Abstract 264TiP
Background
Vepdegestrant (ARV-471) is an investigational, orally administered PROTAC ER degrader. Initial results from a phase Ib cohort of a first-in-human phase I/II study (NCT04072952) showed that vepdegestrant, in combination with the CDK4/6 inhibitor palbociclib, had robust clinical activity (clinical benefit rate [CBR]: 63.0%) in heavily pretreated patients (pts) with ER+/HER2- advanced breast cancer. PF-07220060 is an investigational CDK4-selective inhibitor, which in contrast to CDK4/6 inhibitors, spares CDK6 blockade and demonstrates less neutropenia in in vivo models. A first-in-human phase I/IIa study (NCT04557449) demonstrated promising antitumor activity with PF-07220060 in pts with advanced solid tumors with a CBR of 52.4%. Preclinical tumor models have shown that vepdegestrant + PF-07220060 effectively suppresses tumor growth to a greater extent than either agent alone. This open-label, multicenter phase Ib/II study (NCT06206837) will evaluate the combination of vepdegestrant + PF-07220060 in pts ≥18 y with confirmed ER+/HER2- advanced breast cancer.
Trial design
The phase Ib portion will use an escalation/de-escalation approach to determine the recommended phase II dose (RP2D) of the combination of vepdegestrant and PF-07220060. The phase II portion will further evaluate the preliminary antitumor activity, safety, and pharmacokinetics (PK) of the combination at the RP2D. Pts (N≈65) will receive vepdegestrant orally once daily continuously and PF-07220060 orally twice daily continuously. The primary endpoint of the phase Ib portion is the number of pts with dose-limiting toxicities; secondary endpoints are antitumor activity (objective response rate [ORR], duration of response [DOR], CBR), progression-free survival (PFS), safety, and PK. The primary endpoint of the phase II portion is ORR; secondary endpoints are antitumor activity (DOR, CBR), PFS, safety, plasma concentrations of study drugs, and changes in circulating tumor DNA.
Clinical trial identification
NCT06206837.
Editorial acknowledgement
Justine Lempart, PhD, of Apollo Medical Communications, part of the Helios Global Group.
Legal entity responsible for the study
Pfizer Inc.
Funding
Pfizer Inc. (sponsor) and Arvinas Estrogen Receptor, Inc. (collaborator).
Disclosure
M.L. Telli: Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Advisory Role: Blueprint Medicines, Daiichi Sankyo, Genentech, Gilead (DSMC), GSK Smith Kline, G1 Therapeutics (DSMC), Guardant, Merck, Natera, Novartis, Pfizer, Inc., RefleXion, Replicate, Sanofi Aventis; Financial Interests, Research Grant: Arvinas Operations, Inc., AstraZeneca, Bayer, Genentech/Roche, GSK Smith Kline, Hummingbird Biosciences, Merck, OncoSec Medical, Pfizer, Inc. C. Gawryletz: Financial Interests, Other, Professional Services: Seagen, AstraZeneca, Daiichi Sankyo, Gilead. M. Wei: Financial Interests, Personal, Advisory Role: Gilead Sciences, bioTheranostics; Financial Interests, Royalties, for an immediate family member: Ambry Genetics. A. Patnaik: Financial Interests, Personal, Advisory Role: Bayer, Novartis, Merck, Seagen, Silverback Therapeutics, Ionova, Gilead Sciences, Daiichi Sankyo, HalioDx, Janssen; Financial Interests, Advisory Role, Immediate Family Member: Genentech/Roche, Merck, Bristol Myers Squibb; Financial Interests, Personal, Other, Honoraria: Texas Society of Clinical Oncology; Financial Interests, Institutional, Research Grant: Merck, Pfizer, Inc., Lilly, Plexxikon, Corvus Pharmaceuticals, Tesaro, AbbVie, Forty Seven, Five Prime Therapeutics, Infinity Pharmaceuticals, Pieris Pharmaceuticals, Surface Oncology, Livzon, Vigeo Therapeutics, Astellas Pharma, Klus Pharma, Symphogen, Syndax, Arcus Ventures, Fochon Pharmaceuticals, Upsher-Smith, Exelixis, Seagen, Bolt Biotherapeutics, Ionova, Daiichi Sankyo, Sanofi, Gilead Sciences, Daiichi Sankyo, Seagen, Ionova, Pionyr, Loxo@Lilly, Nektar, Alpine Immune Sciences, Amgen, Institut de Recherches Internationales (I.R.I.S), 1200 Pharma, Arcus Biosciences, Genentech, AADi, Prelude Therapeutics, KSQ Therapeutics, Carrick Therapeutics, Pyrotec Therapeutics. D.R. Lu: Financial Interests, Personal, Full or part-time Employment: Pfizer, Inc.; Financial Interests, Full or part-time Employment, Immediate Family Member: Pfizer, Inc.; Financial Interests, Personal, Stocks/Shares: Pfizer, Inc.; Financial Interests, Stocks/Shares, Immediate Family Member: Pfizer, Inc. M. Mazzoletti, O. Valota, W. Tan: Financial Interests, Personal, Full or part-time Employment: Pfizer, Inc.; Financial Interests, Personal, Stocks/Shares: Pfizer, Inc. S. Parmar: Financial Interests, Personal, Full or part-time Employment: PRA Health Sciences, AstraZeneca/MedImmune, Arvinas Operations, Inc.; Financial Interests, Personal, Stocks/Shares: Pfizer, Inc., Arvinas Operations, Inc. T. Mukohara: Financial Interests, Research Grant: Daiichi Sankyo, Sysmex, Eisai, MSD, Pfizer, Inc., Novartis, Sanofi, Chugai, AstraZeneca, Ono; Financial Interests, Invited Speaker, Lecture Fees: Eisai, Pfizer, Inc., Novartis, Chugai, Eli Lilly, AstraZeneca, Kyowa-Kirin, Taiho.