Nivolumab Versus Gemcitabine or Pegylated Liposomal Doxorubicin for Patients With Platinum-Resistant Ovarian Cancer: Open-Label, Randomized Trial in Japan (NINJA)

Abstract

Purpose: This phase III, multicenter, randomized, open-label study investigated the efficacy and safety of nivolumab versus chemotherapy (gemcitabine [GEM] or pegylated liposomal doxorubicin [PLD]) in patients with platinum-resistant ovarian cancer.

Materials and methods: Eligible patients had platinum-resistant epithelial ovarian cancer, received ≤ 1 regimen after diagnosis of resistance, and had an Eastern Cooperative Oncology Group performance score of ≤ 1. Patients were randomly assigned 1:1 to nivolumab (240 mg once every 2 weeks [as one cycle]) or chemotherapy (GEM 1000 mg/m² for 30 minutes [once on days 1, 8, and 15] followed by a week's rest [as one cycle], or PLD 50 mg/m² once every 4 weeks [as one cycle]). The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), overall response rate, duration of response, and safety.

Results: Patients (n = 316) were randomly assigned to nivolumab (n = 157) or GEM or PLD (n = 159) between October 2015 and December 2017. Median OS was 10.1 (95% CI, 8.3 to 14.1) and 12.1 (95% CI, 9.3 to 15.3) months with nivolumab and GEM or PLD, respectively (hazard ratio, 1.0; 95% CI, 0.8 to 1.3; P = .808). Median PFS was 2.0 (95% CI, 1.9 to 2.2) and 3.8 (95% CI, 3.6 to 4.2) months with nivolumab and GEM or PLD, respectively (hazard ratio, 1.5; 95% CI, 1.2 to 1.9; P = .002). There was no statistical difference in overall response rate between groups (7.6% v 13.2%; odds ratio, 0.6; 95% CI, 0.2 to 1.3; P = .191). Median duration of response was numerically longer with nivolumab than GEM or PLD (18.7 v 7.4 months). Fewer treatment-related adverse events were observed with nivolumab versus GEM or PLD (61.5% v 98.1%), with no additional or new safety risks.

Conclusion: Although well-tolerated, nivolumab did not improve OS and showed worse PFS compared with GEM or PLD in patients with platinum-resistant ovarian cancer.

FIG 1.

CONSORT diagram of patient disposition. NOTE. Patients may have had more than one reason for exclusion. GEM, gemcitabine; ITT, intention-to-treat; PLD, pegylated liposomal doxorubicin; RES, response-evaluable set; SAF, safety analysis set.

FIG 2.

Kaplan-Meier curve of (A) OS and (B) PFS according to RECIST v1.1 (ITT population). GEM, gemcitabine; HR, hazard ratio; ITT, intention-to-treat; OS, overall survival; PFS, progression-free survival; PLD, pegylated liposomal doxorubicin.

FIG 3.

Forest plot of OS by subgroup (ITT population). Note: The HR was not calculated for subgroups where the number of patients in either the nivolumab group or the GEM or PLD group was < 10 patients. HRs (95% CI) were estimated using the Cox proportional hazards model. The UICC TNM Classification version 7 was used. BRCA1, breast cancer susceptibility gene 1; BRCA2, breast cancer susceptibility gene 2; ECOG, Eastern Cooperative Oncology Group; FIGO, International Federation of Obstetrics and Gynecology; GEM, gemcitabine; HR, hazard ratio; ITT, intention-to-treat; NA, not applicable; NLR, neutrophil to lymphocyte ratio; OS, overall survival; PD-L1, programmed cell death ligand-1; PLD, pegylated liposomal doxorubicin; TNM, TNM Classification of Malignant Tumors; UICC, Union for International Cancer Control.

FIG 4.

TRAEs (≥ 5% in any group; SAF population). Note: All AEs were evaluated according to MedDRA v21.0J and CTCAE v4.0 Japanese translation of JCOG. No grade 5 TRAEs occurred in either group. AE, adverse event; ALT, alanine aminotransferase; CTCAE, Common Terminology Criteria for Adverse Events; GEM, gemcitabine; JCOG, Journal of Clinical Obstetrics & Gynecology; MedDRA, Medical Dictionary for Regulatory Activities; PLD, pegylated liposomal doxorubicin; PPE, palmar-plantar erythrodysesthesia; SAF, safety analysis set; TRAE, treatment-related adverse event; WBC, white blood cell.

FIG A1.

Percentage change in target tumor diameter from baseline over time for the RES population: (A) Nivolumab and (B) GEM or PLD; and for the responders: (C) Nivolumab and (D) GEM or PLD. GEM, gemcitabine; PLD, pegylated liposomal doxorubicin; RES, response-evaluable set.

FIG A2.

TTR and DOR of responders according to RECIST v1.1 (RES population). TTR was defined as the time from randomization to first CR or PR. DOR was defined as the time from first CR or PR to first PD or death (from any cause), whichever occurred first. Each bar represents the time from randomization to PD or death, or last data collection, in one responding patient. Patients who did not have PD or death and had not received poststudy treatment were considered as having continued response. For patients without PD or death who received poststudy treatment, the date of last diagnostic imaging performed before the start of poststudy treatment was used as the last data collection date. CR, complete response; DOR, duration of response; GEM, gemcitabine; PD, progressive disease; PLD, pegylated liposomal doxorubicin; PR, partial response; RES, response-evaluable set; TTR, time to response.

FIG A3.

Mean change in QOL over time: (A) FACT-O total score, (B) EQ-5D index score, (C) EQ-5D VAS score (ITT population). Error bars indicate standard deviation. EQ-5D, EuroQol-5 Dimensions; FACT-O, Functional Assessment of Cancer Therapy–Ovarian; GEM, gemcitabine; ITT, intention-to-treat; PLD, pegylated liposomal doxorubicin; QOL, quality of life; VAS, visual analog scale.