TBD Meeting (4748-19)

BARCELONA – A progressive aerobic and resistance exercise intervention improved the android:gynoid fat ratio (AGFR) in breast cancer survivors, which could provide important health benefits.

AGFR is associated with increased risk for cardiovascular disease and type 2 diabetes in breast cancer survivors, therefore exercise-induced AGFR improvement may reduce the risk for such comorbid conditions, Christina Dieli-Conwright, PhD, of the University of Southern California Norris Comprehensive Cancer Center, Los Angeles, and colleagues reported in a poster at the European Society for Medical Oncology Congress.

A significant decrease in AGFR from baseline was noted in 50 survivors of stage I-III breast cancer who participated in the exercise intervention, compared with 50 such survivors randomized to a usual care group (P less than .001), and strong correlations were found between AGFR and homeostatic model assessment of insulin resistance (HOMA-IR; r = 0.95; P less than .01), the investigators found.

Study participants had a mean age of 53 years, 54% were overweight (body mass index greater than 25 kg/m²), 63% were Hispanic, 90% had undergone a mastectomy, and 76% received chemotherapy and radiation therapy. Adherence to the intervention, which involved three weekly sessions of supervised, progressive, moderate-to-vigorous aerobic and resistance exercise for 16 weeks, was 95%.

AGFR was calculated using whole-body dual-energy x-ray absorptiometry and HOMA-IR was calculated using fasting insulin and glucose levels.

“Exercise reduces fat mass in breast cancer survivors, however, few studies have focused on AGFR,” the investigators wrote.

The findings of the current study suggest that a progressive aerobic and resistance exercise intervention is an effective strategy for decreasing AGFR in breast cancer survivors, they concluded.

The National Cancer Institute funded the study. The authors reported having no disclosures.

SOURCE: Dieli-Conwright C et al. ESMO 2019, Abstract 228P.

BARCELONA – A progressive aerobic and resistance exercise intervention improved the android:gynoid fat ratio (AGFR) in breast cancer survivors, which could provide important health benefits.

AGFR is associated with increased risk for cardiovascular disease and type 2 diabetes in breast cancer survivors, therefore exercise-induced AGFR improvement may reduce the risk for such comorbid conditions, Christina Dieli-Conwright, PhD, of the University of Southern California Norris Comprehensive Cancer Center, Los Angeles, and colleagues reported in a poster at the European Society for Medical Oncology Congress.

A significant decrease in AGFR from baseline was noted in 50 survivors of stage I-III breast cancer who participated in the exercise intervention, compared with 50 such survivors randomized to a usual care group (P less than .001), and strong correlations were found between AGFR and homeostatic model assessment of insulin resistance (HOMA-IR; r = 0.95; P less than .01), the investigators found.

Study participants had a mean age of 53 years, 54% were overweight (body mass index greater than 25 kg/m²), 63% were Hispanic, 90% had undergone a mastectomy, and 76% received chemotherapy and radiation therapy. Adherence to the intervention, which involved three weekly sessions of supervised, progressive, moderate-to-vigorous aerobic and resistance exercise for 16 weeks, was 95%.

AGFR was calculated using whole-body dual-energy x-ray absorptiometry and HOMA-IR was calculated using fasting insulin and glucose levels.

“Exercise reduces fat mass in breast cancer survivors, however, few studies have focused on AGFR,” the investigators wrote.

The findings of the current study suggest that a progressive aerobic and resistance exercise intervention is an effective strategy for decreasing AGFR in breast cancer survivors, they concluded.

The National Cancer Institute funded the study. The authors reported having no disclosures.

SOURCE: Dieli-Conwright C et al. ESMO 2019, Abstract 228P.

BARCELONA – A progressive aerobic and resistance exercise intervention improved the android:gynoid fat ratio (AGFR) in breast cancer survivors, which could provide important health benefits.

AGFR is associated with increased risk for cardiovascular disease and type 2 diabetes in breast cancer survivors, therefore exercise-induced AGFR improvement may reduce the risk for such comorbid conditions, Christina Dieli-Conwright, PhD, of the University of Southern California Norris Comprehensive Cancer Center, Los Angeles, and colleagues reported in a poster at the European Society for Medical Oncology Congress.

A significant decrease in AGFR from baseline was noted in 50 survivors of stage I-III breast cancer who participated in the exercise intervention, compared with 50 such survivors randomized to a usual care group (P less than .001), and strong correlations were found between AGFR and homeostatic model assessment of insulin resistance (HOMA-IR; r = 0.95; P less than .01), the investigators found.

Study participants had a mean age of 53 years, 54% were overweight (body mass index greater than 25 kg/m²), 63% were Hispanic, 90% had undergone a mastectomy, and 76% received chemotherapy and radiation therapy. Adherence to the intervention, which involved three weekly sessions of supervised, progressive, moderate-to-vigorous aerobic and resistance exercise for 16 weeks, was 95%.

AGFR was calculated using whole-body dual-energy x-ray absorptiometry and HOMA-IR was calculated using fasting insulin and glucose levels.

“Exercise reduces fat mass in breast cancer survivors, however, few studies have focused on AGFR,” the investigators wrote.

The findings of the current study suggest that a progressive aerobic and resistance exercise intervention is an effective strategy for decreasing AGFR in breast cancer survivors, they concluded.

The National Cancer Institute funded the study. The authors reported having no disclosures.

SOURCE: Dieli-Conwright C et al. ESMO 2019, Abstract 228P.

BARCELONA – A supervised and adapted exercise program improved quality of life, physical functioning, and strength in breast cancer survivors participating in the MAMA MOVE Gaia study.

Of 19 women who initiated participation in the program, which included a 16-week control phase followed by a 16-week exercise training intervention phase, 15 completed the program, and, after the training intervention, they experienced a significant increase in handgrip strength and sit-to-stand repetitions, Ana Joaquim, MD, of Centro Hospitalar de Vila Nova de Gaia/Espinho, Portugal, and colleagues reported in a poster at the European Society for Medical Oncology Congress.

During the control phase of the prospective nonrandomized study, participants experienced no significant changes over time in any domain of quality of life as measured by the EORTC QLQ-C30 questionnaire, although a trend toward improved physical functioning was noted at an evaluation performed 8 weeks after the control phase, compared with one performed just prior to the intervention phase (77.3 to 85.3 points, P = .051), the investigators said.

After the intervention phase, however, handgrip strength improved significantly at both the limb where surgery was performed and at the nonoperated limb (from 22.2 to 25.6 kg.f and from 22.6 to 26.9 kg.f). Similar results were observed for a sit-to-stand test (improvement from 12 to 17 repetitions).

Participants in the single-arm clinical trial were assessed after 8 weeks of the control phase, immediately prior to the intervention period, 8 weeks after the control phase, and 16 weeks into the invention phase.

The intervention phase consisted of 3 60-minute sessions per week of combined moderate to vigorous aerobic and strength exercise, defined as exercise at 65%-85% of maximum heart rate or at 6-8 points on the OMNI scale. Mean compliance among the participants was 63.6%.

The participants had a median age of 59 and 15 of the 19 were diagnosed with invasive carcinoma. Following surgery, 13 underwent radiotherapy, 15 received chemotherapy, and 18 received hormone therapy.

“Treatments for early breast cancer have side effects that affect quality of life and cause deconditioning,” the investigators wrote, adding that “physical exercise might have a supportive and coadjuvant role in the rehabilitation of breast cancer survivors.”

The MAMA MOVE trial aimed to assess the potential benefits of a community-based supervised exercise training program, and the findings suggest such programs could help improve quality of life, particularly with respect to physical functioning, they concluded.

The MAMA MOVE Gaia study was funded by Liga Portuguesa Contra o Cancro. The investigators reported having no disclosures.
 

SOURCE: Joaquim A et al. ESMO 2019, Abstract 234P.

BARCELONA – A supervised and adapted exercise program improved quality of life, physical functioning, and strength in breast cancer survivors participating in the MAMA MOVE Gaia study.

Of 19 women who initiated participation in the program, which included a 16-week control phase followed by a 16-week exercise training intervention phase, 15 completed the program, and, after the training intervention, they experienced a significant increase in handgrip strength and sit-to-stand repetitions, Ana Joaquim, MD, of Centro Hospitalar de Vila Nova de Gaia/Espinho, Portugal, and colleagues reported in a poster at the European Society for Medical Oncology Congress.

During the control phase of the prospective nonrandomized study, participants experienced no significant changes over time in any domain of quality of life as measured by the EORTC QLQ-C30 questionnaire, although a trend toward improved physical functioning was noted at an evaluation performed 8 weeks after the control phase, compared with one performed just prior to the intervention phase (77.3 to 85.3 points, P = .051), the investigators said.

After the intervention phase, however, handgrip strength improved significantly at both the limb where surgery was performed and at the nonoperated limb (from 22.2 to 25.6 kg.f and from 22.6 to 26.9 kg.f). Similar results were observed for a sit-to-stand test (improvement from 12 to 17 repetitions).

Participants in the single-arm clinical trial were assessed after 8 weeks of the control phase, immediately prior to the intervention period, 8 weeks after the control phase, and 16 weeks into the invention phase.

The intervention phase consisted of 3 60-minute sessions per week of combined moderate to vigorous aerobic and strength exercise, defined as exercise at 65%-85% of maximum heart rate or at 6-8 points on the OMNI scale. Mean compliance among the participants was 63.6%.

The participants had a median age of 59 and 15 of the 19 were diagnosed with invasive carcinoma. Following surgery, 13 underwent radiotherapy, 15 received chemotherapy, and 18 received hormone therapy.

“Treatments for early breast cancer have side effects that affect quality of life and cause deconditioning,” the investigators wrote, adding that “physical exercise might have a supportive and coadjuvant role in the rehabilitation of breast cancer survivors.”

The MAMA MOVE trial aimed to assess the potential benefits of a community-based supervised exercise training program, and the findings suggest such programs could help improve quality of life, particularly with respect to physical functioning, they concluded.

The MAMA MOVE Gaia study was funded by Liga Portuguesa Contra o Cancro. The investigators reported having no disclosures.
 

SOURCE: Joaquim A et al. ESMO 2019, Abstract 234P.

BARCELONA – A supervised and adapted exercise program improved quality of life, physical functioning, and strength in breast cancer survivors participating in the MAMA MOVE Gaia study.

Of 19 women who initiated participation in the program, which included a 16-week control phase followed by a 16-week exercise training intervention phase, 15 completed the program, and, after the training intervention, they experienced a significant increase in handgrip strength and sit-to-stand repetitions, Ana Joaquim, MD, of Centro Hospitalar de Vila Nova de Gaia/Espinho, Portugal, and colleagues reported in a poster at the European Society for Medical Oncology Congress.

During the control phase of the prospective nonrandomized study, participants experienced no significant changes over time in any domain of quality of life as measured by the EORTC QLQ-C30 questionnaire, although a trend toward improved physical functioning was noted at an evaluation performed 8 weeks after the control phase, compared with one performed just prior to the intervention phase (77.3 to 85.3 points, P = .051), the investigators said.

After the intervention phase, however, handgrip strength improved significantly at both the limb where surgery was performed and at the nonoperated limb (from 22.2 to 25.6 kg.f and from 22.6 to 26.9 kg.f). Similar results were observed for a sit-to-stand test (improvement from 12 to 17 repetitions).

Participants in the single-arm clinical trial were assessed after 8 weeks of the control phase, immediately prior to the intervention period, 8 weeks after the control phase, and 16 weeks into the invention phase.

The intervention phase consisted of 3 60-minute sessions per week of combined moderate to vigorous aerobic and strength exercise, defined as exercise at 65%-85% of maximum heart rate or at 6-8 points on the OMNI scale. Mean compliance among the participants was 63.6%.

The participants had a median age of 59 and 15 of the 19 were diagnosed with invasive carcinoma. Following surgery, 13 underwent radiotherapy, 15 received chemotherapy, and 18 received hormone therapy.

“Treatments for early breast cancer have side effects that affect quality of life and cause deconditioning,” the investigators wrote, adding that “physical exercise might have a supportive and coadjuvant role in the rehabilitation of breast cancer survivors.”

The MAMA MOVE trial aimed to assess the potential benefits of a community-based supervised exercise training program, and the findings suggest such programs could help improve quality of life, particularly with respect to physical functioning, they concluded.

The MAMA MOVE Gaia study was funded by Liga Portuguesa Contra o Cancro. The investigators reported having no disclosures.
 

SOURCE: Joaquim A et al. ESMO 2019, Abstract 234P.

BARCELONA – Nivolumab was associated with improved overall survival and a favorable safety profile, compared with chemotherapy, in patients with previously treated advanced esophageal squamous cell carcinoma (ESCC) in the open-label phase 3 ATTRACTION-3 study.

The overall survival (OS) benefit was observed regardless of tumor programmed death-ligand 1 (PD-L1) expression, Byoung Chul Cho, MD, reported at the European Society for Medical Oncology Congress.

The findings were reported online simultaneously in The Lancet Oncology.

Median OS at a minimum follow-up of 17.6 months was 10.9 vs. 8.4 months in 210 patients randomized to receive treatment with the PD-1 inhibitor nivolumab and 209 who received chemotherapy, respectively (hazard ratio, 0.77), said Dr. Cho of Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.

“Notably, there was a 13% and 10% improvement in overall survival rates at 12 months (47% vs. 34%) and 18 months (31% vs. 21%), respectively,” he said, also noting that the HRs for death favored nivolumab vs. chemotherapy across multiple prespecified subgroups, including those based on tumor PD-L1 expression (HRs, 0.69 and 0.84 for PD-L1 of 1% or greater and less than 1%, respectively).

No meaningful difference was seen in progression-free survival between the nivolumab and chemotherapy groups (12% vs. 7%; HR, 1.08), or in objective response rates (19% vs. 22%), he said.

“However, responses were substantially more durable with nivolumab, compared to chemotherapy; duration of response was 6.9 months with nivolumab vs. 3.9 months in the chemotherapy arm,” he said. “Notably, 21% of patients in the nivolumab arm were still in response, compared to only 6% in the chemotherapy arm.”

Patients enrolled in the open label study had unresectable advanced or recurrent ESCC refractory or intolerant to one prior fluoropyrimidine/platinum-based therapy. They were randomized 1:1 to receive 240 mg of nivolumab every 2 weeks or investigators’ choice of paclitaxel or docetaxel.

Fewer treatment-related adverse events (TRAEs) were reported with nivolumab, Dr. Cho said.

Any grade TRAEs occurred in 66% vs. 95% of patients in the groups, respectively, and grade 3-4 TRAEs occurred in 18% vs. 63%. The majority of select TRAEs – defined as those with potential immunologic etiology, including endocrine, gastrointestinal, hepatic, pulmonary, renal, and skin effects – were grade 1 or 2, and the only difference between the nivolumab and chemotherapy groups with respect to those was in endocrine effects, which affected 11% vs. less than 1% of patients, respectively.

Grade 3/4 select TRAEs occurred in less than 2% of patients, Dr. Cho noted.

An exploratory analysis further showed significant overall improvement in health-related quality of life with nivolumab through week 42 on treatment, he added.

The findings are of note, because metastatic esophageal cancer has a 5-year relative survival rate of less than 8%, and ESCC accounts for about 90% of cases worldwide, he said, adding that current second-line chemotherapy options for ESCC offer poor long-term survival and are associated with toxicity.

Nivolumab, which showed promising antitumor activity and manageable toxicity for advanced ESCC in patients who were refractory to or intolerant of standard chemotherapies in the phase 2 ATTRACTION-1 study, is the first immune checkpoint inhibitor to demonstrate a statistically significant, clinically meaningful improvement in OS vs. chemotherapy in this setting, he said.

The findings of this final analysis of ATTRACTION-3, which shows a 23% reduction in the risk of death, a 2.5-month improvement in median OS, benefit across PD-L1 subgroups, and a favorable safety profile, suggest that nivolumab represents a new standard second-line treatment option for patients with advanced ESCC, he concluded.

ATTRACTION-3 was funded by Ono Pharmaceutical Co., in collaboration with Bristol-Myers Squibb. Dr. Cho reported relationships with Bristol-Myers Squibb, Ono Pharmaceutical, and others. He also reported stock ownership and/or patents with TheraCanVac and Champions Oncology.

SOURCE: Cho B et al. ESMO 2019, Abstract LBA11.

BARCELONA – Nivolumab was associated with improved overall survival and a favorable safety profile, compared with chemotherapy, in patients with previously treated advanced esophageal squamous cell carcinoma (ESCC) in the open-label phase 3 ATTRACTION-3 study.

The overall survival (OS) benefit was observed regardless of tumor programmed death-ligand 1 (PD-L1) expression, Byoung Chul Cho, MD, reported at the European Society for Medical Oncology Congress.

The findings were reported online simultaneously in The Lancet Oncology.

Median OS at a minimum follow-up of 17.6 months was 10.9 vs. 8.4 months in 210 patients randomized to receive treatment with the PD-1 inhibitor nivolumab and 209 who received chemotherapy, respectively (hazard ratio, 0.77), said Dr. Cho of Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.

“Notably, there was a 13% and 10% improvement in overall survival rates at 12 months (47% vs. 34%) and 18 months (31% vs. 21%), respectively,” he said, also noting that the HRs for death favored nivolumab vs. chemotherapy across multiple prespecified subgroups, including those based on tumor PD-L1 expression (HRs, 0.69 and 0.84 for PD-L1 of 1% or greater and less than 1%, respectively).

No meaningful difference was seen in progression-free survival between the nivolumab and chemotherapy groups (12% vs. 7%; HR, 1.08), or in objective response rates (19% vs. 22%), he said.

“However, responses were substantially more durable with nivolumab, compared to chemotherapy; duration of response was 6.9 months with nivolumab vs. 3.9 months in the chemotherapy arm,” he said. “Notably, 21% of patients in the nivolumab arm were still in response, compared to only 6% in the chemotherapy arm.”

Patients enrolled in the open label study had unresectable advanced or recurrent ESCC refractory or intolerant to one prior fluoropyrimidine/platinum-based therapy. They were randomized 1:1 to receive 240 mg of nivolumab every 2 weeks or investigators’ choice of paclitaxel or docetaxel.

Fewer treatment-related adverse events (TRAEs) were reported with nivolumab, Dr. Cho said.

Any grade TRAEs occurred in 66% vs. 95% of patients in the groups, respectively, and grade 3-4 TRAEs occurred in 18% vs. 63%. The majority of select TRAEs – defined as those with potential immunologic etiology, including endocrine, gastrointestinal, hepatic, pulmonary, renal, and skin effects – were grade 1 or 2, and the only difference between the nivolumab and chemotherapy groups with respect to those was in endocrine effects, which affected 11% vs. less than 1% of patients, respectively.

Grade 3/4 select TRAEs occurred in less than 2% of patients, Dr. Cho noted.

An exploratory analysis further showed significant overall improvement in health-related quality of life with nivolumab through week 42 on treatment, he added.

The findings are of note, because metastatic esophageal cancer has a 5-year relative survival rate of less than 8%, and ESCC accounts for about 90% of cases worldwide, he said, adding that current second-line chemotherapy options for ESCC offer poor long-term survival and are associated with toxicity.

Nivolumab, which showed promising antitumor activity and manageable toxicity for advanced ESCC in patients who were refractory to or intolerant of standard chemotherapies in the phase 2 ATTRACTION-1 study, is the first immune checkpoint inhibitor to demonstrate a statistically significant, clinically meaningful improvement in OS vs. chemotherapy in this setting, he said.

The findings of this final analysis of ATTRACTION-3, which shows a 23% reduction in the risk of death, a 2.5-month improvement in median OS, benefit across PD-L1 subgroups, and a favorable safety profile, suggest that nivolumab represents a new standard second-line treatment option for patients with advanced ESCC, he concluded.

