ARV-471 Monotherapy Demonstrates Clinical Benefit in ER+/HER2- Advanced Breast Cancer

ARV-471 monotherapy elicited a significant clinical benefit rate (CBR) in patients with estrogen receptor (ER)–positive/HER2-negative locally advanced or metastatic breast cancer who had undergone prior hormonal therapy and chemotherapy, including those with ESR1 mutations, according to expansion cohort analysis from the phase 1/2 VERITAC trial (NCT04072952) presented by Anne F. Schott, MD, at the 2022 San Antonio Breast Cancer Symposium.¹

The phase 2, part B trial evaluated an expansion cohort who received 200 mg of ARV-471 orally, once a day (n = 35) or 500 mg of ARV-471 orally, once a day (n = 36). Enrollment in the 200-mg arm began before enrollment in the 500-mg arm.

The CBR for the 200-mg arm was 37.1% (95% CI, 21.5%-55.1%) and 38.9% (95% CI, 23.1%-56.5%) for the 500-mg arm. The CBR for all 71 patients was 38.0% (95% CI, 26.8%-50.3%).

In patients whose tumor harbors an ESR1 mutation, the CBR in the 200-mg arm (n = 19) was 47.4% (95% CI, 24.4%-71.1%) compared with 54.5% (95% CI, 32.2%-75.6%) in the 500-mg arm (n = 41). In this population, the total CBR was 51.2% (95% CI, 35.1%-67.1%).

In the phase 1 dose escalation trial presented previously at the 2021 San Antonio Breast Cancer Symposium,2 ARV-471 was well tolerated at all doses and the CBR was 40% (95% CI, 26%-56%) in 47 evaluable patients.

ARV-471 is a protein degrader, which causes degradation secondary to ER conformational changes or immobilization and differs from selective ER degraders such as fulvestrant (Faslodex).

“The mechanism of action of ARV-471 may provide more robust ER degradation, which may translate to stronger antitumor effects,” Schott, a professor of medicine at the University of Michigan Health and associate director of clinical research at the Rogel Cancer Center in Ann Arbor, Michigan, said in her presentation.1

The primary end point of the phase 2 trial was CBR and secondary end points included objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

Of the 71 patients who were enrolled, 69 were women, and the median age was 60 years (range, 41-86). The majority of patients had an ECOG performance status of 0 (66.2%) and 54.9% had visceral disease at enrollment.

At baseline, 57.7% of patients had mutant ESR1 and 35.2% had wild type. Overall, patients were heavily pretreated with a median of 3 prior lines of therapy in the metastatic setting. All patients received prior CDK4/6 inhibitor therapy per the inclusion criteria, 90.1% received prior aromatase inhibitors, and 78.9% were previously treated with fulvestrant. These characteristics were similar in both dosage groups.

Regarding safety, 3 patients in the 500-mg arm had adverse events (AEs) that necessitated a dose reduction to 400 mg but no patients required dose reduction in the 200-mg arm. One patient in the 200-mg arm and 2 patients in the 500-mg arm required dose discontinuation.

The majority of treatment related adverse events (TRAEs) were mild or moderate. Overall, 34% of patients had grade 1 TRAEs, 31% had grade 2 TRAEs, and 7% experienced grade 3/4 level TRAEs.

“The proportions of grade 1, 2, and 3 or higher TRAEs were similar in the 2 dosing groups,” Schott said. The most common TRAEs were fatigue, nausea, arthralgia, hot flushes, and increased aspartate aminotransferase (AST) levels. “Apart from one grade 3 fatigue event, all were grade 1 or 2,” said Schott.

Turning to the secondary end points, 1 patient in the 200-mg arm and 1 patient in the 500-mg arm had a confirmed partial response, according to Schott. “An additional 5 patients with target lesion reductions greater than 30% had unconfirmed partial responses, and therefore, their best response was reported as stable disease,” Schott said.

PFS was evaluated in the overall population and the ESR1-mutation positive population for both dose levels combined. The 500-mg arm, which started enrollment after the 200-mg arm, was not mature at the time of data cut off of June 6, 2022, and was not evaluated.

The preliminary median PFS was 3.5 months (95% CI, 1.8-7.8) in the 200-mg arm and 3.7 months (95% CI, 1.9-8.3) in the overall population. In patients with the ESR1 mutation, preliminary median PFS was 5.5 months (95% CI, 1.8-8.5) in the 200-mg arm and 5.7 months (95% CI, 3.6-9.4) in the total ESR1 subgroup.

When reviewing ER degradation in the 200-mg arm, investigators reported a median degradation of 69% (range, 28%-95%) and a mean degradation of 71%, which is consistent with the mechanism of action of ARV-471.

“Based on the totality of the data, including comparable efficacy, favorable tolerability, and robust ER degradation, ARV-471 at 200 mg was selected as the phase 3 monotherapy dose,” Schott said. The phase 3 VERITAC-2 trial is planned to enroll 560 patients and will evaluate ARV-471 at 200 mg vs fulvestrant at 500 mg with a primary end point of PFS by blinded independent central review and secondary end points of OS, ORR, DOR, and CBR.

References

1. Hurvitz S, Ma C, Hamilton E, et al. GS3-03 ARV-471, a PROTAC® estrogen receptor (ER) degrader in advanced ER-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer: phase 2 expansion (VERITAC) of a phase 1/2 study. Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Abstract GS3-03.
2. Hamilton E, Vahdat L, Han HS, et al. First-in-human safety and activity of ARV-471, a novel PROTAC® estrogen receptor degrader, in ER+/HER2– locally advanced or metastatic breast cancer. Presented at: 2021 San Antonio Breast Cancer Symposium. Accessed December 8, 2022. https://bit.ly/3FDUgas