Nivolumab for mismatch-repair-deficient or hypermutated gynecologic cancers: A phase 2 trial with biomarker analyses Journal Article
| Authors: | Friedman, C. F.; Manning-Geist, B. L.; Zhou, Q.; Soumerai, T.; Holland, A.; Da Cruz Paula, A.; Green, H.; Ozsoy, M. A.; Iasonos, A.; Hollmann, T.; Leitao, M. M. Jr; Mueller, J. J.; Makker, V.; Tew, W. P.; O’Cearbhaill, R. E.; Liu, Y. L.; Rubinstein, M. M.; Troso-Sandoval, T.; Lichtman, S. M.; Schram, A.; Kyi, C.; Grisham, R. N.; Causa Andrieu, P.; Wherry, E. J.; Aghajanian, C.; Weigelt, B.; Hensley, M. L.; Zamarin, D. |
| Article Title: | Nivolumab for mismatch-repair-deficient or hypermutated gynecologic cancers: A phase 2 trial with biomarker analyses |
| Abstract: | 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. © The Author(s) 2024. |
| Keywords: | adult; clinical article; human tissue; aged; aged, 80 and over; middle aged; overall survival; somatic mutation; genetics; mutation; prednisone; clinical trial; fatigue; diarrhea; drug safety; follow up; endometrioid carcinoma; endometrium cancer; ovarian neoplasms; biological marker; progression free survival; drug eruption; ovary cancer; pain; phase 2 clinical trial; hemolysis; pathology; tumor marker; arthralgia; dyspnea; pruritus; genital neoplasms, female; mismatch repair; dna mismatch repair; ovary tumor; nausea and vomiting; skin disease; clear cell carcinoma; immune deficiency; drug therapy; disease control; immunosuppressive treatment; insulin dependent diabetes mellitus; diplopia; neurologic disease; gastrointestinal disease; beta adrenergic receptor blocking agent; female genital tract tumor; dna mismatch repair deficiency; carcinosarcoma; programmed death 1 ligand 1; programmed death 1 receptor; progression-free survival; optic neuritis; female genital tract cancer; myocarditis; mycophenolate mofetil; nivolumab; very elderly; humans; human; female; article; programmed cell death 1 receptor; whole exome sequencing; complete heart block; biomarkers, tumor; immunological antineoplastic agent; antineoplastic agents, immunological; b7-h1 antigen |
| Journal Title: | Nature Medicine |
| Volume: | 30 |
| Issue: | 5 |
| ISSN: | 1078-8956 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-05-01 |
| Start Page: | 1330 |
| End Page: | 1338 |
| Language: | English |
| DOI: | 10.1038/s41591-024-02942-7 |
| PUBMED: | 38653864 |
| PROVIDER: | scopus |
| PMCID: | PMC11108776 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF. Corresponding MSK author is Claire F. Friedman -- Source: Scopus |
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