Avelumab Plus Talazoparib Demonstrates Tolerable Safety Profile in pMMR Endometrial Cancer

In patients with mismatch repair proficient (pMMR) endometrial cancer who were treated with avelumab (Bavencio) and talazoparib (Talzenna), investigators observed a promising safety profile and reported that predetermined criteria were met warranting further evaluation according to findings from a phase 2 study (NCT02912572) published in JAMA Oncology.

A confirmed objective response was observed in 11.4% of patients (95% CI, 3.2%-26.7%), with a 6-month progression-free survival (PFS) rate of 22.9%. Patients who had tumors with homologous recombination repair (HRR) alterations experienced a clinical benefit after treatment of 83.3% compared with 17.4% in non-HRR tumors (P = .01). These patients also had a better progression-free survival (PFS; P = .03).

“In this nonrandomized clinical trial, treatment with avelumab and talazoparib met the prespecified criteria to be considered worthy of further investigation in patients with recur- rent pMMR endometrial cancer. Tumor genomic profiling identified a sizeable subset of patients (those with HRR alterations and/or a platinum-free interval of ≥6 months) who may benefit from treatment with avelumab and talazoparib and supports prioritization of further development of this combination among this subset of patients,” investigators of the study wrote.

A total of 35 patients enrolled in the trial. The population had received previous treatment with carboplatin and paclitaxel, which resulted in an ORR of 11.4%. Stable disease of any duration was observed in 57.1% of patients, with a median duration of stable disease of 3.8 months. Moreover, 25.7% of patients had progressive disease. Two patients were unevaluable because they discontinued participation in the trial prior to the first baseline imaging and because of clinical progression or transitioning to hospice.

Patients were given 10 mg/kg of avelumab every 2 weeks intravenously and 1 mg of talazoparib orally each day until disease progression or unacceptable toxicity.

At a median follow-up of 12.9 months, the median PFS at data cutoff was 3.6 months (95% CI, 2.4-5.4). The clinical benefit rate was 25.7% among those treated with avelumab and talazoparib. After data cutoff, 6 patients remained on treatment.

Grade 3 treatment-related adverse effects (TRAEs) included anemia (46%), thrombocytopenia (29%), and neutropenia (11%). The only grade 4 TRAE was thrombocytopenia, which occurred in 9% of patients, with no reports of grade 5 TRAEs.

Dose reductions were necessary in 17% of patients because of toxicities, although no patients discontinued treatment because of toxic effects. Serious AEs occurred in 25.7% of patients, the most frequent of which were decreased platelet count (n = 3) and small intestinal obstruction (n = 3), although they were not associated with treatment.

Investigators conducted a biomarker analysis in which it was reported that no tumor had a polymerase epsilon mutation. The post-hoc analysis indicated that a platinum-free interval lasting 6 months or longer was associated with clinical benefit from treatment with the combination (55.6% vs 15.4%; P = .03). If patients had the ARID1A mutation or switch/sucrose nonfermentable complex alteration, there was an absence of clinical benefit (0% vs 40.9%; P = .07) and lower PFS.

Among 9 patients who experienced benefit from treatment with avelumab and talazoparib, 7 had a platinum-free interval lasting 6 months or longer and/or an HRR alteration. In the remaining patients, 1 had a hotspot for the U2AF1 spliceosome gene variation, with immune-inflamed phenotype with high tumor infiltrating lymphocytes and positive PD-L1 expression with a combined positive score of 30.

Reference

Konstantinopoulos PA, Gockley AA, Xiong N, et al. Evaluation of treatment with talazoparib and avelumab in patients with recurrent mismatch repair proficient endometrial cancer. JAMA Oncol. Published online July 28, 2022. doi:10.1001/jamaoncol.2022.2181