Gedatolisib Combo Approved for Advanced Breast Cancer

The FDA has approved gedatolisib (Revtorpyk, Celcuity) plus fulvestrant, with or without palbociclib, for patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer without a PIK3CA mutation detected following progression on or after treatment with at least 1 line of endocrine therapy in the metastatic setting.

Gedatolisib is a multitarget inhibitor of the PI3K/AKT/mTOR (PAM) pathway, a key oncogenic driver of HR-positive, HER2-negative breast cancer that contributes to treatment resistance. While previously approved medications target single components of the pathway, gedatolisib blocks PI3K and mTOR together, leading to more comprehensive suppression, which may in turn help restore sensitivity to endocrine therapy and anti-CDK4/6 inhibition.

Approval was based on the VIKTORIA-1 trial, which randomly assigned 392 patients evenly to either gedatolisib, palbociclib, and fulvestrant (gedatolisib triplet); gedatolisib plus fulvestrant (gedatolisib doublet); or fulvestrant alone.

Median progression-free survival, the major efficacy outcome, was 9.3 months in the gedatolisib-triplet group, 7.4 months in the gedatolisib-doublet arm, and 2 months with fulvestrant monotherapy. Overall survival data were not yet mature.

In a paper published in the Journal of Clinical Oncology in March, the investigators acknowledged that fulvestrant monotherapy is no longer standard of care in the second line after anti-CDK4/6 and aromatase inhibitor failure, and that it was chosen as a comparator to meet regulatory requirements.

Still, they said the median progression-free survival in the triplet arm is “among the longest reported for a chemotherapy-free second- to third-line regimen in a phase III trial.”

Grade 3 or higher treatment-related adverse events in the triplet and doublet groups included neutropenia (62.3%, 0.8%), stomatitis (19.2%, 12.3%), rash (4.6%, 5.4%), hyperglycemia (2.3%, 2.3%), and diarrhea (1.5%, 0.8%). Overall, 2.3% of triplet and 3.1% of doublet patients stopped treatment due to adverse events. There were two treatment-related deaths in the triplet arm, one from pneumonia and the other from liver failure.

In June, Celcuity reported similarly favorable survival outcomes among 350 patients in VIKTORIA-1 who had PIK3CA mutations. Median progression-free survival was over 11 months with both the gedatolisib triplet and doublet vs 5.6 months with alpelisib plus fulvestrant, which was the comparator in the cohort with PIK3CA mutations.

The company said it planned to submit a supplemental application to the FDA for approval in patients with PIK3CA mutations.

The recommended dosage for gedatolisib is 180 mg as an intravenous infusion once weekly on days 1, 8, and 15 of every 28-day cycle, in combination with fulvestrant, with or without palbociclib, until disease progression or unacceptable toxicity.

M. Alexander Otto is a physician assistant and award-winning journalist. He is also an MIT science journalism fellow. Email: aotto@medscape.net

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

The FDA has approved gedatolisib (Revtorpyk, Celcuity) plus fulvestrant, with or without palbociclib, for patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer without a PIK3CA mutation detected following progression on or after treatment with at least 1 line of endocrine therapy in the metastatic setting.

Gedatolisib is a multitarget inhibitor of the PI3K/AKT/mTOR (PAM) pathway, a key oncogenic driver of HR-positive, HER2-negative breast cancer that contributes to treatment resistance. While previously approved medications target single components of the pathway, gedatolisib blocks PI3K and mTOR together, leading to more comprehensive suppression, which may in turn help restore sensitivity to endocrine therapy and anti-CDK4/6 inhibition.

Approval was based on the VIKTORIA-1 trial, which randomly assigned 392 patients evenly to either gedatolisib, palbociclib, and fulvestrant (gedatolisib triplet); gedatolisib plus fulvestrant (gedatolisib doublet); or fulvestrant alone.

Median progression-free survival, the major efficacy outcome, was 9.3 months in the gedatolisib-triplet group, 7.4 months in the gedatolisib-doublet arm, and 2 months with fulvestrant monotherapy. Overall survival data were not yet mature.

In a paper published in the Journal of Clinical Oncology in March, the investigators acknowledged that fulvestrant monotherapy is no longer standard of care in the second line after anti-CDK4/6 and aromatase inhibitor failure, and that it was chosen as a comparator to meet regulatory requirements.

