Arvinas Releases Interim Clinical Data Further Demonstrating the Powerful Potential of PROTAC Protein Degraders ARV-471 and ARV-110 - Seite 3

In metastatic breast cancer, prior treatment with CDK4/6 inhibitors predicts high tumor ER-independence, rendering ER-targeting therapies ineffective. However, one patient in the ARV-471 trial had a confirmed PR with a 51% reduction in target lesion size as assessed by RECIST. Two additional patients had unconfirmed PRs and one additional patient demonstrated stable disease with >50% target lesion shrinkage. For evaluation of CBR, 12 patients had sufficient follow-up to be included. Five of 12 patients (42%) achieved CBR (CBR defined as PRs + complete responses + stable disease at 6 months). Three of these five patients had previously received fulvestrant, and another was treated with two investigational SERDs.

ARV-471 has been well tolerated at all dose levels, as of the data cut-off date. The most common treatment-related Grade 1-2 adverse events were nausea (24%), arthralgia (19%), fatigue (19%), and decreased appetite (14%). None of these led to discontinuation or dose reduction of ARV-471. No patients reported treatment-related Grade 3 of 4 adverse events, and no dose-limiting toxicities (DLTs) have been reported. A maximum tolerated dose (MTD) has not been reached and dose escalation continues.

The plasma exposures of ARV-471 have been dose proportional up to and including 360 mg orally once daily and have substantially exceeded Arvinas’ predicted thresholds of efficacy based on preclinical studies. The estimated half-life of ARV-471 is 28 hours, supporting a once-daily schedule of administration. Analysis of five paired tumor biopsies at doses up to 120 mg provide compelling proof of mechanism for ARV-471, which has demonstrated ER degradation up to 90% (average of 62%) at those doses, while dose escalation continues.

The combined profile of ARV-471, including efficacy signals in a highly refractory population, excellent tolerability profile, and high levels of ER degradation, support a potential best-in-class ER-targeting therapy.

A Phase 2 dose expansion of ARV-471 is expected to begin in the first half of 2021. Arvinas also expects to initiate a Phase 1b cohort expansion of ARV-471 in combination with Ibrance (palbociclib) in December 2020. This trial will evaluate the safety and tolerability of ARV-471 in combination with palbociclib and seek to identify a recommended combination dose. Arvinas expects to begin two additional studies of ARV-471 in the second half of 2021: a combination trial of ARV-471 and another targeted therapy in 2L/3L metastatic breast cancer, and a window of opportunity study in adjuvant breast cancer. The combined data from these studies will inform Arvinas’ global development strategy and path forward toward the goal for ARV-471 to become the leading endocrine therapy in ER+/HER2- breast cancer.