Safety and Efficacy of Nivolumab Monotherapy in Recurrent or Metastatic Cervical, Vaginal, or Vulvar Carcinoma: Results From the Phase I/II CheckMate 358 Trial

Abstract

Purpose: Nivolumab was assessed in patients with virus-associated tumors in the phase I/II CheckMate 358 trial (ClinicalTrials.gov identifier: NCT02488759). We report on patients with recurrent/metastatic cervical, vaginal, or vulvar cancers.

Patients and methods: Patients received nivolumab 240 mg every 2 weeks. Although patients with unknown human papillomavirus status were enrolled, patients known to have human papillomavirus-negative tumors were ineligible. The primary end point was objective response rate. Duration of response (DOR), progression-free survival, and overall survival were secondary end points. Safety and patient-reported outcomes were exploratory end points.

Results: Twenty-four patients (cervical, n = 19; vaginal/vulvar, n = 5) were enrolled. Most patients had received prior systemic therapy for metastatic disease (cervical, 78.9%; vaginal/vulvar, 80.0%). Objective response rates were 26.3% (95% CI, 9.1 to 51.2) for cervical cancer and 20.0% (95% CI, 0.5 to 71.6) for vaginal/vulvar cancers. At a median follow-up of 19.2 months, median DOR was not reached (range, 23.3 to 29.5+ months; + indicates a censored observation) in the five responding patients in the cervical cohort; the DOR was 5.0 months in the single responding patient in the vaginal/vulvar cohort. Median overall survival was 21.9 months (95% CI, 15.1 months to not reached) among patients with cervical cancer. Any-grade treatment-related adverse events were reported in 12 of 19 patients (63.2%) in the cervical cohort and all five patients in the vaginal/vulvar cohort; there were no treatment-related deaths. In the cervical cohort, nivolumab treatment generally resulted in stabilization of patient-reported outcomes associated with health status and health-related quality of life.

Conclusion: The efficacy of nivolumab in patients with recurrent/metastatic cervical and vaginal or vulvar cancers is promising and warrants additional investigation. No new safety signals were identified with nivolumab treatment in this population.

FIG 1.

Characteristics of treatment response. (A) Maximum change from baseline in the sum of tumor target lesion diameters, according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST). Tumor reduction data (bars) correspond to maximum change from baseline in only target lesions and not to best overall response. (B) Kinetics of change in tumor burden over time on therapy. Dotted horizontal lines in panels A and B indicate 30% target lesion reduction (consistent with a response in the absence of new lesions) and 20% increase (consistent with progressive disease), per RECIST. (*) Bars with asterisks represent confirmed responses (complete response or partial response). Bars without asterisks represent unconfirmed responses.

FIG 2.

Computed tomography scans at baseline and cycle 77 are shown for a 75-year-old white woman with human papillomavirus–positive metastatic cervical cancer with tumor cell programmed death-ligand 1 expression of 1% or greater. This patient was initially diagnosed in April 2014 with stage IIB disease (per Fédération Internationale de Gynécologie et d’Obstétrique staging) and underwent chemoradiotherapy with cisplatin. She was diagnosed with recurrent metastatic disease in October 2015 and enrolled in CheckMate 358 in November 2015 with stage IV disease and an Eastern Cooperative Oncology Group performance status of 0. Target lesions at baseline included mediastinal lymph node lesion (20 mm), subcarinal lymph node lesion (25 mm), and right lung lesion (19 mm). The patient received her first dose of nivolumab on December 3, 2015. Her best overall response was complete response (CR), documented in November 2017 after 50 cycles of treatment. She was cancer-free as of January 8, 2019, and is continuing in this study.

FIG 3.

(A) Overall survival (OS) and (B) progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST) in patients with cervical cancer. Owing to the high percentage of censored responses, median and rate estimators may be misleading. NR, not reached.

FIG A1.

Treatment exposure, time to response, and duration of response in all patients. Patient 2 in the cervical cohort was documented as having progressive disease 5 days after last nivolumab dose; this information is not included in the figure as it was not captured in the data cut reported in the manuscript.

FIG A2.

Overall survival (OS) in patients with cervical cancer by (A) Tumor cell programmed death ligand 1 (PD-L1) expression (defined as the percentage of tumor cells exhibiting plasma membrane staining at any intensity) and (B) prior systemic cancer therapy (PSCT) for metastatic disease. Owing to the high percentage of censored responses, median and rate estimators may be misleading. CI, confidence interval; NR, not reached. (*) Point estimates are derived from Kaplan-Meier analyses; 95% CIs are derived from Greenwood’s formula.