TBD Meeting (5163-20)

The oral selective estrogen receptor degrader (SERD) LSZ102 plus either ribociclib or alpelisib shows manageable safety and encouraging clinical activity in heavily pretreated estrogen receptor (ER)–positive breast cancer patients who progressed after prior endocrine therapy, according to interim results of an open-label phase 1/1b study.

The effects seen in the study, which is the first to report on an oral SERD in combination with both CDK4/6 and PI3Ka inhibitors, occurred regardless of ESR1 and PIK3CA mutations, said Komal Jhaveri, MD, of Memorial Sloan Kettering Cancer Center in New York.

Dr. Jhaveri reported the results at the European Society of Medical Oncology: Breast Cancer virtual meeting.

The overall response rate (ORR) among 78 patients enrolled in an LSZ102 monotherapy arm (arm A) was 1.3%, and the progression-free survival (PFS) was 1.8 months. The clinical benefit rate (CBR) was 9.1%.

Among 76 patients enrolled in an LSZ102+ribociclib arm (arm B), the ORR was 15.8%, the PFS was 6.2 months, and the CBR was 35.5%.

Among the 39 patients enrolled in an LSZ102+alpelisib arm (arm C), the ORR was 5.4%, the PFS was 3.5 months, and the CBR was 18.9%.

After the data cutoff, one additional partial response (PR) was reported in arm C, Dr. Jhaveri said, noting that two of three confirmed responses were in known PIKC3A-mutant patients.

Study participants were aged 18 years and older with a confirmed diagnosis of ER-positive breast cancer and good performance status, as well as evidence of progression after endocrine therapy for metastatic disease or evidence of progression while on therapy or within 12 months from the end of adjuvant therapy.

“For all arms, prior fulvestrant, CDK46 inhibitor, or chemotherapy were allowed. For arm C, patients with or without PIK3C were eligible, and no prior treatment with PIK3, mTOR, or AKT inhibitors was allowed,” Dr. Jhaveri said.

Dosing in the LSZ102 monotherapy arm ranged from 200 to 900 mg. Arm B patients received LSZ102 at doses of 200-600 mg and ribociclib at doses of 200-600 mg. Both continuous ribociclib and 3 weeks on/1 week off dosing were evaluated. Arm C patients received LSZ102 at doses of 300-450 mg and alpelisib at 200-300 mg.

The recommended expansion doses were 450 mg daily of LSZ102 for arm A and 450 mg LSZ102 with 400 mg of daily ribociclib for arm B. For arm C, they were 300 mg LSZ102 with 250 mg of alpelisib daily.

Of note, two of three patients with a PR in arm C had received 300 mg LSZ102 and 300 mg alpelisib, Dr. Jhaveri said.

Arm A and arm B results were presented at the San Antonio Breast Cancer Symposium in 2018 and 2019, respectively. The current report updates those findings and presents arm C data for the first time, Dr. Jhaveri said.

LSZ102 was relatively well-tolerated as a single agent and in combination with ribociclib and alpelisib, according to Dr. Jhaveri. The most frequent adverse events were gastrointestinal toxicities, including nausea, vomiting, diarrhea, and decreased appetite, which occurred across all arms.

Neutropenia and aspartate aminotransferase abnormalities, including grade 3 cases, were reported in arm B and were most likely driven by the ribociclib, Dr. Jhaveri said. Grade 3 hypoglycemia and skin rash commonly occurred in arm C, most likely driven by the alpelisib.

Five dose-limiting toxicities occurred in four patients in arm A, three occurred in two patients in arm B, and seven occurred in seven patients in arm C.

Paired biopsies collected at the time of screening and at day 15 of cycle 1 showed consistent down-regulation of ER protein levels across arms.

“No substantial dose-dependent down-regulation of the ER was observed with increasing doses of LSZ,” Dr. Jhaveri said.

Circulating tumor DNA (ctDNA) analysis showed that the dominant mutations across the arms were ESR1, PIK3CA, and TP53. These were not shown to correlate with response and were not enriched upon progression in patients with matched baseline and end-of-treatment samples, she noted.

An exploratory analysis, conducted in “a preliminary attempt to correlate clinical activity with specific mutations,” showed that, in arms B and C, respectively, ORR, CBR, and PFS weren’t correlated with the presence or absence of ESR1 and PIK3CA mutations, respectively, or the absence of detectable ctDNA from baseline samples, Dr. Jhaveri said.

“While numerically higher responses and better CBR were seen in patients with undetectable ctDNA at baseline, no statistically significant difference in any of these outcomes was observed in arms B and C,” she said.

In arm C, the numbers were small at the time of data cutoff, but incoming data suggest relatively enhanced activity of the LSZ102 plus alpelisib combination in PIKC3A-mutant patients, she noted.

“We know that inhibiting ER signaling is the mainstay of treatment for ER-positive breast cancer,” Dr. Jhaveri explained, adding that aromatase inhibitors, estrogen receptor modulators, and SERDs are important classes of antiestrogenic agents, but fulvestrant is the only approved SERD. These are effective, but many patients develop resistance, she said.

“Proposed mechanisms for endocrine resistance include activation of the cell-cycle and cell-survival signaling pathways, or of the PI3K-AKT-mTOR pathway,” Dr. Jhaveri said. “To that end, ribociclib, a CDK46 inhibitor plus fulvestrant improved survival compared to fulvestrant alone in patients with ER-positive metastatic breast cancer.”

More recently, the PI3K inhibitor alpelisib plus fulvestrant also nearly doubled PFS vs. fulvestrant alone in PIKC3A-mutant, ER-positive metastatic breast cancer, which led to the approval of the combination in the United States.

Another mechanism of endocrine resistance includes acquisition of activating mutations in the estrogen receptor gene itself that allow tumors to survive and proliferate without depending on estrogen.

EGFR mutations appear to predict resistance to aromatase inhibitor therapies, but not outcomes in patients treated with fulvestrant. However, fulvestrant, which is delivered by intramuscular injection, has its own limitations, Dr. Jhaveri said.

“LSZ102 is a novel SERD that could achieve higher exposure than fulvestrant, leading to enhanced efficacy,” she said, noting that it was shown in preclinical models to have activity and to be synergistic in combination with ribociclib and alpelisib, forming the basis for the current study.

Invited discussant, Saverio Cinieri, MD, of Ospedale Antonio Perrino, Brindisi, Italy, said the study “elegantly demonstrated that estrogen receptor protein is down-regulated by LSZ102; [that] the genomic landscape of heavily pretreated patients is dominated by mutations in ESR1, PIK3CA, and TP53; [that] common mutations do not correlate with response and are not enriched on progression; [and that] ctDNA analysis at baseline shows similar outcomes with LSZ plus ribociclib or alpelisib, regardless of mutational status.”

LSZ102 is one of four new-generation SERDs in early-phase studies, he said, concluding that “in the COVID-19 era, the use of oral therapies will be even more necessary to limit access to the hospital.”

Dr. Cinieri also said that overcoming the limitations “of a molecule like the intramuscularly administered fulvestrant goes in this direction,” and that “the clinical efficacy and the biomolecular profile of LSZ102 seems to be able to meet these real needs.”

