’t definitive evidence for baby TAM in these women, Dr. Evans said.

The vast weight of evidence for tamoxifen prophylaxis, he added, is in trials involving tens of thousands of women, followed in some cases for 20 years, who received the 20 mg dose for 5 years.

As a result, women in Manchester are started on 20 mg and dropped down to 5 mg only for side effects. That way, Evans explained, we are not taking away the benefit among women who can tolerate 20 mg.

Meanwhile, there’s no evidence that baby TAM improves medication adherence, he noted. Trials have reported similar adherence rates to baby TAM and standard dose tamoxifen as well as no definitive evidence that the risk for cancer and thrombosis is less with baby TAM, he said.

In fact, Dr. Evans noted, “many women take tamoxifen 20 mg for 5 years with no side effects.”

Overall, “I don’t think we’ve got the evidence yet to drop” dosages, particularly in women without high-risk lesions, Dr. Evans said. A real concern, he added, is poor metabolizers for whom 5 mg won’t be enough to have a preventive effect.

Dr. De Censi noted, however, that there will likely never be a definitive answer to the question of baby TAM vs standard dosing because industry has no financial incentive to do a head-to-head trial; tamoxifen went off patent over 30 years ago.

Still, a poll of the audience favored Evans’ approach — 80% said they would start high-risk women on 20 mg for breast cancer prophylaxis and reduce for side effects as needed.

Dr. De Censi didn’t have any disclosures. Dr. Evans is a consultant/advisor for AstraZeneca, SpringWorks, Recursion, Everything Genetic, and Syantra.

A version of this article first appeared on Medscape.com.

Should 5 mg of tamoxifen — known as “baby TAM” — or the usual 20 mg dose be standard of care for breast cancer prevention in high-risk women?

Research to date clearly shows that tamoxifen can reduce the risk for breast cancer in high-risk individuals by 30%-50%. Recent evidence also indicates that this chemoprevention approach can reduce the risk of dying from breast cancer by as much as 57%.

In 2019, the US Preventive Services Task Force issued updated recommendations that clinicians offer risk-reducing medications, such as tamoxifen, raloxifene, or aromatase inhibitors, to women at an increased risk for breast cancer and a low risk for adverse medication effects.

However, this prophylactic strategy remains underused.

A major roadblock: The drugs’ side effects, which include venous thromboembolic events and endometrial cancer as well as symptoms of menopause, such as hot flashes and sexual issues, have made uptake and adherence a challenge.

Offering women a lower dose of tamoxifen could allay fears about toxicities and improve uptake as well as reduce side effects and boost long-term adherence among those receiving baby TAM.

However, experts remain uncertain about whether patients need the standard dose to experience the full prevention benefit.
 

The Debate

Years ago, Andrea De Censi, MD, a breast cancer researcher at the Galliera Hospital in Genova, Italy, and his colleagues reasoned that, because tamoxifen is a competitive estrogen receptor inhibitor, it may indeed have a minimal effective dose below 20 mg/d.

The fruits of that line of thought were presented to the world in the TAM-01 trial, first published in 2019, which pitted tamoxifen 5 mg/d for 3 years against placebo in 500 women with high-risk lesions, including lobular and ductal carcinoma in situ.

Dr. De Censi and colleagues found that baby TAM reduced the risk for invasive breast cancer by 52% and the risk for contralateral breast cancer by 75%.

Treatment adherence was slightly higher in the baby TAM group at 65% vs 61% in the placebo group.

A recent 10-year follow-up showed ongoing benefits associated with baby TAM vs placebo — a 42% reduction in breast cancer and a 64% drop in contralateral lesions.

The baby TAM group vs placebo experienced a slight increase in hot flashes but no significant increase in other common side effects.

Regarding serious adverse events, the baby TAM arm had one case of stage 1 endometrial cancer (0.4% of patients) and 20 cases of endometrial polyps (5%) vs 13 cases of endometrial polyps in the placebo arm. But there were no significant differences in thrombosis, cataracts, bone fractures, and other serious events.

Dr. De Censi said he’s surprised the baby TAM vs tamoxifen topic is still being debated. “Baby TAM, in my opinion, is a new standard of care for endocrine prevention of breast cancer in high-risk [women],” and baby TAM over 3 years is enough, said Dr. De Censi during a debate on the topic at the 2024 European Society for Medical Oncology Breast Cancer Congress in Berlin.

Gareth Evans, MD, a cancer genetics and prevention specialist at the University of Manchester, Manchester, England, however, isn’t convinced.

During the debate, Dr. Evans explained that  his main concern was that the baby TAM trial was limited to women with high-risk lesions, not other common reasons for tamoxifen prophylaxis, such as a positive family history or BRCA mutations.

