413P - Longitudinal circulating tumor DNA (ctDNA) dynamics in phase I/IIa study of the first-in-class CDK4-selective inhibitor, PF-07220060, in combination with endocrine therapy in patients with HR+/HER2− metastatic breast cancer (mBC) who progressed on prior CDK4/6 inhibitors

Background

The CDK4-selective inhibitor PF-07220060 in combination with endocrine therapy (ET) has demonstrated favorable tolerability and promising clinical activity in an ongoing phase 1 trial (NCT04557449). We present data from the exploratory ctDNA analysis of the study.

Methods

ctDNA samples were collected at baseline (cycle 1, day 1 [C1D1]), C1D15 and end-of-treatment (EOT) in patients (pts) with HR+/HER2− mBC treated with oral 300 or 400 mg BID PF-07220060, with fulvestrant (Part 1B, n=18) or letrozole (Part 1C, n=15) and analyzed with the Guardant360 platform (Guardant Health). Mean variant allele frequency (meanVAF) was used to determine the ctDNA molecular response (MR) between timepoints.

Results

At data cutoff (Nov 1, 2023), ctDNA data were available for all 33 enrolled pts. The top altered genes in pts at C1D1 were ESR1 (64%), PIK3CA (45%), and TP53 (33%). RECIST v1.1 complete/partial responses were observed in pts irrespective of alterations in ESR1 or PIK3CA/AKT1/PTEN genes. In pts with evaluable MR (n=26), marked early ctDNA decreases were observed, with the median meanVAF declining from C1D1 to C1D15 by −79.5% in Part 1B and −74.0% in Part 1C. C1D15 meanVAF decrease of ≥50% was necessary for achieving ≥30% best tumor dimension reduction and RECIST v1.1 partial response. Pts without progressive disease (PD) as their best overall response tended to have greater ctDNA reduction than pts with PD. Pts with undetectable ctDNA at C1D15 were more likely to have longer progression-free survival (PFS) than those with detectable ctDNA. ctDNA increased to baseline levels at EOT when pts discontinued the study, mostly due to PD.

Conclusions

Longitudinal ctDNA profiling enabled the identification of key genetic alterations and demonstrated that PF-07220060 plus ET may benefit pts with or without ESR1 and PI3K pathway mutations. Early ctDNA MR trended with favorable clinical outcomes, while pts with undetectable ctDNA on treatment had improved PFS.

Clinical trial identification

NCT04557449.

Editorial acknowledgement

Medical editorial support, conducted in accordance with Good Publication Practice (GPP3) and the International Committee of Medical Journal Editors (ICMJE) guidelines, was provided by Dominique Verlaan, PhD of Oxford PharmaGenesis, Inc., Newtown, PA, USA with funding provided by Pfizer Inc., USA.

Legal entity responsible for the study

Pfizer Inc.

Funding

Pfizer Inc.