ATTRACTION-3 was funded by Ono Pharmaceutical Co., in collaboration with Bristol-Myers Squibb. Dr. Cho reported relationships with Bristol-Myers Squibb, Ono Pharmaceutical, and others. He also reported stock ownership and/or patents with TheraCanVac and Champions Oncology.

SOURCE: Cho B et al. ESMO 2019, Abstract LBA11.

BARCELONA – Nivolumab was associated with improved overall survival and a favorable safety profile, compared with chemotherapy, in patients with previously treated advanced esophageal squamous cell carcinoma (ESCC) in the open-label phase 3 ATTRACTION-3 study.

The overall survival (OS) benefit was observed regardless of tumor programmed death-ligand 1 (PD-L1) expression, Byoung Chul Cho, MD, reported at the European Society for Medical Oncology Congress.

The findings were reported online simultaneously in The Lancet Oncology.

Median OS at a minimum follow-up of 17.6 months was 10.9 vs. 8.4 months in 210 patients randomized to receive treatment with the PD-1 inhibitor nivolumab and 209 who received chemotherapy, respectively (hazard ratio, 0.77), said Dr. Cho of Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.

“Notably, there was a 13% and 10% improvement in overall survival rates at 12 months (47% vs. 34%) and 18 months (31% vs. 21%), respectively,” he said, also noting that the HRs for death favored nivolumab vs. chemotherapy across multiple prespecified subgroups, including those based on tumor PD-L1 expression (HRs, 0.69 and 0.84 for PD-L1 of 1% or greater and less than 1%, respectively).

No meaningful difference was seen in progression-free survival between the nivolumab and chemotherapy groups (12% vs. 7%; HR, 1.08), or in objective response rates (19% vs. 22%), he said.

“However, responses were substantially more durable with nivolumab, compared to chemotherapy; duration of response was 6.9 months with nivolumab vs. 3.9 months in the chemotherapy arm,” he said. “Notably, 21% of patients in the nivolumab arm were still in response, compared to only 6% in the chemotherapy arm.”

Patients enrolled in the open label study had unresectable advanced or recurrent ESCC refractory or intolerant to one prior fluoropyrimidine/platinum-based therapy. They were randomized 1:1 to receive 240 mg of nivolumab every 2 weeks or investigators’ choice of paclitaxel or docetaxel.

Fewer treatment-related adverse events (TRAEs) were reported with nivolumab, Dr. Cho said.

Any grade TRAEs occurred in 66% vs. 95% of patients in the groups, respectively, and grade 3-4 TRAEs occurred in 18% vs. 63%. The majority of select TRAEs – defined as those with potential immunologic etiology, including endocrine, gastrointestinal, hepatic, pulmonary, renal, and skin effects – were grade 1 or 2, and the only difference between the nivolumab and chemotherapy groups with respect to those was in endocrine effects, which affected 11% vs. less than 1% of patients, respectively.

Grade 3/4 select TRAEs occurred in less than 2% of patients, Dr. Cho noted.

An exploratory analysis further showed significant overall improvement in health-related quality of life with nivolumab through week 42 on treatment, he added.

The findings are of note, because metastatic esophageal cancer has a 5-year relative survival rate of less than 8%, and ESCC accounts for about 90% of cases worldwide, he said, adding that current second-line chemotherapy options for ESCC offer poor long-term survival and are associated with toxicity.

Nivolumab, which showed promising antitumor activity and manageable toxicity for advanced ESCC in patients who were refractory to or intolerant of standard chemotherapies in the phase 2 ATTRACTION-1 study, is the first immune checkpoint inhibitor to demonstrate a statistically significant, clinically meaningful improvement in OS vs. chemotherapy in this setting, he said.

The findings of this final analysis of ATTRACTION-3, which shows a 23% reduction in the risk of death, a 2.5-month improvement in median OS, benefit across PD-L1 subgroups, and a favorable safety profile, suggest that nivolumab represents a new standard second-line treatment option for patients with advanced ESCC, he concluded.

ATTRACTION-3 was funded by Ono Pharmaceutical Co., in collaboration with Bristol-Myers Squibb. Dr. Cho reported relationships with Bristol-Myers Squibb, Ono Pharmaceutical, and others. He also reported stock ownership and/or patents with TheraCanVac and Champions Oncology.

SOURCE: Cho B et al. ESMO 2019, Abstract LBA11.

BARCELONA – Programmed death-ligand 1 (PD-L1) status in patients with advanced triple negative or HER2-positive breast cancer appears to identify distinct disease entities with varying likelihood of benefit from immune checkpoint inhibition, according to Giampaolo Bianchini, MD.

This observation, which contrasts with findings in other solid tumors and expands the road map to improved outcomes with immunotherapy for metastatic breast cancer, is based in part on new findings presented at the European Society for Medical Oncology Congress.

Among additional lessons from those findings: PD-L1 assays are not easily interchangeable, and studies with a “one size fits all” approach should be avoided, Dr. Bianchini, head of the Breast Cancer Group – Medical Oncology and clinical translational and immunotherapy research at Ospedale San Raffaele, Milan, said at the congress.
 

IMPassion130 and PD-L1 assays

In the phase 3 IMpassion130 trial assessing nanoparticle, albumin-bound (nab)-paclitaxel chemotherapy + either the anti-PD-L1 monoclonal antibody atezolizumab or placebo for the first-line treatment of metastatic triple-negative breast cancer (mTNBC), investigators used, and validated, the VENTANA PD-L1 SP142 assay to evaluate PD-L1 expression in immune cells (IC). PD-L1 positivity was defined using a 1% cutoff, meaning that PD-L1-stained IC encompassed at least 1% of the tumor area.

The trial demonstrated significantly improved progression-free survival (PFS) in the atezolizumab arm, both in the intention-to-treat (ITT) analysis (7.2 vs. 5.5 months in the placebo arm; hazard ratio, 0.80), and the PD-L1-positive subgroup (7.5 vs. 5.0 months; HR, 0.62), and the results were published in November 2018 (N Engl J Med. 2018; 379:2108-21).

“IMpassion130 is the first phase 3 trial demonstrating clinical benefit of cancer immunotherapy in patients with PD-L1-positive, metastatic triple-negative breast cancer,” Hope S. Rugo, MD, said at the congress. “The combination of atezolizumab and nab-paclitaxel is now approved in the United States and Europe for this indication.”

Subgroup analyses indicated that PFS and OS benefit with atezolizumab + nab-paclitaxel vs. nab-paclitaxel alone was greater in double-positive patients (those with SP142 positivity and either SP263 or 22C3 positivity) than in patients who were SP263-positive/SP142-negative or 22C3-positive/SP142-negative.

Dr. Rugo and her colleagues also found that the benefits with atezolizumab + nab-paclitaxel in PD-L1-positive patients were apparent regardless of the source of tissue for testing (breast or distant metastases).

They concluded that the findings of the assays are not equivalent; 22C3 and SP263 identified more patients as PD-L1 positive, and SP142-positivity was encompassed in positive tests for both.

“The clinical benefit in the 22C3-positive and the SP263-positive subgroups appear to be driven by the SP142-positive subgroup, and [SP142] identifies patients with the longest median progression-free and overall survival from the addition of atezolizumab to nab-paclitaxel,” she said “The SP142 assay with an IC cutoff of 1% or greater is the approved diagnostic test used to identify patients with metastatic triple-negative breast cancer who are most likely to benefit from the addition of the checkpoint inhibitor atezolizumab to nab-paclitaxel.”

As for whether the SP142 should be the assay of choice in other settings in which it hasn’t been validated, Dr. Rugo said it is advisable to use the assay that has been validated in a positive trial.

“That’s what we would generally do ... however, recognizing that some countries are not using SP142, and some sites may not have access, certainly you encompass that population in the patients whose tumors are positive by both other assays,” she said. “The risk is that you might overtreat, and the cost of treatment is greater.”

Excess toxicity is also a concern in that situation, she said, adding that “hopefully in the future we’ll be able to figure out ways to have even more patients benefit from the addition of immunotherapy so that won’t be an issue.”

“What this data shows is that you can feel secure that you are encompassing the patient population identified by the parent trial to benefit from the addition of atezolizumab by using either of the other two assays; you’re only missing 1% – so that’s very reasonable,” she said. “The risk is that you’re overtreating; it’s quite likely that there’s a population there that isn’t benefiting as much, but that’s a balance.”

The findings from IMPassion130 with regard to OS in the unselected population that included PD-L1-negative patients (18.7 vs. 21.0 months with vs. without atezolizumab; HR, 0.86) underscore the fact that “one size does not fit all” when it comes to immunotherapy benefit, Dr. Bianchini said.

This is further demonstrated by the post hoc analysis comparing IHC assays, he said, explaining that 63% of IMPassion130 patients who were considered PD-L1-negative based on the SP142 “actually scored as PD-L1-positive by the other tests.

“So the very clinically important question is if there is any evidence from the data that [the PD-L1-negative group] benefits in a significant way from the addition of atezolizumab,” he said. “I don’t see evidence for a clinical benefit, I see evidence to look for new biomarkers to identify a potential population who will benefit.”

The “absence of evidence is not evidence of absence,” he stressed, noting that it may be possible – with the right biomarkers – to identify PD-L1-negative patients who would benefit.

What the findings do show, however, is support for the FDA decision to approve the SP142 assay with an IC cutoff of 1% as a companion diagnostic tool, and that PD-L1 is ideally assessed using samples from both the primary and metastatic site, as the IMPassion130 data “do not inform whether PD-L1 assessment in primary and metastatic sites is equally informative,” he said.

In addition, Dr. Bianchini said the findings suggest that more information is needed about using different cutoffs for SP263 and 22C3, and he cautioned against “directly translating these finding to other disease settings or immune combinations.

“Defining new biomarkers to identify who within the PD-L1-negative group might benefit from this combination remains an unmet need,” he said. “For sure, I don’t see a space for the other tests to define this population,” he added.

KEYNOTE-119, KATE2, and future directions

Both the randomized, open-label, phase 3 KEYNOTE-119 study of the checkpoint inhibitor pembrolizumab vs. single-agent chemotherapy for mTNBC, and the phase 2 KATE2 trial of the antibody-drug conjugate trastuzumab emtansine (T-DM1) + either atezolizumab or placebo in previously treated HER2-positive breast cancer patients, failed to meet their respective primary study endpoints.

But the news isn’t all bad, Dr. Bianchini said.

For example, in KEYNOTE-119, second- or third-line pembrolizumab monotherapy did not significantly improve OS vs. chemotherapy for mTNBC, but the pembrolizumab treatment effect increased as PD-L1 enrichment increased, he explained.

Pembrolizumab showed promising antitumor activity and manageable safety in mTNBC in prior trials, and was therefore further assessed in the KEYNOTE-119 study of 601 patients with centrally confirmed TNBC, 1-2 prior systemic treatments for mTNBC, progression on the latest therapy, and a prior anthracycline or taxane, Javier Cortés, MD, PhD, of Instituto Oncológico, Madrid, reported at the congress.

Sharon Worcester/MDedge News

Pembrolizumab was given at a dose of 200 mg every 3 weeks, and chemotherapy was physician’s choice of capecitabine, eribulin, gemcitabine, or vinorelbine.

At a median follow-up of 9.9 months in the pembrolizumab group and 10.9 months in the chemotherapy group, OS did not differ significantly between the groups; this was true overall, in patients with a CPS of 10 or greater, and in those with a CPS of 1 or greater.

In all-comers, the HR for OS was 0.97, compared with 0.78 in patients with CPS of 10 or greater, and 0.86 in those with CPS of 1 or greater, Dr. Cortés said.

“One of the most interesting exploratory analyses was OS in those patients with CPS of 20 or higher,” he said, noting that median OS in that group was 14.9 vs.12.5 months with pembrolizumab vs. with chemotherapy (HR, 0.58).

Pembrolizumab did not improve overall PFS, but again, the rates improved with higher CPS. Duration of response, however, was longer with pembrolizumab vs. chemotherapy (12.2 vs. 8.3 months overall; 12.2 vs. 6.5 months for CPS of 1 or greater; and not reached vs. 7.1 months for CPS of 10 or greater).

Grade 3-5 AEs occurred in 35% vs. 49% of patients in the pembrolizumab vs. chemotherapy groups, with nine deaths occurring in each, Dr. Cortés said, adding that treatment-related AEs occurred in 14% (with one death) and 36% (with two deaths), respectively, and grade 3-4 immune-mediated AEs and infusion reactions occurred in 3.2% vs. 1.0% (no deaths), respectively.

In the double-blind, signal-seeking KATE2 trial, as reported in 2018 at the San Antonio Breast Cancer Symposium, no overall PFS improvement was seen with atezolizumab + T-DM1 (median of 8.2 vs. 6.8 months; HR, 0.82; 12-month PFS 38% vs. 34%), but again, a possible benefit was seen in PD-L1-positive patients (8.5 vs. 4.1 months; HR, 0.60).

KATE2 included 202 patients with advanced HER2-positive breast cancer that progressed after treatment with T-DM1 and a taxane. They were randomized 2:1 to receive intravenous T-DM1 at a dose of 3.6 mg/kg plus atezolizumab (1,200 mg) or placebo every 3 weeks until loss of clinical benefit or intolerable toxicity.

The “overall survival and final safety results” show that at a median follow-up of 19.0 months in the atezolizumab arm and 18.2 months in the placebo arm, with 52 OS events reported, median OS was not reached in either arm and 1-year survival was similar in the two groups (89.1% and 89.0%), Leisha A. Emens, MD, PhD, professor of medicine in hematology/oncology and co-leader of the Hillman Cancer Immunology and Immunotherapy Program at Hillman Cancer Center, University of Pittsburgh Medical Center (UPMC) reported at the congress.

“And when you look at duration of response, you see an increase not just in the number ... but the quality of the response,” he said, noting that for PFS, as well, a trend toward superiority is seen “that is consistent with all the other endpoints.”

“So overall, the application of incrementally restrictive cut-off of CPS lends weight to the exploratory analysis showing better survival from pembrolizumab in tumors with CPS more than 20,” Dr. Bianchini said, noting that the “real question,” however, is whether the finding “is worth clinical implementation.

“We know a lot about the primary tumor and immune infiltration. We’ve learned ... that if you wait and look ahead at immune infiltration in the advanced stage, you find that the tumor becomes smart,” he said, explaining that tumor/immune co-evolution leads to increased immuno-editing and immune subversion and it becomes “much harder to just hit the tumor with PD-L1, because this is not the only mechanism of immune escape.”

A review of several studies shows that in similar populations defined by biomarkers, response rates in patients treated with checkpoint inhibitors decrease in the second- and third-line setting vs. the first-line setting, he said.

For example, pembrolizumab response rates in the first-line and second-line or greater setting in cohort B of the KEYNOTE-086 study were 21.4% and 5.7%, respectively, compared with 12.3% in the second- to third-line setting in KEYNOTE-119, he said.

Another consideration is whether monotherapy or combination therapy is preferable, and the data suggest that regardless of how PD-L1-positivity is defined (by CPS cutoff of 1 vs. 20, for example), most patients treated with monotherapy progress within the first 3 months, he said.

“I don’t see that this is a safe approach for the majority of these patients. So without better biomarkers, combinations should always be preferred, at least to avoid early progression,” Dr. Bianchini said, adding that the open question, then, is: “If we set the new standard in the first-line as the combination of nab-paclitaxel and atezolizumab for PD-L1-positive patients defined by the VENTANA [SP142 assay], should we continue with immune checkpoint [inhibition] using different combinations?”

“Of course, at the time the trial was designed, the results of IMpassion were not available, but it’s very important, because [the findings] add to the evidence that immunotherapy is extremely relevant for some patients,” he said.

KATE2 further demonstrated the importance of PD-L1 status, he said, adding that due to its limitations, including small sample size and short follow-up, longer follow-up is needed to better evaluate duration of response and PFS.

“Despite the trial limitations, the qualitative effect seen in all clinical endpoints – overall response rate, progression-free survival, overall survival – in PD-L1-positive tumors defined by SP142 ... provided strong and robust signals supporting the investigation of immune checkpoint inhibitors in HER-positive breast cancer,” he said, noting that “many trials are ongoing in the early setting and the advanced setting.”

In addition to the lessons of these trials with respect to the interchangeability of PD-L1 IHC assays and the value of PD-L1 assessment for identifying the likelihood of benefit from immune checkpoint inhibitors, the findings highlight the possibility that PD-L1-negative tumors require different immunotherapy approaches or alternative therapeutic strategies, and underscore that the benefit of immunotherapy in PD-L1-positive patients is still restricted to a minority.

“So new studies and approaches with immuno-oncology are needed, and we need more effective biomarkers, because we need to have precision oncology applied – we need to go in that direction,” he concluded.

Dr. Bianchini reported consultancy/honorarium and or advisory board activity associated with Roche, MSD, AstraZeneca, Pfizer, Chugai, EISAI, Lilly, Novartis, Amgen, Sanofi, Neopharm, and Genomic Health. The IMPassion30 trial was funded by F. Hoffmann-La Roche Ltd.; Dr. Rugo reported research grants, other funding, and or travel/accommodation/expenses from Pfizer, Novartis, Eli Lilly, Merck, OBI, EISAI, Plexxikon, Genentech/Roche, MacroGenics, PUMA, Mylan, Immunomedics, Daiichi Sankyo, and Celltrion. KEYNOTE-119 was funded by Merck Sharp & Dohme Corp.; Dr. Cortés and Dr. Emens reported numerous funding relationships but none with F. Hoffman-La Roche. KATE2 was funded by F. Hoffmann-La Roche.
 

Sources: IMPassion130; ESMO Abstract LBA20; KEYNOTE-119: ESMO Abstract LBA21; KATE2: ESMO Abstract 305O.

BARCELONA – Programmed death-ligand 1 (PD-L1) status in patients with advanced triple negative or HER2-positive breast cancer appears to identify distinct disease entities with varying likelihood of benefit from immune checkpoint inhibition, according to Giampaolo Bianchini, MD.

This observation, which contrasts with findings in other solid tumors and expands the road map to improved outcomes with immunotherapy for metastatic breast cancer, is based in part on new findings presented at the European Society for Medical Oncology Congress.

Among additional lessons from those findings: PD-L1 assays are not easily interchangeable, and studies with a “one size fits all” approach should be avoided, Dr. Bianchini, head of the Breast Cancer Group – Medical Oncology and clinical translational and immunotherapy research at Ospedale San Raffaele, Milan, said at the congress.
 

IMPassion130 and PD-L1 assays

In the phase 3 IMpassion130 trial assessing nanoparticle, albumin-bound (nab)-paclitaxel chemotherapy + either the anti-PD-L1 monoclonal antibody atezolizumab or placebo for the first-line treatment of metastatic triple-negative breast cancer (mTNBC), investigators used, and validated, the VENTANA PD-L1 SP142 assay to evaluate PD-L1 expression in immune cells (IC). PD-L1 positivity was defined using a 1% cutoff, meaning that PD-L1-stained IC encompassed at least 1% of the tumor area.

The trial demonstrated significantly improved progression-free survival (PFS) in the atezolizumab arm, both in the intention-to-treat (ITT) analysis (7.2 vs. 5.5 months in the placebo arm; hazard ratio, 0.80), and the PD-L1-positive subgroup (7.5 vs. 5.0 months; HR, 0.62), and the results were published in November 2018 (N Engl J Med. 2018; 379:2108-21).

