Avelumab/Talazoparib Combo Worthy of Further Exploration in Recurrent MMRP Endometrial Cancer

The combination of avelumab (Bavencio) and talazoparib (Talzenna) showcased a favorable toxicity profile and overall modest activity in patients with mismatch repair–proficient (MMRP) endometrial cancer, according to data from a phase 2 study (NCT02912572) published in JAMA Oncology. However, immunogenomic profiling revealed a certain subset who might derive benefit from the doublet, warranting further investigation.

The objective response rate achieved with the regimen was 11.4% (95% CI, 3.2%-26.7%). All the 4 confirmed responses were partial responses. Twenty patients (57.1%) had stable disease of any duration, with a median duration of 3.8 months (range, 1.7-12.8). Nine (25.7%) patients had progressive disease and 2 were unevaluable because they left the trial prior to first postbaseline imaging due to clinical progression and transitioning to hospice care.

Additionally, 22.9% (95% CI, 10.4%-40.1%) of patients were alive and progression free at 6 months. As of the data cutoff November 30, 2020, and with a median follow-up of 12.9 months (range, 1.3-20.9), the median progression-free survival was 3.6 months (95% CI, 2.4-5.4) with the doublet. Nine patients (25.7%) derived clinical benefit from the combination, after meeting at least 1 of the 2 coprimary end points.

“In this nonrandomized clinical trial, treatment with avelumab and talazoparib met the prespecified criteria to be considered worthy of further investigation in patients with recurrent MMRP endometrial cancer,” Panagiotis A. Konstantinopoulos, MD, PhD, of Dana-Farber Cancer Institute, and colleagues, wrote in the paper. “Tumor genomic profiling identified a sizeable subset of patients (those with homologous recombination repair [HRR] alterations and/or a platinum-free interval [PFI] 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.”

At present, pembrolizumab (Keytruda) plus lenvatinib (Lenvima) is the only FDA-approved immunotherapy regimen for MMRP endometrial cancer. However, most patients do not tolerate, do not respond to, or develop resistance to this regimen. Furthermore, there are no biomarkers predictive for response. Therefore, there is a high unmet need for additional, potentially biomarker-driven, therapeutic approaches.

Investigators initiated the study to evaluate the activity of avelumab/talazoparib by the co-primary end points of frequency of patients who survived progression free for 6 months or longer after initiating protocol therapy or objective response by RECIST v1.1 criteria. Secondary end points included PFS and toxicity.

Eligible participants had a diagnosis of recurrent or persistent endometrial cancer of any histology that was determined to be MMRP by immunohistochemistry.

From February 2019 to December 2019, 35 patients received 10 mg/kg avelumab every 2 weeks in combination with 1 mg of oral talazoparib daily until disease progression or unacceptable toxicity. All patients had previously received carboplatin/paclitaxel chemotherapy.

In prespecified exploratory biomarker analyses, investigators found no association between outcomes and PD-L1 status, tumor-infiltrating lymphocytes (TILs), or tumor mutational burden. Patients with HRR-altered tumors were more likely to derive clinical benefit vs those who had non–HRR-altered tumors (83.3% vs 17.4%; P = .01) and experienced better PFS (P = .030).

In post-hoc analyses, patients who had a PFI, defined as the time between the last cycle of platinum and disease progression, of 6 months or longer were more likely to derive clinical benefit (55.6% vs 15.4%; P = .030) and had better PFS (P = .009) than those with a shorter PFI.

In contrast, the presence of ARID1A and other switch/sucrose nonfermentable complex alterations was associated with a trend toward absence of clinical benefit (0% vs 40.9%; P = .07) and poorer PFS (P = .060).

Of the 9 patients who derived benefit from treatment, 7 had a PFI of 6 months or longer and/or HRR alterations. One of the remaining 2 patients harbored a hotspot U2AF1 spliceosome gene variation. This tumor had an immune-inflamed phenotype with high TILs and PD-L1 combined positive score of 30.

The most common grade 3 treatment-emergent adverse effects (TRAEs) were anemia (46%), thrombocytopenia (29%), and neutropenia (11%). The only grade 4 TRAE reported with the doublet was thrombocytopenia (9%) and there no grade 5 TRAEs were observed.

Six patients (17%) required dose reductions because of toxic effects and no patients discontinued receipt of therapy due to AEs. Nine (25.7%) patients experienced serious AEs, most often decreased platelet counts and small intestinal obstruction (3 patients each), although these toxicities were not determined to be related to the study treatment.

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