Disclosure

T.A. Yap: Financial Interests, Personal, Advisory Role: Pfizer, EMD Serono, Clovis Oncology, Ignyta, AstraZeneca, Atrin Pharmaceuticals, Aduro Biotech, Merck, Almac Group, Bayer, Bristol-Myers Squibb, Calithera Biosciences, Cybrexa Therapeutics, Janssen, Roche, Axiom Biotechnologies, F-Star, Guidepoint Global, I-Mab, Repare Therapeutics, Varian Medical Systems, Zai Lab, Artios, Athenahealth, Gerson Lehrman Group, ImmuneSensor Therapeutics, ZielBio, Abbvie, Acrivon Therapeutics, Adagene, Amphista Therapeutics, Avoro Capital Advisors, Baptist Health, BeiGene, C4 Therapeutics, Cancer Research UK, Diffusion Pharmaceuticals, Genmab, Glenmark, Globe Life Science, GSK, Idience, Gustave Roussy Cancer Center, Intellisphere, Kyn Therapeutics, MEI Pharma, Mereo BioPharma, Natera, Nexys Therapeutics, Novocure, Oregon Health & Science University, OncoSec, Ono Pharmaceutical, Pegascy, PER, Piper Sandler, ProLynk, resTORbio, Theragnostics, Versant Health, Vibliome Therapeutics, Xinthera, Blueprint Medicines, Circle Pharma, Dark Blue Therapeutics, Terremoto Biosciences, Astex Pharmaceuticals, Avenzo Therapeutics, BioCity, Boxer, Carrick Therapeutics, Daiichi Sankyo, Duke Street Bio, 858 Therapeutics, EcoR1 Capital, Ellipses Pharma, Entos, Genesis Therapeutics, IDEAYA Biosciences, IMPAC Medical Systems, Merit Inc., Monte Rosa Therapeutics, Nested Therapeutics, Nimbus Therapeutics, Odyssey Therapeutics, Onxeo, PanAngium Therapeutics, Pliant, Radiopharm Theranostics, Ryvu Therapeutics, Swiss Group for Clinical Cancer Research, Sanofi, SERVIER, Synnovation Therapeutics, Synthis Therapeutics, Tango Therapeutics, TCG Crossover, TD2, Tessellate Bio, Terns Pharmaceuticals, Tolremo, Tome Biosciences, Thryv Therapeutics, Trevarx Biomedical, Veeva Systems, Voronoi Health Analytics, BeiGene; Financial Interests, Personal, Stocks or ownership: Seagen; Financial Interests, Institutional, Research Funding: AstraZeneca, Pfizer, Bayer, Tesaro, Jounce Therapeutics, Seagen, Kyowa Kirin, Constellation Pharmaceuticals, Lilly, Artios, Clovis Oncology, Cyteir, EMD Serono, Forbius, F-Star, GSK, Genentech, ImmuneSensor Therapeutics, Ipsen, Karyopharm Therapeutics, Merck, Novartis, Ribon Therapeutics, Regeneron, Repare Therapeutics, Sanofi, Scholar Rock, BeiGene, BioNTech, Bristol-Myers Squibb, Haihe Biopharma, Ionis Pharmaceuticals, KSQ Therapeutics, Rubius Therapeutics, Vivace Therapeutics, Acrivon Therapeutics, Blueprint Medicines, Mirati Therapeutics, Zenith Epigenetics, Boundless Bio, IDEAYA Biosciences, InSilico Medicine, Tango Therapeutics. F. Liu: Financial Interests, Personal, Full or part-time Employment: Pfizer Inc.; Financial Interests, Personal, Stocks or ownership: Pfizer Inc. H. Zhang: Financial Interests, Personal, Full or part-time Employment: Pfizer Inc.; Financial Interests, Personal, Stocks or ownership: Pfizer Inc. W. Roh: Financial Interests, Personal, Full or part-time Employment: Pfizer Inc.; Financial Interests, Personal, Stocks or ownership: Pfizer Inc. A. Giordano: Financial Interests, Personal, Speaker, Consultant, Advisor: Pfizer Inc. E.P. Hamilton: Financial Interests, Personal, Speaker, Consultant, Advisor: Genentech/Roche, Lilly, Daiichi Sankyo, Mersana, AstraZeneca, Novartis, Ellipses Pharma, Olema Pharmaceuticals, Stemline Therapeutics, Tubulis GmbH, Verascity Science, Theratechnologies, Accutar Biotech, Entos, Fosun Pharma, Gilead Sciences, Jaxx Pharmaceuticals, MphaR, Zentalis, Jefferies, Tempus; Financial Interests, Institutional, Research Funding: AstraZeneca, Hutchison