“IMpassion130 is the first phase 3 trial demonstrating clinical benefit of cancer immunotherapy in patients with PD-L1-positive, metastatic triple-negative breast cancer,” Hope S. Rugo, MD, said at the congress. “The combination of atezolizumab and nab-paclitaxel is now approved in the United States and Europe for this indication.”

Subgroup analyses indicated that PFS and OS benefit with atezolizumab + nab-paclitaxel vs. nab-paclitaxel alone was greater in double-positive patients (those with SP142 positivity and either SP263 or 22C3 positivity) than in patients who were SP263-positive/SP142-negative or 22C3-positive/SP142-negative.

Dr. Rugo and her colleagues also found that the benefits with atezolizumab + nab-paclitaxel in PD-L1-positive patients were apparent regardless of the source of tissue for testing (breast or distant metastases).

They concluded that the findings of the assays are not equivalent; 22C3 and SP263 identified more patients as PD-L1 positive, and SP142-positivity was encompassed in positive tests for both.

“The clinical benefit in the 22C3-positive and the SP263-positive subgroups appear to be driven by the SP142-positive subgroup, and [SP142] identifies patients with the longest median progression-free and overall survival from the addition of atezolizumab to nab-paclitaxel,” she said “The SP142 assay with an IC cutoff of 1% or greater is the approved diagnostic test used to identify patients with metastatic triple-negative breast cancer who are most likely to benefit from the addition of the checkpoint inhibitor atezolizumab to nab-paclitaxel.”

As for whether the SP142 should be the assay of choice in other settings in which it hasn’t been validated, Dr. Rugo said it is advisable to use the assay that has been validated in a positive trial.

“That’s what we would generally do ... however, recognizing that some countries are not using SP142, and some sites may not have access, certainly you encompass that population in the patients whose tumors are positive by both other assays,” she said. “The risk is that you might overtreat, and the cost of treatment is greater.”

Excess toxicity is also a concern in that situation, she said, adding that “hopefully in the future we’ll be able to figure out ways to have even more patients benefit from the addition of immunotherapy so that won’t be an issue.”

“What this data shows is that you can feel secure that you are encompassing the patient population identified by the parent trial to benefit from the addition of atezolizumab by using either of the other two assays; you’re only missing 1% – so that’s very reasonable,” she said. “The risk is that you’re overtreating; it’s quite likely that there’s a population there that isn’t benefiting as much, but that’s a balance.”

The findings from IMPassion130 with regard to OS in the unselected population that included PD-L1-negative patients (18.7 vs. 21.0 months with vs. without atezolizumab; HR, 0.86) underscore the fact that “one size does not fit all” when it comes to immunotherapy benefit, Dr. Bianchini said.

This is further demonstrated by the post hoc analysis comparing IHC assays, he said, explaining that 63% of IMPassion130 patients who were considered PD-L1-negative based on the SP142 “actually scored as PD-L1-positive by the other tests.

“So the very clinically important question is if there is any evidence from the data that [the PD-L1-negative group] benefits in a significant way from the addition of atezolizumab,” he said. “I don’t see evidence for a clinical benefit, I see evidence to look for new biomarkers to identify a potential population who will benefit.”

The “absence of evidence is not evidence of absence,” he stressed, noting that it may be possible – with the right biomarkers – to identify PD-L1-negative patients who would benefit.

What the findings do show, however, is support for the FDA decision to approve the SP142 assay with an IC cutoff of 1% as a companion diagnostic tool, and that PD-L1 is ideally assessed using samples from both the primary and metastatic site, as the IMPassion130 data “do not inform whether PD-L1 assessment in primary and metastatic sites is equally informative,” he said.

In addition, Dr. Bianchini said the findings suggest that more information is needed about using different cutoffs for SP263 and 22C3, and he cautioned against “directly translating these finding to other disease settings or immune combinations.

“Defining new biomarkers to identify who within the PD-L1-negative group might benefit from this combination remains an unmet need,” he said. “For sure, I don’t see a space for the other tests to define this population,” he added.

KEYNOTE-119, KATE2, and future directions

Both the randomized, open-label, phase 3 KEYNOTE-119 study of the checkpoint inhibitor pembrolizumab vs. single-agent chemotherapy for mTNBC, and the phase 2 KATE2 trial of the antibody-drug conjugate trastuzumab emtansine (T-DM1) + either atezolizumab or placebo in previously treated HER2-positive breast cancer patients, failed to meet their respective primary study endpoints.

But the news isn’t all bad, Dr. Bianchini said.

For example, in KEYNOTE-119, second- or third-line pembrolizumab monotherapy did not significantly improve OS vs. chemotherapy for mTNBC, but the pembrolizumab treatment effect increased as PD-L1 enrichment increased, he explained.

Pembrolizumab showed promising antitumor activity and manageable safety in mTNBC in prior trials, and was therefore further assessed in the KEYNOTE-119 study of 601 patients with centrally confirmed TNBC, 1-2 prior systemic treatments for mTNBC, progression on the latest therapy, and a prior anthracycline or taxane, Javier Cortés, MD, PhD, of Instituto Oncológico, Madrid, reported at the congress.

Sharon Worcester/MDedge News

Pembrolizumab was given at a dose of 200 mg every 3 weeks, and chemotherapy was physician’s choice of capecitabine, eribulin, gemcitabine, or vinorelbine.

At a median follow-up of 9.9 months in the pembrolizumab group and 10.9 months in the chemotherapy group, OS did not differ significantly between the groups; this was true overall, in patients with a CPS of 10 or greater, and in those with a CPS of 1 or greater.

In all-comers, the HR for OS was 0.97, compared with 0.78 in patients with CPS of 10 or greater, and 0.86 in those with CPS of 1 or greater, Dr. Cortés said.

“One of the most interesting exploratory analyses was OS in those patients with CPS of 20 or higher,” he said, noting that median OS in that group was 14.9 vs.12.5 months with pembrolizumab vs. with chemotherapy (HR, 0.58).

Pembrolizumab did not improve overall PFS, but again, the rates improved with higher CPS. Duration of response, however, was longer with pembrolizumab vs. chemotherapy (12.2 vs. 8.3 months overall; 12.2 vs. 6.5 months for CPS of 1 or greater; and not reached vs. 7.1 months for CPS of 10 or greater).

Grade 3-5 AEs occurred in 35% vs. 49% of patients in the pembrolizumab vs. chemotherapy groups, with nine deaths occurring in each, Dr. Cortés said, adding that treatment-related AEs occurred in 14% (with one death) and 36% (with two deaths), respectively, and grade 3-4 immune-mediated AEs and infusion reactions occurred in 3.2% vs. 1.0% (no deaths), respectively.

In the double-blind, signal-seeking KATE2 trial, as reported in 2018 at the San Antonio Breast Cancer Symposium, no overall PFS improvement was seen with atezolizumab + T-DM1 (median of 8.2 vs. 6.8 months; HR, 0.82; 12-month PFS 38% vs. 34%), but again, a possible benefit was seen in PD-L1-positive patients (8.5 vs. 4.1 months; HR, 0.60).

KATE2 included 202 patients with advanced HER2-positive breast cancer that progressed after treatment with T-DM1 and a taxane. They were randomized 2:1 to receive intravenous T-DM1 at a dose of 3.6 mg/kg plus atezolizumab (1,200 mg) or placebo every 3 weeks until loss of clinical benefit or intolerable toxicity.

The “overall survival and final safety results” show that at a median follow-up of 19.0 months in the atezolizumab arm and 18.2 months in the placebo arm, with 52 OS events reported, median OS was not reached in either arm and 1-year survival was similar in the two groups (89.1% and 89.0%), Leisha A. Emens, MD, PhD, professor of medicine in hematology/oncology and co-leader of the Hillman Cancer Immunology and Immunotherapy Program at Hillman Cancer Center, University of Pittsburgh Medical Center (UPMC) reported at the congress.

“And when you look at duration of response, you see an increase not just in the number ... but the quality of the response,” he said, noting that for PFS, as well, a trend toward superiority is seen “that is consistent with all the other endpoints.”

“So overall, the application of incrementally restrictive cut-off of CPS lends weight to the exploratory analysis showing better survival from pembrolizumab in tumors with CPS more than 20,” Dr. Bianchini said, noting that the “real question,” however, is whether the finding “is worth clinical implementation.

“We know a lot about the primary tumor and immune infiltration. We’ve learned ... that if you wait and look ahead at immune infiltration in the advanced stage, you find that the tumor becomes smart,” he said, explaining that tumor/immune co-evolution leads to increased immuno-editing and immune subversion and it becomes “much harder to just hit the tumor with PD-L1, because this is not the only mechanism of immune escape.”

A review of several studies shows that in similar populations defined by biomarkers, response rates in patients treated with checkpoint inhibitors decrease in the second- and third-line setting vs. the first-line setting, he said.

For example, pembrolizumab response rates in the first-line and second-line or greater setting in cohort B of the KEYNOTE-086 study were 21.4% and 5.7%, respectively, compared with 12.3% in the second- to third-line setting in KEYNOTE-119, he said.

Another consideration is whether monotherapy or combination therapy is preferable, and the data suggest that regardless of how PD-L1-positivity is defined (by CPS cutoff of 1 vs. 20, for example), most patients treated with monotherapy progress within the first 3 months, he said.

“I don’t see that this is a safe approach for the majority of these patients. So without better biomarkers, combinations should always be preferred, at least to avoid early progression,” Dr. Bianchini said, adding that the open question, then, is: “If we set the new standard in the first-line as the combination of nab-paclitaxel and atezolizumab for PD-L1-positive patients defined by the VENTANA [SP142 assay], should we continue with immune checkpoint [inhibition] using different combinations?”

“Of course, at the time the trial was designed, the results of IMpassion were not available, but it’s very important, because [the findings] add to the evidence that immunotherapy is extremely relevant for some patients,” he said.

KATE2 further demonstrated the importance of PD-L1 status, he said, adding that due to its limitations, including small sample size and short follow-up, longer follow-up is needed to better evaluate duration of response and PFS.

“Despite the trial limitations, the qualitative effect seen in all clinical endpoints – overall response rate, progression-free survival, overall survival – in PD-L1-positive tumors defined by SP142 ... provided strong and robust signals supporting the investigation of immune checkpoint inhibitors in HER-positive breast cancer,” he said, noting that “many trials are ongoing in the early setting and the advanced setting.”

In addition to the lessons of these trials with respect to the interchangeability of PD-L1 IHC assays and the value of PD-L1 assessment for identifying the likelihood of benefit from immune checkpoint inhibitors, the findings highlight the possibility that PD-L1-negative tumors require different immunotherapy approaches or alternative therapeutic strategies, and underscore that the benefit of immunotherapy in PD-L1-positive patients is still restricted to a minority.

“So new studies and approaches with immuno-oncology are needed, and we need more effective biomarkers, because we need to have precision oncology applied – we need to go in that direction,” he concluded.

Dr. Bianchini reported consultancy/honorarium and or advisory board activity associated with Roche, MSD, AstraZeneca, Pfizer, Chugai, EISAI, Lilly, Novartis, Amgen, Sanofi, Neopharm, and Genomic Health. The IMPassion30 trial was funded by F. Hoffmann-La Roche Ltd.; Dr. Rugo reported research grants, other funding, and or travel/accommodation/expenses from Pfizer, Novartis, Eli Lilly, Merck, OBI, EISAI, Plexxikon, Genentech/Roche, MacroGenics, PUMA, Mylan, Immunomedics, Daiichi Sankyo, and Celltrion. KEYNOTE-119 was funded by Merck Sharp & Dohme Corp.; Dr. Cortés and Dr. Emens reported numerous funding relationships but none with F. Hoffman-La Roche. KATE2 was funded by F. Hoffmann-La Roche.
 

Sources: IMPassion130; ESMO Abstract LBA20; KEYNOTE-119: ESMO Abstract LBA21; KATE2: ESMO Abstract 305O.

BARCELONA – Programmed death-ligand 1 (PD-L1) status in patients with advanced triple negative or HER2-positive breast cancer appears to identify distinct disease entities with varying likelihood of benefit from immune checkpoint inhibition, according to Giampaolo Bianchini, MD.

This observation, which contrasts with findings in other solid tumors and expands the road map to improved outcomes with immunotherapy for metastatic breast cancer, is based in part on new findings presented at the European Society for Medical Oncology Congress.

Among additional lessons from those findings: PD-L1 assays are not easily interchangeable, and studies with a “one size fits all” approach should be avoided, Dr. Bianchini, head of the Breast Cancer Group – Medical Oncology and clinical translational and immunotherapy research at Ospedale San Raffaele, Milan, said at the congress.
 

IMPassion130 and PD-L1 assays

In the phase 3 IMpassion130 trial assessing nanoparticle, albumin-bound (nab)-paclitaxel chemotherapy + either the anti-PD-L1 monoclonal antibody atezolizumab or placebo for the first-line treatment of metastatic triple-negative breast cancer (mTNBC), investigators used, and validated, the VENTANA PD-L1 SP142 assay to evaluate PD-L1 expression in immune cells (IC). PD-L1 positivity was defined using a 1% cutoff, meaning that PD-L1-stained IC encompassed at least 1% of the tumor area.

The trial demonstrated significantly improved progression-free survival (PFS) in the atezolizumab arm, both in the intention-to-treat (ITT) analysis (7.2 vs. 5.5 months in the placebo arm; hazard ratio, 0.80), and the PD-L1-positive subgroup (7.5 vs. 5.0 months; HR, 0.62), and the results were published in November 2018 (N Engl J Med. 2018; 379:2108-21).

“IMpassion130 is the first phase 3 trial demonstrating clinical benefit of cancer immunotherapy in patients with PD-L1-positive, metastatic triple-negative breast cancer,” Hope S. Rugo, MD, said at the congress. “The combination of atezolizumab and nab-paclitaxel is now approved in the United States and Europe for this indication.”

Subgroup analyses indicated that PFS and OS benefit with atezolizumab + nab-paclitaxel vs. nab-paclitaxel alone was greater in double-positive patients (those with SP142 positivity and either SP263 or 22C3 positivity) than in patients who were SP263-positive/SP142-negative or 22C3-positive/SP142-negative.

Dr. Rugo and her colleagues also found that the benefits with atezolizumab + nab-paclitaxel in PD-L1-positive patients were apparent regardless of the source of tissue for testing (breast or distant metastases).

They concluded that the findings of the assays are not equivalent; 22C3 and SP263 identified more patients as PD-L1 positive, and SP142-positivity was encompassed in positive tests for both.

“The clinical benefit in the 22C3-positive and the SP263-positive subgroups appear to be driven by the SP142-positive subgroup, and [SP142] identifies patients with the longest median progression-free and overall survival from the addition of atezolizumab to nab-paclitaxel,” she said “The SP142 assay with an IC cutoff of 1% or greater is the approved diagnostic test used to identify patients with metastatic triple-negative breast cancer who are most likely to benefit from the addition of the checkpoint inhibitor atezolizumab to nab-paclitaxel.”

As for whether the SP142 should be the assay of choice in other settings in which it hasn’t been validated, Dr. Rugo said it is advisable to use the assay that has been validated in a positive trial.

“That’s what we would generally do ... however, recognizing that some countries are not using SP142, and some sites may not have access, certainly you encompass that population in the patients whose tumors are positive by both other assays,” she said. “The risk is that you might overtreat, and the cost of treatment is greater.”

Excess toxicity is also a concern in that situation, she said, adding that “hopefully in the future we’ll be able to figure out ways to have even more patients benefit from the addition of immunotherapy so that won’t be an issue.”

“What this data shows is that you can feel secure that you are encompassing the patient population identified by the parent trial to benefit from the addition of atezolizumab by using either of the other two assays; you’re only missing 1% – so that’s very reasonable,” she said. “The risk is that you’re overtreating; it’s quite likely that there’s a population there that isn’t benefiting as much, but that’s a balance.”

The findings from IMPassion130 with regard to OS in the unselected population that included PD-L1-negative patients (18.7 vs. 21.0 months with vs. without atezolizumab; HR, 0.86) underscore the fact that “one size does not fit all” when it comes to immunotherapy benefit, Dr. Bianchini said.

This is further demonstrated by the post hoc analysis comparing IHC assays, he said, explaining that 63% of IMPassion130 patients who were considered PD-L1-negative based on the SP142 “actually scored as PD-L1-positive by the other tests.

“So the very clinically important question is if there is any evidence from the data that [the PD-L1-negative group] benefits in a significant way from the addition of atezolizumab,” he said. “I don’t see evidence for a clinical benefit, I see evidence to look for new biomarkers to identify a potential population who will benefit.”

The “absence of evidence is not evidence of absence,” he stressed, noting that it may be possible – with the right biomarkers – to identify PD-L1-negative patients who would benefit.

What the findings do show, however, is support for the FDA decision to approve the SP142 assay with an IC cutoff of 1% as a companion diagnostic tool, and that PD-L1 is ideally assessed using samples from both the primary and metastatic site, as the IMPassion130 data “do not inform whether PD-L1 assessment in primary and metastatic sites is equally informative,” he said.

In addition, Dr. Bianchini said the findings suggest that more information is needed about using different cutoffs for SP263 and 22C3, and he cautioned against “directly translating these finding to other disease settings or immune combinations.

“Defining new biomarkers to identify who within the PD-L1-negative group might benefit from this combination remains an unmet need,” he said. “For sure, I don’t see a space for the other tests to define this population,” he added.

KEYNOTE-119, KATE2, and future directions

Both the randomized, open-label, phase 3 KEYNOTE-119 study of the checkpoint inhibitor pembrolizumab vs. single-agent chemotherapy for mTNBC, and the phase 2 KATE2 trial of the antibody-drug conjugate trastuzumab emtansine (T-DM1) + either atezolizumab or placebo in previously treated HER2-positive breast cancer patients, failed to meet their respective primary study endpoints.

But the news isn’t all bad, Dr. Bianchini said.

For example, in KEYNOTE-119, second- or third-line pembrolizumab monotherapy did not significantly improve OS vs. chemotherapy for mTNBC, but the pembrolizumab treatment effect increased as PD-L1 enrichment increased, he explained.

Pembrolizumab showed promising antitumor activity and manageable safety in mTNBC in prior trials, and was therefore further assessed in the KEYNOTE-119 study of 601 patients with centrally confirmed TNBC, 1-2 prior systemic treatments for mTNBC, progression on the latest therapy, and a prior anthracycline or taxane, Javier Cortés, MD, PhD, of Instituto Oncológico, Madrid, reported at the congress.

Sharon Worcester/MDedge News

Pembrolizumab was given at a dose of 200 mg every 3 weeks, and chemotherapy was physician’s choice of capecitabine, eribulin, gemcitabine, or vinorelbine.

At a median follow-up of 9.9 months in the pembrolizumab group and 10.9 months in the chemotherapy group, OS did not differ significantly between the groups; this was true overall, in patients with a CPS of 10 or greater, and in those with a CPS of 1 or greater.

In all-comers, the HR for OS was 0.97, compared with 0.78 in patients with CPS of 10 or greater, and 0.86 in those with CPS of 1 or greater, Dr. Cortés said.

“One of the most interesting exploratory analyses was OS in those patients with CPS of 20 or higher,” he said, noting that median OS in that group was 14.9 vs.12.5 months with pembrolizumab vs. with chemotherapy (HR, 0.58).

Pembrolizumab did not improve overall PFS, but again, the rates improved with higher CPS. Duration of response, however, was longer with pembrolizumab vs. chemotherapy (12.2 vs. 8.3 months overall; 12.2 vs. 6.5 months for CPS of 1 or greater; and not reached vs. 7.1 months for CPS of 10 or greater).

