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Avelumab active in mismatch repair-deficient endometrial cancer
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Avelumab induced promising activity among women with mismatch repair-deficient endometrial cancer regardless of PD-L1 status, according to results of a prospective phase 2 trial published in Journal of Clinical Oncology.
The drug, however, did not show enough activity to warrant further review among women with mismatch repair-proficient endometrial cancer without POLE mutations.
“Although early-stage [endometrial cancer] is associated with an excellent prognosis, long-term outcomes for patients with advanced-stage or recurrent disease are poor,” Panagiotis A. Konstantinopoulos, MD, PhD, director of translational research in gynecologic oncology at Dana-Farber Cancer Institute and assistant professor of medicine at Harvard University, and colleagues wrote. “As such, [endometrial cancer] represents an important unmet medical need, and novel approaches to treatment are needed.”
Pembrolizumab (Keytruda, Merck) received tissue-agnostic FDA approval for patients with mismatch repair-deficient (MMRD) solid tumors; however, questions remain regarding the role of immune checkpoint inhibitors in MMRD and mismatch repair-proficient (MMRP) endometrial cancer, according to researchers.
Konstantinopoulos and colleagues assessed the PD-L1 inhibitor avelumab (Bavencio; EMD Serono, Pfizer) among 31 women with endometrial cancer, including 15 women with a loss of expression of at least one mismatch repair protein and a mutation in the exonuclease domain of POLE (MMRD/POLE cohort) and 16 women with normal immunohistochemical expression of all mismatch repair proteins (MMRP cohort).
All women received avelumab at 10 mg/kg IV every 2 weeks until progression or unacceptable toxicity.
Objective response rate and PFS at 6 months served as the study’s primary endpoints.
Median follow-up was 18.6 months (range, 4.4-22.2).
Four women in the MMRD/POLE cohort exhibited an objective response, including one complete response and three partial responses, for an ORR of 26.7% (95% CI, 7.8-55.1).
Six women, including all four who responded to treatment, remained progression free at 6 months (PFS = 40%; 95% CI, 16.3-66.7). Researchers observed responses among women without PD-L1 expression.
Immunohistochemistry captured all cases of MMRD later confirmed by polymerase chain reaction or through targeted sequencing.
Only one patient in the MMRP cohort (6.25%; 95% CI, 0.16-30.2) demonstrated response and was progression free at 6 months.
Overall, median PFS was 4.4 months (95% CI, 1.7-not reached) in the MMRD/POLE cohort and 1.9 months (95% CI, 1.6-2.8) in the MMRP cohort.
Median OS was 6.6 months (95% CI, 2-10.2) in the MMRP cohort and had not been reached in the MMRD/POLE cohort.
Six women experienced grade 3 treatment-related toxicities. No grade 4 or grade 5 toxicities were observed.
“Our findings support routine use of immunohistochemistry to determine MMRD status in [endometrial cancer] when considering treatment with immune checkpoint blockade,” Konstantinopoulos and colleagues wrote. “Conversely, avelumab did not demonstrate activity worthy of additional evaluation in MMRP/nonPOLE-mutated endometrial cancer, suggesting that alternative approaches are needed.” – by John DeRosier
Disclosures: Konstantinopoulos reports consultant/advisory roles with and/or institutional research funding from AstraZeneca, Eli Lilly, Merck, Pfizer, Tesaro and Vertex. Please see the study for all other authors’ relevant financial disclosures.
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