Nivolumab Misses Mark in Japanese Patients With Platinum-Resistant Ovarian Cancer

Junzo Hamanishi, MD, PhD

Nivolumab (Opdivo) did not significantly improve overall survival (OS) compared with chemotherapy in Japanese patients with platinum-resistant ovarian cancer, missing the primary end point of the phase 3 NINJA trial (JapicCTI-153004).¹

Results, which were published in the Journal of Clinical Oncology, showed that treatment with the immunotherapy resulted in a median OS of 10.1 months (95% CI, 8.3-14.1) vs 12.1 months (95% CI, 9.3-15.3) with gemcitabine or pegylated liposomal doxorubicin (PLD; HR, 1.0; 95% CI, 0.8-1.3; P = .808). Moreover, the median progression-free survival (PFS) was 2.0 months (95% CI, 1.9-2.2) with nivolumab vs 3.8 months (95% CI, 3.6-4.2) with gemcitabine or PLD (HR, 1.5; 95% CI, 1.2-1.9; P = .002).

“Although nivolumab was well tolerated, with fewer adverse effects [AEs] than with gemcitabine or PLD, nivolumab monotherapy did not demonstrate superiority over gemcitabine or PLD in OS and showed worse PFS in patients with platinum-resistant ovarian cancer,” lead study author Junzo Hamanishi, MD, PhD, Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, and colleagues, wrote in the paper.

Although gemcitabine and PLD are among the most frequently used chemotherapy regimens for patients with platinum-resistant ovarian cancer, these drugs have demonstrated suboptimal responses, with a median of OS of less than 12 months. As such, there is an urgent unmet need for new therapeutic options for this patient population.

In a prior phase 2 trial (UMIN000005714), nivolumab elicited an ORR of 15% (95% CI, 3.2%-37.9%) and a disease control rate of 45% (95% CI, 23.1%-68.5%) in patients with platinum-resistant ovarian cancer.² The promising data in this disease supported further investigation of nivolumab in a large, phase 3, randomized trial.

To this end, the key objective of the NINJA trial was to compare the safety and efficacy of nivolumab with the standard chemotherapy agents, gemcitabine and PLD, in patients with platinum-resistant ovarian cancer.

The trial enrolled female patients who were at least 20 years of age and had epithelial ovarian cancer, including fallopian tube cancer and peritoneal cancer, that was platinum resistant, which was defined as disease progression or recurrence within 6 months of platinum-based treatment. Other inclusion criteria included having received 1 or fewer prior regimens after being diagnosed with platinum resistance, having an ECOG performance status of 0 or 1, and having tumor tissue samples available for PD-L1 expression analysis.

Patients could not have previously received nivolumab, other anti–PD-1, anti–PD-L1, or anti–PD-L2 therapies, or other drugs that regulate T cells, nor could they have received prior gemcitabine or PLD. Those with borderline malignant tumors, current or previous severe hypersensitivity reactions to antibody products, autoimmune disease, severe cardiovascular disease, or multiple primary cancers and/or central nervous system metastases, were excluded.

Study participants were randomized 1:1 to receive either intravenous (IV) nivolumab at a dose of 240 mg once every 2 weeks, or chemotherapy. Patients in the chemotherapy arm were treated with either IV gemcitabine at 1,000 mg/m² for 30 minutes on days 1, 8, and 15 followed by a week of rest, or IV PLD at 50 mg/m² once every 4 weeks. The type of chemotherapy administered was determined by investigators at the time of enrollment. Dose reductions of nivolumab were not permitted, although dose omissions were.

Patients were stratified by histology (clear cell carcinoma vs non–clear cell carcinoma), and the number of previous chemotherapy regimens received after platinum-resistance diagnosis (0 vs 1).

Treatment on the study continued until patients experienced a complete response (CR), progressive disease, or unacceptable toxicity. Notably, treatment with nivolumab was permitted to continue after progression.

The primary end point of the trial was OS, and secondary end points included PFS, best overall response, overall response rate (ORR), duration of response (DOR), time to response (TTR), and safety.