Grade 3-5 AEs occurred in 35% vs. 49% of patients in the pembrolizumab vs. chemotherapy groups, with nine deaths occurring in each, Dr. Cortés said, adding that treatment-related AEs occurred in 14% (with one death) and 36% (with two deaths), respectively, and grade 3-4 immune-mediated AEs and infusion reactions occurred in 3.2% vs. 1.0% (no deaths), respectively.

In the double-blind, signal-seeking KATE2 trial, as reported in 2018 at the San Antonio Breast Cancer Symposium, no overall PFS improvement was seen with atezolizumab + T-DM1 (median of 8.2 vs. 6.8 months; HR, 0.82; 12-month PFS 38% vs. 34%), but again, a possible benefit was seen in PD-L1-positive patients (8.5 vs. 4.1 months; HR, 0.60).

KATE2 included 202 patients with advanced HER2-positive breast cancer that progressed after treatment with T-DM1 and a taxane. They were randomized 2:1 to receive intravenous T-DM1 at a dose of 3.6 mg/kg plus atezolizumab (1,200 mg) or placebo every 3 weeks until loss of clinical benefit or intolerable toxicity.

The “overall survival and final safety results” show that at a median follow-up of 19.0 months in the atezolizumab arm and 18.2 months in the placebo arm, with 52 OS events reported, median OS was not reached in either arm and 1-year survival was similar in the two groups (89.1% and 89.0%), Leisha A. Emens, MD, PhD, professor of medicine in hematology/oncology and co-leader of the Hillman Cancer Immunology and Immunotherapy Program at Hillman Cancer Center, University of Pittsburgh Medical Center (UPMC) reported at the congress.

“And when you look at duration of response, you see an increase not just in the number ... but the quality of the response,” he said, noting that for PFS, as well, a trend toward superiority is seen “that is consistent with all the other endpoints.”

“So overall, the application of incrementally restrictive cut-off of CPS lends weight to the exploratory analysis showing better survival from pembrolizumab in tumors with CPS more than 20,” Dr. Bianchini said, noting that the “real question,” however, is whether the finding “is worth clinical implementation.

“We know a lot about the primary tumor and immune infiltration. We’ve learned ... that if you wait and look ahead at immune infiltration in the advanced stage, you find that the tumor becomes smart,” he said, explaining that tumor/immune co-evolution leads to increased immuno-editing and immune subversion and it becomes “much harder to just hit the tumor with PD-L1, because this is not the only mechanism of immune escape.”

A review of several studies shows that in similar populations defined by biomarkers, response rates in patients treated with checkpoint inhibitors decrease in the second- and third-line setting vs. the first-line setting, he said.

For example, pembrolizumab response rates in the first-line and second-line or greater setting in cohort B of the KEYNOTE-086 study were 21.4% and 5.7%, respectively, compared with 12.3% in the second- to third-line setting in KEYNOTE-119, he said.

Another consideration is whether monotherapy or combination therapy is preferable, and the data suggest that regardless of how PD-L1-positivity is defined (by CPS cutoff of 1 vs. 20, for example), most patients treated with monotherapy progress within the first 3 months, he said.

“I don’t see that this is a safe approach for the majority of these patients. So without better biomarkers, combinations should always be preferred, at least to avoid early progression,” Dr. Bianchini said, adding that the open question, then, is: “If we set the new standard in the first-line as the combination of nab-paclitaxel and atezolizumab for PD-L1-positive patients defined by the VENTANA [SP142 assay], should we continue with immune checkpoint [inhibition] using different combinations?”

“Of course, at the time the trial was designed, the results of IMpassion were not available, but it’s very important, because [the findings] add to the evidence that immunotherapy is extremely relevant for some patients,” he said.

KATE2 further demonstrated the importance of PD-L1 status, he said, adding that due to its limitations, including small sample size and short follow-up, longer follow-up is needed to better evaluate duration of response and PFS.

“Despite the trial limitations, the qualitative effect seen in all clinical endpoints – overall response rate, progression-free survival, overall survival – in PD-L1-positive tumors defined by SP142 ... provided strong and robust signals supporting the investigation of immune checkpoint inhibitors in HER-positive breast cancer,” he said, noting that “many trials are ongoing in the early setting and the advanced setting.”

In addition to the lessons of these trials with respect to the interchangeability of PD-L1 IHC assays and the value of PD-L1 assessment for identifying the likelihood of benefit from immune checkpoint inhibitors, the findings highlight the possibility that PD-L1-negative tumors require different immunotherapy approaches or alternative therapeutic strategies, and underscore that the benefit of immunotherapy in PD-L1-positive patients is still restricted to a minority.

“So new studies and approaches with immuno-oncology are needed, and we need more effective biomarkers, because we need to have precision oncology applied – we need to go in that direction,” he concluded.

Dr. Bianchini reported consultancy/honorarium and or advisory board activity associated with Roche, MSD, AstraZeneca, Pfizer, Chugai, EISAI, Lilly, Novartis, Amgen, Sanofi, Neopharm, and Genomic Health. The IMPassion30 trial was funded by F. Hoffmann-La Roche Ltd.; Dr. Rugo reported research grants, other funding, and or travel/accommodation/expenses from Pfizer, Novartis, Eli Lilly, Merck, OBI, EISAI, Plexxikon, Genentech/Roche, MacroGenics, PUMA, Mylan, Immunomedics, Daiichi Sankyo, and Celltrion. KEYNOTE-119 was funded by Merck Sharp & Dohme Corp.; Dr. Cortés and Dr. Emens reported numerous funding relationships but none with F. Hoffman-La Roche. KATE2 was funded by F. Hoffmann-La Roche.
 

Sources: IMPassion130; ESMO Abstract LBA20; KEYNOTE-119: ESMO Abstract LBA21; KATE2: ESMO Abstract 305O.

BARCELONA – Adding veliparib to chemotherapy improved progression-free survival and provided a more durable benefit than did chemotherapy alone for HER2-negative advanced germline BRCA-associated breast cancer in the randomized, placebo-controlled, phase 3 BROCADE3 study.

Investigator-assessed median progression-free survival (PFS), the primary study endpoint, was 14.5 vs. 12.6 months in 337 patients randomized to receive the poly (ADP-ribose) polymerase inhibitor (PARPi) veliparib along with carboplatin/paclitaxel (CP) and 172 who received placebo and CP (hazard ratio, 0.71), Veronique C. Diéras, MD, reported at the European Society for Medical Oncology Congress.

“The benefit looks durable; more patients in the veliparib arm were still progression free at 2 years (34% vs. 20%), and at 3 years (26% vs. 11%),” said Dr. Diéras of Institut Curie, Paris, and Centre Eugene Marquis, Rennes, France.

The PFS benefit was confirmed by independent central review, and was apparent in all subgroups analyzed, except perhaps in patients with prior brain metastases, who comprised a very small group, she noted.

Among the secondary study endpoints were median overall survival (33.5 vs. 28.2 months at an interim analysis; HR, 0.95), clinical benefit rate (90.7% and 93.2% at 24 weeks), and objective response rate (75.8% and 74.1%).

“This is very important to note,” she said, referring to the high percentage of patients who benefited from CP alone. “But, again, if we look at the duration of response, in the veliparib arm the median duration of response was 14.7 months, whereas it was 11 months in the placebo arm.”

Participants in the double-blind trial were adults with a median age of 47 years who were randomized 2:1 to CP with veliparib or placebo for the treatment of germline BRCA1- or BRCA2-mutated metastatic breast cancer and had received no more than two prior lines of cytotoxic therapy; 48% were estrogen receptor– and/or progesterone receptor–negative, 8% had prior platinum therapy, 4% had a history of central nervous system metastases, and 19% had prior chemotherapy for metastatic disease.

They received placebo or veliparib at an oral dose of 120 mg twice daily on days −2 to 5 with carboplatin (area under the curve 6 on day 1) and weekly paclitaxel (80 mg/m² on days 1, 8, and 15) in 21-day cycles until disease progression, and as allowed per study protocol, 44% crossed over from the placebo to veliparib group, Dr. Diéras said.

Common adverse events in the veliparib and placebo groups, respectively, included neutropenia (in 89% and 91% of patients), thrombocytopenia (81% and 71%), anemia (80% and 70%), and nausea (73% and 64%), she said, adding that the most common grade 3 adverse events were anemia (42% and 40%), neutropenia (81% and 84%), and thrombocytopenia (40% and 28%).

However, less than 10% of patients discontinued the study drug because of adverse events, she noted.

“In fact, the addition of veliparib to cytotoxic chemotherapy didn’t impair the administration of cytotoxic chemotherapy,” she said, adding that the mean number of CP cycles was 11 in both arms.

Select adverse events of special interest in the veliparib and placebo groups, respectively, included infection within 14 days of neutropenia (any grade, 37% and 36%; grade 3+, 5.4% and 1.8%), hemorrhage within 14 days of thrombocytopenia (any grade, 10% and 7%; grade 3+, 0.3% and 0%), and myelodysplastic syndromes (0.3% in both groups, with 0 grade 3+ events), she said.

“We know that germline BRCA-mutated breast cancers have increased sensitivity to platinum agents. Moreover, according to the concept of synthetic lethality, we do know also that these mutated tumors are very good candidates for PARP inhibition, so there is a strong rationale to combine a PARP inhibitor with cytotoxic chemotherapy with platinum,” she said.

Early studies of such combinations have been challenging because of exacerbation of myelosuppression, which may be the result of “the PARP trapping activity of some compounds,” but veliparib potently inhibits PARP with minimal PARP trapping, and thus may be better tolerated in combination with CP, she explained.

“In fact, in a phase 2 randomized trial – BROCADE2 – we did observe numerical increases in PFS and overall survival with [veliparib+CP],” she said.

In BROCADE3, the addition to veliparib to CP provided “a statistically significant and clinically meaningful benefit in patients with HER-negative advanced breast cancer and a germline BRCA mutation” without substantially altering the toxicity profile of C/P, she said.

“Considering these results, in my opinion, patients harboring BRCA mutations with advanced breast cancer [who are] candidates for chemotherapy should be offered this treatment option,” she concluded.

Invited discussant Sherene Loi, MBBS, PhD, head of the Translational Breast Cancer Genomics and Therapeutics Laboratory at Peter MacCallum Cancer Center, Victoria, Australia, said the investigators should be commended for conducting this phase 3 trial, and agreed that the approach is “reasonable to consider in a patient who does need chemotherapy.”

However, Dr. Loi said, it remains unclear if the PFS benefit seen in BROCADE3 is “due to the combination upfront and/or the monotherapy,” and suggested waiting for additional data before considering veliparib + CP as the new standard of care for germline BRCA1- and BRCA2-mutated advanced breast cancer.

“Current ESMO guidelines advise that single-agent chemotherapy be given sequentially in the absence of visceral crisis, therefore I think it’s important to await further for mature OS data and patient-reported outcomes,” she said, adding that it is also important to wait for the correlative analyses to “try to understand the rate of BRCA reversions and other resistance mechanisms in plasma.”

BROCADE3 was funded by AbbVie. Dr. Diéras reported advisory/consultancy roles for several pharmaceutical companies including AbbVie. Dr. Loi reported relationships with numerous pharmaceutical companies.

[email protected]

SOURCE: Diéras V et al. ESMO 2019, Abstract LBA9.

BARCELONA – Adding veliparib to chemotherapy improved progression-free survival and provided a more durable benefit than did chemotherapy alone for HER2-negative advanced germline BRCA-associated breast cancer in the randomized, placebo-controlled, phase 3 BROCADE3 study.

Investigator-assessed median progression-free survival (PFS), the primary study endpoint, was 14.5 vs. 12.6 months in 337 patients randomized to receive the poly (ADP-ribose) polymerase inhibitor (PARPi) veliparib along with carboplatin/paclitaxel (CP) and 172 who received placebo and CP (hazard ratio, 0.71), Veronique C. Diéras, MD, reported at the European Society for Medical Oncology Congress.

“The benefit looks durable; more patients in the veliparib arm were still progression free at 2 years (34% vs. 20%), and at 3 years (26% vs. 11%),” said Dr. Diéras of Institut Curie, Paris, and Centre Eugene Marquis, Rennes, France.

The PFS benefit was confirmed by independent central review, and was apparent in all subgroups analyzed, except perhaps in patients with prior brain metastases, who comprised a very small group, she noted.

Among the secondary study endpoints were median overall survival (33.5 vs. 28.2 months at an interim analysis; HR, 0.95), clinical benefit rate (90.7% and 93.2% at 24 weeks), and objective response rate (75.8% and 74.1%).

“This is very important to note,” she said, referring to the high percentage of patients who benefited from CP alone. “But, again, if we look at the duration of response, in the veliparib arm the median duration of response was 14.7 months, whereas it was 11 months in the placebo arm.”

Participants in the double-blind trial were adults with a median age of 47 years who were randomized 2:1 to CP with veliparib or placebo for the treatment of germline BRCA1- or BRCA2-mutated metastatic breast cancer and had received no more than two prior lines of cytotoxic therapy; 48% were estrogen receptor– and/or progesterone receptor–negative, 8% had prior platinum therapy, 4% had a history of central nervous system metastases, and 19% had prior chemotherapy for metastatic disease.

They received placebo or veliparib at an oral dose of 120 mg twice daily on days −2 to 5 with carboplatin (area under the curve 6 on day 1) and weekly paclitaxel (80 mg/m² on days 1, 8, and 15) in 21-day cycles until disease progression, and as allowed per study protocol, 44% crossed over from the placebo to veliparib group, Dr. Diéras said.

Common adverse events in the veliparib and placebo groups, respectively, included neutropenia (in 89% and 91% of patients), thrombocytopenia (81% and 71%), anemia (80% and 70%), and nausea (73% and 64%), she said, adding that the most common grade 3 adverse events were anemia (42% and 40%), neutropenia (81% and 84%), and thrombocytopenia (40% and 28%).

However, less than 10% of patients discontinued the study drug because of adverse events, she noted.

“In fact, the addition of veliparib to cytotoxic chemotherapy didn’t impair the administration of cytotoxic chemotherapy,” she said, adding that the mean number of CP cycles was 11 in both arms.

Select adverse events of special interest in the veliparib and placebo groups, respectively, included infection within 14 days of neutropenia (any grade, 37% and 36%; grade 3+, 5.4% and 1.8%), hemorrhage within 14 days of thrombocytopenia (any grade, 10% and 7%; grade 3+, 0.3% and 0%), and myelodysplastic syndromes (0.3% in both groups, with 0 grade 3+ events), she said.

“We know that germline BRCA-mutated breast cancers have increased sensitivity to platinum agents. Moreover, according to the concept of synthetic lethality, we do know also that these mutated tumors are very good candidates for PARP inhibition, so there is a strong rationale to combine a PARP inhibitor with cytotoxic chemotherapy with platinum,” she said.

Early studies of such combinations have been challenging because of exacerbation of myelosuppression, which may be the result of “the PARP trapping activity of some compounds,” but veliparib potently inhibits PARP with minimal PARP trapping, and thus may be better tolerated in combination with CP, she explained.

“In fact, in a phase 2 randomized trial – BROCADE2 – we did observe numerical increases in PFS and overall survival with [veliparib+CP],” she said.

In BROCADE3, the addition to veliparib to CP provided “a statistically significant and clinically meaningful benefit in patients with HER-negative advanced breast cancer and a germline BRCA mutation” without substantially altering the toxicity profile of C/P, she said.

“Considering these results, in my opinion, patients harboring BRCA mutations with advanced breast cancer [who are] candidates for chemotherapy should be offered this treatment option,” she concluded.

Invited discussant Sherene Loi, MBBS, PhD, head of the Translational Breast Cancer Genomics and Therapeutics Laboratory at Peter MacCallum Cancer Center, Victoria, Australia, said the investigators should be commended for conducting this phase 3 trial, and agreed that the approach is “reasonable to consider in a patient who does need chemotherapy.”

However, Dr. Loi said, it remains unclear if the PFS benefit seen in BROCADE3 is “due to the combination upfront and/or the monotherapy,” and suggested waiting for additional data before considering veliparib + CP as the new standard of care for germline BRCA1- and BRCA2-mutated advanced breast cancer.

“Current ESMO guidelines advise that single-agent chemotherapy be given sequentially in the absence of visceral crisis, therefore I think it’s important to await further for mature OS data and patient-reported outcomes,” she said, adding that it is also important to wait for the correlative analyses to “try to understand the rate of BRCA reversions and other resistance mechanisms in plasma.”

BROCADE3 was funded by AbbVie. Dr. Diéras reported advisory/consultancy roles for several pharmaceutical companies including AbbVie. Dr. Loi reported relationships with numerous pharmaceutical companies.

[email protected]

SOURCE: Diéras V et al. ESMO 2019, Abstract LBA9.

BARCELONA – Adding veliparib to chemotherapy improved progression-free survival and provided a more durable benefit than did chemotherapy alone for HER2-negative advanced germline BRCA-associated breast cancer in the randomized, placebo-controlled, phase 3 BROCADE3 study.

Investigator-assessed median progression-free survival (PFS), the primary study endpoint, was 14.5 vs. 12.6 months in 337 patients randomized to receive the poly (ADP-ribose) polymerase inhibitor (PARPi) veliparib along with carboplatin/paclitaxel (CP) and 172 who received placebo and CP (hazard ratio, 0.71), Veronique C. Diéras, MD, reported at the European Society for Medical Oncology Congress.

“The benefit looks durable; more patients in the veliparib arm were still progression free at 2 years (34% vs. 20%), and at 3 years (26% vs. 11%),” said Dr. Diéras of Institut Curie, Paris, and Centre Eugene Marquis, Rennes, France.

The PFS benefit was confirmed by independent central review, and was apparent in all subgroups analyzed, except perhaps in patients with prior brain metastases, who comprised a very small group, she noted.

Among the secondary study endpoints were median overall survival (33.5 vs. 28.2 months at an interim analysis; HR, 0.95), clinical benefit rate (90.7% and 93.2% at 24 weeks), and objective response rate (75.8% and 74.1%).

“This is very important to note,” she said, referring to the high percentage of patients who benefited from CP alone. “But, again, if we look at the duration of response, in the veliparib arm the median duration of response was 14.7 months, whereas it was 11 months in the placebo arm.”

Participants in the double-blind trial were adults with a median age of 47 years who were randomized 2:1 to CP with veliparib or placebo for the treatment of germline BRCA1- or BRCA2-mutated metastatic breast cancer and had received no more than two prior lines of cytotoxic therapy; 48% were estrogen receptor– and/or progesterone receptor–negative, 8% had prior platinum therapy, 4% had a history of central nervous system metastases, and 19% had prior chemotherapy for metastatic disease.

They received placebo or veliparib at an oral dose of 120 mg twice daily on days −2 to 5 with carboplatin (area under the curve 6 on day 1) and weekly paclitaxel (80 mg/m² on days 1, 8, and 15) in 21-day cycles until disease progression, and as allowed per study protocol, 44% crossed over from the placebo to veliparib group, Dr. Diéras said.

Common adverse events in the veliparib and placebo groups, respectively, included neutropenia (in 89% and 91% of patients), thrombocytopenia (81% and 71%), anemia (80% and 70%), and nausea (73% and 64%), she said, adding that the most common grade 3 adverse events were anemia (42% and 40%), neutropenia (81% and 84%), and thrombocytopenia (40% and 28%).

However, less than 10% of patients discontinued the study drug because of adverse events, she noted.

“In fact, the addition of veliparib to cytotoxic chemotherapy didn’t impair the administration of cytotoxic chemotherapy,” she said, adding that the mean number of CP cycles was 11 in both arms.