This study was funded by Novartis. Dr. Jhaveri reported advisory and consultancy roles and/or research grants or other funding to her institution from Novartis, ADC Therapeutics, Pfizer, and numerous other pharmaceutical and biotechnology companies. Dr. Cinieri reported relationships with Lily Oncology, Pfizer, Roche, AstraZeneca, Amgen, Novartis, including honoraria, grant and research support to his institution, advisory board participation, and scientific meeting support.

[email protected]

SOURCE: Jhaveri K et al. ESMO Breast Cancer, Abstract LBA1.

The oral selective estrogen receptor degrader (SERD) LSZ102 plus either ribociclib or alpelisib shows manageable safety and encouraging clinical activity in heavily pretreated estrogen receptor (ER)–positive breast cancer patients who progressed after prior endocrine therapy, according to interim results of an open-label phase 1/1b study.

The effects seen in the study, which is the first to report on an oral SERD in combination with both CDK4/6 and PI3Ka inhibitors, occurred regardless of ESR1 and PIK3CA mutations, said Komal Jhaveri, MD, of Memorial Sloan Kettering Cancer Center in New York.

Dr. Jhaveri reported the results at the European Society of Medical Oncology: Breast Cancer virtual meeting.

The overall response rate (ORR) among 78 patients enrolled in an LSZ102 monotherapy arm (arm A) was 1.3%, and the progression-free survival (PFS) was 1.8 months. The clinical benefit rate (CBR) was 9.1%.

Among 76 patients enrolled in an LSZ102+ribociclib arm (arm B), the ORR was 15.8%, the PFS was 6.2 months, and the CBR was 35.5%.

Among the 39 patients enrolled in an LSZ102+alpelisib arm (arm C), the ORR was 5.4%, the PFS was 3.5 months, and the CBR was 18.9%.

After the data cutoff, one additional partial response (PR) was reported in arm C, Dr. Jhaveri said, noting that two of three confirmed responses were in known PIKC3A-mutant patients.

Study participants were aged 18 years and older with a confirmed diagnosis of ER-positive breast cancer and good performance status, as well as evidence of progression after endocrine therapy for metastatic disease or evidence of progression while on therapy or within 12 months from the end of adjuvant therapy.

“For all arms, prior fulvestrant, CDK46 inhibitor, or chemotherapy were allowed. For arm C, patients with or without PIK3C were eligible, and no prior treatment with PIK3, mTOR, or AKT inhibitors was allowed,” Dr. Jhaveri said.

Dosing in the LSZ102 monotherapy arm ranged from 200 to 900 mg. Arm B patients received LSZ102 at doses of 200-600 mg and ribociclib at doses of 200-600 mg. Both continuous ribociclib and 3 weeks on/1 week off dosing were evaluated. Arm C patients received LSZ102 at doses of 300-450 mg and alpelisib at 200-300 mg.

The recommended expansion doses were 450 mg daily of LSZ102 for arm A and 450 mg LSZ102 with 400 mg of daily ribociclib for arm B. For arm C, they were 300 mg LSZ102 with 250 mg of alpelisib daily.

Of note, two of three patients with a PR in arm C had received 300 mg LSZ102 and 300 mg alpelisib, Dr. Jhaveri said.

Arm A and arm B results were presented at the San Antonio Breast Cancer Symposium in 2018 and 2019, respectively. The current report updates those findings and presents arm C data for the first time, Dr. Jhaveri said.

LSZ102 was relatively well-tolerated as a single agent and in combination with ribociclib and alpelisib, according to Dr. Jhaveri. The most frequent adverse events were gastrointestinal toxicities, including nausea, vomiting, diarrhea, and decreased appetite, which occurred across all arms.

Neutropenia and aspartate aminotransferase abnormalities, including grade 3 cases, were reported in arm B and were most likely driven by the ribociclib, Dr. Jhaveri said. Grade 3 hypoglycemia and skin rash commonly occurred in arm C, most likely driven by the alpelisib.

Five dose-limiting toxicities occurred in four patients in arm A, three occurred in two patients in arm B, and seven occurred in seven patients in arm C.

Paired biopsies collected at the time of screening and at day 15 of cycle 1 showed consistent down-regulation of ER protein levels across arms.

“No substantial dose-dependent down-regulation of the ER was observed with increasing doses of LSZ,” Dr. Jhaveri said.

Circulating tumor DNA (ctDNA) analysis showed that the dominant mutations across the arms were ESR1, PIK3CA, and TP53. These were not shown to correlate with response and were not enriched upon progression in patients with matched baseline and end-of-treatment samples, she noted.

An exploratory analysis, conducted in “a preliminary attempt to correlate clinical activity with specific mutations,” showed that, in arms B and C, respectively, ORR, CBR, and PFS weren’t correlated with the presence or absence of ESR1 and PIK3CA mutations, respectively, or the absence of detectable ctDNA from baseline samples, Dr. Jhaveri said.

“While numerically higher responses and better CBR were seen in patients with undetectable ctDNA at baseline, no statistically significant difference in any of these outcomes was observed in arms B and C,” she said.

In arm C, the numbers were small at the time of data cutoff, but incoming data suggest relatively enhanced activity of the LSZ102 plus alpelisib combination in PIKC3A-mutant patients, she noted.

“We know that inhibiting ER signaling is the mainstay of treatment for ER-positive breast cancer,” Dr. Jhaveri explained, adding that aromatase inhibitors, estrogen receptor modulators, and SERDs are important classes of antiestrogenic agents, but fulvestrant is the only approved SERD. These are effective, but many patients develop resistance, she said.

“Proposed mechanisms for endocrine resistance include activation of the cell-cycle and cell-survival signaling pathways, or of the PI3K-AKT-mTOR pathway,” Dr. Jhaveri said. “To that end, ribociclib, a CDK46 inhibitor plus fulvestrant improved survival compared to fulvestrant alone in patients with ER-positive metastatic breast cancer.”

More recently, the PI3K inhibitor alpelisib plus fulvestrant also nearly doubled PFS vs. fulvestrant alone in PIKC3A-mutant, ER-positive metastatic breast cancer, which led to the approval of the combination in the United States.

Another mechanism of endocrine resistance includes acquisition of activating mutations in the estrogen receptor gene itself that allow tumors to survive and proliferate without depending on estrogen.

EGFR mutations appear to predict resistance to aromatase inhibitor therapies, but not outcomes in patients treated with fulvestrant. However, fulvestrant, which is delivered by intramuscular injection, has its own limitations, Dr. Jhaveri said.

“LSZ102 is a novel SERD that could achieve higher exposure than fulvestrant, leading to enhanced efficacy,” she said, noting that it was shown in preclinical models to have activity and to be synergistic in combination with ribociclib and alpelisib, forming the basis for the current study.

Invited discussant, Saverio Cinieri, MD, of Ospedale Antonio Perrino, Brindisi, Italy, said the study “elegantly demonstrated that estrogen receptor protein is down-regulated by LSZ102; [that] the genomic landscape of heavily pretreated patients is dominated by mutations in ESR1, PIK3CA, and TP53; [that] common mutations do not correlate with response and are not enriched on progression; [and that] ctDNA analysis at baseline shows similar outcomes with LSZ plus ribociclib or alpelisib, regardless of mutational status.”

