618MO - Phase Ib/II first-in-class novel combination trial of next generation CDK4-selective inhibitor PF-07220060 and next generation CDK2-selective inhibitor PF-07104091 in HR+ HER2- metastatic breast cancer and advanced solid tumors

Background

We present dose escalation multicenter data of PF-07220060 (PF-60, CDK4-selective inhibitor) plus PF-07104091 (PF-91, CDK2-selective inhibitor) in patients (pts) with HR+ HER2- metastatic breast cancer (mBC) and advanced solid tumors (NCT05262400).

Methods

PF-60/PF-91 (100/225, 200/75, 200/150, 300/75, 300/150 mg) was given orally twice daily (BID) in 28-day cycles. BC pts could start fulvestrant at Cycle 3. Primary objective: safety and tolerability; secondary objectives: pharmacokinetics and anti-tumor activity. Efficacy data reported for mBC pts.

Results

At data cutoff 9 of Oct 23, 33 pts median age 56y, median 3 prior lines of systemic therapy (range 1–14) were enrolled. 26 (78.8%) had mBC (all prior CDK4/6i, 80.8% fulvestrant, 50.0% chemotherapy); 7 pts had other solid tumors. Treatment-emergent adverse events (AEs) occurred in 32 pts (97.0%; 21 [63.6%] grade [G] ≥ 3). Most common were nausea (66.7%; 3.0% G3), neutropenia (66.7%; 33.3% ≥ G3) and diarrhea (63.6%; 3.0% G3).One pt discontinued due to treatment related AEs. Dose-limiting toxicity occurred in 2/6 pts at 200/150 mg [1 G3 nausea; 1 G2-3 hematological AEs], and 3/8 pts at 300/150 mg [1 G4 thrombocytopenia; 1 G3 fatigue; 1 G2-3 fatigue and gastrointestinal AEs]. Steady state exposures were comparable to monotherapy. Early (cycle 1 day 15) decreases in circulating tumor DNA were seen. Based on safety, 2 recommended doses for expansion (BID: 100 mg PF-60/225 mg PF-91; 300 mg PF-60/75 mg PF-91) were chosen in combination with endocrine therapy. Of 18 mBC pts with measurable disease, 5 (27.8%, all with known ESR1 mutations) had RECIST v1.1 partial responses (PR) with duration of response up to 12.1 months (mo), 5 pts (27.8%) had stable disease. For mBC pts (n=26) median progression free survival (mPFS) was 8.3 months, disease control rate was 69.2%; 6 pts are ongoing at data cutoff.

Conclusions

PF-60/PF-91 combination was generally well tolerated with promising antitumor activity in heavily pretreated post-CDK4/6i mBC pts, including 5 PRs in mBC pts with ESR1 mutations and mPFS 8.3 months. Dose expansions are enrolling CDK4/6i-treated and naïve mBC pts.

Clinical trial identification

NCT05262400.

Editorial acknowledgement

Editorial support was provided by David Sunter PhD of Engage Scientific Solutions.

Legal entity responsible for the study

Pfizer.

Funding

Pfizer.