Select adverse events of special interest in the veliparib and placebo groups, respectively, included infection within 14 days of neutropenia (any grade, 37% and 36%; grade 3+, 5.4% and 1.8%), hemorrhage within 14 days of thrombocytopenia (any grade, 10% and 7%; grade 3+, 0.3% and 0%), and myelodysplastic syndromes (0.3% in both groups, with 0 grade 3+ events), she said.

“We know that germline BRCA-mutated breast cancers have increased sensitivity to platinum agents. Moreover, according to the concept of synthetic lethality, we do know also that these mutated tumors are very good candidates for PARP inhibition, so there is a strong rationale to combine a PARP inhibitor with cytotoxic chemotherapy with platinum,” she said.

Early studies of such combinations have been challenging because of exacerbation of myelosuppression, which may be the result of “the PARP trapping activity of some compounds,” but veliparib potently inhibits PARP with minimal PARP trapping, and thus may be better tolerated in combination with CP, she explained.

“In fact, in a phase 2 randomized trial – BROCADE2 – we did observe numerical increases in PFS and overall survival with [veliparib+CP],” she said.

In BROCADE3, the addition to veliparib to CP provided “a statistically significant and clinically meaningful benefit in patients with HER-negative advanced breast cancer and a germline BRCA mutation” without substantially altering the toxicity profile of C/P, she said.

“Considering these results, in my opinion, patients harboring BRCA mutations with advanced breast cancer [who are] candidates for chemotherapy should be offered this treatment option,” she concluded.

Invited discussant Sherene Loi, MBBS, PhD, head of the Translational Breast Cancer Genomics and Therapeutics Laboratory at Peter MacCallum Cancer Center, Victoria, Australia, said the investigators should be commended for conducting this phase 3 trial, and agreed that the approach is “reasonable to consider in a patient who does need chemotherapy.”

However, Dr. Loi said, it remains unclear if the PFS benefit seen in BROCADE3 is “due to the combination upfront and/or the monotherapy,” and suggested waiting for additional data before considering veliparib + CP as the new standard of care for germline BRCA1- and BRCA2-mutated advanced breast cancer.

“Current ESMO guidelines advise that single-agent chemotherapy be given sequentially in the absence of visceral crisis, therefore I think it’s important to await further for mature OS data and patient-reported outcomes,” she said, adding that it is also important to wait for the correlative analyses to “try to understand the rate of BRCA reversions and other resistance mechanisms in plasma.”

BROCADE3 was funded by AbbVie. Dr. Diéras reported advisory/consultancy roles for several pharmaceutical companies including AbbVie. Dr. Loi reported relationships with numerous pharmaceutical companies.

[email protected]

SOURCE: Diéras V et al. ESMO 2019, Abstract LBA9.

BARCELONA – The androgen receptor inhibitor apalutamide was associated with a 45% improvement in time to second progression in patients with nonmetastatic, castration-resistant prostate cancer as well as an overall survival edge, although the latter fell just short of statistical significance in an interim analysis of results from the SPARTAN trial.

Among 1,207 men with nonmetastatic castration-resistant prostate cancer (CRPC), those randomly assigned to apalutamide had significantly longer second progression-free survival (PFS2), an exploratory endpoint defined as the time of study entry to progression on subsequent treatment.

In all, 69% of patients on placebo and 40% of those on apalutamide went on to another life-prolonging therapy, usually abiraterone acetate (Zytiga) plus prednisone. The respective median PFS2s were 43.8 and 55.6 months, translating into a hazard ratio for second progression in the apalutamide group of 0.55 (P less than .0001).

Overall survival (OS) also trended toward a benefit for apalutamide, but the difference did not reach the prespecified boundary for significance in this planned interim analysis, reported Matthew R. Smith, MD, PhD, from the Massachusetts General Hospital Cancer Center in Boston.

Among men randomly assigned in the phase 3 trial to receive apalutamide (Erleada), the 4-year OS rate was 72.1%, compared with 64.7% for patients assigned to placebo.

“This OS benefit for apalutamide was observed despite crossover of placebo patients to apalutamide, and higher rates of subsequent life-prolonging therapy in the placebo group,” he said at the European Society for Medical Oncology Congress.

Apalutamide was approved by the Food and Drug Administration in 2018 for treatment of patients with nonmetastatic CRPC who were on androgen deprivation therapy with a rapidly rising prostate-specific antigen level and no detectable distant metastases on conventional imaging.

That approval was based on the primary results from SPARTAN, which showed a median metastasis-free survival for patients taking apalutamide of 40.5 months, compared with 16.2 months for patients taking placebo.

The drug also recently received FDA approval for treatment of men with metastatic CRPC, based on results of the TITAN trial.

Overall survival

At the time of the primary analysis of SPARTAN for metastasis-free survival, the OS data were immature, with only 104 of 427 events required for the prespecified analysis.

At ESMO 2019, Dr. Smith presented results of the second interim survival analysis looking at the effects of apalutamide on OS, as well as time to chemotherapy, PFS2, and safety.

In the trial, men with nonmetastatic CRPC were randomized on a 2:1 basis to receive either apalutamide 240 mg daily (806 patients) or placebo (401) plus androgen deprivation therapy, either with gonadotropin-releasing hormone analogue therapy or with surgical castration.

At a median follow-up of 41 months, median OS was not reached in either arm. As noted before, the 4-year OS rate was higher in the apalutamide group, translating into a HR for death of 0.75. However, the P value of .0197 was higher than the prespecified O’Brien-Fleming boundary of 0.0121, which means that the study follow-up will continue per protocol, with the final analysis for overall survival planned after 427 deaths have occurred, Dr. Smith said.

The survival benefit with apalutamide either trended toward significance across all subgroups, with notable benefits in patients aged younger than 65 years, those with good performance status, prostate-specific antigen doubling time longer than 6 months, and those with locoregional disease status of N1 versus N0.

The secondary endpoint of time to chemotherapy initiation was not formally tested because OS did not reach statistical significance, but proportionally fewer patients on apalutamide had started cytotoxic chemotherapy at the time of the interim analysis (14% vs. 20% of patients on placebo). The median time to initiation of chemotherapy has not been reached in either trial arm, however.

The safety profile of the androgen receptor inhibitor was consistent with that seen in the primary PFS analysis, with any adverse event seen in 97.3% of patients versus 93.7% of patients on placebo, grade 3-4 adverse events in 53.1% versus 36.7%, any serious adverse event in 33.5% versus 24.9%, events leading to treatment discontinuation in 13.8% versus 7.3%, and fatal adverse events in 2.1 versus .5%.

“Of some note, discontinuation due to disease progression was 34% in the apalutamide group, compared to 74% in the placebo group,” Dr. Smith said.

“These results further support apalutamide as a standard-of-care option for men with high-risk, nonmetastatic CRPC,” he concluded.

PFS2 data ‘important’

Invited discussant Karim Fizazi, MD, PhD, from the Institut Gustave Roussy in Villejuif, France, acknowledged it’s too early to draw conclusions about OS, but added that the PFS2 data are important.

Neil Osterweil/MDedge News

The 45% reduction in risk of progression “is particularly important in this trial because abiraterone was provided as a potential salvage treatment in both arms. So in other words, in that trial they were almost truly comparing early AR [androgen receptor] targeting versus deferred AR targeting, at least in some patients, and it seems that [apalutamide] is making a difference in terms of second progression,” he said.

An unanswered question about the trial, however, is how active abiraterone was post apalutamide in the experimental, because there are data suggesting minimal efficacy in sequential therapy of AR-targeted agents, he added.

The SPARTAN trial was funded by Janssen. Dr. Smith disclosed an advisory role, research funding, and travel reimbursement for Janssen and others. Dr. Fizazi disclosed consulting for Janssen and others.

SOURCE: Smith MR et al. ESMO 2019, Abstract 843O

BARCELONA – The androgen receptor inhibitor apalutamide was associated with a 45% improvement in time to second progression in patients with nonmetastatic, castration-resistant prostate cancer as well as an overall survival edge, although the latter fell just short of statistical significance in an interim analysis of results from the SPARTAN trial.

Among 1,207 men with nonmetastatic castration-resistant prostate cancer (CRPC), those randomly assigned to apalutamide had significantly longer second progression-free survival (PFS2), an exploratory endpoint defined as the time of study entry to progression on subsequent treatment.

In all, 69% of patients on placebo and 40% of those on apalutamide went on to another life-prolonging therapy, usually abiraterone acetate (Zytiga) plus prednisone. The respective median PFS2s were 43.8 and 55.6 months, translating into a hazard ratio for second progression in the apalutamide group of 0.55 (P less than .0001).

Overall survival (OS) also trended toward a benefit for apalutamide, but the difference did not reach the prespecified boundary for significance in this planned interim analysis, reported Matthew R. Smith, MD, PhD, from the Massachusetts General Hospital Cancer Center in Boston.

Among men randomly assigned in the phase 3 trial to receive apalutamide (Erleada), the 4-year OS rate was 72.1%, compared with 64.7% for patients assigned to placebo.

“This OS benefit for apalutamide was observed despite crossover of placebo patients to apalutamide, and higher rates of subsequent life-prolonging therapy in the placebo group,” he said at the European Society for Medical Oncology Congress.

Apalutamide was approved by the Food and Drug Administration in 2018 for treatment of patients with nonmetastatic CRPC who were on androgen deprivation therapy with a rapidly rising prostate-specific antigen level and no detectable distant metastases on conventional imaging.

That approval was based on the primary results from SPARTAN, which showed a median metastasis-free survival for patients taking apalutamide of 40.5 months, compared with 16.2 months for patients taking placebo.

The drug also recently received FDA approval for treatment of men with metastatic CRPC, based on results of the TITAN trial.

Overall survival

At the time of the primary analysis of SPARTAN for metastasis-free survival, the OS data were immature, with only 104 of 427 events required for the prespecified analysis.

At ESMO 2019, Dr. Smith presented results of the second interim survival analysis looking at the effects of apalutamide on OS, as well as time to chemotherapy, PFS2, and safety.

In the trial, men with nonmetastatic CRPC were randomized on a 2:1 basis to receive either apalutamide 240 mg daily (806 patients) or placebo (401) plus androgen deprivation therapy, either with gonadotropin-releasing hormone analogue therapy or with surgical castration.

At a median follow-up of 41 months, median OS was not reached in either arm. As noted before, the 4-year OS rate was higher in the apalutamide group, translating into a HR for death of 0.75. However, the P value of .0197 was higher than the prespecified O’Brien-Fleming boundary of 0.0121, which means that the study follow-up will continue per protocol, with the final analysis for overall survival planned after 427 deaths have occurred, Dr. Smith said.

The survival benefit with apalutamide either trended toward significance across all subgroups, with notable benefits in patients aged younger than 65 years, those with good performance status, prostate-specific antigen doubling time longer than 6 months, and those with locoregional disease status of N1 versus N0.

The secondary endpoint of time to chemotherapy initiation was not formally tested because OS did not reach statistical significance, but proportionally fewer patients on apalutamide had started cytotoxic chemotherapy at the time of the interim analysis (14% vs. 20% of patients on placebo). The median time to initiation of chemotherapy has not been reached in either trial arm, however.

The safety profile of the androgen receptor inhibitor was consistent with that seen in the primary PFS analysis, with any adverse event seen in 97.3% of patients versus 93.7% of patients on placebo, grade 3-4 adverse events in 53.1% versus 36.7%, any serious adverse event in 33.5% versus 24.9%, events leading to treatment discontinuation in 13.8% versus 7.3%, and fatal adverse events in 2.1 versus .5%.

“Of some note, discontinuation due to disease progression was 34% in the apalutamide group, compared to 74% in the placebo group,” Dr. Smith said.

“These results further support apalutamide as a standard-of-care option for men with high-risk, nonmetastatic CRPC,” he concluded.

PFS2 data ‘important’

Invited discussant Karim Fizazi, MD, PhD, from the Institut Gustave Roussy in Villejuif, France, acknowledged it’s too early to draw conclusions about OS, but added that the PFS2 data are important.

Neil Osterweil/MDedge News

The 45% reduction in risk of progression “is particularly important in this trial because abiraterone was provided as a potential salvage treatment in both arms. So in other words, in that trial they were almost truly comparing early AR [androgen receptor] targeting versus deferred AR targeting, at least in some patients, and it seems that [apalutamide] is making a difference in terms of second progression,” he said.

An unanswered question about the trial, however, is how active abiraterone was post apalutamide in the experimental, because there are data suggesting minimal efficacy in sequential therapy of AR-targeted agents, he added.

The SPARTAN trial was funded by Janssen. Dr. Smith disclosed an advisory role, research funding, and travel reimbursement for Janssen and others. Dr. Fizazi disclosed consulting for Janssen and others.

SOURCE: Smith MR et al. ESMO 2019, Abstract 843O

BARCELONA – The androgen receptor inhibitor apalutamide was associated with a 45% improvement in time to second progression in patients with nonmetastatic, castration-resistant prostate cancer as well as an overall survival edge, although the latter fell just short of statistical significance in an interim analysis of results from the SPARTAN trial.

Among 1,207 men with nonmetastatic castration-resistant prostate cancer (CRPC), those randomly assigned to apalutamide had significantly longer second progression-free survival (PFS2), an exploratory endpoint defined as the time of study entry to progression on subsequent treatment.

In all, 69% of patients on placebo and 40% of those on apalutamide went on to another life-prolonging therapy, usually abiraterone acetate (Zytiga) plus prednisone. The respective median PFS2s were 43.8 and 55.6 months, translating into a hazard ratio for second progression in the apalutamide group of 0.55 (P less than .0001).

Overall survival (OS) also trended toward a benefit for apalutamide, but the difference did not reach the prespecified boundary for significance in this planned interim analysis, reported Matthew R. Smith, MD, PhD, from the Massachusetts General Hospital Cancer Center in Boston.

Among men randomly assigned in the phase 3 trial to receive apalutamide (Erleada), the 4-year OS rate was 72.1%, compared with 64.7% for patients assigned to placebo.

“This OS benefit for apalutamide was observed despite crossover of placebo patients to apalutamide, and higher rates of subsequent life-prolonging therapy in the placebo group,” he said at the European Society for Medical Oncology Congress.

Apalutamide was approved by the Food and Drug Administration in 2018 for treatment of patients with nonmetastatic CRPC who were on androgen deprivation therapy with a rapidly rising prostate-specific antigen level and no detectable distant metastases on conventional imaging.

That approval was based on the primary results from SPARTAN, which showed a median metastasis-free survival for patients taking apalutamide of 40.5 months, compared with 16.2 months for patients taking placebo.

The drug also recently received FDA approval for treatment of men with metastatic CRPC, based on results of the TITAN trial.

Overall survival

At the time of the primary analysis of SPARTAN for metastasis-free survival, the OS data were immature, with only 104 of 427 events required for the prespecified analysis.

At ESMO 2019, Dr. Smith presented results of the second interim survival analysis looking at the effects of apalutamide on OS, as well as time to chemotherapy, PFS2, and safety.

In the trial, men with nonmetastatic CRPC were randomized on a 2:1 basis to receive either apalutamide 240 mg daily (806 patients) or placebo (401) plus androgen deprivation therapy, either with gonadotropin-releasing hormone analogue therapy or with surgical castration.

At a median follow-up of 41 months, median OS was not reached in either arm. As noted before, the 4-year OS rate was higher in the apalutamide group, translating into a HR for death of 0.75. However, the P value of .0197 was higher than the prespecified O’Brien-Fleming boundary of 0.0121, which means that the study follow-up will continue per protocol, with the final analysis for overall survival planned after 427 deaths have occurred, Dr. Smith said.

The survival benefit with apalutamide either trended toward significance across all subgroups, with notable benefits in patients aged younger than 65 years, those with good performance status, prostate-specific antigen doubling time longer than 6 months, and those with locoregional disease status of N1 versus N0.

The secondary endpoint of time to chemotherapy initiation was not formally tested because OS did not reach statistical significance, but proportionally fewer patients on apalutamide had started cytotoxic chemotherapy at the time of the interim analysis (14% vs. 20% of patients on placebo). The median time to initiation of chemotherapy has not been reached in either trial arm, however.

The safety profile of the androgen receptor inhibitor was consistent with that seen in the primary PFS analysis, with any adverse event seen in 97.3% of patients versus 93.7% of patients on placebo, grade 3-4 adverse events in 53.1% versus 36.7%, any serious adverse event in 33.5% versus 24.9%, events leading to treatment discontinuation in 13.8% versus 7.3%, and fatal adverse events in 2.1 versus .5%.

“Of some note, discontinuation due to disease progression was 34% in the apalutamide group, compared to 74% in the placebo group,” Dr. Smith said.

“These results further support apalutamide as a standard-of-care option for men with high-risk, nonmetastatic CRPC,” he concluded.

PFS2 data ‘important’

Invited discussant Karim Fizazi, MD, PhD, from the Institut Gustave Roussy in Villejuif, France, acknowledged it’s too early to draw conclusions about OS, but added that the PFS2 data are important.

Neil Osterweil/MDedge News

The 45% reduction in risk of progression “is particularly important in this trial because abiraterone was provided as a potential salvage treatment in both arms. So in other words, in that trial they were almost truly comparing early AR [androgen receptor] targeting versus deferred AR targeting, at least in some patients, and it seems that [apalutamide] is making a difference in terms of second progression,” he said.

An unanswered question about the trial, however, is how active abiraterone was post apalutamide in the experimental, because there are data suggesting minimal efficacy in sequential therapy of AR-targeted agents, he added.

The SPARTAN trial was funded by Janssen. Dr. Smith disclosed an advisory role, research funding, and travel reimbursement for Janssen and others. Dr. Fizazi disclosed consulting for Janssen and others.

SOURCE: Smith MR et al. ESMO 2019, Abstract 843O

BARCELONA – Adding veliparib to frontline chemotherapy and maintenance therapy significantly extended progression-free survival in women with high-grade serous epithelial ovarian cancer (HGSC) in the phase 3 VELIA/GOG-3005 trial.

The benefit associated with the oral poly (ADP-ribose) polymerase (PARP) inhibitor was seen in all women with newly diagnosed HGSC included in the randomized, placebo-controlled trial, regardless of BRCA mutation (BRCAm) status or homologous recombination deficiency (HRD) status, Robert L. Coleman, MD, reported at the European Society for Medical Oncology Congress.

Of 1,140 patients enrolled in the international, multicenter trial, 26% had a BRCAm and 55% were HRD positive. In the intent-to-treat population, median progression-free survival (PFS) was 23.5 months in 382 patients who received carboplatin/paclitaxel (CP) plus veliparib followed by veliparib maintenance (veliparib group 1) versus 17.3 months in 375 patients treated with CP alone followed by placebo maintenance (the control group) (hazard ratio, 0.68), according to Dr. Coleman, professor and Ann Rife Cox Chair in Gynecology in the department of gynecologic oncology and reproductive medicine in the division of surgery at the University of Texas MD Anderson Cancer Center, Houston.

Among 200 patients with a deleterious BRCAm, including 108 in the veliparib 1 group and 92 in the control group, median PFS was 34.7 and 22.0 months, respectively (HR, 0.44), and among 421 patients with HRD and BRCAm, including 214 in the veliparib 1 group and 207 in the control group, median PFS was 31.9 versus 20.5 months (HR, 0.57).

In the non-HRD population of 249 patients (125 in the veliparib 1 arm and 124 in the control arm), median PFS was 15.0 and 11.5 months, respectively.

The PFS for an additional group of 383 patients treated with CP plus veliparib followed by placebo maintenance (veliparib group 2) didn’t differ significantly from either the veliparib 1 or the control group (HR, 1.07 vs. the control group in the intent-to-treat population), and the PFS rates were also similar for the BRCAm and HRD-positive patients in the veliparib 2 group and control group, he noted, explaining that the main focus of his presentation was the primary study endpoint of median PFS in the veliparib 1 versus control group.

