In the Journals

Avelumab active in mismatch repair-deficient endometrial cancer

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.

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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