ARV-471: SABCS 2022 Ron Peck Phase 2 Expansion VERITAC Trial
What can this PROTAC estrogen receptor degrader do for patients with metastatic breast cancer? ARV-471 is a PROTAC targeted protein degrader, so unlike surges, what it does is it tar targets the estrogen receptor and it hijacks. The cell zone machinery for degrading proteins the ubiquitous proteasome system.
So this is a very potent ER degrader and the trial that was presented this morning was the VERITAC phase 2 study. And this is a study that was evaluating 2 different doses that were determined based on our phase one. To evaluate the efficacy of this drug in patients who were a hundred percent previously treated with the CDK4/6 therapy, and to also evaluate which dose was the optimal dose to put into phase 3.
What is the current standard of care for patients with metastatic breast cancer?
So the the trial was conducted as I mentioned, in a patient population that had previously all received a CDK4/6 inhibitor in conjunction with other endocrine therapy so this is now a population where there is no current standard of care, and it’s also a population that very rapidly progresses on established treatments today.
And it’s a population that’s highly resistant to other therapies, including endocrine treatments. So this is an area that is a tremendous need for new treatments for patients. These patients ordinarily progress within about 2 months on Fulvestrant therapy which is now the standard of care endocrine treatment in this population.
So that is clearly very poor outcome. So we’re really excited to take ARV-471 into this setting because, believe that this very targeted ER degrader can have efficacy that would exceed what current treatments can provide in this setting.
What is the trial design and why was it set up this way?
So this is a trial that is evaluating 471 at two different doses. So the first dose is 200 milligrams and the second dose is 500 milligrams, and the population is entirely pretreated with a CDK4/6 in combination with established endocrine therapy. And we also admitted prior Fulvestrant treatment chemotherapy and other lines of endocrine therapy.
Did this trail have a primary endpoint and was it met?
Endpoint of the trial was clinical benefit rate, which is the summation of complete response, partial response, and durable stable disease, meaning a minimum of six months duration of stable disease. And the frame of reference here constitutes an interesting and important result is how it may compare with something like Fulvestrant, which is the standard of care.
In two recently completed clinical trials in this 100% post CDK4/6 setting. The clinical benefit rate for Fulvestrant was between 11 and 14%. Those were in the VERONICA trial that was reported at ASCO about a year and a half ago, and then the EMERALD trial that has since been published.
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4 Key takeaways from this Clinical Trial in Pts with ER+/HER2- Locally Advanced or Metastatic Breast Cancer (mBC)
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ARV-471 Parts A and B: QD or BID administration of ARV-471 for 28-day cycles.
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ARV-471 with palbociclib – Part C: Daily oral doses of ARV-471 for 28 days with palbociclib for 21 days.
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ARV-471 – Parts A and B: QD or BID administration of ARV-471 for 28-day cycles.
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ARV-471 used with palbociclib as a medication. – Part C: Oral administration of ARV-471 for 28 days in conjunction with palbociclib for 21 days.
Who are the metastatic breast cancer patient population of this trial?
So the population was a very particularly heavily pretreated population. In, as I mentioned earlier, 100% of patients had to have received prior CDK4/6 inhibitor therapy. But also this population also received approximately about, 80% of the patients had received Fulvestrant and there was also extensive prior chemotherapy usage.
For instance, roughly about 75% of patients had received prior chemotherapy, and in total about 45% had received the chemotherapy in the metastatic setting. So to sum up, this is a from our assessment as resistant, a population has ever that has ever been evaluated to test a drug that targets the ER receptor.
What are the most common questions your colleagues ask you about this research on ARV-471?
The first question that we get, of course is what was the result in the primary endpoint? Clinical benefit rate in our trial was 38%. And that is considered, very exciting among the investigators who’ve been participating in this trial. In that when you look at Fulvestrant, you see a clinical benefit rate that’s much lower between 11 and 14%.
So I think that this has generated a lot of excitement. And also when you look at a progression-free survival, which was reported in this trial. We’re seeing progression-free survival, both in all comers and patients with the ESR1 mutations that is exceeding what would’ve been expected by far with Fulvestrant.
What are the key takeaways from the ARV-471 trial?
I think that the the main takeaways is number one, that I think the investigators and we certainly agree that ARV-471 has really established very clear efficacy in a highly resistant population with results that I think provide a lot of confidence as this program goes now into phase 3, we are initiating a phase 3 study.
The first site had opened this week, and I think that there is already some evidence that tells us that this may be a therapy that will ultimately distinguish from the other types of therapies that are now being, in targeting ER. And then aside from the initiation of our second line study, our first line study is also due to initiate in the first quarter of next year.
So with our partners, Pfizer, we’re very excited to launch a very robust program. And we’re also looking at novel combinations also for 471. So all in all, we’re very excited with the data that we have today.
Ron Peck, MD – About The Author, Credentials, and Affiliations
The newly created position of Chief Medical Officer (CMO) at Arvinas has been filled by Dr. Ronald Peck. Dr. Peck brings more than two decades of clinical and drug development experience to Arvinas. Most recently, he served as Senior Vice President, Clinical Research at Tesaro, where he oversaw all clinical development efforts for the company’s entire pipeline, including niraparib and Tesaro’s immuno-oncology programs.
Prior to joining Tesaro, Dr. Peck managed the clinical development of monoclonal antibodies targeting receptor tyrosine kinases as the chief medical officer (CMO) of Kolltan Pharmaceuticals, a privately-held clinical-stage biotechnology business. Dr. Peck began his career in the pharmaceutical sector at Bristol Myers Squibb (BMS), where he spent 15 years in drug development and finally became Vice President, Global Development Lead for ipilimumab. At BMS, he was instrumental in the approval and commercialization of ipilimumab across all indications and contributed to the successful development of numerous other cancer assets, such as ixabepilone. Early in his BMS career, Dr. Peck helped to the neuroscience clinical research organization’s life cycle development of aripiprazole. Dr. Peck received his bachelor’s degree in chemistry from Georgetown University in Washington, D.C., his medical degree from Thomas Jefferson University Medical College in Philadelphia, PA., and completed his residency and hematology/oncology fellowship at Georgetown University in Washington, D.C. before becoming an assistant professor at the University of Virginia.