PURPOSE: Despite the tissue-agnostic approval of pembrolizumab in mismatch repair deficient (MMRD) solid tumors, important unanswered questions remain about the role of immune checkpoint blockade in mismatch repair-proficient (MMRP) and -deficient endometrial cancer (EC). METHODS: This phase II study evaluated the PD-L1 inhibitor avelumab in two cohorts of patients with EC: (1) MMRD/POLE (polymerase ε) cohort, as defined by immunohistochemical (IHC) loss of expression of one or more mismatch repair (MMR) proteins and/or documented mutation in the exonuclease domain of POLE; and (2) MMRP cohort with normal IHC expression of all MMR proteins. Coprimary end points were objective response (OR) and progression-free survival at 6 months (PFS6). Avelumab 10 mg/kg intravenously was administered every 2 weeks until progression or unacceptable toxicity. RESULTS: Thirty-three patients were enrolled. No patient with POLE-mutated tumor was enrolled in the MMRD cohort, and all MMRP tumors were not POLE-mutated. The MMRP cohort was closed at the first stage because of futility: Only one of 16 patients exhibited both OR and PFS6 responses. The MMRD cohort met the predefined primary end point of four ORs after accrual of only 17 patients; of 15 patients who initiated avelumab, four exhibited OR (one complete response, three partial responses; OR rate, 26.7%; 95% CI, 7.8% to 55.1%) and six (including all four ORs) PFS6 responses (PFS6, 40.0%; 95% CI, 16.3% to 66.7%), four of which are ongoing as of data cutoff date. Responses were observed in the absence of PD-L1 expression. IHC captured all cases of MMRD subsequently determined by polymerase chain reaction or genomically via targeted sequencing. CONCLUSION: Avelumab exhibited promising activity in MMRD EC regardless of PD-L1 status. IHC for MMR assessment is a useful tool for patient selection. The activity of avelumab in MMRP/non-POLE-mutated ECs was low.
PURPOSE: Despite the tissue-agnostic approval of pembrolizumab in mismatch repair deficient (MMRD) solid tumors, important unanswered questions remain about the role of immune checkpoint blockade in mismatch repair-proficient (MMRP) and -deficient endometrial cancer (EC). METHODS: This phase II study evaluated the PD-L1 inhibitor avelumab in two cohorts of patients with EC: (1) MMRD/POLE (polymerase ε) cohort, as defined by immunohistochemical (IHC) loss of expression of one or more mismatch repair (MMR) proteins and/or documented mutation in the exonuclease domain of POLE; and (2) MMRP cohort with normal IHC expression of all MMR proteins. Coprimary end points were objective response (OR) and progression-free survival at 6 months (PFS6). Avelumab 10 mg/kg intravenously was administered every 2 weeks until progression or unacceptable toxicity. RESULTS: Thirty-three patients were enrolled. No patient with POLE-mutated tumor was enrolled in the MMRD cohort, and all MMRP tumors were not POLE-mutated. The MMRP cohort was closed at the first stage because of futility: Only one of 16 patients exhibited both OR and PFS6 responses. The MMRD cohort met the predefined primary end point of four ORs after accrual of only 17 patients; of 15 patients who initiated avelumab, four exhibited OR (one complete response, three partial responses; OR rate, 26.7%; 95% CI, 7.8% to 55.1%) and six (including all four ORs) PFS6 responses (PFS6, 40.0%; 95% CI, 16.3% to 66.7%), four of which are ongoing as of data cutoff date. Responses were observed in the absence of PD-L1 expression. IHC captured all cases of MMRD subsequently determined by polymerase chain reaction or genomically via targeted sequencing. CONCLUSION: Avelumab exhibited promising activity in MMRD EC regardless of PD-L1 status. IHC for MMR assessment is a useful tool for patient selection. The activity of avelumab in MMRP/non-POLE-mutated ECs was low.
Authors: Roman M Chabanon; Mathieu Rouanne; Christopher J Lord; Jean-Charles Soria; Philippe Pasero; Sophie Postel-Vinay Journal: Nat Rev Cancer Date: 2021-08-10 Impact factor: 60.716
Authors: Marina Stasenko; Irina Tunnage; Charles W Ashley; Maria M Rubinstein; Alicia J Latham; Arnaud Da Cruz Paula; Jennifer J Mueller; Mario M Leitao; Claire F Friedman; Vicky Makker; Robert A Soslow; Deborah F DeLair; David M Hyman; Dimitriy Zamarin; Kaled M Alektiar; Carol A Aghajanian; Nadeem R Abu-Rustum; Britta Weigelt; Karen A Cadoo Journal: Gynecol Oncol Date: 2019-11-19 Impact factor: 5.482
Authors: Panagiotis A Konstantinopoulos; Barbara Norquist; Christina Lacchetti; Deborah Armstrong; Rachel N Grisham; Paul J Goodfellow; Elise C Kohn; Douglas A Levine; Joyce F Liu; Karen H Lu; Dorinda Sparacio; Christina M Annunziata Journal: J Clin Oncol Date: 2020-01-27 Impact factor: 44.544