Novel CDK4 Inhibitor Shows Activity and Safety in HR+/HER2– Metastatic Breast Cancer

Timothy A. Yap, MBBS, PhD, FRCP

The novel CDK4 inhibitor PF-07220060 in combination with endocrine therapy demonstrated a favorable safety profile and generated robust response rates in heavily pretreated patients with hormone receptor (HR)–positive, HER2-negative metastatic breast cancer who progressed on prior CDK4/6 inhibitors, regardless of mutation status, according to updated findings from a phase 1/2a trial (NCT04557449) presented at the 2024 ESMO Breast Cancer Congress.¹

At a data cutoff of November 1, 2023, the combination elicited best responses of complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), and non-CR/non-PD in 3.0%, 21.2%, 42.4%, 18.2%, and 15.2% of patients, respectively, who were enrolled in parts 1B and 1C of the trial (n = 33). The disease control rate (DCR) was 81.8%, and the median progression-free survival was 8.1 months (95% CI, 5.3-10.9).

Furthermore, PF-07220060 “has a favorable safety and tolerability profile, with low hematologic toxicities, and mainly grade 1 to grade 2 toxicities,” lead study author Timothy A. Yap, MBBS, PhD, FRCP, said during the presentation.

Yap is a professor in the Department for Investigational Cancer Therapeutics (Phase I Program) and the Department of Thoracic/Head and Neck Medical Oncology; vice president and head of Clinical Development in the Therapeutics Discovery Division; and the associate director of Translational Research in the Khalifa Institute for Personalized Cancer Therapy at The University of Texas MD Anderson Cancer Center in Houston.

PF-07220060 is a novel, potent, oral, selective CDK4 inhibitor that significantly spares CDK6.

Part 1 of this first-in-human, 2-part, phase 1/2a trial was a dose-escalation portion. In part 1A, which aimed to find the maximum tolerated dose/recommended dose for expansion of PF-07220060, patients with solid tumors, including breast cancer, non–small cell lung cancer, prostate cancer, colorectal cancer, liposarcoma, and other tumors with CDK4/CCND1 amplification received twice-daily doses of PF-07220060 monotherapy ranging from 100 mg to 500 mg. Yap explained that this patient population was enriched for patients with HR-positive breast cancer. Parts 1B through 1F evaluated escalated dosing of PF-07220060­–based combination therapy, drug-drug interactions, and food effects.

In parts 1B and 1C, PF-07220060 was assessed at twice-daily doses of 300 mg of 400 mg in combination with letrozole and fulvestrant (Faslodex), respectively, in patients with HR-positive, HER2-negative metastatic breast cancer who had progressed on a prior CDK4/6 inhibitor and endocrine therapy. To be eligible, patients needed to have an ECOG performance status of 0 or 1. Patients were permitted to have received prior fulvestrant and chemotherapy in any line for the management of metastatic disease.

Part 2 of the study was a dose-expansion combination portion. In part 2A, PF-07220060 plus fulvestrant was evaluated in patients with HR-positive, HER2-negative metastatic breast cancer with prior exposure to CDK4/6 inhibitors. Part 2B evaluated PF-07220060 plus letrozole in treatment-naive patients with HR-positive, HER2-negative metastatic breast cancer. Part 2C evaluated PF-07220060 plus fulvestrant in the second-line or later setting for CDK4/6 inhibitor–naive patients with HR-positive, HER2-negative metastatic breast cancer who had progressed on prior endocrine therapy. Part 2D investigated PF-07220060 plus enzalutamide (Xtandi) in metastatic castration-resistant prostate cancer.

At the data cutoff, 33 patients were enrolled in parts 1B (300 mg cohort, n = 11; 400 mg cohort, n = 7) and 1C (n = 8; n = 7) combined. The median age of patients across cohorts was 62.0 years (range, 41-82), and most patients were White (667%). Patients had received a median of 4.0 prior lines of therapy (range, 1-11). All patients had received prior CDK4/6 inhibitors; 72.7% and 66.7% of patients had received prior fulvestrant or chemotherapy, respectively.

Among patients with measurable disease at baseline (n = 25), at a median follow-up of 13.0 months (95% CI, 10.8-not evaluable), the confirmed objective response rate (ORR) per RECIST v1.1 criteria was 32.0% (95% CI, 14.9%-53.5%), including 1 CR and 7 PRs. The median time to response was 3.6 months (range, 1.6-5.4), and the clinical benefit rate (CBR) was 64.0% (95% CI, 42.5%-82.0%).