The overall response rates at the end of treatment in the intent-to-treat populations were 84% in the veliparib 1 group, 74% in the control group, and 79% in the veliparib 2 group, Dr. Coleman said, adding that response rates were numerically higher in both veliparib-containing arms.

Additional analyses, including overall survival, will be reported at a future date, he noted.

Study participants were adults with a mean age of 62 years who had previously untreated stage III-IV HGSC. Treatment included six cycles of CP at 21-day intervals, with paclitaxel given either weekly or every 3 weeks following primary cytoreduction or neoadjuvant chemotherapy with interval cytoreduction. The veliparib dose when given with CP was 150 mg twice daily, and the veliparib maintenance dose was 400 mg twice daily for 30 cycles.

Relative CP dose intensities were similar between arms, and grade 3-4 adverse events were similar in the veliparib 1 and control groups during CP – with the exception of thrombocytopenia, which occurred in 27% and 8% of patients in the groups, respectively. During maintenance, the rates of any grade 3-4 adverse events were higher in the veliparib 1 group versus the control group (45% vs. 32%), but serious adverse event rates were similar in the groups (17% and 19%).

Observed toxicities were consistent with the known veliparib safety profile, Dr. Coleman said.

The findings are notable, as PARP inhibitors have proven effective in ovarian cancer, but their use in combination with chemotherapy has been challenging because of hematologic toxicity, he added, explaining, however, that veliparib has not only been shown to have single agent activity in germline BRCAm recurrent ovarian cancer patients, but also has binding characteristics – namely increased protein poly ADP-ribosylation and decreased PARP trapping – that could allow for its use in combination with chemotherapy.

VELIA/GOG-3005 is the first randomized trial designed to enroll only untreated patients with advanced-stage HGSC regardless of BRCA status, surgical management, or response to treatment, and the findings suggest that veliparib can be safely administered with CP and should be considered a new treatment option for women with newly diagnosed, advanced-stage serous ovarian cancer, he concluded.

In an ESMO press release, Ana Oaknin, MD, PhD, head of the gynecologic cancer program at Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, Barcelona, said that this trial, along with others such as the SOLO-1 trial, the PAOLA-1/ENGOT-Ov25 trial, and the PRIMA/ENGOT-OV26/GOG-3012 trial, which each looked at integrating PARP inhibitors into first-line treatment, represents “a milestone for patients.”

“After decades studying different chemotherapy approaches, it is the first time we have meaningfully prolonged progression free survival and hopefully we will improve long-term outcome,” she said.

The study was sponsored by AbbVie. Dr. Coleman and Dr. Oaknin reported relationships with numerous pharmaceutical companies.

SOURCE: Coleman RL et al. ESMO 2019, Abstract LBA3-PR.

BARCELONA – Adding veliparib to frontline chemotherapy and maintenance therapy significantly extended progression-free survival in women with high-grade serous epithelial ovarian cancer (HGSC) in the phase 3 VELIA/GOG-3005 trial.

The benefit associated with the oral poly (ADP-ribose) polymerase (PARP) inhibitor was seen in all women with newly diagnosed HGSC included in the randomized, placebo-controlled trial, regardless of BRCA mutation (BRCAm) status or homologous recombination deficiency (HRD) status, Robert L. Coleman, MD, reported at the European Society for Medical Oncology Congress.

Of 1,140 patients enrolled in the international, multicenter trial, 26% had a BRCAm and 55% were HRD positive. In the intent-to-treat population, median progression-free survival (PFS) was 23.5 months in 382 patients who received carboplatin/paclitaxel (CP) plus veliparib followed by veliparib maintenance (veliparib group 1) versus 17.3 months in 375 patients treated with CP alone followed by placebo maintenance (the control group) (hazard ratio, 0.68), according to Dr. Coleman, professor and Ann Rife Cox Chair in Gynecology in the department of gynecologic oncology and reproductive medicine in the division of surgery at the University of Texas MD Anderson Cancer Center, Houston.

Among 200 patients with a deleterious BRCAm, including 108 in the veliparib 1 group and 92 in the control group, median PFS was 34.7 and 22.0 months, respectively (HR, 0.44), and among 421 patients with HRD and BRCAm, including 214 in the veliparib 1 group and 207 in the control group, median PFS was 31.9 versus 20.5 months (HR, 0.57).

In the non-HRD population of 249 patients (125 in the veliparib 1 arm and 124 in the control arm), median PFS was 15.0 and 11.5 months, respectively.

The PFS for an additional group of 383 patients treated with CP plus veliparib followed by placebo maintenance (veliparib group 2) didn’t differ significantly from either the veliparib 1 or the control group (HR, 1.07 vs. the control group in the intent-to-treat population), and the PFS rates were also similar for the BRCAm and HRD-positive patients in the veliparib 2 group and control group, he noted, explaining that the main focus of his presentation was the primary study endpoint of median PFS in the veliparib 1 versus control group.

The overall response rates at the end of treatment in the intent-to-treat populations were 84% in the veliparib 1 group, 74% in the control group, and 79% in the veliparib 2 group, Dr. Coleman said, adding that response rates were numerically higher in both veliparib-containing arms.

Additional analyses, including overall survival, will be reported at a future date, he noted.

Study participants were adults with a mean age of 62 years who had previously untreated stage III-IV HGSC. Treatment included six cycles of CP at 21-day intervals, with paclitaxel given either weekly or every 3 weeks following primary cytoreduction or neoadjuvant chemotherapy with interval cytoreduction. The veliparib dose when given with CP was 150 mg twice daily, and the veliparib maintenance dose was 400 mg twice daily for 30 cycles.

Relative CP dose intensities were similar between arms, and grade 3-4 adverse events were similar in the veliparib 1 and control groups during CP – with the exception of thrombocytopenia, which occurred in 27% and 8% of patients in the groups, respectively. During maintenance, the rates of any grade 3-4 adverse events were higher in the veliparib 1 group versus the control group (45% vs. 32%), but serious adverse event rates were similar in the groups (17% and 19%).

Observed toxicities were consistent with the known veliparib safety profile, Dr. Coleman said.

The findings are notable, as PARP inhibitors have proven effective in ovarian cancer, but their use in combination with chemotherapy has been challenging because of hematologic toxicity, he added, explaining, however, that veliparib has not only been shown to have single agent activity in germline BRCAm recurrent ovarian cancer patients, but also has binding characteristics – namely increased protein poly ADP-ribosylation and decreased PARP trapping – that could allow for its use in combination with chemotherapy.

VELIA/GOG-3005 is the first randomized trial designed to enroll only untreated patients with advanced-stage HGSC regardless of BRCA status, surgical management, or response to treatment, and the findings suggest that veliparib can be safely administered with CP and should be considered a new treatment option for women with newly diagnosed, advanced-stage serous ovarian cancer, he concluded.

In an ESMO press release, Ana Oaknin, MD, PhD, head of the gynecologic cancer program at Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, Barcelona, said that this trial, along with others such as the SOLO-1 trial, the PAOLA-1/ENGOT-Ov25 trial, and the PRIMA/ENGOT-OV26/GOG-3012 trial, which each looked at integrating PARP inhibitors into first-line treatment, represents “a milestone for patients.”

“After decades studying different chemotherapy approaches, it is the first time we have meaningfully prolonged progression free survival and hopefully we will improve long-term outcome,” she said.

The study was sponsored by AbbVie. Dr. Coleman and Dr. Oaknin reported relationships with numerous pharmaceutical companies.

SOURCE: Coleman RL et al. ESMO 2019, Abstract LBA3-PR.

BARCELONA – Adding veliparib to frontline chemotherapy and maintenance therapy significantly extended progression-free survival in women with high-grade serous epithelial ovarian cancer (HGSC) in the phase 3 VELIA/GOG-3005 trial.

The benefit associated with the oral poly (ADP-ribose) polymerase (PARP) inhibitor was seen in all women with newly diagnosed HGSC included in the randomized, placebo-controlled trial, regardless of BRCA mutation (BRCAm) status or homologous recombination deficiency (HRD) status, Robert L. Coleman, MD, reported at the European Society for Medical Oncology Congress.

Of 1,140 patients enrolled in the international, multicenter trial, 26% had a BRCAm and 55% were HRD positive. In the intent-to-treat population, median progression-free survival (PFS) was 23.5 months in 382 patients who received carboplatin/paclitaxel (CP) plus veliparib followed by veliparib maintenance (veliparib group 1) versus 17.3 months in 375 patients treated with CP alone followed by placebo maintenance (the control group) (hazard ratio, 0.68), according to Dr. Coleman, professor and Ann Rife Cox Chair in Gynecology in the department of gynecologic oncology and reproductive medicine in the division of surgery at the University of Texas MD Anderson Cancer Center, Houston.

Among 200 patients with a deleterious BRCAm, including 108 in the veliparib 1 group and 92 in the control group, median PFS was 34.7 and 22.0 months, respectively (HR, 0.44), and among 421 patients with HRD and BRCAm, including 214 in the veliparib 1 group and 207 in the control group, median PFS was 31.9 versus 20.5 months (HR, 0.57).

In the non-HRD population of 249 patients (125 in the veliparib 1 arm and 124 in the control arm), median PFS was 15.0 and 11.5 months, respectively.

The PFS for an additional group of 383 patients treated with CP plus veliparib followed by placebo maintenance (veliparib group 2) didn’t differ significantly from either the veliparib 1 or the control group (HR, 1.07 vs. the control group in the intent-to-treat population), and the PFS rates were also similar for the BRCAm and HRD-positive patients in the veliparib 2 group and control group, he noted, explaining that the main focus of his presentation was the primary study endpoint of median PFS in the veliparib 1 versus control group.

The overall response rates at the end of treatment in the intent-to-treat populations were 84% in the veliparib 1 group, 74% in the control group, and 79% in the veliparib 2 group, Dr. Coleman said, adding that response rates were numerically higher in both veliparib-containing arms.

Additional analyses, including overall survival, will be reported at a future date, he noted.

Study participants were adults with a mean age of 62 years who had previously untreated stage III-IV HGSC. Treatment included six cycles of CP at 21-day intervals, with paclitaxel given either weekly or every 3 weeks following primary cytoreduction or neoadjuvant chemotherapy with interval cytoreduction. The veliparib dose when given with CP was 150 mg twice daily, and the veliparib maintenance dose was 400 mg twice daily for 30 cycles.

Relative CP dose intensities were similar between arms, and grade 3-4 adverse events were similar in the veliparib 1 and control groups during CP – with the exception of thrombocytopenia, which occurred in 27% and 8% of patients in the groups, respectively. During maintenance, the rates of any grade 3-4 adverse events were higher in the veliparib 1 group versus the control group (45% vs. 32%), but serious adverse event rates were similar in the groups (17% and 19%).

Observed toxicities were consistent with the known veliparib safety profile, Dr. Coleman said.

The findings are notable, as PARP inhibitors have proven effective in ovarian cancer, but their use in combination with chemotherapy has been challenging because of hematologic toxicity, he added, explaining, however, that veliparib has not only been shown to have single agent activity in germline BRCAm recurrent ovarian cancer patients, but also has binding characteristics – namely increased protein poly ADP-ribosylation and decreased PARP trapping – that could allow for its use in combination with chemotherapy.

VELIA/GOG-3005 is the first randomized trial designed to enroll only untreated patients with advanced-stage HGSC regardless of BRCA status, surgical management, or response to treatment, and the findings suggest that veliparib can be safely administered with CP and should be considered a new treatment option for women with newly diagnosed, advanced-stage serous ovarian cancer, he concluded.

In an ESMO press release, Ana Oaknin, MD, PhD, head of the gynecologic cancer program at Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, Barcelona, said that this trial, along with others such as the SOLO-1 trial, the PAOLA-1/ENGOT-Ov25 trial, and the PRIMA/ENGOT-OV26/GOG-3012 trial, which each looked at integrating PARP inhibitors into first-line treatment, represents “a milestone for patients.”

“After decades studying different chemotherapy approaches, it is the first time we have meaningfully prolonged progression free survival and hopefully we will improve long-term outcome,” she said.

The study was sponsored by AbbVie. Dr. Coleman and Dr. Oaknin reported relationships with numerous pharmaceutical companies.

SOURCE: Coleman RL et al. ESMO 2019, Abstract LBA3-PR.

BARCELONA – Checkpoint inhibition with nivolumab led to a clinically meaningful, but not statistically significant, improvement in overall survival, compared with sorafenib for the first-line treatment of advanced hepatocellular carcinoma (HCC) in the phase 3 CheckMate 459 study.

Median overall survival (OS), the primary study endpoint, was 16.4 months in 371 patients randomized to receive the programmed death-1 (PD-1) inhibitor nivolumab, and 14.7 months in 372 patients who received the tyrosine kinase inhibitor sorafenib – the current standard for advanced HCC therapy (hazard ratio, 0.85; P = .0752), Thomas Yau, MD, reported at the European Society for Medical Oncology Congress.

The median OS seen with nivolumab is the longest ever reported in a first-line phase 3 HCC trial, but the difference between the arms did not meet the predefined threshold for statistical significance (HR, 0.84 and P = .419). However, clinical benefit was observed across predefined subgroups of patients, including those with hepatitis infection and those with vascular invasion and/or extrahepatic spread, said Dr. Yau of the University of Hong Kong.

The overall response rates (ORR) were 15% and 7% in the nivolumab and sorafenib arms, with 14 and 5 patients in each group experiencing a complete response (CR), respectively, he said.

At 12 and 24 months, the OS rates in the groups were 59.7% vs. 55.1%, and 36.5% vs. 33.1%, respectively. Median progression-free survival (PFS) was similar in the groups, at 3.7 and 3.8 months, respectively, and analysis by baseline tumor programmed death-ligand 1 (PD-L1) expression showed that ORR was 28% vs. 9% with PD-L1 expression of 1% or greater in the groups, respectively, and 12% vs. 7% among those with PD-L1 expression less than 1%.

Additionally, nivolumab had a more tolerable safety profile; grade 3/4 treatment-related adverse events were reported in 22% and 49% of patients in the groups, respectively, and led to discontinuation in 4% and 8%, respectively. No new safety signals were observed, Dr. Yau said.

Participants in the multicenter study were systemic therapy–naive adults with advanced disease. They were randomized 1:1 to receive intravenous nivolumab at a dose of 240 mg every 2 weeks or oral sorafenib at a dose of 400 mg twice daily, and were followed for at least 22.8 months.

“These results are important in the treatment of hepatocellular carcinoma, as there have been no significant advances over sorafenib in the first-line setting in more than a decade,” Dr. Yau said in an ESMO press release. “HCC is often diagnosed in the advanced stage, where effective treatment options are limited. The encouraging efficacy and favorable safety profile seen with nivolumab demonstrates the potential benefit of immunotherapy as a first-line treatment for patients with this aggressive cancer.”

He further noted that the OS benefit seen in this study is “particularly impactful considering the high frequency of subsequent use of systemic therapy, including immunotherapy, in the sorafenib arm,” and that the OS impact is bolstered by patient-reported outcomes suggesting improved quality of life in the nivolumab arm.

Nevertheless, the fact that CheckMate 459 did not meet its primary OS endpoint means the findings are unlikely to change the current standard of care, according to Angela Lamarca, MD, PhD, consultant medical oncologist and honorary senior lecturer at the Christie NHS Foundation Trust, University of Manchester (England).

She added, however, that the findings do underscore a potential role for immunotherapy in the first-line treatment of advanced HCC and noted that the clinically meaningful improvement in response rates with nivolumab, along with the checkpoint inhibitor’s favorable safety profile in this study, raise the possibility of its selection in this setting.

“In a hypothetical scenario in which both options ... were available and reimbursed, and if quality of life was shown to be better with nivolumab ... clinicians and patients may favor the option with a more tolerable safety profile,” she said in the press release.

She added, however, that at this point conclusions should be made cautiously and the high cost of immunotherapy should be considered.

Dr. Lamarca also highlighted the finding that patients with high PD-L1 expression had an increased response rate only in the nivolumab arm. This suggests a potential role for PD-L1 expression as a predictive biomarker in advanced HCC, but more research is needed to better understand how to select patients for immunotherapy, she said, adding that the lack of a reliable biomarker may have contributed to the study’s failure to show improved OS with nivolumab.

“In addition, the study design with a ‘high’ predefined threshold of statistical significance is generating confusion in the community, with potentially beneficial therapies generating statistically negative studies,” she noted.

CheckMate 459 was funded by Bristol-Myers Squibb. Dr. Yau is an advisor and/or consultant to Bristol-Myers Squibb, and reported honoraria from the company to his institution. Dr. Lamarca reported honoraria, consultation fees, travel funding, and/or education funding from Eisai, Nutricia, Ipsen, Pfizer, Bayer, AAA, Sirtex, Delcath, Novartis, and Mylan, as well as participation in company-sponsored speaker bureaus for Pfizer, Ipsen, Merck, and Incyte.

SOURCE: Yau T et al. ESMO 2019, Abstract LBA38-PR
 

BARCELONA – Checkpoint inhibition with nivolumab led to a clinically meaningful, but not statistically significant, improvement in overall survival, compared with sorafenib for the first-line treatment of advanced hepatocellular carcinoma (HCC) in the phase 3 CheckMate 459 study.

Median overall survival (OS), the primary study endpoint, was 16.4 months in 371 patients randomized to receive the programmed death-1 (PD-1) inhibitor nivolumab, and 14.7 months in 372 patients who received the tyrosine kinase inhibitor sorafenib – the current standard for advanced HCC therapy (hazard ratio, 0.85; P = .0752), Thomas Yau, MD, reported at the European Society for Medical Oncology Congress.

The median OS seen with nivolumab is the longest ever reported in a first-line phase 3 HCC trial, but the difference between the arms did not meet the predefined threshold for statistical significance (HR, 0.84 and P = .419). However, clinical benefit was observed across predefined subgroups of patients, including those with hepatitis infection and those with vascular invasion and/or extrahepatic spread, said Dr. Yau of the University of Hong Kong.

The overall response rates (ORR) were 15% and 7% in the nivolumab and sorafenib arms, with 14 and 5 patients in each group experiencing a complete response (CR), respectively, he said.

At 12 and 24 months, the OS rates in the groups were 59.7% vs. 55.1%, and 36.5% vs. 33.1%, respectively. Median progression-free survival (PFS) was similar in the groups, at 3.7 and 3.8 months, respectively, and analysis by baseline tumor programmed death-ligand 1 (PD-L1) expression showed that ORR was 28% vs. 9% with PD-L1 expression of 1% or greater in the groups, respectively, and 12% vs. 7% among those with PD-L1 expression less than 1%.

Additionally, nivolumab had a more tolerable safety profile; grade 3/4 treatment-related adverse events were reported in 22% and 49% of patients in the groups, respectively, and led to discontinuation in 4% and 8%, respectively. No new safety signals were observed, Dr. Yau said.

Participants in the multicenter study were systemic therapy–naive adults with advanced disease. They were randomized 1:1 to receive intravenous nivolumab at a dose of 240 mg every 2 weeks or oral sorafenib at a dose of 400 mg twice daily, and were followed for at least 22.8 months.

“These results are important in the treatment of hepatocellular carcinoma, as there have been no significant advances over sorafenib in the first-line setting in more than a decade,” Dr. Yau said in an ESMO press release. “HCC is often diagnosed in the advanced stage, where effective treatment options are limited. The encouraging efficacy and favorable safety profile seen with nivolumab demonstrates the potential benefit of immunotherapy as a first-line treatment for patients with this aggressive cancer.”

