Treatment with a CDK4/6 inhibitor (CDK4/6i) combined with endocrine therapy (ET) is the front-line (1L) standard of care for HR+/HER2- advanced breast cancer (ABC). Resistance to a CDK4/6i can arise in a number of ways, including adaptive activation of the PI3K/mTOR pathway, which may be prevented by addition of a PI3K/mTOR inhibitor to the 1L CDK4/6i + ET regimen. To evaluate this hypothesis, we conducted a phase Ib study of gedatolisib, a pan-PI3K/mTOR inhibitor, palbociclib (palbo), a CDK4/6i, and ET (letrozole [LET] or fulvestrant) in 138 women with HR+/HER2- ABC. Promising preliminary antitumor activity was observed (Wesolowski, SABCS 2022). Here, we report updated baseline characteristics, safety, and efficacy data in treatment naïve patients (pts) treated with gedatolisib + palbo + LET.
We analyzed the treatment naive subgroup of pts with HR+/HER2- ABC who were treated with gedatolisib + palbo + LET as 1L treatment (Escalation and Expansion Arms A; n=41). The primary endpoint was investigator assessed objective response rate (ORR). Secondary endpoints included safety, duration of response, and progression free survival (PFS).
Of these 41 pts, 95% had Stage 4 disease, 37% had metastases to the liver, 17% had metastases to the lung, 93% had measurable lesions, and 24% had PIK3CA mutations. The most common Grade 3-4 adverse events (AE) in the treatment naïve subgroup were neutropenia (61%), rash (39%), stomatitis (29%), and leukopenia (22%). Five of 41 pts (12%) discontinued treatment due to an AE. As of December 12, 2022, for Expansion Arm A, median PFS was 48.6 months (n=30) and ORR was 85% (n=26, measurable and evaluable disease). When treatment naïve pts from both arms are combined, mPFS was 48.6 months (n=41) and ORR was 79% (n=33, measurable and evaluable disease).
The gedatolisib + palbo + LET combination demonstrated promising activity in treatment-naïve pts with ABC. The safety profile of gedatolisib + palbo + LET was similar to palbo + LET. These encouraging results warrant further evaluation of gedatolisib in combination with a CDK4/6i + LET in the front-line setting.
NCT02684032.
Celcuity, Inc.
Celcuity, Inc.
H.S. Rugo: Financial Interests, Personal, Research Grant: AstraZeneca, Ayala, Boehringer Ingelheim, Daiichi Sankyo, Genentech, Gilead Sciences, Lilly, Macrogenics, Merck, Novartis, OBI Pharma, Odonate Therapeutics, Pfizer, Seattle Genetics, Sermonix Pharmaceuticals; Financial Interests, Personal, Other, Honoraria: Blueprint, Mylan, Puma Biotechnology. R. Wesolowski: Financial Interests, Personal, Other, advisory boards, scientific steering committee: Celcuity; Financial Interests, Personal, Advisory Board: Seagen. E. Stringer-Reasor: Financial Interests, Personal, Advisory Board: AstraZeneca, Immunomedics, Novartis, Lilly, OncoSec, Merck, Seattle Genetics, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Lilly; Financial Interests, Personal, Other, Honoraria: Breast Cancer Index, Lilly, Mylan; Financial Interests, Personal, Research Grant: Susan G. Komen for the Cure, V Foundation; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Cascadian Therapeutics, Lilly; Non-Financial Interests, Personal, Other, Uncompensated Relationship: Genentech. H. Han: Financial Interests, Personal, Advisory Board: Novartis, Gilead, AstraZeneca; Financial Interests, Personal, Other, Speaker's Bureau: Lilly; Financial Interests, Institutional, Invited Speaker: Zymeworks, arvinas, AbbVie, Daiichi Sankyo, Marker therapeutics, Pfizer, Seagen, Quantum Leap Healthcare Collaborative. J. Specht: Financial Interests, Personal, Other, Investigator Meeting participant: A2 Biotherapeutics; Financial Interests, Personal, Advisory Board: GE Healthcare, GSK, Sensei Biotherapeutics; Financial Interests, Personal, Other, Consultant: Volastra Therapeutics; Financial Interests, Institutional, Research Grant: Seattle Genetics, Pfizer, Merck, Xencor, Genentech, Celcuity, Minerva, Myriad