Safety and efficacy profile of first-in-class oral p53 reactivator rezatapopt

1. In this phase 1-2 single-group trial, the p53 reactivator rezatapopt was well-tolerated in adults with solid tumors harboring the TP53 Y220C mutation. 

2. Preliminary efficacy data showed dose-dependent tumor regression in participants with ovarian, breast, and other cancers.  

Evidence Rating Level: 2 (Good)

Study Rundown: TP53 is the most commonly mutated gene in cancer, accounting for more than half of solid tumors. The TP53 Y220C mutation results in a thermodynamically unstable protein product with loss of tumor suppressor function. Rezatapopt is a first-in-class small molecule oral p53 reactivator that binds specifically to Y220C-mutated p53 and restores its wild-type conformation. This study, titled the PYNNACLE trial, aimed to evaluate the dosing, safety, and efficacy of rezatapopt in heavily pre-treated adults with TP53 Y220C mutated cancers. Nearly eighty patients received escalating doses of rezatapopt in three week cycles, with the optimal dose eventually determined to be 2000 mg once daily.  Nearly ninety percent of patients had at least one adverse event deemed to be related to rezatapopt, although these were mostly mild to moderate in severity. Anemia was the most frequent adverse event of grade three or higher, and all treatment-related serious adverse events resolved by the end of the trial. In preliminary efficacy analyses, one in five participants had a partial or complete response to the treatment, as evidenced by significantly reduced tumor size on imaging. Notably, all responders were determined to also harbor a wild-type KRAS gene. This study was limited by small sample sizes for subgroup analyses and inability to generalize to cancers with alternate genetic profiles. However, study strengths were the inclusion of various types of cancer (breast, ovarian, colon, head and neck, etc.) and the genotypic analyses of responders to therapy. Overall, this trial demonstrated that rezatapopt had a favorable safety profile and promising early efficacy data for patients with TP53 Y220C-mutated solid tumors.

Click to read the study in NEJM

Relevant Reading: Small-molecule correctors and stabilizers to target p53

In-Depth [prospective cohort]: This phase 1-2 single-group trial, titled PYNNACLE, evaluated the optimal dosing, safety, and efficacy of rezatapopt, a first-in-class oral p53 reactivator, in adults with tumors expressing the TP53 Y220C mutation. Eligible participants had locally advanced or metastatic solid tumors with a TP53 Y220C mutation and had been treated with at least one previous line of systemic therapy. A total of 77 adults were enrolled and received rezatapopt at one of eight escalating doses from 150mg to 3000mg daily in continuous 21 day treatment cycles. Nearly all patients experienced at least one adverse event, with nausea (58%) and vomiting (44%) being the most common. Anemia occurred in 16% of patients and was the most common grade 3 adverse event. Treatment related events were less frequent in those receiving 2000 mg daily with food, and this dosage was recommended for the ongoing phase 2 study. Regarding secondary efficacy outcomes, the overall response rate, defined as at least a 30% decrease in the sum of the target lesion diameters, was 20% and was observed mostly among those with ovarian and breast cancer. All patients with a response had a solid tumor with both the TP53 Y220C mutation and wild-type KRAS. In summary, this phase 1 trial demonstrated that rezatapopt was well-tolerated and had some early efficacy signal amongst patients with the Y220C TP53 mutation.

Image: PD

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