麻豆传媒

Dual immune-checkpoint inhibition almost tripled the response rate in patients with advanced ovarian cancer as compared with a single agent, a small randomized trial showed.

The overall response rate increased from 12.2% with nivolumab (Opdivo) alone to 31.4% with nivolumab and ipilimumab (Yervoy). The improved response rate, however, did not translate into a major jump in progression-free survival (PFS), which increased by less than 2 months, although it still achieved statistical significance.

Stratification by platinum-free interval (PFI) showed that patients with a briefer PFI derived greater benefit from the combination, reported Dmitriy Zamarin, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York City, and co-authors.

"Results of this trial justify ongoing investigation of T-cell-targeted immunotherapy for patients with ovarian cancer," the team concluded in the study online in the . "They also support the general hypothesis that for this disease, as has been observed for other solid tumors, combined PD-1 and CTLA-4 inhibition as an induction regimen before sustained anti-PD-1 therapy enhances antitumor activity compared with PD-1 inhibition alone."

"The relatively improved response rate observed in the combination 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 this study," the researchers added. "These findings highlight the need to build on this experience for the greater good, likely through additional combinations incorporating the dual regimen."

The trial needed to be done to determine whether the combination would improve on historically low response rates with single-agent PD-1/L1 inhibition in advanced ovarian cancer, said Jenna Z. Marcus, MD, of the Rutgers New Jersey Medical School in Newark, who was not involved with the study. However, the low response rates in both arms showed that a majority of patients still do not benefit from immunotherapy.

"The PFS, although it was statistically significant, was still a difference of only 1.9 months," Marcus told 麻豆传媒. "We always have to ask ourselves, is that clinically meaningful. What does it mean for our patients, who are going to consider this as a potential therapy?"

"It shows some degree of activity and might be an option for the patients who have been through more robust therapies that we have that are known to be beneficial in patients who have had multiple cytotoxic therapies and are in this partially platinum-sensitive or platinum-resistance setting," she added. "But I think we have to use the data with caution."

Study Background

In general, the early promise and rapid adoption of anti-PD-1/L1 agents in oncology has not included ovarian cancer. An of single-agent nivolumab demonstrated encouraging activity, but subsequent phase I-II trials of anti-PD-1/L1 agents showed only modest activity in recurrent or persistent ovarian cancer (response rates of only , median PFS ).

Dual immune-checkpoint inhibition with nivolumab and ipilimumab showed enhanced antitumor activity in preclinical models, as compared with either agent alone. The combination subsequently received approval for advanced melanoma, renal cell carcinoma, and mismatch repair-deficient colorectal cancer, the authors noted.

To evaluate the safety and efficacy of nivolumab and ipilimumab in recurrent/persistent ovarian cancer, Zamarin and colleagues conducted a randomized phase II trial in 100 patients with previously treated ovarian cancers, including primary peritoneal and fallopian-tube carcinomas.

All the patients had a history of primary platinum-based chemotherapy, a maximum of three prior cytotoxic regimens, and at least one platinum- or taxane-based regimen for recurrent disease for patients who had received three prior regimens. Other entry criteria included a last platinum-free interval (PFI) of less than 10 months, an ECOG performance status of 0-2, and no history of autoimmune disease. PD-L1 expression was evaluated by immunohistochemistry, but a positive test was not a prerequisite for participation.

Zamarin and co-authors randomized the patients to nivolumab alone or in combination with ipilimumab. The primary endpoint was objective tumor response within 6 months, and secondary endpoints included PFS and overall survival (OS). Enrollment occurred in two stages -- the second beginning after accrual of the first 48 patients only if the first stage met the prespecified target for responses within 6 months.

Key Findings

The results showed six responses (three complete) in the single-agent nivolumab group and 16 (three complete) with the combination. An additional 14 patients (29%) in the nivolumab arm and 20 (39%) in the combination arm had stable disease.

The difference in response rates represented more than a threefold increase in the odds ratio (OR) for response with the combination (OR 3.28, 85% CI 1.54-∞, P=0.034). More than twice as many responses were confirmed radiographically in the combination arm (21.6% vs 8.2%, OR 3.09, 85% CI 1.38-∞, P=0.054), and more than twice as many patients treated with the combination had response durations of at least 6 months.

After a median follow-up of 33 months for patients in the first enrollment stage and 11 months for those in the second stage, the median PFS was 2.0 months with single-agent nivolumab and 3.9 months with the combination. The difference represented almost a 50% decrease in the hazard ratio (HR) for progression or death with the combination (HR 0.528, 95% CI 0.339-0.821, P=0.004).

Grade 3 or greater adverse events occurred in 33% of patients treated with nivolumab alone and 49% of the combination group. No treatment-related deaths occurred in either arm, and adverse event profiles were consistent with the historical experience with the individual drugs and the combination, the authors reported.

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