MediPharma, OncoMed, MedImmune, Stem CentRx, Genentech/Roche, Curis, Verastem, Zymeworks, Syndax, Lycera, Rgenix, Novartis, Mersana, Millennium, TapImmune Inc., Lilly, Pfizer, Tesaro, Boehringer Ingelheim, H3 Biomedicine, Radius Health, Acerta Pharma, Macrogenics, Abbvie, Immunomedics, Fujifilm, eFFECTOR Therapeutics, Merus, Nucana, Regeneron, Leap Therapeutics, Taiho Pharmaceutical, EMD Serono, Daiichi Sankyo, ArQule, Syros Pharmaceuticals, Clovis Oncology, CytomX Therapeutics, InventisBio, Deciphera, Sermonix Pharmaceuticals, Sutro Biopharma, Zenith Epigenetics, Arvinas, Harpoon, Black Diamond Therapeutics, Orinove, Molecular Templates, Seagen, Compugen, G1 Therapeutics, Karyopharm Therapeutics, Dana Farber Cancer Hospital, Onconova Therapeutics, Shattuck Labs, PharmaMar, Olema Pharmaceuticals, Immunogen, Plexxikon, Amgen, Akeso Biopharma, ADC Therapeutics, AtlasMedx, Aravive, Ellipses Pharma, Incyte, MabSpace Biosciences, ORIC Pharmaceuticals, Pieris Pharmaceuticals, Pionyr, Repertoire Immune Medicines, Treadwell Therapeutics, Jacobio, Accutar Biotech, Artios, Bliss Biopharmaceutical, Cascadian Therapeutics, Dantari, Duality Biologics, Elucida Oncology, Infinity Pharmaceuticals, Relay Therapeutics, Tolmar, Torque, BeiGene, Context Therapeutics, K-Group Beta, Kind Pharmaceuticals, Loxo, Oncothyreon, Orum Therapeutics, Prelude Therapeutics, ProfoundBio, Cullinan Oncology, Bristol-Myers Squibb, Eisai, Fochon Pharmaceuticals, Gilead Sciences, Inspirna, Myriad Genetics, Silverback Therapeutics, Stemline Therapeutics. M.L. Delioukina: Financial Interests, Personal, Full or part-time Employment: Pfizer Inc.; Financial Interests, Personal, Stocks or ownership: Pfizer Inc. M. Lira: Financial Interests, Personal, Full or part-time Employment: Pfizer Inc.; Financial Interests, Personal, Stocks or ownership: Pfizer Inc. J. Park: Financial Interests, Personal, Full or part-time Employment: Pfizer Inc.; Financial Interests, Personal, Stocks or ownership: Pfizer Inc. C. Basu: Financial Interests, Personal, Full or part-time Employment: Pfizer Inc.; Financial Interests, Personal, Stocks or ownership: Pfizer Inc. M.R. Sharma: Financial Interests, Personal, Speaker, Consultant, Advisor: Pliant; Financial Interests, Personal, Stocks or ownership: Abbott Laboratories, Abbvie, Bristol-Myers Squibb, Lilly, Merck, Pfizer, Regeneron, Amgen, Gilead Sciences, Johnson & Johnson/Janssen, Moderna Therapeutics, Vertex, West Pharmaceutical; Financial Interests, Institutional, Research Funding: AstraZeneca, Bolt Biotherapeutics, Bristol-Myers Squibb, Compugen, Exelixis, Ikena Oncology, InhibRx, Jounce Therapeutics, KLUS Pharma, Loxo, Macrogenics, Merck, Pfizer, Regeneron, Symphogen, Syros Pharmaceuticals, Astellas Pharma, Celgene, Treadwell Therapeutics, eFFECTOR Therapeutics, Genmab, PureTech, GSK/Tesaro, Seagen, Shattuck Labs, Sapience Therapeutics, Tempest Therapeutics, Mersana, NGM Biopharmaceuticals, Onconova Therapeutics, Gilead Sciences, Abbvie, Agenus, Alkermes, Alpine Immune Sciences, Johnson & Johnson/Janssen, Seven and Eight Biopharmaceuticals, Cullinan Oncology, Debiopharm Group, Palleon Pharmaceuticals, Helsinn Therapeutics, Kinnate Biopharma, KSQ Therapeutics, Repare Therapeutics, SK Life Sciences; Theratechnologies, Tizona Therapeutics Inc., Boundless Bio, IgM Biosciences, Adcentrix Therapeutics, ALX Oncology, Artios, Black Diamond Therapeutics, Boehringer Ingelheim, Deciphera, Elevation Oncology, Incyte, Chugai Pharma, Mirati Therapeutics, Pliant, Qualigen Therapeutics.