Nivolumab/Ipilimumab Induction Therapy Boosts Responses and Prolongs PFS in Epithelial Ovarian Cancer

The combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) was found to induce a superior response rate and longer progression-free survival (PFS) compared with nivolumab alone in patients with persistent or recurrent epithelial ovarian cancer, according to results from the phase 2 NRG GY003 trial published in the Journal of Clinical Oncology.¹

A total of 100 patients were enrolled in the open-label trial and they were randomized to receive either the combination (n = 51) or nivolumab alone (n = 49), with a platinum-free interval (PFI) of <6 months in 62% of patients. Results showed that 16 responses (31.4%) within 6 months were observed in the combination arm versus 6 responses (12.2%) in the nivolumab arm and (odds ratio [OR], 3.28; 85% CI, 1.54 to infinity; P = .034).

Moreover, the median PFS rate was almost doubled in the combination arm versus the monotherapy arm, at 3.9 months versus 2 months, respectively, with a PFI-stratified hazard ratio (HR) of 0.53 (95% CI, 0.34-0.82); the respective HR for death was 0.79 (95% CI, 0.44-1.42).

“The combination of nivolumab and ipilimumab induction followed by nivolumab maintenance in ovarian cancer resulted in superior response rate and improvement in PFS when compared with nivolumab alone, and toxicities were manageable,” wrote lead investigator, Dmitriy Zamarin, MD, PhD, of Memorial Sloan Kettering Cancer Center, and co-investigators.

“The relatively improved response rate observed in the combination therapy group, however, must be balanced by the lack of benefit for the majority of patients enrolled as well as limited duration of PFS observed in the study,” they added. “These findings highlight the need to build on this experience for the greater good, likely through additional combinations incorporating the dual regimen.”

To be eligible for enrollment on the trial, patients had to have recurrent or persistent ovarian, primary peritoneal, or fallopian tube carcinoma of all histologic types with the exception of mucinous adenocarcinoma and carcinosarcoma. Patients also had to have measurable disease per RECIST v. 1.1 criteria and a history of primary platinum-based chemotherapy with a maximum of 3 prior cytotoxic regimens. Additionally, their last PFI had to be <12 months, they had to have an ECOG performance score ranging from 0 to 2, and they could not have a history of autoimmune disease that impacted vital organ function or required immunosuppressive therapy.

The primary end point of the trial was objective tumor response by RECIST v. 1.1 criteria within 6 months of enrollment Furthermore, the study was conducted in 2 stages. Accrual to the first stage was held after approximately 48 patients were enrolled, and accrual to the second stage was contingent on the proportion of responses reported within 6 months of enrollment for the combination arm exceeding that of the monotherapy arm as well as the assessment by an independent data safety monitoring committee. Secondary end points of the trial included PFS, duration of OS, as well as incidence and severity of adverse events.²

Between June 29, 2015, and August 28, 2017, 100 patients were enrolled at 37 academic and community centers across the United States. Of these patients, 51 were randomized to induction therapy with nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg every 3 weeks for 4 doses followed by maintenance nivolumab at 3 mg/kg every 2 weeks for a maximum of 42 doses. Forty-nine patients were randomized to receive induction treatment with nivolumab at 3 mg/kg every 2 weeks for 4 doses followed by maintenance nivolumab at the same dosage and scheduled used in the combination arm.

Results from the primary analysis showed that a total of 16 responses versus 6 responses occurred within 6 months of enrollment in the combination and monotherapy arms, respectively. Of the 16 responses reported with the combination, 3 were complete responses (CRs), while 13 were partial responses (PRs). Moreover, of the 6 responses in the monotherapy arm, 3 were CRs and 3 were PRs. An additional 14 (29%) and 20 (39%) patients in the nivolumab and nivolumab/ipilimumab arms, respectively, experienced stable disease.

The difference in response rates was determined to be statistically significant. Notably, the difference in confirmed response rate between the 2 arms continued to be statistically significant at the 15% level of significance (OR, 3.09; 85% CI, 1.38 to infinity; P = .054).

