Arvinas, Inc. announced initial results from the Phase 2 cohort expansion portion (VERITAC) of a phase 1/2 study with ARV-471, a novel PROTAC® estrogen receptor (ER) protein degrader. ARV-471 is being co-developed with Pfizer Inc. for the treatment of patients with locally advanced or metastatic ER positive /human epidermal growth factor receptor 2 (HER2) negative (ER+/HER2-) breast cancer. In the VERITAC trial, ARV-471 shows a favorable tolerability profile and demonstrates a clinical benefit rate of 38% (total n=71) (CBR: rate of confirmed complete response, confirmed partial response, or stable disease > 24 weeks), the primary endpoint in the trial.

These results are consistent with the Phase 1 portion of this trial. Patients in VERITAC had a median of four lines of prior therapies, in a population where 100% of patients were treated with prior cyclin-dependent kinase (CDK4/6) inhibitors, 79% with prior fulvestrant, and 73% with prior chemotherapy. At the time of data cutoff (June 6, 2022), ARV-471 administered at 200 mg (n=35) and 500 mg (n=36) demonstrated: Antitumor activity in 100% CDK4/6 inhibitor-pretreated patients, as measured by a CBR of 38% (total n=71) in all patients and 51.2% in patients with mutant ESR1 tumors (n=41).

Preliminary median progression-free survival (mPFS) of 3.7 months, a key secondary endpoint, in all evaluable patients and 5.7 months in patients with mutant ESR1 tumors (n=41). A favorable tolerability profile, with the majority of treatment-related adverse events (TRAEs) reported as Grade 1 or 2. ARV-471 Clinical Update: Study Design: VERITAC is the Phase 2 cohort expansion portion of a Phase 1/2 single-arm trial of ARV-471 alone and in combination with palbociclib in patients with ER+/HER2- locally advanced or metastatic breast cancer (mBC) (NCT04072952). In VERITAC, patients were treated with either 200 mg or 500 mg ARV-471 with a primary endpoint of CBR (CR, PR or SD > 24 weeks).

Secondary endpoints include ORR, DOR, PFS and OS as well as safety (AEs) and pharmacokinetics. Enrollment: As of the data cut-off date of June 6, 2022, 71 patients with locally advanced or metastatic ER+/HER2- breast cancer in the VERITAC expansion cohort were treated once-daily with oral doses of ARV-471 at 200 mg (n=35) or 500 mg (n=36). 100% of patients were previously treated with CDK 4/6 inhibitors.

79% of patients were previously treated with fulvestrant. 73% of patients were previously treated with chemotherapy. 45% received chemotherapy in the metastatic setting.

Efficacy Data: Clinical benefit rate (the primary endpoint, defined as a confirmed complete response, partial response, or stable disease = 24 weeks) in all patients (n=71) and in patients with tumors harboring ESR1 mutations (n=41): All patients (200 mg and 500 mg, n=71): 38%; Patients with tumors harboring ESR1 mutations (n=41): 51.2%; Patients with ESR1 wild-type tumors (n=25): 20%. All patients at 200 mg (n=35): 37.1%; Patients with tumors harboring ESR1 mutations (n=19): 47%. All patients at 500 mg (n=36): 39%; Patients with tumors harboring ESR1 mutations (n=22): 55%.

Progression free survival: All patients receiving 200 mg or 500 mg qd ARV-471 (n=71): median 3.7 months; Patients with mutant ESR1 tumors (n=41): median 5.7 months. Patients receiving 200 mg qd ARV-471 (n=35): median 3.5 months; Patients with mutant ESR1 tumors (n=19): median 5.5 months. At the time of the data cutoff, data for 500 mg cohort were immature and therefore not included in a separate analysis.

Safety Data: ARV-471 was well tolerated across both dose levels. TRAEs were primarily Grade 1 and 2, with 5 patients experiencing Grade 3/4 TRAEs: 200 mg cohort: Grade 1 (n=13): 37%; Grade 2 (n=13): 37%; Grade 3 or 4 (n=2): 6%; Grade 3/4 TRAEs in the 200 mg cohort were Grade 3 QT prolonged (n=1) and Grade 3 thrombocytopenia and Grade 4 hyperbilirubinemia (n=1). 500 mg cohort: Grade 1 (n=11): 31%; Grade 2 (n=9): 25%; Grade 3 or 4 (n=3): 8%; Grade 3/4 TRAEs in the 500 mg cohort were Grade 3 fatigue (n=1), Grade 3 decreased appetite (n=1), and Grade 3 neutropenia (n=1).

There was 1 discontinuation due to a treatment-emergent adverse event (TEAE) and no dose reductions in the 200 mg cohort. There were 2 discontinuations and 3 dose reductions in the 500 mg cohort. Anticipated 2022/2023 Milestones: Initiate a Phase 3 trial (First Subject First Visit) with ARV-471 as a second-line treatment in patients with ER+/HER2- metastatic breast cancer (4Q 2022).

Initiate a Phase 3 trial (First Subject First Visit) with ARV-471 in combination with palbociclib as a first-line treatment in patients with ER+/HER2- metastatic breast cancer (1Q 2023). Initiate the first two cohorts (First Subject First Visit) and initiate additional arms with other targeted therapies in the ongoing Phase 1b combination trial (TACTIVE-U) (2023). Present data from the Phase 1b combination trial with palbociclib (Part C of the Phase 1/2 trial) at a medical conference (1H 2023).