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Ref Type Journal Article
PMID (38653864)
Authors Friedman CF, Manning-Geist BL, Zhou Q, Soumerai T, Holland A, Da Cruz Paula A, Green H, Ozsoy MA, Iasonos A, Hollmann T, Leitao MM, Mueller JJ, Makker V, Tew WP, O'Cearbhaill RE, Liu YL, Rubinstein MM, Troso-Sandoval T, Lichtman SM, Schram A, Kyi C, Grisham RN, Causa Andrieu P, Wherry EJ, Aghajanian C, Weigelt B, Hensley ML, Zamarin D
Title Nivolumab for mismatch-repair-deficient or hypermutated gynecologic cancers: a phase 2 trial with biomarker analyses.
URL
Abstract Text Programmed death-1 (PD-1) inhibitors are approved for therapy of gynecologic cancers with DNA mismatch repair deficiency (dMMR), although predictors of response remain elusive. We conducted a single-arm phase 2 study of nivolumab in 35 patients with dMMR uterine or ovarian cancers. Co-primary endpoints included objective response rate (ORR) and progression-free survival at 24 weeks (PFS24). Secondary endpoints included overall survival (OS), disease control rate (DCR), duration of response (DOR) and safety. Exploratory endpoints included biomarkers and molecular correlates of response. The ORR was 58.8% (97.5% confidence interval (CI): 40.7-100%), and the PFS24 rate was 64.7% (97.5% one-sided CI: 46.5-100%), meeting the pre-specified endpoints. The DCR was 73.5% (95% CI: 55.6-87.1%). At the median follow-up of 42.1 months (range, 8.9-59.8 months), median OS was not reached. One-year OS rate was 79% (95% CI: 60.9-89.4%). Thirty-two patients (91%) had a treatment-related adverse event (TRAE), including arthralgia (n = 10, 29%), fatigue (n = 10, 29%), pain (n = 10, 29%) and pruritis (n = 10, 29%); most were grade 1 or grade 2. Ten patients (29%) reported a grade 3 or grade 4 TRAE; no grade 5 events occurred. Exploratory analyses show that the presence of dysfunctional (CD8+PD-1+) or terminally dysfunctional (CD8+PD-1+TOX+) T cells and their interaction with programmed death ligand-1 (PD-L1)+ cells were independently associated with PFS24. PFS24 was associated with presence of MEGF8 or SETD1B somatic mutations. This trial met its co-primary endpoints (ORR and PFS24) early, and our findings highlight several genetic and tumor microenvironment parameters associated with response to PD-1 blockade in dMMR cancers, generating rationale for their validation in larger cohorts.ClinicalTrials.gov identifier: NCT03241745 .

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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
MSH6 negative endometrial carcinoma sensitive Nivolumab Phase II Actionable In a Phase II trial, Opdivo (nivolumab) treatment resulted in an objective response rate of 58.8% (20/34, 7 complete and 13 partial responses) and a progression-free survival rate at 24 mo of 64.7% in patients with MSI-high or deficient mismatch repair (dMMR defined by the loss of MLH1, PMS2, MSH2, or MSH6 expression by IHC) ovarian or endometrial carcinoma, including responses in 2 patients with uterine clear cell carcinoma and 1 patient with ovarian clear cell carcinoma (PMID: 38653864; NCT03241745). 38653864
MSH6 negative ovarian carcinoma predicted - sensitive Nivolumab Phase II Actionable In a Phase II trial, Opdivo (nivolumab) treatment resulted in an objective response rate of 58.8% (20/34, 7 complete and 13 partial responses) and a progression-free survival rate at 24 mo of 64.7% in patients with MSI-high or deficient mismatch repair (dMMR defined by the loss of MLH1, PMS2, MSH2, or MSH6 expression by IHC) ovarian or endometrial carcinoma, including responses in 2 patients with uterine clear cell carcinoma and 1 patient with ovarian clear cell carcinoma (PMID: 38653864; NCT03241745). 38653864
MLH1 negative ovarian carcinoma predicted - sensitive Nivolumab Phase II Actionable In a Phase II trial, Opdivo (nivolumab) treatment resulted in an objective response rate of 58.8% (20/34, 7 complete and 13 partial responses) and a progression-free survival rate at 24 mo of 64.7% in patients with MSI-high or deficient mismatch repair (dMMR defined by the loss of MLH1, PMS2, MSH2, or MSH6 expression by IHC) ovarian or endometrial carcinoma, including responses in 2 patients with uterine clear cell carcinoma and 1 patient with ovarian clear cell carcinoma (PMID: 38653864; NCT03241745). 38653864
MLH1 negative endometrial carcinoma sensitive Nivolumab Phase II Actionable In a Phase II trial, Opdivo (nivolumab) treatment resulted in an objective response rate of 58.8% (20/34, 7 complete and 13 partial responses) and a progression-free survival rate at 24 mo of 64.7% in patients with MSI-high or deficient mismatch repair (dMMR defined by the loss of MLH1, PMS2, MSH2, or MSH6 expression by IHC) ovarian or endometrial carcinoma, including responses in 2 patients with uterine clear cell carcinoma and 1 patient with ovarian clear cell carcinoma (PMID: 38653864; NCT03241745). 38653864