LSZ102 is one of four new-generation SERDs in early-phase studies, he said, concluding that “in the COVID-19 era, the use of oral therapies will be even more necessary to limit access to the hospital.”

Dr. Cinieri also said that overcoming the limitations “of a molecule like the intramuscularly administered fulvestrant goes in this direction,” and that “the clinical efficacy and the biomolecular profile of LSZ102 seems to be able to meet these real needs.”

This study was funded by Novartis. Dr. Jhaveri reported advisory and consultancy roles and/or research grants or other funding to her institution from Novartis, ADC Therapeutics, Pfizer, and numerous other pharmaceutical and biotechnology companies. Dr. Cinieri reported relationships with Lily Oncology, Pfizer, Roche, AstraZeneca, Amgen, Novartis, including honoraria, grant and research support to his institution, advisory board participation, and scientific meeting support.

[email protected]

SOURCE: Jhaveri K et al. ESMO Breast Cancer, Abstract LBA1.

The oral selective estrogen receptor degrader (SERD) LSZ102 plus either ribociclib or alpelisib shows manageable safety and encouraging clinical activity in heavily pretreated estrogen receptor (ER)–positive breast cancer patients who progressed after prior endocrine therapy, according to interim results of an open-label phase 1/1b study.

The effects seen in the study, which is the first to report on an oral SERD in combination with both CDK4/6 and PI3Ka inhibitors, occurred regardless of ESR1 and PIK3CA mutations, said Komal Jhaveri, MD, of Memorial Sloan Kettering Cancer Center in New York.

Dr. Jhaveri reported the results at the European Society of Medical Oncology: Breast Cancer virtual meeting.

The overall response rate (ORR) among 78 patients enrolled in an LSZ102 monotherapy arm (arm A) was 1.3%, and the progression-free survival (PFS) was 1.8 months. The clinical benefit rate (CBR) was 9.1%.

Among 76 patients enrolled in an LSZ102+ribociclib arm (arm B), the ORR was 15.8%, the PFS was 6.2 months, and the CBR was 35.5%.

Among the 39 patients enrolled in an LSZ102+alpelisib arm (arm C), the ORR was 5.4%, the PFS was 3.5 months, and the CBR was 18.9%.

After the data cutoff, one additional partial response (PR) was reported in arm C, Dr. Jhaveri said, noting that two of three confirmed responses were in known PIKC3A-mutant patients.

Study participants were aged 18 years and older with a confirmed diagnosis of ER-positive breast cancer and good performance status, as well as evidence of progression after endocrine therapy for metastatic disease or evidence of progression while on therapy or within 12 months from the end of adjuvant therapy.

“For all arms, prior fulvestrant, CDK46 inhibitor, or chemotherapy were allowed. For arm C, patients with or without PIK3C were eligible, and no prior treatment with PIK3, mTOR, or AKT inhibitors was allowed,” Dr. Jhaveri said.

Dosing in the LSZ102 monotherapy arm ranged from 200 to 900 mg. Arm B patients received LSZ102 at doses of 200-600 mg and ribociclib at doses of 200-600 mg. Both continuous ribociclib and 3 weeks on/1 week off dosing were evaluated. Arm C patients received LSZ102 at doses of 300-450 mg and alpelisib at 200-300 mg.

The recommended expansion doses were 450 mg daily of LSZ102 for arm A and 450 mg LSZ102 with 400 mg of daily ribociclib for arm B. For arm C, they were 300 mg LSZ102 with 250 mg of alpelisib daily.

Of note, two of three patients with a PR in arm C had received 300 mg LSZ102 and 300 mg alpelisib, Dr. Jhaveri said.

Arm A and arm B results were presented at the San Antonio Breast Cancer Symposium in 2018 and 2019, respectively. The current report updates those findings and presents arm C data for the first time, Dr. Jhaveri said.

LSZ102 was relatively well-tolerated as a single agent and in combination with ribociclib and alpelisib, according to Dr. Jhaveri. The most frequent adverse events were gastrointestinal toxicities, including nausea, vomiting, diarrhea, and decreased appetite, which occurred across all arms.

Neutropenia and aspartate aminotransferase abnormalities, including grade 3 cases, were reported in arm B and were most likely driven by the ribociclib, Dr. Jhaveri said. Grade 3 hypoglycemia and skin rash commonly occurred in arm C, most likely driven by the alpelisib.

Five dose-limiting toxicities occurred in four patients in arm A, three occurred in two patients in arm B, and seven occurred in seven patients in arm C.

Paired biopsies collected at the time of screening and at day 15 of cycle 1 showed consistent down-regulation of ER protein levels across arms.

“No substantial dose-dependent down-regulation of the ER was observed with increasing doses of LSZ,” Dr. Jhaveri said.

Circulating tumor DNA (ctDNA) analysis showed that the dominant mutations across the arms were ESR1, PIK3CA, and TP53. These were not shown to correlate with response and were not enriched upon progression in patients with matched baseline and end-of-treatment samples, she noted.

An exploratory analysis, conducted in “a preliminary attempt to correlate clinical activity with specific mutations,” showed that, in arms B and C, respectively, ORR, CBR, and PFS weren’t correlated with the presence or absence of ESR1 and PIK3CA mutations, respectively, or the absence of detectable ctDNA from baseline samples, Dr. Jhaveri said.

“While numerically higher responses and better CBR were seen in patients with undetectable ctDNA at baseline, no statistically significant difference in any of these outcomes was observed in arms B and C,” she said.

In arm C, the numbers were small at the time of data cutoff, but incoming data suggest relatively enhanced activity of the LSZ102 plus alpelisib combination in PIKC3A-mutant patients, she noted.

“We know that inhibiting ER signaling is the mainstay of treatment for ER-positive breast cancer,” Dr. Jhaveri explained, adding that aromatase inhibitors, estrogen receptor modulators, and SERDs are important classes of antiestrogenic agents, but fulvestrant is the only approved SERD. These are effective, but many patients develop resistance, she said.

“Proposed mechanisms for endocrine resistance include activation of the cell-cycle and cell-survival signaling pathways, or of the PI3K-AKT-mTOR pathway,” Dr. Jhaveri said. “To that end, ribociclib, a CDK46 inhibitor plus fulvestrant improved survival compared to fulvestrant alone in patients with ER-positive metastatic breast cancer.”

More recently, the PI3K inhibitor alpelisib plus fulvestrant also nearly doubled PFS vs. fulvestrant alone in PIKC3A-mutant, ER-positive metastatic breast cancer, which led to the approval of the combination in the United States.

Another mechanism of endocrine resistance includes acquisition of activating mutations in the estrogen receptor gene itself that allow tumors to survive and proliferate without depending on estrogen.

EGFR mutations appear to predict resistance to aromatase inhibitor therapies, but not outcomes in patients treated with fulvestrant. However, fulvestrant, which is delivered by intramuscular injection, has its own limitations, Dr. Jhaveri said.