Still, they said the median progression-free survival in the triplet arm is “among the longest reported for a chemotherapy-free second- to third-line regimen in a phase III trial.”

Grade 3 or higher treatment-related adverse events in the triplet and doublet groups included neutropenia (62.3%, 0.8%), stomatitis (19.2%, 12.3%), rash (4.6%, 5.4%), hyperglycemia (2.3%, 2.3%), and diarrhea (1.5%, 0.8%). Overall, 2.3% of triplet and 3.1% of doublet patients stopped treatment due to adverse events. There were two treatment-related deaths in the triplet arm, one from pneumonia and the other from liver failure.

In June, Celcuity reported similarly favorable survival outcomes among 350 patients in VIKTORIA-1 who had PIK3CA mutations. Median progression-free survival was over 11 months with both the gedatolisib triplet and doublet vs 5.6 months with alpelisib plus fulvestrant, which was the comparator in the cohort with PIK3CA mutations.

The company said it planned to submit a supplemental application to the FDA for approval in patients with PIK3CA mutations.

The recommended dosage for gedatolisib is 180 mg as an intravenous infusion once weekly on days 1, 8, and 15 of every 28-day cycle, in combination with fulvestrant, with or without palbociclib, until disease progression or unacceptable toxicity.

M. Alexander Otto is a physician assistant and award-winning journalist. He is also an MIT science journalism fellow. Email: aotto@medscape.net

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

The FDA has approved gedatolisib (Revtorpyk, Celcuity) plus fulvestrant, with or without palbociclib, for patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer without a PIK3CA mutation detected following progression on or after treatment with at least 1 line of endocrine therapy in the metastatic setting.

Gedatolisib is a multitarget inhibitor of the PI3K/AKT/mTOR (PAM) pathway, a key oncogenic driver of HR-positive, HER2-negative breast cancer that contributes to treatment resistance. While previously approved medications target single components of the pathway, gedatolisib blocks PI3K and mTOR together, leading to more comprehensive suppression, which may in turn help restore sensitivity to endocrine therapy and anti-CDK4/6 inhibition.

Approval was based on the VIKTORIA-1 trial, which randomly assigned 392 patients evenly to either gedatolisib, palbociclib, and fulvestrant (gedatolisib triplet); gedatolisib plus fulvestrant (gedatolisib doublet); or fulvestrant alone.

Median progression-free survival, the major efficacy outcome, was 9.3 months in the gedatolisib-triplet group, 7.4 months in the gedatolisib-doublet arm, and 2 months with fulvestrant monotherapy. Overall survival data were not yet mature.

In a paper published in the Journal of Clinical Oncology in March, the investigators acknowledged that fulvestrant monotherapy is no longer standard of care in the second line after anti-CDK4/6 and aromatase inhibitor failure, and that it was chosen as a comparator to meet regulatory requirements.

Still, they said the median progression-free survival in the triplet arm is “among the longest reported for a chemotherapy-free second- to third-line regimen in a phase III trial.”

Grade 3 or higher treatment-related adverse events in the triplet and doublet groups included neutropenia (62.3%, 0.8%), stomatitis (19.2%, 12.3%), rash (4.6%, 5.4%), hyperglycemia (2.3%, 2.3%), and diarrhea (1.5%, 0.8%). Overall, 2.3% of triplet and 3.1% of doublet patients stopped treatment due to adverse events. There were two treatment-related deaths in the triplet arm, one from pneumonia and the other from liver failure.

In June, Celcuity reported similarly favorable survival outcomes among 350 patients in VIKTORIA-1 who had PIK3CA mutations. Median progression-free survival was over 11 months with both the gedatolisib triplet and doublet vs 5.6 months with alpelisib plus fulvestrant, which was the comparator in the cohort with PIK3CA mutations.

The company said it planned to submit a supplemental application to the FDA for approval in patients with PIK3CA mutations.

The recommended dosage for gedatolisib is 180 mg as an intravenous infusion once weekly on days 1, 8, and 15 of every 28-day cycle, in combination with fulvestrant, with or without palbociclib, until disease progression or unacceptable toxicity.

M. Alexander Otto is a physician assistant and award-winning journalist. He is also an MIT science journalism fellow. Email: aotto@medscape.net

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