Targeting p53 Y220C: Dr Dale Shepard Discusses Rezatapopt Findings

The TP53 gene has long been the "white whale" of oncology. Mutated in roughly half of all human cancers, it was considered undruggable for decades. However, data from the PYNNACLE phase 1 trial (NCT04585750), recently published in The New England Journal of Medicine, suggests that a precision medicine approach may finally be turning the tide.

The study investigated rezatapopt (PC14586), a first-in-class small molecule designed to selectively bind and reactivate the p53 Y220C mutation. To discuss the clinical implications and the excitement surrounding these findings, we spoke with Dale Shepard, MD, PhD, of the Cleveland Clinic and investigator on the study.

Targeted Oncology: To start, could you provide some background on the agent and explain why targeting p53 is such a milestone?

Dale Shepard, MD, PhD: I think that’s, quite honestly, what makes this most interesting. We know that p53 mutations are really important for driving many, many cancers; about 50% of cancers have a p53 mutation. Previously, despite the fact we knew there was a mutation, we couldn’t do anything about it—it wasn’t targetable.

p53 is important because it leads to the development of tumor suppressor genes. By mutating p53, you no longer have tumor suppressor genes, and then tumors grow. This is a very specific small molecule that binds to p53 that has this Y220C mutation. It binds to the p53, makes it back into a normal conformation, and now it works again. It is an oral medication that can be taken daily with minimal adverse effects shown in the trial. Previously, we knew p53 was a bad actor, we just couldn’t do anything about it. This is really the first time we’ve been able to drug that target.

As a phase 1 trial in The New England Journal of Medicine, there is significant buzz. What can you tell us about the findings and the optimized dose?

Since it is a phase 1 trial, we can’t lose track of the fact that the primary end point was an appropriate dose for further studies and toxicity. We ran through a number of different dose levels and picked a dose that was the maximum tolerated dose.

Based on the new guidelines to optimize doses, we came up with an optimal dose, which is a daily dose of medication taken with food. As you do these toxicity studies, it was found that gastrointesintal adverse effects—nausea and vomiting—were improved if we gave food with the medication. Really, the striking thing is how well-tolerated it has been. Treatment-related events were nausea, vomiting, fatigue, and some elevations in creatinine, but all in all, it was surprisingly well-tolerated for a new class of drugs.

Looking at efficacy, what is the significance of the response rate observed in this heavily pretreated population?

We looked at 77 patients in the trial who were highly pretreated; on average, they had at least three prior therapies. The response rate in evaluable patients was 20%. It’s important to put that in perspective: this was a wide range of different cancers, and a 20% response rate is what we see as first-line therapy in some cancers.

To editorialize a bit, I think we’ve gotten a little spoiled when we think about mutation-specific drugs and the fact that we think everything should be getting an 80% response. A 20% response rate in people who are heavily pretreated is a really good response. The biggest success was actually in ovarian cancer; about half of the patients who responded had ovarian cancer. As it turns out, about 95% of patients with ovarian cancers have a p53 mutation.

There are also mentions of this research moving into hematologic malignancies. What is the status there?

It’s true. I’ve already had my hematologic colleagues come up to me and say, "Hey, we have it in our disease." I've already had a fair amount of buzz within our department of people looking for ways to use the drug.

Are there any final takeaways regarding the specificity of this protein abnormality?

I think the key will be expanding within this mutation. But this is a very specific mutation that causes a very specific change in the p53 protein. It’s exciting that we can now target the protein, but we’re going to have to come up with another innovation for the other mutations, because those cause different changes in the p53 molecule.

It’s going to be a while before we have another. This will end up making an impact in other diseases with this mutation, but is not likely to make an impact in people that have other p53 mutations because of the very specific way it works on that gene and that protein.

REFERENCE

Dumbrava EE, Shapiro GI, Parikh AR, et al. Phase 1 Study of Rezatapopt, a p53 Reactivator, in TP53 Y220C-Mutated Tumors. N Engl J Med. 2026 Feb 26;394(9):872-883. doi: 10.1056/NEJMoa2508820. PMID: 41740031.