“LSZ102 is a novel SERD that could achieve higher exposure than fulvestrant, leading to enhanced efficacy,” she said, noting that it was shown in preclinical models to have activity and to be synergistic in combination with ribociclib and alpelisib, forming the basis for the current study.

Invited discussant, Saverio Cinieri, MD, of Ospedale Antonio Perrino, Brindisi, Italy, said the study “elegantly demonstrated that estrogen receptor protein is down-regulated by LSZ102; [that] the genomic landscape of heavily pretreated patients is dominated by mutations in ESR1, PIK3CA, and TP53; [that] common mutations do not correlate with response and are not enriched on progression; [and that] ctDNA analysis at baseline shows similar outcomes with LSZ plus ribociclib or alpelisib, regardless of mutational status.”

LSZ102 is one of four new-generation SERDs in early-phase studies, he said, concluding that “in the COVID-19 era, the use of oral therapies will be even more necessary to limit access to the hospital.”

Dr. Cinieri also said that overcoming the limitations “of a molecule like the intramuscularly administered fulvestrant goes in this direction,” and that “the clinical efficacy and the biomolecular profile of LSZ102 seems to be able to meet these real needs.”

This study was funded by Novartis. Dr. Jhaveri reported advisory and consultancy roles and/or research grants or other funding to her institution from Novartis, ADC Therapeutics, Pfizer, and numerous other pharmaceutical and biotechnology companies. Dr. Cinieri reported relationships with Lily Oncology, Pfizer, Roche, AstraZeneca, Amgen, Novartis, including honoraria, grant and research support to his institution, advisory board participation, and scientific meeting support.

[email protected]

SOURCE: Jhaveri K et al. ESMO Breast Cancer, Abstract LBA1.

In an update of the PREDIX-HER2 trial, trastuzumab emtansine (T-DM1) remained equivalent to standard neoadjuvant chemotherapy plus dual-targeted HER2 therapy in producing pathologic complete remissions (pCRs) among patients with HER2-positive, metastatic breast cancer.

The new data also suggest tumor-infiltrating lymphocytes (TILs) and dramatic improvements in PET-CT scans can predict favorable outcomes in both treatment groups. Though these findings will be useful for research purposes, they likely won’t influence routine clinical practice.

Thomas Hatschek, MD, PhD, of Karolinska Institutet in Stockholm, presented the updated results from PREDIX-HER2 during the European Society for Medical Oncology: Breast Cancer virtual meeting.

PREDIX-HER2 included patients with HER2-positive breast cancer and tumor size greater than 20 mm or lymph node metastases.

Patients received neoadjuvant therapy (NAT) with docetaxel and trastuzumab plus pertuzumab (DTP) or T-DM1 every 3 weeks for a planned total of six courses. The protocol permitted switching to the competing treatment for progression, lack of response, or drug-related severe toxicity.

Postoperatively, all patients received triweekly epirubicin plus cyclophosphamide – four courses for the T-DM1 arm and two courses for the DTP arm. All patients then received triweekly adjuvant trastuzumab for 11 courses. The 62% of patients whose tumors were hormone receptor (HR)–positive received standard endocrine therapy postoperatively.
 

Updated results, predictors of pCR

At the 2019 ASCO annual meeting, PREDIX-HER2 investigators reported that, when compared with DTP, T-DM1 produced the same likelihood of pCR with less toxicity (ASCO 2019, Abstract 501). Updated data presented at ESMO Breast Cancer 2020 showed similar results.

The pCR rate was 45.5% in the DTP arm and 43.9% in the T-DM1 arm (P = .824). pCR rates were higher for HR-negative tumors – 63.6% in the DTP arm and 59% in the T-DM1 arm – than for HR-positive tumors – 36.4% in the DTP arm and 33.9% in the TDM-1 arm.

Three patients had disease progression with T-DM1, and none progressed with DTP. However, almost twice as many patients switched from DTP to T-DM1, compared with the other sequence.

Dr. Hatschek reported that the presence of at least 10% TILs predicted pCR in both treatment groups. Among patients who achieved a pCR, 52.2% had at least 10% TILs in baseline biopsies, and 30.4% had less than 10% TILs.

In addition, a decrease of FDG maximum standardized uptake value by more than 75% on protocol-required PET-CT scans was highly predictive of pCR. Among patients who achieved a pCR, 70.3% had a maximum standardized uptake value decrease of more than 75%, and 22.5% had a decrease of 75% or less.

At median follow-up of 28.5 months, event-free survival was similar between the treatment arms. Overall, there were 13 cases of progression, relapse, contralateral breast cancer, distant metastases, or death from any cause. There were five such events in the DTP arm and eight in the TDM-1 arm.

Dr. Hatschek concluded that neoadjuvant T-DM1 may be as effective as standard NAT in all clinical subgroups evaluated. Both TILs and PET-CT showed the potential to predict pCR and merit further study in the NAT setting.
 

An imperfect surrogate

By definition, a surrogate is “one appointed to act in place of another.” In the case of PREDIX-HER2 and most other NAT studies in HER2-positive breast cancer patients, pCR is a surrogate for the endpoint about which doctors and patients really care – cancer-free survival.

As such, pCR is not a perfect surrogate. Reproducibly, pCR has been highly predictive of disease-free survival and overall survival, especially in the HR-negative subset of HER2-positive patients.

However, despite improvements with dual targeting of HER2 in the TRYPHAENA trial (Eur J Cancer. 2018;89:27-35) and the use of T-DM1 for patients failing to achieve pCR in the immediately practice-changing KATHERINE trial (N Engl J Med. 2019;380:617-28), eventual relapse is seen in 10%-20% of patients in various clinical-pathologic subgroups.

In PREDIX-HER2, the pCR rate for node-positive patients was considerably lower with T-DM1 than with DTP (54.1% vs. 38%), noted Valentina Guarneri, MD, of the University of Padova (Italy), in her discussion of the trial at ESMO Breast Cancer 2020.

Patients with larger initial tumor size and multiple involved axillary nodes at diagnosis remain at increased risk of death because of cancer relapse.

Central nervous system relapse remains a vexing problem. Among patients with triple-positive breast cancer, relapses may occur late, despite pCR.

Patients whose tumors transform from HER2 positive to HER2 negative with NAT, seen in approximately 8% of cases in the KATHERINE trial (ESMO Breast Cancer 2020, Abstract 96O), may be another poor-risk group.
 

Clinical implications

PREDIX-HER2 is an important study. At the early time point of 2.4 years (especially early since most patients were HR-positive), if pCR is achieved, event-free survival is excellent with T-DM1 or an aggressive multiagent cytotoxic combination plus dual HER2 targeting followed by anthracyclines.

It is ideal to have clinical-pathologic tests to distinguish those patients destined to achieve the surrogate endpoint of pCR from those who will not achieve it.

Despite linkage of TILs to improved outcome for triple-negative and HER2-enriched molecular subtypes (Lancet Oncol. 2018 Jan;19[1]:40-50), analysis of TILs is not standard practice in HER2-positive breast cancer in community settings. Optimal cutoffs are not well established, and TILs have not been linked to the choice of particular treatment options.

