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Ref Type Journal Article
PMID (31461377)
Authors Konstantinopoulos PA, Luo W, Liu JF, Gulhan DC, Krasner C, Ishizuka JJ, Gockley AA, Buss M, Growdon WB, Crowe H, Campos S, Lindeman NI, Hill S, Stover E, Schumer S, Wright AA, Curtis J, Quinn R, Whalen C, Gray KP, Penson RT, Cannistra SA, Fleming GF, Matulonis UA
Title Phase II Study of Avelumab in Patients With Mismatch Repair Deficient and Mismatch Repair Proficient Recurrent/Persistent Endometrial Cancer.
URL
Abstract Text 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).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.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.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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
MLH1 negative endometrial cancer sensitive Avelumab Phase II Actionable In a Phase II trial, Bavencio (avelumab) treatment resulted in an objective response rate of 26.7% (4/15, 1 complete response, 3 partial responses) and 6-month progression-free survival rate of 40% (6/15) in patients with mismatch repair deficient (dMMR, defined by the loss of MLH1, PMS2, MSH2, or MSH6 expression by IHC) recurrent or persistent endometrial cancer (PMID: 31461377; NCT02912572). 31461377
MSH6 negative endometrial cancer sensitive Avelumab Phase II Actionable In a Phase II trial, Bavencio (avelumab) treatment resulted in an objective response rate of 26.7% (4/15, 1 complete response, 3 partial responses) and 6-month progression-free survival rate of 40% (6/15) in patients with mismatch repair deficient (dMMR, defined by the loss of MLH1, PMS2, MSH2, or MSH6 expression by IHC) recurrent or persistent endometrial cancer (PMID: 31461377; NCT02912572). 31461377