He further noted that the OS benefit seen in this study is “particularly impactful considering the high frequency of subsequent use of systemic therapy, including immunotherapy, in the sorafenib arm,” and that the OS impact is bolstered by patient-reported outcomes suggesting improved quality of life in the nivolumab arm.

Nevertheless, the fact that CheckMate 459 did not meet its primary OS endpoint means the findings are unlikely to change the current standard of care, according to Angela Lamarca, MD, PhD, consultant medical oncologist and honorary senior lecturer at the Christie NHS Foundation Trust, University of Manchester (England).

She added, however, that the findings do underscore a potential role for immunotherapy in the first-line treatment of advanced HCC and noted that the clinically meaningful improvement in response rates with nivolumab, along with the checkpoint inhibitor’s favorable safety profile in this study, raise the possibility of its selection in this setting.

“In a hypothetical scenario in which both options ... were available and reimbursed, and if quality of life was shown to be better with nivolumab ... clinicians and patients may favor the option with a more tolerable safety profile,” she said in the press release.

She added, however, that at this point conclusions should be made cautiously and the high cost of immunotherapy should be considered.

Dr. Lamarca also highlighted the finding that patients with high PD-L1 expression had an increased response rate only in the nivolumab arm. This suggests a potential role for PD-L1 expression as a predictive biomarker in advanced HCC, but more research is needed to better understand how to select patients for immunotherapy, she said, adding that the lack of a reliable biomarker may have contributed to the study’s failure to show improved OS with nivolumab.

“In addition, the study design with a ‘high’ predefined threshold of statistical significance is generating confusion in the community, with potentially beneficial therapies generating statistically negative studies,” she noted.

CheckMate 459 was funded by Bristol-Myers Squibb. Dr. Yau is an advisor and/or consultant to Bristol-Myers Squibb, and reported honoraria from the company to his institution. Dr. Lamarca reported honoraria, consultation fees, travel funding, and/or education funding from Eisai, Nutricia, Ipsen, Pfizer, Bayer, AAA, Sirtex, Delcath, Novartis, and Mylan, as well as participation in company-sponsored speaker bureaus for Pfizer, Ipsen, Merck, and Incyte.

SOURCE: Yau T et al. ESMO 2019, Abstract LBA38-PR
 

BARCELONA – Checkpoint inhibition with nivolumab led to a clinically meaningful, but not statistically significant, improvement in overall survival, compared with sorafenib for the first-line treatment of advanced hepatocellular carcinoma (HCC) in the phase 3 CheckMate 459 study.

Median overall survival (OS), the primary study endpoint, was 16.4 months in 371 patients randomized to receive the programmed death-1 (PD-1) inhibitor nivolumab, and 14.7 months in 372 patients who received the tyrosine kinase inhibitor sorafenib – the current standard for advanced HCC therapy (hazard ratio, 0.85; P = .0752), Thomas Yau, MD, reported at the European Society for Medical Oncology Congress.

The median OS seen with nivolumab is the longest ever reported in a first-line phase 3 HCC trial, but the difference between the arms did not meet the predefined threshold for statistical significance (HR, 0.84 and P = .419). However, clinical benefit was observed across predefined subgroups of patients, including those with hepatitis infection and those with vascular invasion and/or extrahepatic spread, said Dr. Yau of the University of Hong Kong.

The overall response rates (ORR) were 15% and 7% in the nivolumab and sorafenib arms, with 14 and 5 patients in each group experiencing a complete response (CR), respectively, he said.

At 12 and 24 months, the OS rates in the groups were 59.7% vs. 55.1%, and 36.5% vs. 33.1%, respectively. Median progression-free survival (PFS) was similar in the groups, at 3.7 and 3.8 months, respectively, and analysis by baseline tumor programmed death-ligand 1 (PD-L1) expression showed that ORR was 28% vs. 9% with PD-L1 expression of 1% or greater in the groups, respectively, and 12% vs. 7% among those with PD-L1 expression less than 1%.

Additionally, nivolumab had a more tolerable safety profile; grade 3/4 treatment-related adverse events were reported in 22% and 49% of patients in the groups, respectively, and led to discontinuation in 4% and 8%, respectively. No new safety signals were observed, Dr. Yau said.

Participants in the multicenter study were systemic therapy–naive adults with advanced disease. They were randomized 1:1 to receive intravenous nivolumab at a dose of 240 mg every 2 weeks or oral sorafenib at a dose of 400 mg twice daily, and were followed for at least 22.8 months.

“These results are important in the treatment of hepatocellular carcinoma, as there have been no significant advances over sorafenib in the first-line setting in more than a decade,” Dr. Yau said in an ESMO press release. “HCC is often diagnosed in the advanced stage, where effective treatment options are limited. The encouraging efficacy and favorable safety profile seen with nivolumab demonstrates the potential benefit of immunotherapy as a first-line treatment for patients with this aggressive cancer.”

He further noted that the OS benefit seen in this study is “particularly impactful considering the high frequency of subsequent use of systemic therapy, including immunotherapy, in the sorafenib arm,” and that the OS impact is bolstered by patient-reported outcomes suggesting improved quality of life in the nivolumab arm.

Nevertheless, the fact that CheckMate 459 did not meet its primary OS endpoint means the findings are unlikely to change the current standard of care, according to Angela Lamarca, MD, PhD, consultant medical oncologist and honorary senior lecturer at the Christie NHS Foundation Trust, University of Manchester (England).

She added, however, that the findings do underscore a potential role for immunotherapy in the first-line treatment of advanced HCC and noted that the clinically meaningful improvement in response rates with nivolumab, along with the checkpoint inhibitor’s favorable safety profile in this study, raise the possibility of its selection in this setting.

“In a hypothetical scenario in which both options ... were available and reimbursed, and if quality of life was shown to be better with nivolumab ... clinicians and patients may favor the option with a more tolerable safety profile,” she said in the press release.

She added, however, that at this point conclusions should be made cautiously and the high cost of immunotherapy should be considered.

Dr. Lamarca also highlighted the finding that patients with high PD-L1 expression had an increased response rate only in the nivolumab arm. This suggests a potential role for PD-L1 expression as a predictive biomarker in advanced HCC, but more research is needed to better understand how to select patients for immunotherapy, she said, adding that the lack of a reliable biomarker may have contributed to the study’s failure to show improved OS with nivolumab.

“In addition, the study design with a ‘high’ predefined threshold of statistical significance is generating confusion in the community, with potentially beneficial therapies generating statistically negative studies,” she noted.

CheckMate 459 was funded by Bristol-Myers Squibb. Dr. Yau is an advisor and/or consultant to Bristol-Myers Squibb, and reported honoraria from the company to his institution. Dr. Lamarca reported honoraria, consultation fees, travel funding, and/or education funding from Eisai, Nutricia, Ipsen, Pfizer, Bayer, AAA, Sirtex, Delcath, Novartis, and Mylan, as well as participation in company-sponsored speaker bureaus for Pfizer, Ipsen, Merck, and Incyte.

SOURCE: Yau T et al. ESMO 2019, Abstract LBA38-PR
 

BARCELONA – Adding the immune checkpoint inhibitor atezolizumab (Tecentriq) to standard platinum-based chemotherapy was associated with a small but statistically significant progression-free survival benefit for patients with previously untreated metastatic urothelial carcinoma, investigators in the IMvigor130 trial found.

Neil Osterweil/MDedge News

Among 1,213 patients with newly diagnosed metastatic urothelial carcinoma assigned to receive either atezolizumab monotherapy or chemotherapy with a platinum compound and gemcitabine plus either atezolizumab or placebo, the median progression-free survival (PFS) at a median follow-up of 11.8 months was 8.2 months with atezolizumab/chemotherapy, compared with 6.3 months with chemotherapy plus placebo, reported Enrique Grande, MD, of MD Anderson Cancer Center Madrid.

“IMvigor130 is the first immune checkpoint inhibitor study to demonstrate an improvement in progression-free survival over the standard of care in first-line metastatic urothelial carcinoma. At this interim analysis, we observed a clinically meaningful improvement in the overall survival for the combination of atezolizumab plus chemotherapy that did not meet the prespecified interim boundary for significance,” he said at the European Society for Medical Oncology Congress.

Median overall survival (OS) at the interim analysis was 16.0 months in the atezolizumab arm, vs. 13.4 months in the placebo arm, translating into a hazard ratio (HR) of 0.83 trending in favor of the combination. But as noted by Dr. Grande, the P value was .027, which did not reach the interim efficacy boundary of .007.

IMvigor130 investigators enrolled patients with locally advanced metastatic urothelial carcinoma with no prior systemic therapy in the metastatic setting who had good performance status (ECOG 2 or less) and were eligible for chemotherapy with either cisplatin or carboplatin plus gemcitabine.

The patients were stratified by programmed death ligand-1 (PD-L1) status, prognostic (Bajorin) risk factor scores, and investigator choice of cisplatin or carboplatin, and then randomized to either atezolizumab plus chemotherapy, atezolizumab monotherapy, or placebo plus chemotherapy.

As noted, the co-primary endpoint of PFS in the chemotherapy arms in the intention-to-treat population was statistically significant at the preplanned interim analysis, but the other primary endpoint of OS had not reached significance.

At the time of the data cutoff in May 2019, the stratified HR for progression with atezolizumab was 0.82 (P = .007).

An analysis by subgroup showed either significant benefit or a trend favoring atezolizumab across all stratification factors, Dr. Grande said.

A hierarchical analysis of atezolizumab monotherapy vs. chemotherapy in the placebo-control arm showed a median OS of 15.7 vs. 13.1 months, respectively, with a hazard ratio of 1.02 (nonsignificant).

The benefit of atezolizumab appeared to be almost entirely among patients whose tumors had higher levels of PD-L1 expression according to immunohistochemistry (IC). The interim OS among patients with PD-L1 IC0/1 was a median of 13.5 months with atezolizumab vs. 12.9 months with chemotherapy alone, with an unstratified HR of 1.07 (nonsignificant). In contrast, among patients with PD-L1 IC2/3 status, the median OS was not reached for patients in the atezolizumab arm, vs. 17.8 months in the chemotherapy alone arm, for a stratified HR of 0.68, although this too did not reach statistical significance.

Responses were similar between the two chemotherapy arms, with an overall response rate (ORR) of 47% with atezolizumab added, vs. 44% with placebo added. The complete response (CR) rates were 13% and 7%, respectively. The ORR in the monotherapy arm was 23%, consisting of 6% complete and 17% partial responses.

Grade 3 or 4 treatment-related adverse events occurred in 81% of patients in each chemotherapy arm, compared with 15% in the atezolizumab monotherapy arm. Nine patients in the atezolizumab/chemotherapy arm died from a treatment-related cause, compared with four in the chemotherapy alone arm, and three in the atezolizumab monotherapy arm.

Adverse events leading to treatment discontinuation occurred in one-fourth of patients in each chemotherapy-containing arm, vs. less than 1% of patients in the monotherapy arm.

“The results from the IMvigor130 trial support the use of atezolizumab in combination with chemotherapy as an important new treatment option for patients with untreated metastatic urothelial carcinoma,” Dr. Grande concluded.

But invited discussant Thomas Powles, MD, of Barts Cancer Institute in London, cautioned that more data are needed to conclude that the addition of atezolizumab should become a standard of care.

Neil Osterweil/MDedge News

“Does this change practice? Well, the for and against: significant delay in PFS, but how meaningful is that? OS trending the right way, but not significant yet. CR rates, yes with 13% CRs, but response rates weren’t very different from one another, and as response rates are similar, it’s hard to argue that the two are synergistic together, for example,” he said.

He added that the adverse event profiles “actually are very acceptable to me, and I’m really looking forward to the quality-of-life data.”

The IMvigor130 study is sponsored by F. Hoffman-La Roche. Dr. Grande disclosed honoraria and research grants from Roche and others. Dr. Powles disclosed research funding, honoraria, and travel costs from Roche and others.
 

SOURCE: Grande E et al. ESMO 2019. Abstract LBA14_PR.

BARCELONA – Adding the immune checkpoint inhibitor atezolizumab (Tecentriq) to standard platinum-based chemotherapy was associated with a small but statistically significant progression-free survival benefit for patients with previously untreated metastatic urothelial carcinoma, investigators in the IMvigor130 trial found.

Neil Osterweil/MDedge News

Among 1,213 patients with newly diagnosed metastatic urothelial carcinoma assigned to receive either atezolizumab monotherapy or chemotherapy with a platinum compound and gemcitabine plus either atezolizumab or placebo, the median progression-free survival (PFS) at a median follow-up of 11.8 months was 8.2 months with atezolizumab/chemotherapy, compared with 6.3 months with chemotherapy plus placebo, reported Enrique Grande, MD, of MD Anderson Cancer Center Madrid.

“IMvigor130 is the first immune checkpoint inhibitor study to demonstrate an improvement in progression-free survival over the standard of care in first-line metastatic urothelial carcinoma. At this interim analysis, we observed a clinically meaningful improvement in the overall survival for the combination of atezolizumab plus chemotherapy that did not meet the prespecified interim boundary for significance,” he said at the European Society for Medical Oncology Congress.

Median overall survival (OS) at the interim analysis was 16.0 months in the atezolizumab arm, vs. 13.4 months in the placebo arm, translating into a hazard ratio (HR) of 0.83 trending in favor of the combination. But as noted by Dr. Grande, the P value was .027, which did not reach the interim efficacy boundary of .007.

IMvigor130 investigators enrolled patients with locally advanced metastatic urothelial carcinoma with no prior systemic therapy in the metastatic setting who had good performance status (ECOG 2 or less) and were eligible for chemotherapy with either cisplatin or carboplatin plus gemcitabine.

The patients were stratified by programmed death ligand-1 (PD-L1) status, prognostic (Bajorin) risk factor scores, and investigator choice of cisplatin or carboplatin, and then randomized to either atezolizumab plus chemotherapy, atezolizumab monotherapy, or placebo plus chemotherapy.

As noted, the co-primary endpoint of PFS in the chemotherapy arms in the intention-to-treat population was statistically significant at the preplanned interim analysis, but the other primary endpoint of OS had not reached significance.

At the time of the data cutoff in May 2019, the stratified HR for progression with atezolizumab was 0.82 (P = .007).

An analysis by subgroup showed either significant benefit or a trend favoring atezolizumab across all stratification factors, Dr. Grande said.

A hierarchical analysis of atezolizumab monotherapy vs. chemotherapy in the placebo-control arm showed a median OS of 15.7 vs. 13.1 months, respectively, with a hazard ratio of 1.02 (nonsignificant).

The benefit of atezolizumab appeared to be almost entirely among patients whose tumors had higher levels of PD-L1 expression according to immunohistochemistry (IC). The interim OS among patients with PD-L1 IC0/1 was a median of 13.5 months with atezolizumab vs. 12.9 months with chemotherapy alone, with an unstratified HR of 1.07 (nonsignificant). In contrast, among patients with PD-L1 IC2/3 status, the median OS was not reached for patients in the atezolizumab arm, vs. 17.8 months in the chemotherapy alone arm, for a stratified HR of 0.68, although this too did not reach statistical significance.

Responses were similar between the two chemotherapy arms, with an overall response rate (ORR) of 47% with atezolizumab added, vs. 44% with placebo added. The complete response (CR) rates were 13% and 7%, respectively. The ORR in the monotherapy arm was 23%, consisting of 6% complete and 17% partial responses.

Grade 3 or 4 treatment-related adverse events occurred in 81% of patients in each chemotherapy arm, compared with 15% in the atezolizumab monotherapy arm. Nine patients in the atezolizumab/chemotherapy arm died from a treatment-related cause, compared with four in the chemotherapy alone arm, and three in the atezolizumab monotherapy arm.

Adverse events leading to treatment discontinuation occurred in one-fourth of patients in each chemotherapy-containing arm, vs. less than 1% of patients in the monotherapy arm.

“The results from the IMvigor130 trial support the use of atezolizumab in combination with chemotherapy as an important new treatment option for patients with untreated metastatic urothelial carcinoma,” Dr. Grande concluded.

But invited discussant Thomas Powles, MD, of Barts Cancer Institute in London, cautioned that more data are needed to conclude that the addition of atezolizumab should become a standard of care.

Neil Osterweil/MDedge News

“Does this change practice? Well, the for and against: significant delay in PFS, but how meaningful is that? OS trending the right way, but not significant yet. CR rates, yes with 13% CRs, but response rates weren’t very different from one another, and as response rates are similar, it’s hard to argue that the two are synergistic together, for example,” he said.

He added that the adverse event profiles “actually are very acceptable to me, and I’m really looking forward to the quality-of-life data.”

The IMvigor130 study is sponsored by F. Hoffman-La Roche. Dr. Grande disclosed honoraria and research grants from Roche and others. Dr. Powles disclosed research funding, honoraria, and travel costs from Roche and others.
 

SOURCE: Grande E et al. ESMO 2019. Abstract LBA14_PR.

BARCELONA – Adding the immune checkpoint inhibitor atezolizumab (Tecentriq) to standard platinum-based chemotherapy was associated with a small but statistically significant progression-free survival benefit for patients with previously untreated metastatic urothelial carcinoma, investigators in the IMvigor130 trial found.

Neil Osterweil/MDedge News

Among 1,213 patients with newly diagnosed metastatic urothelial carcinoma assigned to receive either atezolizumab monotherapy or chemotherapy with a platinum compound and gemcitabine plus either atezolizumab or placebo, the median progression-free survival (PFS) at a median follow-up of 11.8 months was 8.2 months with atezolizumab/chemotherapy, compared with 6.3 months with chemotherapy plus placebo, reported Enrique Grande, MD, of MD Anderson Cancer Center Madrid.

“IMvigor130 is the first immune checkpoint inhibitor study to demonstrate an improvement in progression-free survival over the standard of care in first-line metastatic urothelial carcinoma. At this interim analysis, we observed a clinically meaningful improvement in the overall survival for the combination of atezolizumab plus chemotherapy that did not meet the prespecified interim boundary for significance,” he said at the European Society for Medical Oncology Congress.

Median overall survival (OS) at the interim analysis was 16.0 months in the atezolizumab arm, vs. 13.4 months in the placebo arm, translating into a hazard ratio (HR) of 0.83 trending in favor of the combination. But as noted by Dr. Grande, the P value was .027, which did not reach the interim efficacy boundary of .007.

IMvigor130 investigators enrolled patients with locally advanced metastatic urothelial carcinoma with no prior systemic therapy in the metastatic setting who had good performance status (ECOG 2 or less) and were eligible for chemotherapy with either cisplatin or carboplatin plus gemcitabine.

The patients were stratified by programmed death ligand-1 (PD-L1) status, prognostic (Bajorin) risk factor scores, and investigator choice of cisplatin or carboplatin, and then randomized to either atezolizumab plus chemotherapy, atezolizumab monotherapy, or placebo plus chemotherapy.

As noted, the co-primary endpoint of PFS in the chemotherapy arms in the intention-to-treat population was statistically significant at the preplanned interim analysis, but the other primary endpoint of OS had not reached significance.

At the time of the data cutoff in May 2019, the stratified HR for progression with atezolizumab was 0.82 (P = .007).

An analysis by subgroup showed either significant benefit or a trend favoring atezolizumab across all stratification factors, Dr. Grande said.

A hierarchical analysis of atezolizumab monotherapy vs. chemotherapy in the placebo-control arm showed a median OS of 15.7 vs. 13.1 months, respectively, with a hazard ratio of 1.02 (nonsignificant).

