The clinical benefit rate is 38%, and the latest data on PROTAC therapy are available

Arvinas today disclosed the results of its trial of its innovative PROTAC protein degrader, ARV-471, showing a clinical benefit rate (CBR)
of 38% observed in the patient population receiving pre-median 4-line therapy.
Based on this result, Arvinas plans to initiate two follow-up Phase 3 pivotal trials to further review
the efficacy of the drug.

Breast cancer is one of the most common forms of
cancer.
According to estimates by the National Cancer Institute (NCI), about 250,000 women were diagnosed with breast cancer in 2017, with more than 40,000 patients dying
as a result.
ER+/HER2- breast cancer accounts for about
70% of breast cancer patients.
Such patients can be treated with endocrine blockade therapy initially, but as the disease progresses, tumors become resistant to this therapy, and many mutations accumulate, making treatment difficult
.

The PROTAC molecule is an innovative therapy that binds to the target protein at one end and recruits E3 ubiquitin ligase at the other end, which "tags" the target protein with ubiquitin and promotes their degradation
by the proteasome.
This mode of action may provide new means
of targeting previously "undruggable" targets.

ARV-471 is a widely talked about PROTAC therapy
.
As an oral, targeted PROTAC protein degrader that targets the degradation of estrogen receptors (ER), ARV-471 degrades almost all ER molecules in tumor cells and causes massive tumor shrinkage
in many ER-driven animal tumor models.

The Phase 2 trial of the VERITAC Amplification Cohort published this time examines the efficacy and safety
of ARV-471 as monotherapy in patients with advanced or metastatic ER+/HER2- breast cancer.
The trial endpoint was CBR (i.
e.
, achieving a complete or partial response, or stabilizing ≥24 weeks).

A total of 71 patients were enrolled and treated with ARV-471 at 200 mg (n=35) or 500 mg (n=36) per day
.
The analysis showed that the CBR of all patients (n=71) was 38%, of which two patients had a definite partial response and the rest were stable
.

Some analysts point out that although no complete response was observed in this clinical outcome, and the proportion of patients with partial response was low, it is also important to consider that these patients have more difficult to treat - they have been treated with CDK4/6 inhibitors, and 79% and 73% have been treated
with the hormone drug fulvestrant and chemotherapy, respectively.
In 45% of patients who received chemotherapy, their tumors had metastasized
.
In contrast, the proportion of patients who have received previous treatment in other similar clinical trials is not high
.

An interesting phenomenon was also observed in the trial: patients with the mutant ESR1 gene (n=41) had a higher clinical benefit rate of 51.
2% (20% for wild type).

In addition, the median progression-free survival (PFS) was 3.
7 months for all patients (n=71) compared to 5.
7 months
for patients with the mutant ESR1 gene (n=41).

In terms of safety, both doses of ARV-471 were well tolerated, and most of the treatment-related adverse reactions (TRAEs) were grade
1 and 2.

Dr.
John Houston, President and CEO of Arvinas, said in a press release: "All patients in the trial were treated with at least one CDK4/6 inhibitor, and many patients developed disease progression
after receiving fulvestrant and chemotherapy.
We continue to see positive results from the VERITAC trial in these patients who have undergone extensive upfront treatment, which strengthens our confidence in
ARV-471.
We are preparing to launch two pivotal trials with the goal of providing patients and physicians with a potential new treatment to fight breast cancer
.
”

Arvinas expects to initiate a Phase 3 clinical trial in the fourth quarter of this year to review ARV-471 as a second-line
therapy for the treatment of patients with metastatic ER+/HER2-breast cancer.
Another clinical trial is expected to be initiated in the first quarter of 2023 to review the efficacy and safety
of ARV-471 in combination with the CDK4/6 inhibitor palbociclib as first-line therapy in patients with metastatic ER+/HER2- breast cancer.

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