From October 2015 to July 2016, and March 2017 to December 2017, a total of 363 patients were enrolled at 35 centers, and 316 patients ultimately underwent randomization. Of these patients, 157 of patients received nivolumab and 159 received chemotherapy, and they were included in the intent-to-treat analyses.

Moreover, 233 of these patients (n = 119 in the nivolumab arm; n = 114 in the chemotherapy arm) and 311 patients (n = 156 in the nivolumab arm; n = 156 in the chemotherapy arm) were included in the response-evaluable set and safety analyses, respectively.

Demographic and baseline characteristics were noted to be generally comparable between the arms. In both groups, most patients were younger than 65 years, and more than 55% of patients had stage III disease per the International Federation of Gynecology and Obstetrics classification. Moreover, the most common histology was serous carcinoma.

“At data cutoff, 131 patients receiving nivolumab and 125 patients receiving gemcitabine or PLD had died, 26 and 34 patients, respectively, were censored, and 23 and 32 patients, respectively, were still being followed up,” the study authors wrote. “There was no statistically significant difference in OS between the nivolumab and gemcitabine or PLD groups.”

Additional data did not reveal any difference in OS between the groups for most subsets, including those with a PD-L1 expression of 1% or higher (HR, 1.09; 95% CI, 0.73-1.64). However, the median OS was noted to be numerically longer with nivolumab compared with chemotherapy in those who had a clear cell carcinoma histology (HR, 0.78; 95% CI, 0.46-1.32) and those who received 1 chemotherapy regimen after a platinum resistance diagnosis (HR, 0.74; 95% CI, 0.48-1.14).

No statistical difference in ORR was reported between the investigative and control arms, at 7.6% vs 13.2%, respectively (odds ratio, 0.6; 95% CI, 0.2-1.3; P = .191). However, in the nivolumab arm, 9 patients achieved a CR or partial response, with a 30% or higher reduction in tumor size vs 15 patients in the chemotherapy arm. Moreover, the median DOR was also numerically longer with nivolumab vs chemotherapy, at 18.7 months (95% CI, 2.5–not evaluable) vs 7.4 months (95% CI, 3.0-10.3), respectively.

“At the individual patient level, DOR was usually longer and TTR was similar or shorter with nivolumab than with gemcitabine or PLD,” the study authors noted.

In terms of safety, nivolumab was found to be well tolerated, with a lower incidence of treatment-related AEs (TRAEs) of any grade compared with chemotherapy, at 61.5% and 98.1%, respectively. The incidence of TRAEs that led to treatment discontinuation was also lower with nivolumab vs chemotherapy, at 7% and 10%, respectively.

The most frequent any-grade TRAEs reported with nivolumab included rash (10.3%), fatigue (9.0%), and nausea (6.4%). The most common any-grade TRAEs observed in the chemotherapy group were decreased neutrophil count (64.5%), decreased platelet counts (33.5%), and nausea (32.9%).

Furthermore, fewer grade 3/4 TRAEs were reported in the nivolumab arm vs the chemotherapy arm, at 10.9% and 65.2%, respectively. In the immunotherapy arm, anemia was the most common grade 3 or 4 TRAE reported, and this was experienced by 2.6% of patients; this was still lower than what was observed with either chemotherapy agent, at 14.2%. In the chemotherapy arm, decreased neutrophil count was the most frequent grade 3 or 4 TRAE, and this was reported in 40.0% of patients; this was observed in 0.6% of those who received nivolumab.

References

1. Hamanishi J, Takeshima N, Katsumata N, et al. Nivolumab versus gemcitabine or pegylated liposomal doxorubicin for patients with platinum-resistant ovarian cancer: open-label, randomized trial in Japan (NINJA). J Clin Oncol. 2021;39(33):3671-3681. doi:10.1200/JCO.21.00334
2. Hamanishi J, Mandai M, Ikeda T, et al. Safety and antitumor activity of anti-PD-1 antibody, nivolumab, in patients with platinum-resistant ovarian cancer. J Clin Oncol. 2015;33(34):4015-4022. doi:10.1200/JCO.2015.62.3397