Currently, PET-CT scans are not part of National Comprehensive Cancer Network guidelines for pretreatment evaluation, except in patients for whom there is clinical suspicion of distant disease.

For those reasons, the main results of PREDIX-HER2 remain research tools that will focus our attention on the clinical-pathologic correlations Dr. Hatschek highlighted, but the results should have no influence on routine clinical practice at this time.

PREDIX-HER2 was funded by the Swedish Cancer Society, Radiumhemmet of Karolinska Institutet, Region Stockholm, and Roche Sweden. Dr. Hatschek disclosed relationships with Roche Sweden, Pfizer Sweden, and Pierre Fabre Sweden. Dr. Guarneri disclosed relationships with Roche, Novartis, and Eli Lilly.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

SOURCE: Hatschek T et al. ESMO Breast Cancer 2020, Abstract 97O.

In an update of the PREDIX-HER2 trial, trastuzumab emtansine (T-DM1) remained equivalent to standard neoadjuvant chemotherapy plus dual-targeted HER2 therapy in producing pathologic complete remissions (pCRs) among patients with HER2-positive, metastatic breast cancer.

The new data also suggest tumor-infiltrating lymphocytes (TILs) and dramatic improvements in PET-CT scans can predict favorable outcomes in both treatment groups. Though these findings will be useful for research purposes, they likely won’t influence routine clinical practice.

Thomas Hatschek, MD, PhD, of Karolinska Institutet in Stockholm, presented the updated results from PREDIX-HER2 during the European Society for Medical Oncology: Breast Cancer virtual meeting.

PREDIX-HER2 included patients with HER2-positive breast cancer and tumor size greater than 20 mm or lymph node metastases.

Patients received neoadjuvant therapy (NAT) with docetaxel and trastuzumab plus pertuzumab (DTP) or T-DM1 every 3 weeks for a planned total of six courses. The protocol permitted switching to the competing treatment for progression, lack of response, or drug-related severe toxicity.

Postoperatively, all patients received triweekly epirubicin plus cyclophosphamide – four courses for the T-DM1 arm and two courses for the DTP arm. All patients then received triweekly adjuvant trastuzumab for 11 courses. The 62% of patients whose tumors were hormone receptor (HR)–positive received standard endocrine therapy postoperatively.
 

Updated results, predictors of pCR

At the 2019 ASCO annual meeting, PREDIX-HER2 investigators reported that, when compared with DTP, T-DM1 produced the same likelihood of pCR with less toxicity (ASCO 2019, Abstract 501). Updated data presented at ESMO Breast Cancer 2020 showed similar results.

The pCR rate was 45.5% in the DTP arm and 43.9% in the T-DM1 arm (P = .824). pCR rates were higher for HR-negative tumors – 63.6% in the DTP arm and 59% in the T-DM1 arm – than for HR-positive tumors – 36.4% in the DTP arm and 33.9% in the TDM-1 arm.

Three patients had disease progression with T-DM1, and none progressed with DTP. However, almost twice as many patients switched from DTP to T-DM1, compared with the other sequence.

Dr. Hatschek reported that the presence of at least 10% TILs predicted pCR in both treatment groups. Among patients who achieved a pCR, 52.2% had at least 10% TILs in baseline biopsies, and 30.4% had less than 10% TILs.

In addition, a decrease of FDG maximum standardized uptake value by more than 75% on protocol-required PET-CT scans was highly predictive of pCR. Among patients who achieved a pCR, 70.3% had a maximum standardized uptake value decrease of more than 75%, and 22.5% had a decrease of 75% or less.

At median follow-up of 28.5 months, event-free survival was similar between the treatment arms. Overall, there were 13 cases of progression, relapse, contralateral breast cancer, distant metastases, or death from any cause. There were five such events in the DTP arm and eight in the TDM-1 arm.

Dr. Hatschek concluded that neoadjuvant T-DM1 may be as effective as standard NAT in all clinical subgroups evaluated. Both TILs and PET-CT showed the potential to predict pCR and merit further study in the NAT setting.
 

An imperfect surrogate

By definition, a surrogate is “one appointed to act in place of another.” In the case of PREDIX-HER2 and most other NAT studies in HER2-positive breast cancer patients, pCR is a surrogate for the endpoint about which doctors and patients really care – cancer-free survival.

As such, pCR is not a perfect surrogate. Reproducibly, pCR has been highly predictive of disease-free survival and overall survival, especially in the HR-negative subset of HER2-positive patients.

However, despite improvements with dual targeting of HER2 in the TRYPHAENA trial (Eur J Cancer. 2018;89:27-35) and the use of T-DM1 for patients failing to achieve pCR in the immediately practice-changing KATHERINE trial (N Engl J Med. 2019;380:617-28), eventual relapse is seen in 10%-20% of patients in various clinical-pathologic subgroups.

In PREDIX-HER2, the pCR rate for node-positive patients was considerably lower with T-DM1 than with DTP (54.1% vs. 38%), noted Valentina Guarneri, MD, of the University of Padova (Italy), in her discussion of the trial at ESMO Breast Cancer 2020.

Patients with larger initial tumor size and multiple involved axillary nodes at diagnosis remain at increased risk of death because of cancer relapse.

Central nervous system relapse remains a vexing problem. Among patients with triple-positive breast cancer, relapses may occur late, despite pCR.

Patients whose tumors transform from HER2 positive to HER2 negative with NAT, seen in approximately 8% of cases in the KATHERINE trial (ESMO Breast Cancer 2020, Abstract 96O), may be another poor-risk group.
 

Clinical implications

PREDIX-HER2 is an important study. At the early time point of 2.4 years (especially early since most patients were HR-positive), if pCR is achieved, event-free survival is excellent with T-DM1 or an aggressive multiagent cytotoxic combination plus dual HER2 targeting followed by anthracyclines.

It is ideal to have clinical-pathologic tests to distinguish those patients destined to achieve the surrogate endpoint of pCR from those who will not achieve it.

Despite linkage of TILs to improved outcome for triple-negative and HER2-enriched molecular subtypes (Lancet Oncol. 2018 Jan;19[1]:40-50), analysis of TILs is not standard practice in HER2-positive breast cancer in community settings. Optimal cutoffs are not well established, and TILs have not been linked to the choice of particular treatment options.

Currently, PET-CT scans are not part of National Comprehensive Cancer Network guidelines for pretreatment evaluation, except in patients for whom there is clinical suspicion of distant disease.

For those reasons, the main results of PREDIX-HER2 remain research tools that will focus our attention on the clinical-pathologic correlations Dr. Hatschek highlighted, but the results should have no influence on routine clinical practice at this time.

PREDIX-HER2 was funded by the Swedish Cancer Society, Radiumhemmet of Karolinska Institutet, Region Stockholm, and Roche Sweden. Dr. Hatschek disclosed relationships with Roche Sweden, Pfizer Sweden, and Pierre Fabre Sweden. Dr. Guarneri disclosed relationships with Roche, Novartis, and Eli Lilly.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

SOURCE: Hatschek T et al. ESMO Breast Cancer 2020, Abstract 97O.