Disclosure

T.A. Yap: Financial Interests, Personal, Other, Consultant: Almac, Aduro, AstraZeneca, Atrin, Axiom, Bayer, Bristol Myers Squibb, Clovis, Cybrexa, EMD Serono, Guidepoint, Ignyta, I-Mab, Jansen, Merck, Pfizer, Repare, Roche, Schrodinger, Varian, Zai Labs, AbbVie, Acrivon, Adagene, Amphista, Artios, Athena, Avoro, Baptist Health Systems, BeiGene, Boxer, C4 Therapeutics, Calithera, Cancer Research UK, Diffusion, F-Star, Genmab, Glenmark, GLG, Globe Life Sciences, GSK, Idience, ImmuneSensor, Institut Gustave Roussy, Intellisphere, Kyn, MEI Pharma, Mereo, Natera, Nexys, Novocure, OHSU, OncoSec, Ono Pharma, Pegascy, PER, Piper-Sandler, Prolynx, resTORbio, Theragnostics, Versant, Vibliome, Xinthera, ZielBio, Radiopharm Theranostics, Sanofi, Ellipses.Life, LRG1, Panangium, Pliant Therapeutics, Synthis, Tessellate Bio, TD2 Theragonostics, Tome Biosciences, Zentalis, Amgen Inc., Astex, Avenzo, BioCity Pharma, Blueprint, Carrick Therapeutics, Circle Pharma, Daiichi Sankyo, Dark Blue Therapeutics, Duke Street Bio, 858 Therapeutics, EcoR1 Capital, Entos, FoRx Therapeutics AG, Genesis Therapeutics, Ideaya Biosciences, Impact Therapeutics, Merit, Monte Rosa Therapeutics, Nested Therapeutics, Nimbus, Odyssey, Onxeo, Protai Bio, Ryvu Therapeutics, SAKK, Servier, Synnovation, Tango, TCG Crossover, Terremoto Biosciences, Terns Pharmaceuticals, Tolremo, Tome, Thryv Therapeutics, Trevarx Biomedical, Veeva, Voronoi Inc.; Financial Interests, Personal, Other, University of Texas MD Anderson Cancer Center, where I am Medical Director of the Institute for Applied Cancer Science, which has a commercial interest in DDR and other inhibitors (IACS30380/ART0380 was licensed to Artios): MD Anderson Cancer Center, Institute for Applied Cancer Sciences; Financial Interests, Personal, Stocks/Shares: Seagan; Financial Interests, Institutional, Other, Grant/Research support: Bayer, Cyteir, EMD Serono, GSK, Karyopharm, Pfizer, Repare, Sanofi, Artios, AstraZeneca, BeiGene, BioNTech, Blueprint, BMS, Clovis, Constellation, Eli Lilly, Forbius, F-Star, Genentech, Haihe, ImmuneSensor, Ionis, Ipsen, Jounce, KSQ, Kyowa, Merck, Mirati, Novartis, Ribon Therapeutics, Regeneron, Rubius, Scholar Rock, Seattle Genetics, Tesaro, Vivace, Acrivon, Zenith; Financial Interests, Institutional, Research Grant: Boundless Bio, Ideaya; Financial Interests, Institutional, Other, Grant/Research Support: Insilico Medicine, Tango. F. Yan: Financial Interests, Personal, Invited Speaker: Eli Lilly, Grail, AstraZeneca, Gilead. S. Sadeghi: Financial Interests, Institutional, Speaker, Consultant, Advisor: Eli Lilly, Eisai, Seagen; Financial Interests, Institutional, Research Funding: Pfizer, QED Therapeutics, Radius, Genentech, Zymeworks, Navire Pharma. T.T. Lin, F. Liu, L. Malky, M. Golmakani, A. Moreau, H. Neumann, L. Zhou: Financial Interests, Institutional, Stocks or ownership: Pfizer. D. Juric: Financial Interests, Personal, Other: Novartis, Genentech, Syros, Eisai, Vibliome, PIC Therapeutics, Mapkure, Relay Therapeutics, Pfizer, Takeda; Financial Interests, Institutional, Other: Amgen, InventisBio, Arvinas, Blueprint, AstraZeneca, Ribon Therapeutics, Infinity. M.R. Sharma: Financial Interests, Institutional, Speaker, Consultant, Advisor: Pliant Therapeutics; Financial Interests, Personal, Stocks or ownership: AbbVie, Amgen, Bristol Myers Squibb, Gilead Sciences, Johnson & Johnson, Moderna, Regeneron, West Pharmaceutical; Financial Interests, Institutional, Funding: Arcus Biosciences, AbbVie, Adcentrx Therapeutics, Alkermes, ALX Oncology, Artios Pharma, Astellas, Boundless Bio, Bolt Biotherapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Biontech, Celgene, Chugai Pharmaceutical, Cullinan, Compugen, Constellation Pharmaceuticals, Deciphera Pharmaceuticals, Debiopharm, eFfector, Elevation Oncology, Exelixis, GenMab, Gilead Sciences, GSK, IgM Biosciences, Ikena, Inhibrx, Incyte, Janssen, Jounce Therapeutics, KLUS Pharma, Lilly, Loxo Oncology, Macrogenics, Merck, Mirati, NGM Biosciences, Onconova, Palleon, Pfizer, Pliant Therapeutics, ProfoundBio, PureTech, Qualigen, Repare Therapeutics, Revolution Medicines, Roche, Sapience Therapeutics, Seagen, Shattuck Labs, SK Life Science, Symphogen, Tempest Therapeutics, Theratechnologies, Tizona Therapeutics, Treadwell Therapeutics, Volastra Therapeutics.