“In Manchester, we have put over a thousand women on tamoxifen who have a family history or other risk factors, not high-risk lesions,” and there simply isn’t definitive evidence for baby TAM in these women, Dr. Evans said.

The vast weight of evidence for tamoxifen prophylaxis, he added, is in trials involving tens of thousands of women, followed in some cases for 20 years, who received the 20 mg dose for 5 years.

As a result, women in Manchester are started on 20 mg and dropped down to 5 mg only for side effects. That way, Evans explained, we are not taking away the benefit among women who can tolerate 20 mg.

Meanwhile, there’s no evidence that baby TAM improves medication adherence, he noted. Trials have reported similar adherence rates to baby TAM and standard dose tamoxifen as well as no definitive evidence that the risk for cancer and thrombosis is less with baby TAM, he said.

In fact, Dr. Evans noted, “many women take tamoxifen 20 mg for 5 years with no side effects.”

Overall, “I don’t think we’ve got the evidence yet to drop” dosages, particularly in women without high-risk lesions, Dr. Evans said. A real concern, he added, is poor metabolizers for whom 5 mg won’t be enough to have a preventive effect.

Dr. De Censi noted, however, that there will likely never be a definitive answer to the question of baby TAM vs standard dosing because industry has no financial incentive to do a head-to-head trial; tamoxifen went off patent over 30 years ago.

Still, a poll of the audience favored Evans’ approach — 80% said they would start high-risk women on 20 mg for breast cancer prophylaxis and reduce for side effects as needed.

Dr. De Censi didn’t have any disclosures. Dr. Evans is a consultant/advisor for AstraZeneca, SpringWorks, Recursion, Everything Genetic, and Syantra.

A version of this article first appeared on Medscape.com.

Should 5 mg of tamoxifen — known as “baby TAM” — or the usual 20 mg dose be standard of care for breast cancer prevention in high-risk women?

Research to date clearly shows that tamoxifen can reduce the risk for breast cancer in high-risk individuals by 30%-50%. Recent evidence also indicates that this chemoprevention approach can reduce the risk of dying from breast cancer by as much as 57%.

In 2019, the US Preventive Services Task Force issued updated recommendations that clinicians offer risk-reducing medications, such as tamoxifen, raloxifene, or aromatase inhibitors, to women at an increased risk for breast cancer and a low risk for adverse medication effects.

However, this prophylactic strategy remains underused.

A major roadblock: The drugs’ side effects, which include venous thromboembolic events and endometrial cancer as well as symptoms of menopause, such as hot flashes and sexual issues, have made uptake and adherence a challenge.

Offering women a lower dose of tamoxifen could allay fears about toxicities and improve uptake as well as reduce side effects and boost long-term adherence among those receiving baby TAM.

However, experts remain uncertain about whether patients need the standard dose to experience the full prevention benefit.
 

The Debate

Years ago, Andrea De Censi, MD, a breast cancer researcher at the Galliera Hospital in Genova, Italy, and his colleagues reasoned that, because tamoxifen is a competitive estrogen receptor inhibitor, it may indeed have a minimal effective dose below 20 mg/d.

The fruits of that line of thought were presented to the world in the TAM-01 trial, first published in 2019, which pitted tamoxifen 5 mg/d for 3 years against placebo in 500 women with high-risk lesions, including lobular and ductal carcinoma in situ.

Dr. De Censi and colleagues found that baby TAM reduced the risk for invasive breast cancer by 52% and the risk for contralateral breast cancer by 75%.

Treatment adherence was slightly higher in the baby TAM group at 65% vs 61% in the placebo group.

A recent 10-year follow-up showed ongoing benefits associated with baby TAM vs placebo — a 42% reduction in breast cancer and a 64% drop in contralateral lesions.

The baby TAM group vs placebo experienced a slight increase in hot flashes but no significant increase in other common side effects.

Regarding serious adverse events, the baby TAM arm had one case of stage 1 endometrial cancer (0.4% of patients) and 20 cases of endometrial polyps (5%) vs 13 cases of endometrial polyps in the placebo arm. But there were no significant differences in thrombosis, cataracts, bone fractures, and other serious events.

Dr. De Censi said he’s surprised the baby TAM vs tamoxifen topic is still being debated. “Baby TAM, in my opinion, is a new standard of care for endocrine prevention of breast cancer in high-risk [women],” and baby TAM over 3 years is enough, said Dr. De Censi during a debate on the topic at the 2024 European Society for Medical Oncology Breast Cancer Congress in Berlin.

Gareth Evans, MD, a cancer genetics and prevention specialist at the University of Manchester, Manchester, England, however, isn’t convinced.

During the debate, Dr. Evans explained that  his main concern was that the baby TAM trial was limited to women with high-risk lesions, not other common reasons for tamoxifen prophylaxis, such as a positive family history or BRCA mutations.