In an update of the PREDIX-HER2 trial, trastuzumab emtansine (T-DM1) remained equivalent to standard neoadjuvant chemotherapy plus dual-targeted HER2 therapy in producing pathologic complete remissions (pCRs) among patients with HER2-positive, metastatic breast cancer.

The new data also suggest tumor-infiltrating lymphocytes (TILs) and dramatic improvements in PET-CT scans can predict favorable outcomes in both treatment groups. Though these findings will be useful for research purposes, they likely won’t influence routine clinical practice.

Thomas Hatschek, MD, PhD, of Karolinska Institutet in Stockholm, presented the updated results from PREDIX-HER2 during the European Society for Medical Oncology: Breast Cancer virtual meeting.

PREDIX-HER2 included patients with HER2-positive breast cancer and tumor size greater than 20 mm or lymph node metastases.

Patients received neoadjuvant therapy (NAT) with docetaxel and trastuzumab plus pertuzumab (DTP) or T-DM1 every 3 weeks for a planned total of six courses. The protocol permitted switching to the competing treatment for progression, lack of response, or drug-related severe toxicity.

Postoperatively, all patients received triweekly epirubicin plus cyclophosphamide – four courses for the T-DM1 arm and two courses for the DTP arm. All patients then received triweekly adjuvant trastuzumab for 11 courses. The 62% of patients whose tumors were hormone receptor (HR)–positive received standard endocrine therapy postoperatively.
 

Updated results, predictors of pCR

At the 2019 ASCO annual meeting, PREDIX-HER2 investigators reported that, when compared with DTP, T-DM1 produced the same likelihood of pCR with less toxicity (ASCO 2019, Abstract 501). Updated data presented at ESMO Breast Cancer 2020 showed similar results.

The pCR rate was 45.5% in the DTP arm and 43.9% in the T-DM1 arm (P = .824). pCR rates were higher for HR-negative tumors – 63.6% in the DTP arm and 59% in the T-DM1 arm – than for HR-positive tumors – 36.4% in the DTP arm and 33.9% in the TDM-1 arm.

Three patients had disease progression with T-DM1, and none progressed with DTP. However, almost twice as many patients switched from DTP to T-DM1, compared with the other sequence.

Dr. Hatschek reported that the presence of at least 10% TILs predicted pCR in both treatment groups. Among patients who achieved a pCR, 52.2% had at least 10% TILs in baseline biopsies, and 30.4% had less than 10% TILs.

In addition, a decrease of FDG maximum standardized uptake value by more than 75% on protocol-required PET-CT scans was highly predictive of pCR. Among patients who achieved a pCR, 70.3% had a maximum standardized uptake value decrease of more than 75%, and 22.5% had a decrease of 75% or less.

At median follow-up of 28.5 months, event-free survival was similar between the treatment arms. Overall, there were 13 cases of progression, relapse, contralateral breast cancer, distant metastases, or death from any cause. There were five such events in the DTP arm and eight in the TDM-1 arm.

Dr. Hatschek concluded that neoadjuvant T-DM1 may be as effective as standard NAT in all clinical subgroups evaluated. Both TILs and PET-CT showed the potential to predict pCR and merit further study in the NAT setting.
 

An imperfect surrogate

By definition, a surrogate is “one appointed to act in place of another.” In the case of PREDIX-HER2 and most other NAT studies in HER2-positive breast cancer patients, pCR is a surrogate for the endpoint about which doctors and patients really care – cancer-free survival.

As such, pCR is not a perfect surrogate. Reproducibly, pCR has been highly predictive of disease-free survival and overall survival, especially in the HR-negative subset of HER2-positive patients.

However, despite improvements with dual targeting of HER2 in the TRYPHAENA trial (Eur J Cancer. 2018;89:27-35) and the use of T-DM1 for patients failing to achieve pCR in the immediately practice-changing KATHERINE trial (N Engl J Med. 2019;380:617-28), eventual relapse is seen in 10%-20% of patients in various clinical-pathologic subgroups.

In PREDIX-HER2, the pCR rate for node-positive patients was considerably lower with T-DM1 than with DTP (54.1% vs. 38%), noted Valentina Guarneri, MD, of the University of Padova (Italy), in her discussion of the trial at ESMO Breast Cancer 2020.

Patients with larger initial tumor size and multiple involved axillary nodes at diagnosis remain at increased risk of death because of cancer relapse.

Central nervous system relapse remains a vexing problem. Among patients with triple-positive breast cancer, relapses may occur late, despite pCR.

Patients whose tumors transform from HER2 positive to HER2 negative with NAT, seen in approximately 8% of cases in the KATHERINE trial (ESMO Breast Cancer 2020, Abstract 96O), may be another poor-risk group.
 

Clinical implications

PREDIX-HER2 is an important study. At the early time point of 2.4 years (especially early since most patients were HR-positive), if pCR is achieved, event-free survival is excellent with T-DM1 or an aggressive multiagent cytotoxic combination plus dual HER2 targeting followed by anthracyclines.

It is ideal to have clinical-pathologic tests to distinguish those patients destined to achieve the surrogate endpoint of pCR from those who will not achieve it.

Despite linkage of TILs to improved outcome for triple-negative and HER2-enriched molecular subtypes (Lancet Oncol. 2018 Jan;19[1]:40-50), analysis of TILs is not standard practice in HER2-positive breast cancer in community settings. Optimal cutoffs are not well established, and TILs have not been linked to the choice of particular treatment options.

Currently, PET-CT scans are not part of National Comprehensive Cancer Network guidelines for pretreatment evaluation, except in patients for whom there is clinical suspicion of distant disease.

For those reasons, the main results of PREDIX-HER2 remain research tools that will focus our attention on the clinical-pathologic correlations Dr. Hatschek highlighted, but the results should have no influence on routine clinical practice at this time.

PREDIX-HER2 was funded by the Swedish Cancer Society, Radiumhemmet of Karolinska Institutet, Region Stockholm, and Roche Sweden. Dr. Hatschek disclosed relationships with Roche Sweden, Pfizer Sweden, and Pierre Fabre Sweden. Dr. Guarneri disclosed relationships with Roche, Novartis, and Eli Lilly.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

SOURCE: Hatschek T et al. ESMO Breast Cancer 2020, Abstract 97O.

Adding the AKT inhibitor ipatasertib to paclitaxel may provide an overall survival (OS) benefit for inoperable locally advanced/metastatic triple-negative breast cancer (TNBC), according to final results of the phase 2 LOTUS trial.

The median OS was 25.8 months in patients who received ipatasertib plus paclitaxel and 16.9 months in patients who received paclitaxel plus placebo. Although this difference was not statistically significant, it was “clinically meaningful,” according to Rebecca Dent, MD, of the National Cancer Center Singapore. Dr. Dent presented OS data from the LOTUS trial at the European Society of Medical Oncology: Breast Cancer virtual meeting.

