In an investigator-initiated phase II study, the use of nivolumab for dMMR/MSI-H endometrial or ovarian cancer met the pre-specified endpoint for clinical efficacy, with an objective response rate (ORR) of 57% in the evaluable population and 64.7% of patients remaining progression free at 24 weeks. Response to nivolumab was observed in patients regardless of mechanism of dMMR or histologic subtype. Patients benefitted from substantial disease control, with median duration of response (DoR) and overall survival (OS) not yet reached with nearly 3 years of median follow-up. No new safety signals were noted, although rare immune-mediated toxicities, including myocarditis and type 1 diabetes, were seen.
However, previously described immunotherapy response biomarkers, such as TMB or PD-L1 expression, were not associated with objective response or progression-free survival (PFS). The findings highlight markers of pre-existing T cell response, as defined by T cell functionality, that may present a strategy for patient selection for anti-PD1 therapy in dMMR gynaecologic cancers and generate rationale for validation of these markers in larger cohorts of patients with dMMR cancers according to Drs. Claire F. Friedman of the Memorial Sloan Kettering Cancer Center (MSKCC), Weill Cornell Medical College in New York, NY, US, Dmitriy Zamarin of the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai in New York, NY, US, and colleagues who published the findings on 23 April 2024 in the Nature Medicine.
Approximately 30% to 35% of endometrial cancers are classified as MSI or dMMR. MSI leads to the accumulation of mismatches, insertions, and deletions in repeat sequences of DNA and, thus, a mutation burden approximately 10-fold greater than microsatellite stable tumours. Although most common in endometrioid or clear cell histologies, a subset of ovarian cancers also demonstrates dMMR. However, aside from the presence of dMMR, predictors of response to PD1/PD-L1 inhibition remain elusive.
It has been suggested that the aetiology of dMMR is associated with distinct biology and may be predictive of response to immunotherapy in endometrial cancer, and mutations in JAK1 and B2M are associated with resistance. Several tumour microenvironment features, such as expression of PD-L1 and presence of CD8-positive T cells in tumours, were demonstrated to be predictive of response to PD1/PD-L1 inhibitors in some cancer types; however, their predictive value in dMMR gynaecologic cancers is unknown.
Emerging evidence in other cancer types indicates that T cell functional states, rather than absolute numbers, may serve as a stronger predictor of response to immune checkpoint blockade. Specifically, upregulation of markers of T cell dysfunction/exhaustion, such as PD1, is associated with tumour antigen reactivity. The transcription factor TOX was identified as a master regulator driving the molecular and epigenetic programmes of T cell dysfunction/exhaustion in tumours. However, how these parameters predict response to PD1 inhibition in patients with dMMR gynaecologic cancers is unknown.
In this a single-arm phase II study, the MSKCC researchers explored activity and safety of nivolumab in 35 patients with dMMR/MSI-H advanced or recurrent endometrial or ovarian cancer and identified genomic and tumour microenvironment parameters predictive of response that may help guide patient selection for future trials. Co-primary endpoints included ORR and PFS at 24 weeks (PFS24). Secondary endpoints included OS, disease control rate (DCR), 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%).
A total, 32 patients (91%) had a treatment-related adverse event (TRAE), including arthralgia (29%), fatigue (29%), pain (29%) and pruritis (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 showed that the presence of dysfunctional (CD8-positive, PD1-positive) or terminally dysfunctional (CD8-positive, PD1-positive, TOX-positive) T cells and their interaction with PD-L1-positive cells were independently associated with PFS24. PFS24 was associated with presence of MEGF8 or SETD1B somatic mutations.
The authors concluded that the study met its co-primary endpoints of ORR and PFS24 early, and the findings highlight several genetic and tumour microenvironment parameters associated with response to PD1 blockade in dMMR cancers, generating rationale for their validation in larger cohorts.
This study was supported, in part, by the US National Cancer Institute/National Institutes of Health Cancer Center Support Grant, Stand Up to Cancer, the GOG Foundation, Cycle for Survival and the Breast Cancer Research Foundation. This clinical trial had funding support provided by Bristol Myers Squibb and Stand Up to Cancer.
Reference
Friedman CF, Manning-Geist BL, Zhou Q, et al. Nivolumab for mismatch-repair-deficient or hypermutated gynecologic cancers: a phase 2 trial with biomarker analyses. Nature Medicine; Published online 23 April 2024. DOI: https://doi.org/10.1038/s41591-024-02942-7