Arvinas, Pfizer report interim data from trial of vepdegestrant with palbociclib

Arvinas (ARVN) and Pfizer (PFE) announced clinical data for vepdegestrant in combination with palbociclib. Interim results from the Phase 1b combination cohort demonstrate “encouraging” clinical activity in heavily pre-treated patients with a median of four lines of therapy across disease settings with locally advanced or metastatic ER positive/human epidermal growth factor 2 negative breast cancer. These data will be presented in a spotlight presentation at the 2023 San Antonio Breast Cancer Symposium. Vepdegestrant is a PROTAC ER degrader designed to directly harness one of the cell’s natural protein disposal processes to specifically target and degrade the estrogen receptor. Vepdegestrant is being co-developed by Arvinas and Pfizer and is currently being evaluated as a monotherapy in the second-line setting in the ongoing Phase 3 VERITAC-2 trial and in the first-line setting in combination with palbociclib in the ongoing study lead-in cohort of the Phase 3 VERITAC-3 trial. Pending additional data and agreement with regulatory authorities, Arvinas and Pfizer plan to broaden development of vepdegestrant to include new combinations with cyclin-dependent kinase inhibitors in both the first- and second-line settings. The companies plan to initiate a new second-line Phase 3 trial of vepdegestrant in combination with palbociclib and potentially other CDK4/6 inhibitors, and a new first-line Phase 3 trial of vepdegestrant plus Pfizer’s novel CDK4 inhibitor. Vepdegestrant + Palbociclib Phase 1b Study In a spotlight presentation, interim data from the Phase 1b cohort of the first-in-human ARV-471-mBC-101 study evaluating vepdegestrant in combination with palbociclib assessed the safety, tolerability and anti-tumor activity of the combination among 46 patients with heavily pre-treated locally advanced or metastatic ER+/HER2- breast cancer. At the time of data cutoff, patients had received a median of four prior therapies across all lines; 87% were previously treated with a cyclin-dependent kinase 4 and 6 inhibitor; 80% were previously treated with fulvestrant; and 76% were previously treated with chemotherapy, including 46% in the metastatic setting. Patients were treated once daily with oral doses of vepdegestrant at 180 mg, the recommended Phase 3 dose of 200 mg, 400 mg or 500 mg, plus 125 mg of palbociclib given orally once daily for 21 days, followed by seven days off treatment in 28-day cycles. Vepdegestrant in combination with palbociclib demonstrated: A clinical benefit rate of 63%, or 29/46 patients; at the RP3D of 200 mg, the CBR was 67%, or 14/21 patients CBR in patients with mutant ESR1: 72%, or 21/29 patients; at the RP3D of 200 mg, the CBR was 79%, or 11/14 patients CBR in patients with wild-type ESR1: 53%, or 8/15 patients; at the RP3D of 200 mg, the CBR was 43%, or 3/7 patients An objective response rate in evaluable patients with measurable disease at baseline of 42%, or 13/31 patients; at the RP3D of 200 mg, the ORR was 53% ORR in patients with mutant ESR1: 47% or 8/17 patients ORR at the RP3D of 200 mg: 60% ORR in patients with wild-type ESR1: 42%, or 5/12 patients ORR at the RP3D of 200 mg: 40% Median progression free survival of 11.1 months; 22 of 46 patients across all doses had progression events by time of data cutoff PFS in patients with mutant ESR1: 11.0 months, 13 of 29 patients had progression events by data cutoff PFS in patients with wild-type ESR1: 11.1 months, 8 of 15 patients had progression events by data cutoff In an assay of circulating tumor DNA, patients with ESR1 mutations demonstrated a -96.8% mean decrease in ESR1 mutant allele fraction after 1 cycle of treatment. The safety profile of vepdegestrant plus palbociclib was manageable with palbociclib dose reductions and/or interruptions per protocol which are consistent with those described in the prescribing label. The primary toxicity associated with the vepdegestrant plus palbociclib combination was neutropenia. Grade 4 neutropenia occurred in 8 of 21 patients treated at the RP3D of vepdegestrant plus palbociclib 125 mg. Grade 3/4 neutropenia occurred in 89% of all patients. There was a higher occurrence of Grade 4 neutropenia, although discontinuation rates of palbociclib and rates of infection were in line with historical palbociclib data. No cases of febrile neutropenia were reported in any of the 46 patients treated with the combination. Three of 46 patients discontinued palbociclib due to neutropenia including one out of 21 treated with the RP3D of vepdegestrant plus palbociclib 125 mg. The majority of Grade 4 neutropenia events occurred in the first cycle of treatment and occurrences of Grade 3/4 neutropenia decreased with palbociclib dose reductions as described in the prescribing label. The safety profile was otherwise consistent with the profile of palbociclib and what has been observed in other clinical trials for vepdegestrant. An increase in palbociclib exposure was observed compared to historical pharmacokinetic data, with similar increases observed with vepdegestrant 200 mg and 500 mg QD.