“In Manchester, we have put over a thousand women on tamoxifen who have a family history or other risk factors, not high-risk lesions,” and there simply isn’t definitive evidence for baby TAM in these women, Dr. Evans said.

The vast weight of evidence for tamoxifen prophylaxis, he added, is in trials involving tens of thousands of women, followed in some cases for 20 years, who received the 20 mg dose for 5 years.

As a result, women in Manchester are started on 20 mg and dropped down to 5 mg only for side effects. That way, Evans explained, we are not taking away the benefit among women who can tolerate 20 mg.

Meanwhile, there’s no evidence that baby TAM improves medication adherence, he noted. Trials have reported similar adherence rates to baby TAM and standard dose tamoxifen as well as no definitive evidence that the risk for cancer and thrombosis is less with baby TAM, he said.

In fact, Dr. Evans noted, “many women take tamoxifen 20 mg for 5 years with no side effects.”

Overall, “I don’t think we’ve got the evidence yet to drop” dosages, particularly in women without high-risk lesions, Dr. Evans said. A real concern, he added, is poor metabolizers for whom 5 mg won’t be enough to have a preventive effect.

Dr. De Censi noted, however, that there will likely never be a definitive answer to the question of baby TAM vs standard dosing because industry has no financial incentive to do a head-to-head trial; tamoxifen went off patent over 30 years ago.

Still, a poll of the audience favored Evans’ approach — 80% said they would start high-risk women on 20 mg for breast cancer prophylaxis and reduce for side effects as needed.

Dr. De Censi didn’t have any disclosures. Dr. Evans is a consultant/advisor for AstraZeneca, SpringWorks, Recursion, Everything Genetic, and Syantra.

A version of this article first appeared on Medscape.com.

New tools for monitoring multiple myeloma were a key topic at the European Hematology Society Congress. Advances in drugs and combinations have revolutionized the landscape in multiple myeloma, thus allowing patients to live much longer, according to Bruno Paiva, PhD, director of flow cytometry and the myeloma laboratory at the University of Navarra Clinic in Pamplona, Spain.

“Much better treatment responses are achieved, with long-term remission, so tools are needed for long-term monitoring. The starting point for monitoring is the monoclonal protein secreted by the myeloma tumor cell, which can be measured in serum and urine. Complete remission is defined when that monoclonal component is not detected with routine laboratory techniques, such as immunofixation,” said Dr. Paiva.

Even if the patient may be in complete remission, minimal residual disease is sometimes detected as myeloma can infiltrate the bone marrow. Techniques for identifying minimal residual disease, like cytometry or next-generation sequencing, can detect bone marrow blood aspirate. “The detection of this minimal residual disease corresponds with a significant reduction in survival,” Dr. Paiva warned.

In addition to these techniques, PET-CT is also used. This imaging tool is “very useful for seeing disease both inside and outside the marrow,” said Dr. Paiva. 

“As for the future, the FDA [Food and Drug Administration] has just approved the use of minimal residual disease as one of the trial objectives. This may allow drugs to reach patients much sooner, instead of waiting for survival data, which takes much longer to obtain,” he said.

Researchers are also learning how to use minimal residual disease and these imaging techniques to individualize the treatment of patients with myeloma. “Furthermore, since some of these techniques are invasive, such as bone marrow ones, we are trying to focus on peripheral blood. This way, monitoring is minimally invasive, much more comfortable for the patient, and more informative because it can be done many times,” said Dr. Paiva.

Dr. Paiva is extending these imaging techniques “to different scenarios, such as the precursor stages of the disease. Our laboratory is especially known for flow cytometry, and we are launching the NoMoreMGUS project, the largest ever conducted in Spain (and perhaps in Europe) on monoclonal gammopathy of undetermined significance. This is a condition that precedes myeloma. We are looking to study 5000 patients in Spain once a year for 5 years, which means analyzing 25,000 samples.

“On the other hand,” he continued, “we are taking some of these developments to other neoplasms, such as acute lymphoblastic leukemia. And we are interested in using all the potential of cytometry not only to measure tumor cells but also to characterize the immune system as another important biomarker in the pathogenesis of the disease. And, for example, to predict infections, which is very important in patients with myeloma.”

This story was translated from El Médico Interactivo, which is part of the Medscape Professional Network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article appeared on Medscape.com.

New tools for monitoring multiple myeloma were a key topic at the European Hematology Society Congress. Advances in drugs and combinations have revolutionized the landscape in multiple myeloma, thus allowing patients to live much longer, according to Bruno Paiva, PhD, director of flow cytometry and the myeloma laboratory at the University of Navarra Clinic in Pamplona, Spain.