Pharmaceuticals, Cascadian Therapeutics, AbbVie, Nektar. C. Dees: Financial Interests, Personal, Advisory Board: Novartis, Sanofi. P. Kabos: Financial Interests, Personal, Research Grant: AstraZeneca, Genentech, Lilly, Pfizer, Radius Health, Sanofi; Financial Interests, Personal, Advisory Board: Lilly. U.N. Vaishampayan: Financial Interests, Personal, Advisory Board: Merck, BMS, Exelixis, Gilead, Pfizer, Bayer; Financial Interests, Personal, Invited Speaker: Exelixis, Sanofi, Bayer; Financial Interests, Personal, Research Grant: Merck, BMS. S.A. Wander: Financial Interests, Personal, Advisory Board: Foundation Medicine, Veracyte, Hologic, Biovica, Pfizer, Eli Lilly, Puma Biotechnology; Financial Interests, Personal, Invited Speaker: Eli Lilly, Guardant Health, 2ndMD; Financial Interests, Institutional, Research Grant: Genentech, Eli Lilly, Pfizer, Nuvation Bio, Regor Therapeutics. J. Lu: Financial Interests, Personal, Other, Ownership Interest (stocks, stock options, patent or other intellectual property or other ownership interest excluding diversified mutual funds), Salar: Ambrx; Financial Interests, Personal, Advisory Board: AstraZeneca, Lilly, Pfizer, Sanofi, Seagen. K. Gogineni: Financial Interests, Personal, Other, Honoraria: AmerisourceBergen; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Institutional, Research Grant: Pfizer, Calithera Biosciences, Merck, Genentech, Seagen. A. Spira: Financial Interests, Institutional, Leadership Role: NEXT Oncology Virginia; Financial Interests, Personal, Stocks/Shares: Eli Lilly; Financial Interests, Personal, Other, Honoraria: CytomX Therapeutics, AstraZeneca/MedImmune, Merck, Takeda, Amgen, Janssen Oncology, Novartis, BMS, Bayer; Financial Interests, Personal, Advisory Board: Incyte, Amgen, Novartis, Mirati Therapeutics, Gritstone, Oncology, Jazz Pharmaceuticals, Takeda, Janssen Research and Development, Mersana, Gritstone Bio, Daiichi Sankyo/AstraZeneca, Regeneron, Lilly, Black Diamond Therapeutics; Financial Interests, Institutional, Advisory Board: Array BioPharma, AstraZeneca/MedImmune, Merck, BMS, Blueprint Medicines; Financial Interests, Personal, Research Grant: LAM Therapeutics, Regeneron; Financial Interests, Institutional, Research Grant: Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, Newlink Genetics, Incyte, AbbVie, Ignyta, LAM Therapeutics, Trovagene, Takeda, Macrogenics, CytomX Therapeutics, Astex Pharmaceuticals, BMS, Loxo, Arch Therapeutics, Gritstone. A. Schott: Financial Interests, Personal, Other, Editorial, Intellectual Property: Up to Date; Financial Interests, Personal, Other, Travel: ASCO; Financial Interests, Personal, Other, Intellectual Property: University of Michigan; Financial Interests, Institutional, Research Grant: Arvinas, Celcuity, Takeda, Relay Therapeutics. M. Abu-Khalaf: Financial Interests, Institutional, Research Grant: Novartis, Merck, Pfizer, Genentech/Roche, Immunomedics, AstraZeneca, HiberCell, Gilead Sciences; Financial Interests, Personal, Advisory Board: Pfizer, BioTheranostics, Immunomedics, Lyell Immunopharma, HiberCell; Financial Interests, Personal, Other, global grant- Investigator Meeting: Pfizer. S. Mutka: Financial Interests, Personal, Full or part-time Employment: Celcuity; Financial Interests, Personal, Stocks/Shares: Celcuity, Alpine Immune Sciences. S. Suzuki: Financial Interests, Personal, Full or part-time Employment: Celcuity; Financial Interests, Personal, Other, Consulting: Artiva Biotherapeutics, Elevation Oncology, Kartos Therapeutics, Tellios Pharma. I. Gorbatchevsky: Financial Interests, Personal, Full or part-time Employment: Celcuity; Financial Interests, Personal, Stocks/Shares: Celcuity. R.M. Layman: Financial Interests, Personal, Research Grant: Celcuity, Accutar Biotechnology, Eli Lilly, Novartis, Pfizer, Puma, Zentalis; Financial Interests, Personal, Advisory Board: Celcuity, Eli Lilly, Novartis.