Faeth Therapeutics’ endometrial cancer prospect has cleared the phase 2 efficacy bar, emboldening the biotech to forge ahead with efforts to establish the oral therapy in a field dominated by injectables.
The trial tested the PI3K-alpha-specific inhibitor serabelisib and the mTORC1 and mTORC2 inhibitor sapanisertib in combination. By targeting the PI3K/AKT/mTOR pathway at multiple points, Faeth aims to address one of the most frequent genomic drivers in solid tumors. Celcuity’s Revtorpyk is a similar drug, but it hits multiple PI3K isoforms and is administered in weekly infusions.
While Celcuity is focused on breast cancer, Faeth chose endometrial cancer as its lead indication, starting a phase 2 trial in patients with advanced or recurrent tumors almost two years ago. On Monday, Faeth shared topline data on the serabelisib-sapanisertib combination, which it calls Piktor, plus intravenous paclitaxel in 42 endometrial cancer patients who had received at least one prior line of therapy.
The biotech reported a 33% confirmed overall response rate (ORR) in the 36 efficacy-evaluable patients who received Piktor plus paclitaxel. Preliminary median progression-free survival (PFS) was 7.4 months, with a six-month PFS rate of 62%, in the 42 patients treated with the combination. Three patients discontinued Piktor because of adverse events.
“We believe these preliminary data set Piktor apart: confirmed responses and encouraging preliminary progression-free survival in previously treated patients, with hyperglycemia and stomatitis mostly low grade, in a population in which nearly half of patients had diabetes or prediabetes and none received stomatitis prophylaxis,” Faeth CEO Anand Parikh said in a statement.
Ahead of the readout, TD Cowen analysts wrote in October that a key opinion leader had suggested that a 30% ORR would be a “great result.” William Blair analysts set the same threshold in a note earlier last month, telling investors that Faeth would have a competitive drug if it posted a 30% or higher ORR and interim trends on durability of about five to six months.
The targets reflect the benchmarks set by injectable drugs. Merck & Co. reported a 30.3% ORR in a phase 3 trial that tested its checkpoint inhibitor Keytruda in combination with Eisai’s tyrosine kinase inhibitor Lenvima. The ORR in the chemotherapy control cohort was 15.1%. All patients in Faeth’s study had received taxane-based chemotherapy, and all but one participant had tried immunotherapy.
Piktor stands out in an endometrial cancer pipeline heavy on antibody-drug conjugates (ADCs). Merck recently reported a 35.1% ORR and 7.2-month PFS in a global phase 3 trial of its TROP2-directed ADC sac-TMT. Meanwhile, AstraZeneca and Genmab are developing ADCs aimed at B7-H4 and FR-alpha, respectively.
While the ADCs have different targets, their payloads are all topoisomerase I (TOPO-1) inhibitors. Patients can develop resistance to TOPO-1 inhibitors. If the ADCs become first-line therapies, physicians will need endometrial cancer drugs with different mechanisms of action for relapsed patients.
Faeth plans to test Piktor in a randomized phase 3 trial, pending feedback from the FDA. The biotech is also testing the combination in breast cancer and expects to report data in that setting next year. Breast and endometrial tumors are prone to alterations in the PI3K/AKT/mTOR pathway.
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