Previously reported data showed a progression-free survival benefit in the ipatasertib arm, compared with the placebo arm – 6.2 months and 4.9 months, respectively (Lancet Oncol. 2017 Oct;18[10]:1360-72). An enhanced effect was noted in patients with PIK3CA/AKT1/PTEN–altered tumors, but the OS data were not mature at the time of that primary analysis.
 

Patients, treatment, and safety

LOTUS participants had measurable locally advanced/metastatic TNBC that was previously untreated with systemic therapy, and they were stratified by prior adjuvant therapy, chemotherapy-free interval, and tumor immunohistochemistry PTEN status.

Patients were randomized 1:1 to receive paclitaxel at a dose of 80 mg/m² on days 1, 8, and 15 of each 28-day cycle plus either placebo (n = 62) or ipatasertib at a dose of 400 mg on days 1-21 (n = 62).

The safety results didn’t differ between the primary and updated results, Dr. Dent noted.

“What we can say is that the combination is extremely well tolerated, especially when we compare it to other targeted agents targeting this pathway,” she said. “What we do see is noticeable diarrhea ... [and] an increase in sensory neuropathy, which is not entirely unexpected.”

Subsequent systemic anticancer therapy was required in 77% of patients in the ipatasertib arm and 90% of patients in the placebo arm.
 

OS results

The final OS data show a numerical advantage for patients in the ipatasertib arm compared with the placebo arm. The 1-year OS was 83% in the ipatasertib arm and 68% in the placebo arm. The median OS was 25.8 months and 16.9 months, respectively (stratified hazard ratio, 0.80).

“This is a clinically meaningful improvement of 9 months in overall survival, which is indeed not too dissimilar to what we have seen in patients with PD-L1-positive TNBC who are receiving immune checkpoint inhibition in combination with chemotherapy,” Dr. Dent said.

However, the 95% confidence interval for the stratified OS hazard ratio crossed 1 (0.50-1.28). Therefore, the findings require confirmatory phase 3 trial results, Dr. Dent said.

The OS improvements with ipatasertib were seen “in all biomarker-defined subgroups – PTEN normal or low, PIK3CA/AKT1/PTEN altered or non-altered,” she said. OS benefits were more pronounced in patients with altered PIK3C/AKT1/PTEN status, but the numbers are too small to make definitive conclusions, according to Dr. Dent.
 

‘Promising’ results, confirmation needed

Invited discussant Suzette Delaloge, MD, head of the breast cancer department at Gustave Roussy, Paris, said the OS findings from LOTUS are “quite promising,” and the safety data are “reassuring.”

The findings are comparable to those of the recently published PAKT trial (J Clin Oncol. 2020 Feb 10;38[5]:423-33), she said, noting that “AKT inhibition in combination with paclitaxel deserves phase 3 development, and this is ongoing in major phase 3 trials.”

Dr. Delaloge also noted that the efficacy may not be limited to PIK3CA/AKT–altered tumors, and given the heterogeneity of TNBC – which may explain the differences seen among various studies – “it is very important that such phase 3 trials ideally involve extensive genomical definitions of tumors so that we understand what it is we are talking about and what is the real effect of the drug.”

“The adequate positioning of AKT inhibition in competition/complementation with other ongoing strategies remains to be defined,” she said. “I think these drugs are ready for translation to early phases.”

Dr. Dent said the results of LOTUS warrant confirmation in the ongoing, randomized phase 3 IPATunity130 trial , in which researchers are evaluating first-line ipatasertib plus paclitaxel for metastatic TNBC. She noted that the small sample sizes and heterogeneity of TNBC among LOTUS participants limited the interpretation of the findings.

In another trial, IPATunity170, researchers are evaluating the first-line role of ipatasertib plus paclitaxel and atezolizumab in locally advanced or metastatic TNBC.

“This is an exciting triplet combination that’s been evaluated already in the phase 1 setting, and now we have a phase 3 study evaluating the triplet,” Dr. Dent said.

The LOTUS trial was funded by Roche/Genentech. Dr. Dent reported receiving honoraria from Roche, Novartis, Lilly, Pfizer, Eisai, Merck, and AstraZeneca. Dr. Delaloge reported personal financial interests in AstraZeneca until 2018 and travel and accommodation support from AstraZeneca, Pfizer, Roche, and Pierre Fabre.

[email protected]

SOURCE: Dent R et al. ESMO Breast Cancer 2020, Abstract 139O

Adding the AKT inhibitor ipatasertib to paclitaxel may provide an overall survival (OS) benefit for inoperable locally advanced/metastatic triple-negative breast cancer (TNBC), according to final results of the phase 2 LOTUS trial.

The median OS was 25.8 months in patients who received ipatasertib plus paclitaxel and 16.9 months in patients who received paclitaxel plus placebo. Although this difference was not statistically significant, it was “clinically meaningful,” according to Rebecca Dent, MD, of the National Cancer Center Singapore. Dr. Dent presented OS data from the LOTUS trial at the European Society of Medical Oncology: Breast Cancer virtual meeting.

Previously reported data showed a progression-free survival benefit in the ipatasertib arm, compared with the placebo arm – 6.2 months and 4.9 months, respectively (Lancet Oncol. 2017 Oct;18[10]:1360-72). An enhanced effect was noted in patients with PIK3CA/AKT1/PTEN–altered tumors, but the OS data were not mature at the time of that primary analysis.
 

Patients, treatment, and safety

LOTUS participants had measurable locally advanced/metastatic TNBC that was previously untreated with systemic therapy, and they were stratified by prior adjuvant therapy, chemotherapy-free interval, and tumor immunohistochemistry PTEN status.

Patients were randomized 1:1 to receive paclitaxel at a dose of 80 mg/m² on days 1, 8, and 15 of each 28-day cycle plus either placebo (n = 62) or ipatasertib at a dose of 400 mg on days 1-21 (n = 62).

The safety results didn’t differ between the primary and updated results, Dr. Dent noted.

“What we can say is that the combination is extremely well tolerated, especially when we compare it to other targeted agents targeting this pathway,” she said. “What we do see is noticeable diarrhea ... [and] an increase in sensory neuropathy, which is not entirely unexpected.”

Subsequent systemic anticancer therapy was required in 77% of patients in the ipatasertib arm and 90% of patients in the placebo arm.
 

OS results

The final OS data show a numerical advantage for patients in the ipatasertib arm compared with the placebo arm. The 1-year OS was 83% in the ipatasertib arm and 68% in the placebo arm. The median OS was 25.8 months and 16.9 months, respectively (stratified hazard ratio, 0.80).

“This is a clinically meaningful improvement of 9 months in overall survival, which is indeed not too dissimilar to what we have seen in patients with PD-L1-positive TNBC who are receiving immune checkpoint inhibition in combination with chemotherapy,” Dr. Dent said.

However, the 95% confidence interval for the stratified OS hazard ratio crossed 1 (0.50-1.28). Therefore, the findings require confirmatory phase 3 trial results, Dr. Dent said.

The OS improvements with ipatasertib were seen “in all biomarker-defined subgroups – PTEN normal or low, PIK3CA/AKT1/PTEN altered or non-altered,” she said. OS benefits were more pronounced in patients with altered PIK3C/AKT1/PTEN status, but the numbers are too small to make definitive conclusions, according to Dr. Dent.
 