Investigators observed confirmed objective responses, all of which were PRs, regardless of the presence of ESR1 or PI3K pathway mutations. Among patients with ESR1 mutations (n = 15), the CR, PR, SD, and PD rates were 0.0%, 26.7%, 60.0%, and 13.3%, respectively. The ORR was 26.7% (95% CI, 7.8%-55.1%), the CBR was 53.3% (95% CI, 26.6%-78.7%), and the DCR was 86.7%.

Among patients without ESR1 mutations (n = 10), the CR, PR, SD, and PD rates were 10.0%, 30.0%, 50.0%, and 10.0%, respectively. The ORR was 40.0% (95% CI, 12.2%-73.8%), the CBR was 80.0% (95% CI, 44.4%-97.5%), and the DCR was 90.0%.

Among patients with 1 or more PIK3CA, AKT1, or PTEN mutations (n = 10), the CR, PR, SD, and PD rates were 0.0%, 40.0%, 50.0%, and 10.0%, respectively. The ORR was 40.0% (95% CI, 12.2%-73.8%), the CBR was 70.0% (95% CI, 34.8%-93.3%), and the DCR was 90.0%.

Among patients without PIK3CA, AKT1, or PTEN mutations (n = 15), the CR, PR, SD, and PD rates were 6.7%, 20.0%, 60.0%, and 13.3%, respectively. The ORR was 26.7% (95% CI, 7.8%-55.1%), the CBR was 60.0% (95% CI, 32.3%-83.7%), and the DCR was 86.7%.

In total, 97.0% of patients experienced treatment-related treatment-emergent adverse effects (TEAEs; grade 1, 33.3%; grade 2, 30.3%; grade 3, 33.3%). The most common treatment-related TEAEs were neutropenia (15.2%; 21.2%; 18.2%), diarrhea (39.4%; 3.0%; 0.0%), nausea (24.2%; 6.1%; 3.0%), leukopenia (12.1%; 9.1%; 9.1%), thrombocytopenia (27.3%; 0.0%; 3.0%), fatigue (21.2%; 3.0%; 0.0%), and anemia (9.1%; 3.0%; 9.1%). No grade 4 or higher treatment-related TEAEs were observed. One patient experienced a serious treatment-related TEAE in the form of nausea.

Yap noted that although the most commonly observed grade 3 treatment-related TEAEs were hematologic in nature, these were manageable with dose interruptions or reductions. Dose discontinuations and reductions attributed to treatment-related TEAEs occurred in 1 and 5 patients, respectively.

“These data support the ongoing phase 3, open-label, randomized clinical trial (NCT06105632) evaluating PF-07220060 plus fulvestrant vs investigator’s choice of therapy in patients with HR-positive, HER2-negative advanced or metastatic breast cancer who have progressed on prior CDK4/6 inhibitor–based therapy,” Yap concluded.

The phase 3 trial is currently enrolling.²

Disclosures: Dr Yap reports consultant roles with Almac, Aduro, AstraZeneca, Atrin, Axiom, Bayer, Bristol Myers Squibb, Clovis, Cybrexa, EMD Serono, Guidepoint, Ignyta, I-Mab, Janssen, 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, CUHK Committee, Ellipses.Life, LRG1, Panangium, Pliant Therapeutics, Seagen, Synthis, Tessellate Bio, TD2 Theragonostics, Tome Biosciences, and Zentalis; personal/other financial interests with The University of Texas MD Anderson Cancer Center, where he is 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); ownership of stocks/shares with Seagan; institutional grant/research support from 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, and Zenith; institutional/other grant/research support from Acrivon; and receipt of institutional research grants from Boundless Bio and Ideaya.

References

1. Yap TA, Sharma M, Hamilton EP, et al. First-in-human phase I/IIa study of the first-in-class, next-generation CDK4-selective inhibitor PF-07220060 in combination with endocrine therapy (ET) in patients (pts) with HR+/HER2- metastatic breast cancer (mBC) who progressed on prior CDK4/6 inhibitors (CDK4/6i): safety and efficacy update. Presented at: 2024 ESMO Breast Cancer Congress; May 15-17, 2024; Berlin, Germany. Abstract 184MO.
2. A study to learn about the study medicine called PF-07220060 in combination with fulvestrant in people with HR-positive, HER2-negative advanced or metastatic breast cancer who progressed after a prior line of treatment. ClinicalTrials.gov. Updated April 3, 2024. Accessed May 17, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT06105632