The benefit of atezolizumab appeared to be almost entirely among patients whose tumors had higher levels of PD-L1 expression according to immunohistochemistry (IC). The interim OS among patients with PD-L1 IC0/1 was a median of 13.5 months with atezolizumab vs. 12.9 months with chemotherapy alone, with an unstratified HR of 1.07 (nonsignificant). In contrast, among patients with PD-L1 IC2/3 status, the median OS was not reached for patients in the atezolizumab arm, vs. 17.8 months in the chemotherapy alone arm, for a stratified HR of 0.68, although this too did not reach statistical significance.

Responses were similar between the two chemotherapy arms, with an overall response rate (ORR) of 47% with atezolizumab added, vs. 44% with placebo added. The complete response (CR) rates were 13% and 7%, respectively. The ORR in the monotherapy arm was 23%, consisting of 6% complete and 17% partial responses.

Grade 3 or 4 treatment-related adverse events occurred in 81% of patients in each chemotherapy arm, compared with 15% in the atezolizumab monotherapy arm. Nine patients in the atezolizumab/chemotherapy arm died from a treatment-related cause, compared with four in the chemotherapy alone arm, and three in the atezolizumab monotherapy arm.

Adverse events leading to treatment discontinuation occurred in one-fourth of patients in each chemotherapy-containing arm, vs. less than 1% of patients in the monotherapy arm.

“The results from the IMvigor130 trial support the use of atezolizumab in combination with chemotherapy as an important new treatment option for patients with untreated metastatic urothelial carcinoma,” Dr. Grande concluded.

But invited discussant Thomas Powles, MD, of Barts Cancer Institute in London, cautioned that more data are needed to conclude that the addition of atezolizumab should become a standard of care.

Neil Osterweil/MDedge News

“Does this change practice? Well, the for and against: significant delay in PFS, but how meaningful is that? OS trending the right way, but not significant yet. CR rates, yes with 13% CRs, but response rates weren’t very different from one another, and as response rates are similar, it’s hard to argue that the two are synergistic together, for example,” he said.

He added that the adverse event profiles “actually are very acceptable to me, and I’m really looking forward to the quality-of-life data.”

The IMvigor130 study is sponsored by F. Hoffman-La Roche. Dr. Grande disclosed honoraria and research grants from Roche and others. Dr. Powles disclosed research funding, honoraria, and travel costs from Roche and others.
 

SOURCE: Grande E et al. ESMO 2019. Abstract LBA14_PR.

BARCELONA – Niraparib significantly improves progression-free survival when given after first-line chemotherapy in patients with advanced ovarian cancer, according to “potentially practice-changing” results from the phase 3 PRIMA/ENGOT-OV26/GOG-3012 study.

Sharon Worcester/MDedge News

Overall progression-free survival (PFS) in 484 patients randomized to receive the poly-ADP ribose polymerase inhibitor (PARPi) niraparib was 13.8 months, compared with 8.2 months in 244 patients who received placebo (hazard ratio, 0.62), Antonio González-Martin, MD, PhD, reported at the European Society for Medical Oncology Congress.

The findings were published simultaneously online in the New England Journal of Medicine (N Engl J Med. 2019 Sep 28. doi: 10.1056/NEJMoa1910962).

In patients at high risk for progression based on homologous recombination deficiency (HRd) – defined by certain tumor factors or the presence of BRCA mutation (BRCAm), PFS was 21.9 vs. 10.4 months in the treatment (n = 245) vs. placebo (n = 125) groups, respectively (HR, 0.43), said Dr. González-Martin of Grupo Español de Investigación en Cáncer de Ovario (GEICO), medical oncology department, Clínica Universidad de Navarra, Madrid.

“At 18 months, which means approximately 2 years after the initiation of chemotherapy, 42% of patients treated with niraparib remained alive and progression free,” he said, adding that 59% of the HRd patients remained alive and progression free at 18 months.

Exploratory analyses showed that the niraparib benefits occurred across all prespecified patient subgroups, including those aged 65 and older vs. those under age 65, those with stage III vs. stage IV disease at diagnosis, those receiving vs. not receiving neoadjuvant chemotherapy, those with complete response (CR) vs. partial response (PR) as their best response to platinum chemotherapy, and those with HRd who had BRCAm vs. BRCA wild type (BRCAwt) tumors, he said.

The hazard ratios for the HRd BRCAm vs. BRCAwt tumors were 0.40 and 0.50, respectively.

“So the benefit of niraparib in the HRd tumor is not driven only by the BRCA-mutated patients,” he said. “Importantly, we also saw benefit in the group of patients with tumors that were [homologous recombination] proficient (HRp), with a reduction in the risk of progression of 32%.”

For the key secondary endpoint of overall survival, a preplanned interim analysis showed that 84% vs. 77% in the niraparib and placebo groups, respectively, were alive at 2 years; in the HRd and HRp groups, those rates were 91% vs. 85% and 81% vs. 59%, respectively.

Participants in the double-blind trial had newly diagnosed, advanced high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube cancer; their mean age was 62 years; and they had experienced a CR (69%) or PR (31%) to first-line platinum-based chemotherapy. Overall, 35% had stage IV disease and 67% received neoadjuvant chemotherapy. They were randomized 2:1 to once-daily niraparib at a starting dose of 300 mg or 200 mg depending on body weight and platelet count, with those weighing 77 kg or greater and with platelet count of 150,000/mcL or less starting at the higher dose, and those weighing less than 77 kg and/or with platelet count less than 150,000/mcL starting at the lower dose.

All subgroups showed a sustained and durable treatment effect, and although most patients experienced treatment-related adverse events (TRAEs), those were “manageable with dose interruption or dose reduction,” Dr. González-Martin said.

Discontinuations due to TRAEs occurred in 12% vs. 2.5% in the treatment vs. placebo groups, and this was consistent with prior niraparib experience, he said, adding that no niraparib-related deaths were reported and no new safety signals were identified.

The findings are notable, because the recurrence rate after standard first-line platinum-based chemotherapy in women with advanced ovarian cancer is estimated at up to 85%, and while certain subgroups of patients have options for maintenance therapy, there remains a high unmet need for others, he explained.

For example olaparib is an option, but only for tumors with BRCA mutation, and bevacizumab can be used, but “may be limited due to safety concerns in some patients and also due to limited data from randomized trials in the neoadjuvant setting,” he said.

As a result, surveillance after chemotherapy is the approach used for many patients, he added.

Niraparib is the first oral PARPi approved for maintenance in patients with recurrent ovarian cancer, regardless of BRCA mutation status; in the NOVA study, it demonstrated efficacy after platinum chemotherapy in all biomarker populations, and in the QUADRA study it showed benefit in patients who received at least three prior therapies.

The current study was designed to test the efficacy and safety of niraparib therapy after response to platinum-based chemotherapy in patients with newly diagnosed advanced ovarian cancer, including those at high risk of relapse.

“Niraparib is the first PARP inhibitor that has demonstrated benefit after front-line platinum-based chemotherapy across all the biomarker subgroups, regardless of BRCA status, consistent with data from the recurrent setting,” Dr. González-Martin said, adding that patients with ovarian cancer at the highest risk of early disease progression obtained significant benefit. “What does this mean for our patients and our practice? Based on these results, niraparib after first-line platinum chemotherapy should be considered a new standard of care.”

Invited discussant Ana Oaknin, MD, PhD, head of the gynecologic cancer program at Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, Barcelona, called the findings “striking” and noted that they, along with those from the PAOLA-1/ENGOT-Ov25 trial demonstrating a PFS benefit with the addition of olaparib to bevacizumab maintenance therapy after first-line platinum-based chemotherapy in advanced ovarian cancer, represent important advances.

“We are witnessing a paradigm shift in the first-line treatment of advanced ovarian cancer patients,” she said.

Are the findings of these trials clinically meaningful enough to justify the addition of PARPi maintenance therapy after first-line chemotherapy therapy as a new standard of care?

“Yes, but while the benefit is clinically meaningful in the overall population, we should consider PFS outcomes according to the biomarker status in the selection of optimal therapy; companion diagnostic tests will be needed,” she said.

The PRIMA/ENGOT-OV26/GOG-3012 study was sponsored by TESARO. Dr. González-Martin reported relationships with numerous pharmaceutical companies.

[email protected]

SOURCE: González-Martin A et al. ESMO 2019: Abstract LBA1.

BARCELONA – Niraparib significantly improves progression-free survival when given after first-line chemotherapy in patients with advanced ovarian cancer, according to “potentially practice-changing” results from the phase 3 PRIMA/ENGOT-OV26/GOG-3012 study.

Sharon Worcester/MDedge News

Overall progression-free survival (PFS) in 484 patients randomized to receive the poly-ADP ribose polymerase inhibitor (PARPi) niraparib was 13.8 months, compared with 8.2 months in 244 patients who received placebo (hazard ratio, 0.62), Antonio González-Martin, MD, PhD, reported at the European Society for Medical Oncology Congress.

The findings were published simultaneously online in the New England Journal of Medicine (N Engl J Med. 2019 Sep 28. doi: 10.1056/NEJMoa1910962).

In patients at high risk for progression based on homologous recombination deficiency (HRd) – defined by certain tumor factors or the presence of BRCA mutation (BRCAm), PFS was 21.9 vs. 10.4 months in the treatment (n = 245) vs. placebo (n = 125) groups, respectively (HR, 0.43), said Dr. González-Martin of Grupo Español de Investigación en Cáncer de Ovario (GEICO), medical oncology department, Clínica Universidad de Navarra, Madrid.

“At 18 months, which means approximately 2 years after the initiation of chemotherapy, 42% of patients treated with niraparib remained alive and progression free,” he said, adding that 59% of the HRd patients remained alive and progression free at 18 months.

Exploratory analyses showed that the niraparib benefits occurred across all prespecified patient subgroups, including those aged 65 and older vs. those under age 65, those with stage III vs. stage IV disease at diagnosis, those receiving vs. not receiving neoadjuvant chemotherapy, those with complete response (CR) vs. partial response (PR) as their best response to platinum chemotherapy, and those with HRd who had BRCAm vs. BRCA wild type (BRCAwt) tumors, he said.

The hazard ratios for the HRd BRCAm vs. BRCAwt tumors were 0.40 and 0.50, respectively.

“So the benefit of niraparib in the HRd tumor is not driven only by the BRCA-mutated patients,” he said. “Importantly, we also saw benefit in the group of patients with tumors that were [homologous recombination] proficient (HRp), with a reduction in the risk of progression of 32%.”

For the key secondary endpoint of overall survival, a preplanned interim analysis showed that 84% vs. 77% in the niraparib and placebo groups, respectively, were alive at 2 years; in the HRd and HRp groups, those rates were 91% vs. 85% and 81% vs. 59%, respectively.

Participants in the double-blind trial had newly diagnosed, advanced high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube cancer; their mean age was 62 years; and they had experienced a CR (69%) or PR (31%) to first-line platinum-based chemotherapy. Overall, 35% had stage IV disease and 67% received neoadjuvant chemotherapy. They were randomized 2:1 to once-daily niraparib at a starting dose of 300 mg or 200 mg depending on body weight and platelet count, with those weighing 77 kg or greater and with platelet count of 150,000/mcL or less starting at the higher dose, and those weighing less than 77 kg and/or with platelet count less than 150,000/mcL starting at the lower dose.

All subgroups showed a sustained and durable treatment effect, and although most patients experienced treatment-related adverse events (TRAEs), those were “manageable with dose interruption or dose reduction,” Dr. González-Martin said.

Discontinuations due to TRAEs occurred in 12% vs. 2.5% in the treatment vs. placebo groups, and this was consistent with prior niraparib experience, he said, adding that no niraparib-related deaths were reported and no new safety signals were identified.

The findings are notable, because the recurrence rate after standard first-line platinum-based chemotherapy in women with advanced ovarian cancer is estimated at up to 85%, and while certain subgroups of patients have options for maintenance therapy, there remains a high unmet need for others, he explained.

For example olaparib is an option, but only for tumors with BRCA mutation, and bevacizumab can be used, but “may be limited due to safety concerns in some patients and also due to limited data from randomized trials in the neoadjuvant setting,” he said.

As a result, surveillance after chemotherapy is the approach used for many patients, he added.

Niraparib is the first oral PARPi approved for maintenance in patients with recurrent ovarian cancer, regardless of BRCA mutation status; in the NOVA study, it demonstrated efficacy after platinum chemotherapy in all biomarker populations, and in the QUADRA study it showed benefit in patients who received at least three prior therapies.

The current study was designed to test the efficacy and safety of niraparib therapy after response to platinum-based chemotherapy in patients with newly diagnosed advanced ovarian cancer, including those at high risk of relapse.

“Niraparib is the first PARP inhibitor that has demonstrated benefit after front-line platinum-based chemotherapy across all the biomarker subgroups, regardless of BRCA status, consistent with data from the recurrent setting,” Dr. González-Martin said, adding that patients with ovarian cancer at the highest risk of early disease progression obtained significant benefit. “What does this mean for our patients and our practice? Based on these results, niraparib after first-line platinum chemotherapy should be considered a new standard of care.”

Invited discussant Ana Oaknin, MD, PhD, head of the gynecologic cancer program at Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, Barcelona, called the findings “striking” and noted that they, along with those from the PAOLA-1/ENGOT-Ov25 trial demonstrating a PFS benefit with the addition of olaparib to bevacizumab maintenance therapy after first-line platinum-based chemotherapy in advanced ovarian cancer, represent important advances.

“We are witnessing a paradigm shift in the first-line treatment of advanced ovarian cancer patients,” she said.

Are the findings of these trials clinically meaningful enough to justify the addition of PARPi maintenance therapy after first-line chemotherapy therapy as a new standard of care?

“Yes, but while the benefit is clinically meaningful in the overall population, we should consider PFS outcomes according to the biomarker status in the selection of optimal therapy; companion diagnostic tests will be needed,” she said.

The PRIMA/ENGOT-OV26/GOG-3012 study was sponsored by TESARO. Dr. González-Martin reported relationships with numerous pharmaceutical companies.

[email protected]

SOURCE: González-Martin A et al. ESMO 2019: Abstract LBA1.

BARCELONA – Niraparib significantly improves progression-free survival when given after first-line chemotherapy in patients with advanced ovarian cancer, according to “potentially practice-changing” results from the phase 3 PRIMA/ENGOT-OV26/GOG-3012 study.

Sharon Worcester/MDedge News

Overall progression-free survival (PFS) in 484 patients randomized to receive the poly-ADP ribose polymerase inhibitor (PARPi) niraparib was 13.8 months, compared with 8.2 months in 244 patients who received placebo (hazard ratio, 0.62), Antonio González-Martin, MD, PhD, reported at the European Society for Medical Oncology Congress.

The findings were published simultaneously online in the New England Journal of Medicine (N Engl J Med. 2019 Sep 28. doi: 10.1056/NEJMoa1910962).

In patients at high risk for progression based on homologous recombination deficiency (HRd) – defined by certain tumor factors or the presence of BRCA mutation (BRCAm), PFS was 21.9 vs. 10.4 months in the treatment (n = 245) vs. placebo (n = 125) groups, respectively (HR, 0.43), said Dr. González-Martin of Grupo Español de Investigación en Cáncer de Ovario (GEICO), medical oncology department, Clínica Universidad de Navarra, Madrid.

“At 18 months, which means approximately 2 years after the initiation of chemotherapy, 42% of patients treated with niraparib remained alive and progression free,” he said, adding that 59% of the HRd patients remained alive and progression free at 18 months.

Exploratory analyses showed that the niraparib benefits occurred across all prespecified patient subgroups, including those aged 65 and older vs. those under age 65, those with stage III vs. stage IV disease at diagnosis, those receiving vs. not receiving neoadjuvant chemotherapy, those with complete response (CR) vs. partial response (PR) as their best response to platinum chemotherapy, and those with HRd who had BRCAm vs. BRCA wild type (BRCAwt) tumors, he said.

The hazard ratios for the HRd BRCAm vs. BRCAwt tumors were 0.40 and 0.50, respectively.

“So the benefit of niraparib in the HRd tumor is not driven only by the BRCA-mutated patients,” he said. “Importantly, we also saw benefit in the group of patients with tumors that were [homologous recombination] proficient (HRp), with a reduction in the risk of progression of 32%.”

For the key secondary endpoint of overall survival, a preplanned interim analysis showed that 84% vs. 77% in the niraparib and placebo groups, respectively, were alive at 2 years; in the HRd and HRp groups, those rates were 91% vs. 85% and 81% vs. 59%, respectively.

Participants in the double-blind trial had newly diagnosed, advanced high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube cancer; their mean age was 62 years; and they had experienced a CR (69%) or PR (31%) to first-line platinum-based chemotherapy. Overall, 35% had stage IV disease and 67% received neoadjuvant chemotherapy. They were randomized 2:1 to once-daily niraparib at a starting dose of 300 mg or 200 mg depending on body weight and platelet count, with those weighing 77 kg or greater and with platelet count of 150,000/mcL or less starting at the higher dose, and those weighing less than 77 kg and/or with platelet count less than 150,000/mcL starting at the lower dose.

All subgroups showed a sustained and durable treatment effect, and although most patients experienced treatment-related adverse events (TRAEs), those were “manageable with dose interruption or dose reduction,” Dr. González-Martin said.

Discontinuations due to TRAEs occurred in 12% vs. 2.5% in the treatment vs. placebo groups, and this was consistent with prior niraparib experience, he said, adding that no niraparib-related deaths were reported and no new safety signals were identified.

The findings are notable, because the recurrence rate after standard first-line platinum-based chemotherapy in women with advanced ovarian cancer is estimated at up to 85%, and while certain subgroups of patients have options for maintenance therapy, there remains a high unmet need for others, he explained.

For example olaparib is an option, but only for tumors with BRCA mutation, and bevacizumab can be used, but “may be limited due to safety concerns in some patients and also due to limited data from randomized trials in the neoadjuvant setting,” he said.

As a result, surveillance after chemotherapy is the approach used for many patients, he added.

Niraparib is the first oral PARPi approved for maintenance in patients with recurrent ovarian cancer, regardless of BRCA mutation status; in the NOVA study, it demonstrated efficacy after platinum chemotherapy in all biomarker populations, and in the QUADRA study it showed benefit in patients who received at least three prior therapies.

The current study was designed to test the efficacy and safety of niraparib therapy after response to platinum-based chemotherapy in patients with newly diagnosed advanced ovarian cancer, including those at high risk of relapse.

“Niraparib is the first PARP inhibitor that has demonstrated benefit after front-line platinum-based chemotherapy across all the biomarker subgroups, regardless of BRCA status, consistent with data from the recurrent setting,” Dr. González-Martin said, adding that patients with ovarian cancer at the highest risk of early disease progression obtained significant benefit. “What does this mean for our patients and our practice? Based on these results, niraparib after first-line platinum chemotherapy should be considered a new standard of care.”

Invited discussant Ana Oaknin, MD, PhD, head of the gynecologic cancer program at Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, Barcelona, called the findings “striking” and noted that they, along with those from the PAOLA-1/ENGOT-Ov25 trial demonstrating a PFS benefit with the addition of olaparib to bevacizumab maintenance therapy after first-line platinum-based chemotherapy in advanced ovarian cancer, represent important advances.

“We are witnessing a paradigm shift in the first-line treatment of advanced ovarian cancer patients,” she said.

Are the findings of these trials clinically meaningful enough to justify the addition of PARPi maintenance therapy after first-line chemotherapy therapy as a new standard of care?

“Yes, but while the benefit is clinically meaningful in the overall population, we should consider PFS outcomes according to the biomarker status in the selection of optimal therapy; companion diagnostic tests will be needed,” she said.

The PRIMA/ENGOT-OV26/GOG-3012 study was sponsored by TESARO. Dr. González-Martin reported relationships with numerous pharmaceutical companies.

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SOURCE: González-Martin A et al. ESMO 2019: Abstract LBA1.