Evaluation of Treatment With Talazoparib and Avelumab in Patients With Recurrent Mismatch Repair Proficient Endometrial Cancer

Abstract

Importance: Although the activity of pembrolizumab and lenvatinib (the only US Food and Drug Administration-approved immunotherapy for mismatch repair proficient endometrial cancer [MMRP EC]) is compelling, there are no biomarkers of response and most patients do not tolerate, do not respond to, or develop resistance to this regimen, highlighting the need for additional, potentially biomarker-driven therapeutic approaches for patients with recurrent MMRP EC.

Objective: To assess the potential positive outcomes and safety of the combination of the polyadenosine diphosphate-ribose polymerase inhibitor talazoparib and the programmed cell death ligand 1 (PD-L1) inhibitor avelumab in recurrent MMRP EC.

Design, settings, and participants: This investigator-initiated, open-label, single-arm, 2-stage, phase 2 study nonrandomized controlled trial patients at 4 institutions in the US. Key eligibility criteria included measurable disease, unlimited prior therapies, and all endometrial cancer histologies.

Interventions: Talazoparib, 1 mg, orally, daily, and avelumab, 10 mg/kg, intravenously, every 2 weeks, were administered until disease progression or unacceptable toxic effects.

Main outcomes and measures: Statistical considerations were developed for 2 coprimary objectives of objective response rate and rate of progression-free survival at 6 months, with a 2-stage design that allowed for early discontinuation for futility. Prespecified exploratory objectives included the association of immunogenomic features (determined by targeted-panel next-generation sequencing and immunohistochemistry) with activity.

Results: Thirty-five female patients (mean [SD] age, 67.9 [8.41] years) received protocol therapy; 9 (25.7%) derived clinical benefit after meeting at least 1 of the 2 coprimary end points. Four patients (11.4%) exhibited confirmed objective response rates (4 partial responses), and 8 (22.9%) survived progression free at 6 months. The most common grade 3 and 4 treatment-related toxic effects were anemia (16 [46%]), thrombocytopenia (10 [29%]), and neutropenia (4 [11%]); no patient discontinued receipt of therapy because of toxic effects. Tumors with homologous recombination repair alterations were associated with clinical benefit from treatment with avelumab and talazoparib. Tumor mutational burden, tumor-infiltrating lymphocytes, and PD-L1 status were not associated with clinical benefit.

Conclusions and relevance: The results of this nonrandomized controlled trial suggest that treatment with avelumab and talazoparib demonstrated a favorable toxic effect profile and met the predetermined criteria to be considered worthy of further evaluation in MMRP EC. Immunogenomic profiling provided insights that may inform ongoing and future studies of polyadenosine diphosphate-ribose polymerase and PD-L1 inhibitor combinations in endometrial cancer.

Trial registration: ClinicalTrials.gov Identifier: NCT02912572.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Konstantinopoulos reported grants from Lilly during the conduct of the study as well as personal fees from AlkermesArtios, Bayer, Kadmon, Mersana, AstraZeneca, Repare, GSK, and IMV and grants from Pfizer, Merck, and BMS outside the submitted work. Dr Wright reported grants from the National Comprehensive Cancer Network, AstraZeneca, National Cancer Institute, National Institute of Nursing Research, and Pack Health and personal fees from GSK outside the submitted work. Dr Liu reported personal fees from AstraZeneca, Clovis, Eisai, EpsilaBio, Genentech, Regeneron Pharmaceuticals, and GSK outside the submitted work. Dr Shea reported personal fees from GSK outside the submitted work. Dr Lee reported research support from Merck Sharp & Dohme outside the submitted work. Dr Bouberhan reported personal fees from ImmunoGen outside the submitted work. Dr Spriggs reported research support from Pfizer and Merck during the conduct of the study. Dr Penson reported personal fees from AstraZeneca, GSK, ImmunoGen, Merck, Mersana, Novacure, Roche Pharma, Sutro Biopharma, and Vascular Biogenics Ltd during the conduct of the study. Dr Fleming reported research support from Sermonix, Compugen, Celldex, Corcept, Plexxicon, AstraZeneca, Molecular Templates, CytomX, Astellas, K group beta, DSI, Merck, Caris Dx, Eisai, and Clovis outside the submitted work. Dr Matulonis reported personal fees from Merck, AstraZeneca, 2X Oncology, Trillium, Blueprint Medicines, Boeringer Ingelheim, GSK, Agenus, Symphogen, Advaxis, Alkermes, Novartis, and Immunogen during the conduct of the study as well as personal fees from Clearity Foundation, Rivkin Foundation, and the Ovarian Cancer Research Alliance outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Study Overview

RECIST indicates Response Evaluation Criteria in Solid Tumours.

Figure 2.. Antitumor Activity of Avelumab and Talazoparib

A, Best change in target lesions from baseline in all patients evaluable for Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1 response (data cutoff date, November 30, 2020). The dotted lines at −30% and 20% indicate partial response and progression per RECIST, respectively. B, Avelumab and talazoparib treatment duration. Presence or absence of homologous recombination repair (HRR) alterations and platinum-free interval (PFI) of 6 months or longer vs PFI of less than 6 months is indicated for each patient. PD indicates programmed cell death. aPatients still receiving protocol therapy as of the data cutoff date.

Figure 3.. Progression-Free Survival

A, Patients with and without homologous recombination repair (HRR) alterations. B, Patients with and without switch/sucrose nonfermentable complex (SWI/SNF) alterations. C, Patients with a platinum-free interval (PFI) of 6 months or longer and PFI of less than 6 months. D, Patients with HRR-altered tumors or PFI of 6 months or longer vs those with no HRR alterations and a PFI of less than 6 months.