Arvinas, Inc. and Pfizer Inc. announced clinical data for vepdegestrant (ARV-471), a novel oral PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader, in combination with palbociclib (IBRANCE). 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 (HER2) negative (ER+/HER2-) breast cancer. These data will be presented in a spotlight presentation at the 2023 San Antonio Breast Cancer Symposium (SABCS).

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 (CDK) 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 (PF-07220060). Vepdegestrant + Palbociclib Phase 1b Study: In a spotlight presentation, interim data from the Phase 1b cohort of the first-in-human (FIH) ARV-471-mBC-101 study evaluating vepdegestrant in combination with palbociclib (NCT04072952) 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 (June 6, 2023), patients had received a median of four prior therapies across all lines (median of three in the metastatic setting); 87% were previously treated with a cyclin-dependent kinase 4 and 6 (CDK4/6) 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 (n=2), the recommended Phase 3 dose (RP3D) of 200 mg (n=21), 400 mg (n=3) or 500 mg (n=20), 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 (CBR, defined as the rate of confirmed complete response, partial response, or stable disease = 24 weeks) of 63% (95% CI: 47.5?76.8), or 29/46 patients; at the RP3D of 200 mg (n=21), the CBR was 67% (95% CI: 43.0 ? 85.4), or 14/21 patients; CBR in patients with mutant ESR1: 72% (95% CI: 52.8-87.3), or 21/29 patients; at the RP3D of 200 mg (n=14), the CBR was 79% (95% CI: 49.2 ?

95.3), or 11/14 patients; CBR in patients with wild-type ESR1: 53% (95% CI: 26.6-78.7), or 8/15 patients; at the RP3D of 200 mg (n=7), the CBR was 43% (95% CI: 9.9 ? 81.6), or 3/7 patients. An objective response rate (ORR) in evaluable patients with measurable disease at baseline (n=31) of 42% (95% CI: 24.5?60.9), or 13/31 patients; at the RP3D of 200 mg (n=15), the ORR was 53% (95% CI: 26.6 ?

78.7): ORR in patients with mutant ESR1: 47% (95% CI: 23.0-72.2), or 8/17 patients; ORR at the RP3D of 200 mg (n=10): 60% (95% CI: 26.2 ? 87.8); ORR in patients with wild-type ESR1: 42% (95% CI: 15.2-72.3), or 5/12 patients; ORR at the RP3D of 200 mg (n=5): 40% (95% CI: 26.6 ? 78.7).

Median progression free survival (PFS) of 11.1 months (95% CI: 8.2 ? NE); 22 of 46 patients across all doses had progression events by time of data cutoff: PFS in patients with mutant ESR1: 11.0 months (95% CI: 8.2-NE), 13 of 29 patients had progression events by data cutoff; PFS in patients with wild-type ESR1: 11.1 months (95% CI: 2.8-NE), 8 of 15 patients had progression events by data cutoff. In an assay of circulating tumor DNA (ctDNA), patients with ESR1 mutations (n=22 evaluable for ctDNA analysis after 1 cycle of treatment) demonstrated a -96.8% mean decrease (range: -75.6% to -100%) 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 (38%) treated at the RP3D of vepdegestrant (200 mg) 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.