Following the 6-month evaluation period, 1 additional, unconfirmed PR was reported in the combination arm, translating to a total response rate of 33%. Response durations of ≥6 months without evidence of new disease were observed in 8 (15.7%) patients receiving the combination versus 4 (8.2%) patients receiving nivolumab alone.

With a median follow-up of 33 months for patients with first-stage disease and 11 months for those with second-stage disease, the hazard of progression or death was found to be significantly lower with nivolumab plus ipilimumab arm versus nivolumab alone (HR, 0.528; 95% CI, 0.339-0.821; two-sided P = .004). The proportion with 6-month PFS was 25.5% in the combination arm and 16.3% in the monotherapy arm (OR, 1.75; 95% CI, 0.59-5.43; P = .19).

A total of 5 patients met the criteria for treatment beyond progression at 8 weeks; of these 5 patients, 2 were in the combination arm and 3 were in the monotherapy arm. Of these patients, 4 discontinued treatment at 16 weeks because of confirmed progression, and 1 patient in the combination arm had disease stabilization and continued treatment until 34 weeks. The median OS was 28.1 months with the combination versus 21.8 months with the monotherapy (HR, 0.789; 95% CI, 0.439-1.418; two-sided P = .43).

To examine the association of age, performance status, number of prior cytotoxic regimens, PFI, and histologic type with outcomes, the investigators performed an exploratory subset analysis adjusted for treatment group. Notably, results showed a significant association between longer PFI and OS. Moreover, patients with clear cell carcinoma were found to have an approximately fivefold odds of response versus other disease types.

To evaluate whether any baseline characteristics favored the combination treatment over nivolumab alone, an additional exploratory analysis was conducted. Investigators demonstrated that poor prognostic characteristics such as inferior performance status, platinum resistance, older age, higher number of prior therapies, larger tumor burden at baseline, and obesity were favored in the combination arm.

Regarding safety, grade ≥3 adverse events (AEs) occurred in 34 patients (66.7%) who received the combination versus 27 patients (55.1%) who were given nivolumab alone; however, the difference in the frequency of these events overall and for each system between the treatment arms was not determined to be significant. Grade 5 events were reported in 4 patients (8%) in combination arm and 2 patients (4%) on the monotherapy arm (OR, 2.0; 95% CI, 0.27-23.08; P = .68). Additionally, a total of 6 deaths occurred, with 2 reported in the combination arm and 4 reported in the nivolumab arm. Four of the 6 patients died as a result of disease progression. Seventy-seven percent of patients discontinued treatment because of disease progression and 18% discontinued treatment because of AEs.

The most commonly reported grade ≥3 AEs in the combination arm were asymptomatic elevation in pancreatic enzymes (16%), elevation in liver enzymes (8%), anemia (8%), and colitis or diarrhea (6%). The overall incidence of related events ranging from grade 2 to 4 in severity between the arms were not determined to be statistically different; however, the combination trended toward a greater incidence of colitis or diarrhea (16% vs 4%; P = .09), anemia with or without hemolysis (16% vs 4%; P = .09), and rash (14% vs 4%; P = .16).

Results from the trial support ongoing investigation of T-cell–targeted immunotherapy for patients with ovarian cancer, according to the investigators. The data also support the notion that combining PD-1 with CTLA-4 inhibition as an induction regimen before sustained anti–PD-1 therapy can enhance antitumor activity in comparison with anti–PD-1 treatment alone.

“These findings highlight, however, that in the majority of patients clinical benefit is not durable and that additional exploration of the ipilimumab plus nivolumab regimen, possibly in combination with other agents, is warranted,” the investigators concluded.

References:

1. Zamarin D, Burger RA, Sill MW, et al. Randomized phase II trial of nivolumab versus nivolumab and ipilimumab for recurrent or persistent ovarian cancer: An NRG oncology study. J Clin Oncol. 2020;38(16):1814-1824. doi:10.1200/JCO.19.02059
2. Nivolumab with or without ipilimumab in treating patients with persistent or recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. ClinicalTrials.gov. Updated March 31, 2020. Accessed June 9, 2020. bit.ly/2MKYr7Y.