A first-in-human phase 1/2a dose escalation/expansion study of the first-in-class CDK2/4/6 inhibitor PF-06873600 alone or with endocrine therapy in patients with breast or ovarian cancer

Abstract Introduction: Despite initial efficacy, most patients (pts) with HR+/HER2– advanced breast cancer (BC) eventually progress on endocrine therapy (ET) plus a CDK4/6 inhibitor (CDK4/6i). In preclinical models, resistance to ET + CDK4/6i can be overcome by concomitant inhibition of CDK2. Therefore, simultaneous inhibition of CDK2/4/6 may provide a new therapeutic strategy to prolong clinical benefit. This first-in-human dose escalation/expansion study (NCT03519178) is evaluating the safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary antitumor activity of the first-in-class selective CDK2/4/6 inhibitor PF-06873600 (PF-3600) as monotherapy and combined with ET. The results of Part 1 monotherapy dose escalation and initial combination with ET are presented.Methods: This is a phase 1/2a, open-label, non-randomized, study of PF-3600 as monotherapy and combined with letrozole or fulvestrant (F). Pts with locally advanced/metastatic HR+/HER2– BC whose tumor progressed on previous ET + CDK4/6i and with ≤2 prior lines of chemotherapy (Cx), triple-negative breast cancer (TNBC) with ≤2 prior lines of Cx, and platinum-resistant ovarian cancer (OVCA) with ≤3 prior lines of treatment (Tx) were eligible for Part 1 dose escalation. Pts received escalating doses of PF-3600 (1–50 mg) BID orally. Dose escalation followed the modified toxicity probability interval method. Tx continued until disease progression, toxicity requiring discontinuation or pt withdrawal. Primary objectives for Part 1 were to evaluate safety including dose-limiting toxicities (DLTs) in the 1st 28-day cycle, adverse events (AEs), and laboratory abnormalities; and to select the recommended dose for expansion (RDE) in combination with ET. Results: As of 24 June 2021, 67 pts (HR+/HER2– BC, n=59; TNBC, n=2; OVCA, n=6) received PF-3600 (n=58) or PF-3600 + F (n=9). In the PF-3600 group, 22 (38%) and 36 (62%) pts had ECOG performance status (PS) 0 and 1, respectively. In the PF-3600 + F group, 6 (67%) and 3 (33%) pts had ECOG PS 0 and 1, respectively. The median (range) number of prior Tx in the metastatic setting was 4.0 (1, 8) for PF-3600 and 4.0 (3, 6) for PF-3600 + F. The most frequently reported treatment-related AEs (all grade/grade ≥3) for PF-3600 alone and PF-3600 + F, respectively, were nausea (50%/0% and 67%/0%), anemia (38%/14% and 44%/11%) and neutropenia (29%/16% and 22%/11%). Six (13%) of 48 DLT-evaluable pts treated with monotherapy had DLTs; all occurred at the highest doses (35 and 50 mg BID). At the RDE of 25 mg BID (PF-3600 alone, n=17; PF-3600 + F, n=9), there were no DLTs. PF-3600 exposure increased with dose, was not significantly impacted by F and at the RDE remained above the preclinical efficacious concentrations in most of the tested models for >70% of the dosing interval. The disease control rate was 48% (28/58, PF-3600) and 67% (6/9, PF-3600 + F) including 3 pts who remained stable for >13 mos with one ongoing for >28 mos. Three heavily pre-treated pts with HR+/HER2– BC (including prior ET + CDK4/6i and Cx) treated with PF-3600 alone had partial responses (2 confirmed), including 1 pt who remained on Tx for >13 mos. Modulation of cell cycle PD biomarkers (pRb and Ki-67) in paired tumor biopsies was observed. Data are not final and subject to change. Updated data will be presented.Conclusions: PF-3600 can be combined with ET with a manageable AE profile and demonstrates promising preliminary antitumor activity in heavily pretreated pts, including those with HR+/HER2– BC progressing on ET + CDK4/6i and Cx. Dose expansion in combination with ET in pts with HR+/HER2– BC with and without prior CDK4/6i Tx is ongoing. Citation Format: Timothy A. Yap, Cynthia Basu, Jonathan W. Goldman, Michael Gordon, Erika Hamilton, Adrianne Kelly, Feng Liu, Allison R. Moreau, Heather Neumann, Kyriakos Papadopoulos, Hope S. Rugo, Geoffrey I. Shapiro, Shaveta Vinayak, Li Zhou, Komal Jhaveri. A first-in-human phase 1/2a dose escalation/expansion study of the first-in-class CDK2/4/6 inhibitor PF-06873600 alone or with endocrine therapy in patients with breast or ovarian cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-16-06.