First-in-human phase 1/2a study of a potent and novel CDK2-selective inhibitor PF-07104091 in patients (pts) with advanced solid tumors, enriched for CDK4/6 inhibitor resistant HR+/HER2- breast cancer.
Authors: Yap Timothy A. , Elhaddad Abdelaziz M. , Grisham Rachel N. , Hamm John Turner , Marks Douglas Kanter , Shapiro Geoffrey , Le Corre Christophe , Li Jerry , Lin Tun Tun , Liu Feng , Malky Lara , Moreau Allison R , Neumann Heather , Juric Dejan , Sharma Manish 
Published: June 2023

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Background: PF-07104091 is a novel CDK2-selective inhibitor under investigation in pts with selected advanced or metastatic solid tumors. We present the first disclosure of data from the first-in-human, multicenter, phase 1 study of PF-07104091 monotherapy (NCT04553133). Methods: Pts with HR+/HER2- advanced/metastatic breast cancer (mBC) who received ≥ 2 lines of treatment for mBC including prior endocrine therapy (ET) + CDK4/6 inhibitors (CDK4/6i), and pts with other solid tumors, were included. Prior therapy with fulvestrant and chemotherapy was allowed for pts with mBC. PF-07104091 (75-500 mg) was given twice daily (BID) orally in 28-day cycles, following Bayesian design with overdose control, to determine the maximum tolerated dose (MTD)/recommended dose for expansion (RDE). Primary objective was to assess safety and tolerability. Secondary objectives included pharmacokinetics and preliminary anti-tumor activity. Results: At data cut off (Aug 23, 2022), 35 pts with advanced solid tumors (n = 29 mBC) with median age 62y (range 32-80y), median 4 lines of prior systemic therapy (range 1–12) and ECOG PS 0 (20% pts) or 1 were enrolled. Of 29 pts with mBC, all had prior CDK4/6i, 25 (86.2%) prior fulvestrant, and 21 (72.4%) prior chemotherapy. Treatment-emergent adverse events (TEAEs) were observed in 34 pts (97.1%; 20 [57.1%] grade [G] ≥ 3). The most frequent TEAEs (all G≤3) were nausea (77.1%; 14.3% G3), diarrhea (48.6%; 8.6% G3), vomiting (48.6%; 2.9% G3), fatigue (45.7%; 20.0% G3) and anemia (45.7%; 8.6% G3). Dose-limiting toxicity occurred in 5 pts: 1 pt (G3 fatigue) at 300 mg BID; 2 pts (1 G3 nausea and G3 anorexia, 1 G3 nausea) at 375 mg BID, and 2 pts (1 G3 fatigue and 1 G3 diarrhea) at 500 mg BID. Steady-state PF-07104091 plasma exposures increased proportionally with dose. A trend of early decrease in ctDNA was observed. Further pharmacodynamic studies are ongoing. PF-07104091 300 mg BID was identified as the MTD and selected as the monotherapy RDE. Among 16 response evaluable mBC pts (all prior CDK4/6i+ET) with measurable disease at baseline, confirmed RECIST v1.1 partial responses were observed in 3 (18.8 %) pts (2 pts with duration of response > 6 months and 1 ongoing at data cut off), and stable disease in 6 (37.5%) pts. Disease control rate was 61.5% in mBC pts (response evaluable set, 95% CI: 40.6, 79.8). Conclusions: Treatment with PF-07104091 monotherapy was generally well tolerated and showed antitumor activity in heavily pretreated HR+ HER2- mBC pts who progressed on prior CDK4/6i. Dose expansions of PF-07104091 are ongoing as monotherapy in pts with ovarian cancer and in combination with fulvestrant in pts with breast cancer. Clinical trial information: NCT04553133 .