“Much better treatment responses are achieved, with long-term remission, so tools are needed for long-term monitoring. The starting point for monitoring is the monoclonal protein secreted by the myeloma tumor cell, which can be measured in serum and urine. Complete remission is defined when that monoclonal component is not detected with routine laboratory techniques, such as immunofixation,” said Dr. Paiva.

Even if the patient may be in complete remission, minimal residual disease is sometimes detected as myeloma can infiltrate the bone marrow. Techniques for identifying minimal residual disease, like cytometry or next-generation sequencing, can detect bone marrow blood aspirate. “The detection of this minimal residual disease corresponds with a significant reduction in survival,” Dr. Paiva warned.

In addition to these techniques, PET-CT is also used. This imaging tool is “very useful for seeing disease both inside and outside the marrow,” said Dr. Paiva. 

“As for the future, the FDA [Food and Drug Administration] has just approved the use of minimal residual disease as one of the trial objectives. This may allow drugs to reach patients much sooner, instead of waiting for survival data, which takes much longer to obtain,” he said.

Researchers are also learning how to use minimal residual disease and these imaging techniques to individualize the treatment of patients with myeloma. “Furthermore, since some of these techniques are invasive, such as bone marrow ones, we are trying to focus on peripheral blood. This way, monitoring is minimally invasive, much more comfortable for the patient, and more informative because it can be done many times,” said Dr. Paiva.

Dr. Paiva is extending these imaging techniques “to different scenarios, such as the precursor stages of the disease. Our laboratory is especially known for flow cytometry, and we are launching the NoMoreMGUS project, the largest ever conducted in Spain (and perhaps in Europe) on monoclonal gammopathy of undetermined significance. This is a condition that precedes myeloma. We are looking to study 5000 patients in Spain once a year for 5 years, which means analyzing 25,000 samples.

“On the other hand,” he continued, “we are taking some of these developments to other neoplasms, such as acute lymphoblastic leukemia. And we are interested in using all the potential of cytometry not only to measure tumor cells but also to characterize the immune system as another important biomarker in the pathogenesis of the disease. And, for example, to predict infections, which is very important in patients with myeloma.”

This story was translated from El Médico Interactivo, which is part of the Medscape Professional Network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article appeared on Medscape.com.

New tools for monitoring multiple myeloma were a key topic at the European Hematology Society Congress. Advances in drugs and combinations have revolutionized the landscape in multiple myeloma, thus allowing patients to live much longer, according to Bruno Paiva, PhD, director of flow cytometry and the myeloma laboratory at the University of Navarra Clinic in Pamplona, Spain.

“Much better treatment responses are achieved, with long-term remission, so tools are needed for long-term monitoring. The starting point for monitoring is the monoclonal protein secreted by the myeloma tumor cell, which can be measured in serum and urine. Complete remission is defined when that monoclonal component is not detected with routine laboratory techniques, such as immunofixation,” said Dr. Paiva.

Even if the patient may be in complete remission, minimal residual disease is sometimes detected as myeloma can infiltrate the bone marrow. Techniques for identifying minimal residual disease, like cytometry or next-generation sequencing, can detect bone marrow blood aspirate. “The detection of this minimal residual disease corresponds with a significant reduction in survival,” Dr. Paiva warned.

In addition to these techniques, PET-CT is also used. This imaging tool is “very useful for seeing disease both inside and outside the marrow,” said Dr. Paiva. 

“As for the future, the FDA [Food and Drug Administration] has just approved the use of minimal residual disease as one of the trial objectives. This may allow drugs to reach patients much sooner, instead of waiting for survival data, which takes much longer to obtain,” he said.

Researchers are also learning how to use minimal residual disease and these imaging techniques to individualize the treatment of patients with myeloma. “Furthermore, since some of these techniques are invasive, such as bone marrow ones, we are trying to focus on peripheral blood. This way, monitoring is minimally invasive, much more comfortable for the patient, and more informative because it can be done many times,” said Dr. Paiva.

Dr. Paiva is extending these imaging techniques “to different scenarios, such as the precursor stages of the disease. Our laboratory is especially known for flow cytometry, and we are launching the NoMoreMGUS project, the largest ever conducted in Spain (and perhaps in Europe) on monoclonal gammopathy of undetermined significance. This is a condition that precedes myeloma. We are looking to study 5000 patients in Spain once a year for 5 years, which means analyzing 25,000 samples.

“On the other hand,” he continued, “we are taking some of these developments to other neoplasms, such as acute lymphoblastic leukemia. And we are interested in using all the potential of cytometry not only to measure tumor cells but also to characterize the immune system as another important biomarker in the pathogenesis of the disease. And, for example, to predict infections, which is very important in patients with myeloma.”

This story was translated from El Médico Interactivo, which is part of the Medscape Professional Network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article appeared on Medscape.com.