‘Promising’ results, confirmation needed

Invited discussant Suzette Delaloge, MD, head of the breast cancer department at Gustave Roussy, Paris, said the OS findings from LOTUS are “quite promising,” and the safety data are “reassuring.”

The findings are comparable to those of the recently published PAKT trial (J Clin Oncol. 2020 Feb 10;38[5]:423-33), she said, noting that “AKT inhibition in combination with paclitaxel deserves phase 3 development, and this is ongoing in major phase 3 trials.”

Dr. Delaloge also noted that the efficacy may not be limited to PIK3CA/AKT–altered tumors, and given the heterogeneity of TNBC – which may explain the differences seen among various studies – “it is very important that such phase 3 trials ideally involve extensive genomical definitions of tumors so that we understand what it is we are talking about and what is the real effect of the drug.”

“The adequate positioning of AKT inhibition in competition/complementation with other ongoing strategies remains to be defined,” she said. “I think these drugs are ready for translation to early phases.”

Dr. Dent said the results of LOTUS warrant confirmation in the ongoing, randomized phase 3 IPATunity130 trial , in which researchers are evaluating first-line ipatasertib plus paclitaxel for metastatic TNBC. She noted that the small sample sizes and heterogeneity of TNBC among LOTUS participants limited the interpretation of the findings.

In another trial, IPATunity170, researchers are evaluating the first-line role of ipatasertib plus paclitaxel and atezolizumab in locally advanced or metastatic TNBC.

“This is an exciting triplet combination that’s been evaluated already in the phase 1 setting, and now we have a phase 3 study evaluating the triplet,” Dr. Dent said.

The LOTUS trial was funded by Roche/Genentech. Dr. Dent reported receiving honoraria from Roche, Novartis, Lilly, Pfizer, Eisai, Merck, and AstraZeneca. Dr. Delaloge reported personal financial interests in AstraZeneca until 2018 and travel and accommodation support from AstraZeneca, Pfizer, Roche, and Pierre Fabre.

[email protected]

SOURCE: Dent R et al. ESMO Breast Cancer 2020, Abstract 139O

Adding the AKT inhibitor ipatasertib to paclitaxel may provide an overall survival (OS) benefit for inoperable locally advanced/metastatic triple-negative breast cancer (TNBC), according to final results of the phase 2 LOTUS trial.

The median OS was 25.8 months in patients who received ipatasertib plus paclitaxel and 16.9 months in patients who received paclitaxel plus placebo. Although this difference was not statistically significant, it was “clinically meaningful,” according to Rebecca Dent, MD, of the National Cancer Center Singapore. Dr. Dent presented OS data from the LOTUS trial at the European Society of Medical Oncology: Breast Cancer virtual meeting.

Previously reported data showed a progression-free survival benefit in the ipatasertib arm, compared with the placebo arm – 6.2 months and 4.9 months, respectively (Lancet Oncol. 2017 Oct;18[10]:1360-72). An enhanced effect was noted in patients with PIK3CA/AKT1/PTEN–altered tumors, but the OS data were not mature at the time of that primary analysis.
 

Patients, treatment, and safety

LOTUS participants had measurable locally advanced/metastatic TNBC that was previously untreated with systemic therapy, and they were stratified by prior adjuvant therapy, chemotherapy-free interval, and tumor immunohistochemistry PTEN status.

Patients were randomized 1:1 to receive paclitaxel at a dose of 80 mg/m² on days 1, 8, and 15 of each 28-day cycle plus either placebo (n = 62) or ipatasertib at a dose of 400 mg on days 1-21 (n = 62).

The safety results didn’t differ between the primary and updated results, Dr. Dent noted.

“What we can say is that the combination is extremely well tolerated, especially when we compare it to other targeted agents targeting this pathway,” she said. “What we do see is noticeable diarrhea ... [and] an increase in sensory neuropathy, which is not entirely unexpected.”

Subsequent systemic anticancer therapy was required in 77% of patients in the ipatasertib arm and 90% of patients in the placebo arm.
 

OS results

The final OS data show a numerical advantage for patients in the ipatasertib arm compared with the placebo arm. The 1-year OS was 83% in the ipatasertib arm and 68% in the placebo arm. The median OS was 25.8 months and 16.9 months, respectively (stratified hazard ratio, 0.80).

“This is a clinically meaningful improvement of 9 months in overall survival, which is indeed not too dissimilar to what we have seen in patients with PD-L1-positive TNBC who are receiving immune checkpoint inhibition in combination with chemotherapy,” Dr. Dent said.

However, the 95% confidence interval for the stratified OS hazard ratio crossed 1 (0.50-1.28). Therefore, the findings require confirmatory phase 3 trial results, Dr. Dent said.

The OS improvements with ipatasertib were seen “in all biomarker-defined subgroups – PTEN normal or low, PIK3CA/AKT1/PTEN altered or non-altered,” she said. OS benefits were more pronounced in patients with altered PIK3C/AKT1/PTEN status, but the numbers are too small to make definitive conclusions, according to Dr. Dent.
 

‘Promising’ results, confirmation needed

Invited discussant Suzette Delaloge, MD, head of the breast cancer department at Gustave Roussy, Paris, said the OS findings from LOTUS are “quite promising,” and the safety data are “reassuring.”

The findings are comparable to those of the recently published PAKT trial (J Clin Oncol. 2020 Feb 10;38[5]:423-33), she said, noting that “AKT inhibition in combination with paclitaxel deserves phase 3 development, and this is ongoing in major phase 3 trials.”

Dr. Delaloge also noted that the efficacy may not be limited to PIK3CA/AKT–altered tumors, and given the heterogeneity of TNBC – which may explain the differences seen among various studies – “it is very important that such phase 3 trials ideally involve extensive genomical definitions of tumors so that we understand what it is we are talking about and what is the real effect of the drug.”

“The adequate positioning of AKT inhibition in competition/complementation with other ongoing strategies remains to be defined,” she said. “I think these drugs are ready for translation to early phases.”

Dr. Dent said the results of LOTUS warrant confirmation in the ongoing, randomized phase 3 IPATunity130 trial , in which researchers are evaluating first-line ipatasertib plus paclitaxel for metastatic TNBC. She noted that the small sample sizes and heterogeneity of TNBC among LOTUS participants limited the interpretation of the findings.

In another trial, IPATunity170, researchers are evaluating the first-line role of ipatasertib plus paclitaxel and atezolizumab in locally advanced or metastatic TNBC.

“This is an exciting triplet combination that’s been evaluated already in the phase 1 setting, and now we have a phase 3 study evaluating the triplet,” Dr. Dent said.

The LOTUS trial was funded by Roche/Genentech. Dr. Dent reported receiving honoraria from Roche, Novartis, Lilly, Pfizer, Eisai, Merck, and AstraZeneca. Dr. Delaloge reported personal financial interests in AstraZeneca until 2018 and travel and accommodation support from AstraZeneca, Pfizer, Roche, and Pierre Fabre.

[email protected]

SOURCE: Dent R et al. ESMO Breast Cancer 2020, Abstract 139O