24 ARV-471, a PROTAC Estrogen Receptor (ER) Degrader in Advanced ER+/Human Epidermal Growth Factor Receptor 2 (HER2)– Breast Cancer: Phase 2 Expansion (VERITAC) of a Phase 1/2 Study

TABLE. TREs Reported in ≥10% of Patients Overall

Background

ARV-471 is a selective, orally administered PROTAC protein degrader that targets wild-type and mutant ER1. ARV- 471 directly binds an E3 ubiquitin ligase and ER to trigger ubiquitination of ER and its subsequent proteasomal degradation. In contrast, selective estrogen receptor degraders (SERDs) indirectly recruit the ubiquitin-proteasome system, secondary to conformational changes and/or immobilization of ER2. Limitations of the SERD fulvestrant include its intramuscular route of administration and only 40%–50% ER protein degradation at its optimal dose. ARV-471 treatment yielded substantially greater ER degradation and tumor growth inhibition than fulvestrant in breast cancer xenograft models. ARV-471 is being evaluated alone or in combination with palbociclib in previously treated patients with ER+/HER2– locally advanced/metastatic breast cancer in a first-in-human phase 1/2 study (NCT04072952). Here we present the initial outcomes of the phase 2 cohort expansion (VERITAC), which is investigating ARV-471 at doses of 200 mg QD or 500 mg QD in pretreated patients with ER+/HER– locally advanced/ metastatic breast cancer.

Materials and Methods

Key eligibility criteria for VERITAC:

• Histologically or cytologically confirmed ER+ and HER2– advanced breast cancer
• Measurable or nonmeasurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
• ≥1 prior endocrine regimen (≥1 regimen for ≥6 months in the locally advanced or metastatic setting)
• ≥1 prior CDK4/6 inhibitor
• ≤1 prior chemotherapy regimen in the locally advanced or metastatic setting

Outcome measures:

• Primary end point was CBR (rate of confirmed complete response or partial response [PR] or stable disease ≥24 weeks) analyzed in patients enrolled for ≥24 weeks prior to the data cutoff
• Secondary end points included overall response rate, duration of response, progression-free survival (PFS), and overall survival, safety, and pharmacokinetic parameters
• ESR1 mutational status and ER protein levels were exploratory end points

Results

As of June 6, 2022, 71 pts received ARV-471 (200 mg QD, n = 35; 500 mg QD, n = 36) in VERITAC; 69 (97.2%) pts were female and median age was 60 years (range, 41–86). Pts had received a median of 4 prior regimens (range: 1–10; 100% prior CDK4/6 inhibitors, 78.9% prior fulvestrant, and 73.2% prior chemotherapy). ARV-471 was well tolerated at both doses, with most treatment-related adverse events (TRAEs) grade 1/2 (Table). Three pts (200 mg QD, n = 1; 500 mg QD, n = 2) discontinued ARV-471 due to treatment-emergent AEs (TEAEs); 3 pts had ARV-471 dose reductions due to TEAEs (all from 500 mg QD to 400 mg QD). CBR was 37.1% (95% CI, 21%–55%) in 35 evaluable pts at 200 mg QD and 38.9% (95% CI, 23%–57%) in 36 evaluable pts at 500 mg QD. In evaluable pts with mutant ESR1 at 200 mg QD (n = 19) and 500 mg QD (n = 22), CBR was 47.4% (95% CI, 24%–71%) and 54.5% (95% CI, 32%–76%), respectively.

Conclusions

In the phase 2 VERITAC expansion cohorts, ARV-471 monotherapy showed evidence of clinical activity based on CBR, including in the subgroup with ESR1 mutations, and a manageable safety profile. ARV-471 200 mg QD was selected as the phase 3 monotherapy dose based on comparable efficacy, favorable tolerability, and robust ER degradation. The phase 3 VERITAC-2 study (NCT05654623) is evaluating ARV-471 200 mg QD vs fulvestrant as second-line therapy in patients with ER+/HER2– advanced breast cancer who previously received 1 line of CDK4/6 inhibitor therapy in combination with endocrine therapy.

AFFILIATIONS:

Sara A. Hurvitz,¹ Anne F. Schott,² Cynthia Ma,³ Erika P. Hamilton,⁴ Rita Nanda,⁵ George Zahrah,⁶ Natasha Hunter,⁷ Antoinette R. Tan,⁸ Melinda L. Telli,⁹ Jesus Anampa Mesias,¹⁰ Rinath Jeselsohn,¹¹ Pamela Munster,¹² Haolan Lu,¹³ Richard Gedrich,¹³ Cecile Mather,¹³ Janaki Parameswaran,¹³ Hyo S Han¹⁴

¹UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA.

²Rogel Cancer Center, University of Michigan Health, Ann Arbor, MI.

³Washington University, St Louis, MO.

⁴Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN.

⁵University of Chicago Medicine, Chicago, IL.

⁶Norwalk Hospital, Norwalk, CT.

⁷Seattle Cancer Care Alliance, Seattle, WA.

⁸Levine Cancer Institute, Atrium Health, Charlotte, NC.

⁹Stanford University School of Medicine, Stanford, CA.

¹⁰Albert Einstein College of Medicine, Bronx, NY.

¹¹Dana-Farber Cancer Institute, Boston, MA.

¹²University of California San Francisco, San Francisco, CA.

¹³Arvinas Operations, Inc., New Haven, CT.

¹⁴Moffitt Cancer Center, Tampa, FL.