Does rezatapopt represent a new dawn for the targeted restoration of p53 activity?
An “exciting initial finding” could have significant implications for how a common type of tumour is treated, according to researchers.
The most commonly mutated gene in cancer is TP53, a tumour suppressor gene that encodes p53. This protein controls the expression of hundreds of other genes to maintain cell and tissue homeostasis, as well as suppressing tumour growth, by preventing certain cells from growing and causing cell death in others.
Estimates suggest as many as 50% of all solid tumours have a TP53 mutation, with this figure climbing as high as 95% in some cancers (e.g., high-grade serous ovarian cancer). Patients with TP53 mutations typically have poor prognoses due to aggressive and invasive tumour types.
It’s therefore no surprise that there have been numerous small molecules designed to reactivate mutant p53 tested in clinical settings over the past 25 years, unfortunately with little success.
Now, the results of a new phase 1 study testing rezatapopt, a first-in-class small molecule, has provided proof of concept for p53 reactivation in heavily pretreated patients with locally advanced or metastatic solid tumours.
“Preclinical data showed that rezatapopt is highly selective… and does not activate wild-type p53 or other mutant p53 proteins,” the authors of the new research wrote in the New England Journal of Medicine.
“Here, we report results from the PYNNACLE phase 1 dose-escalation and dose-optimization study of rezatapopt in patients with locally advanced or metastatic solid tumours.”
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The PYNNACLE study saw 77 patients (aged ≥ 18 years) with a locally advanced or metastatic solid tumour harbouring a TP53 Y220C mutation, a score of 0 or 1 on the Eastern Cooperative Oncology Group performance status scale (which ranges from 0-5, with higher scores indicating greater disability) and progressive disease after trying at least one systemic anticancer therapy.
Patients with primary CNS tumours, unstable metastases in the brain and clinically significant heart conditions in the six months prior to screening were excluded.
“The TP53 Y220C mutation occurs in approximately 1% of all solid tumours and is the ninth most frequent TP53 mutation among human cancers. This mutation reduces the melting temperature of p53, which results in thermodynamically unstable p53 and loss of its tumour suppressor function,” the researchers wrote.
“Rezatapopt fits tightly into the [unique pocket created by the TP53 Y220C mutation] by means of noncovalent hydrogen bonding, which enhances hydrophobic and van der Waals interactions and selectively stabilizes the structure of Y220C-mutated p53 in its wild-type conformation.
“This conformation restores the wild-type activity and transcriptional profile of p53, which has led to robust tumour regression in experimental systems.”
The 77 patients had a median age of 62 years and were mostly female (n = 46, 60%). The most common tumour types were ovarian (23, 30%), pancreatic (14; 18%) and breast cancer (10, 13%), with patients undergoing a median of three lines of systemic therapy prior to enrolling in the study.
The phase 1 component of the PYNNACLE study utilised an accelerated dose-adjustment design, where a small number of patients received the lowest dose of rezatapopt (150mg once daily for 21 days) while being evaluated for safety and dose-limiting toxic effects. After at least one patient had completed a treatment cycle and been assessed for adverse events, the next group of patients received a higher dose of rezatapopt.
All patients continued to receive rezatapopt for as long as they displayed clinical benefit or until disease progression occurred, or another endpoint occurred (e.g., an unacceptable adverse event, pregnancy, etc.). Patients were followed up until the end of the study, loss to follow-up, death or two years after stopping rezatapopt treatment.
Eight different doses of rezatapopt were administered over the course of the study: 150mg/per day (n = 3), 300mg/day (n = 3), 600mg/day (n = 4), 1150mg/day (n = 5), 1500mg/day (n = 10), 2000mg/day without food (n = 11), 2000mg/day with food (n = 18), 2500mg/day (n = 13) and 1500mg twice a day (n = 10).
No dose-limiting toxic effects occurred in any of the once-daily doses, but two patients in the twice-daily group experienced grade 3 toxic effects (one had increased alanine and aspartate aminotransferase levels while the other had acute kidney injury). The researchers concluded that 1500mg twice a day was the maximum tolerated dose but recommended that 2000mg/day with food as the dose for the phase 2 study after assessing other safety, efficacy and pharmacokinetic data.
All bar one patient experienced at least one adverse event, with 38% of patients reporting a grade 1 or 2 adverse event. Nausea (58%), vomiting (44%), an increased blood creatinine level (39%) and fatigue (also 39%) were the most common side effects, although constipation, decreased appetite and hyponatremia (all 17%) were also reported. Anaemia was the most common grade 3 or higher adverse event, occurring in 14% of patients.
The principal investigator viewed that 87% of patients had at least one treatment-related adverse event, with nausea (49%), vomiting (38%) and an increased blood creatinine level (26%) again the most common treatment-related effects. Forty-eight patients experienced a grade 1 or 2 treatment-related adverse effect and 29 grade 3 or 4 events occurred across 19 patients.
Of the 71 patients with measurable disease at baseline, 20% displayed an overall response – defined as the “disappearance of all target and nontarget lesions without development of new lesions (complete response) or by a decrease from baseline of at least 30% in the sum of the target lesion diameters without progression of nontarget lesions or development of new lesions (partial response)” – to the rezatapopt treatment.
“A confirmed response was seen in seven patients with ovarian cancer, 3 with breast cancer and 1 each with endometrial cancer, head and neck cancer, prostate cancer and small-cell lung cancer,” the authors noted.
“No patients treated with a dose that was lower than the observed efficacious-dose range [1150mg/day and up] had a response. The median time to a response was 1.4 months, with most of these responses observed at the first tumour assessment after baseline.
“[Furthermore,] the median progression-free survival was 4.3 months (95% CI, 2.8 to 5.5) [and the] median overall survival was 11.4 months (95% CI, 6.4 to 14.9).”
The researchers felt their results offered a proof of concept for p53 reactivation for the treatment of solid tumours but noted that their early findings may not generalise to all patients.
“The concept of p53 reactivation has been previously evaluated. A nonselective p53 inhibitor prodrug whose metabolites bind to any mutant p53 as well as to wild-type p53 was evaluated in two clinical trials, but limited activity was observed with monotherapy, and the drug was subsequently discontinued,” they wrote.
“Rezatapopt appears to effectively reactivate a particular p53 mutant in solid tumours. This first-in-class selective p53 reactivator offers the potential for an orally administered targeted treatment approach in patients with solid tumours harbouring a TP53 Y220C mutation.”
The PYNNACLE phase 2 study is currently underway and is recruiting across several Australian sites.
