LBA54 - Randomized phase III trial of nivolumab in combination with carboplatin, paclitaxel, and bevacizumab as first-line treatment for patients with advanced or recurrent non-squamous NSCLC

Background

Nivolumab has been approved as second or later line therapy for NSCLC. It is becoming evident that cytotoxic chemotherapy and angiogenesis inhibitors may enhance therapeutic benefits of immune checkpoint inhibitors such as nivolumab. ONO-4538-52/TASUKI-52 is the first randomized, double-blinded phase III trial of nivolumab plus platinum chemotherapy with bevacizumab for first-line treatment of non-squamous NSCLC.

Methods

Between May 2017 and June 2019, treatment-naïve stage IIIB/IV or recurrent nsq NSCLC patients without sensitizing EGFR or ALK alterations were randomized 1:1 to receive nivolumab (360 mg) or placebo in combination with carboplatin (AUC 6), paclitaxel (200 mg/m²), and bevacizumab (15 mg/kg) every 3 weeks for up to 6 cycles. Subsequently, the treatments with nivolumab/placebo and bevacizumab were maintained until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) assessed by the independent radiology review committee (IRRC).

Results

Of 550 patients in Japan, Korea, and Taiwan, and 273 (nivolumab) and 275 (placebo) received ≥ 1 dose of the study drugs. At the interim analysis on July 2020 where the median follow-up was 13.7 months, PFS was significantly longer in the nivolumab arm compared to the placebo arm with the median PFS of 12.12 vs 8.11 months (hazard ratio [HR], 0.56; 96.37% CI, 0.43-0.71; p<0.0001) and 12-month PFS rate of 50.1% vs 30.2%. IRRC assessed Objective response rates were 61.5% and 50.5% in the nivolumab and placebo arms, respectively. OS, while not mature, tended to be longer in the nivolumab arm compared to the placebo arm (HR, 0.85; 95% CI, 0.63-1.14). Treatment-related adverse events (TRAEs) with grade 3 or 4 and TRAEs leading to treatment discontinuation were observed in 73.6% and 16.5% in the nivolumab arm and 72.0% and 4.4% in the placebo arm, respectively. Most frequently-observed TRAEs were alopecia, peripheral sensory neuropathy, and decreased neutrophil count.

Conclusions

ONO-4538-52/TASUKI-52 met the primary endpoint; nivolumab in combination with carboplatin, paclitaxel, and bevacizumab significantly prolonged PFS with a manageable safety profile.

Clinical trial identification

NCT03117049.

Editorial acknowledgement

Legal entity responsible for the study

Ono Pharmaceutical Co., Ltd.

Funding

Ono Pharmaceutical Co., Ltd., Bristol-Myers Squibb.

Disclosure

J-S. Lee: Research grant/Funding (institution): Ono Pharmaceutical. S. Sugawara: Honoraria (self), Research grant/Funding (institution): Ono Pharmaceutical; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): MSD; Honoraria (self): Chugai Pharma; Honoraria (self): Nippon Boehringer Ingelheim; Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Pfizer; Honoraria (self): Eli Lilly and Company; Honoraria (self): Novartis; Honoraria (self): Kyowa Hakko Kirin; Honoraria (self): AstraZeneca. J.H. Kang: Research grant/Funding (institution): Ono Pharmaceutical. H.R. Kim: Research grant/Funding (institution): Ono Pharmaceutical. N. Inui: Honoraria (self): Ono Pharmaceutical; Honoraria (self), Research grant/Funding (institution): Taiho Pharmaceutical Co., Ltd; Honoraria (self), Research grant/Funding (institution): MSD K.K; Honoraria (self), Research grant/Funding (institution): Chugai Pharmaceutical Co., Ltd; Honoraria (self), Research grant/Funding (institution): Novarits Japan; Research grant/Funding (institution): Daiichi Sankyo Company, Ltd; Honoraria (self), Research grant/Funding (institution): Eli Lilly Japan K.K; Honoraria (self), Research grant/Funding (institution): Nippon Boehringer Ingelheim Co., Ltd; Honoraria (self): AstraZeneca K.K. T. Hida: Honoraria (self), Research grant/Funding (institution): Ono Pharmaceutical; Honoraria (self), Research grant/Funding (institution): Chugai Pharmaceutical Co., Ltd.; Honoraria (self), Research grant/Funding (institution): Nippon Boehringer Ingelheim; Honoraria (self), Research grant/Funding (institution): Novartis; Honoraria (self), Research grant/Funding (institution): Bristol-Meyers Squibb; Honoraria (self), Research grant/Funding (institution): Kissei; Honoraria (self), Research grant/Funding (institution): Taiho Pharmaceutical Co., Ltd.; Honoraria (self), Research grant/Funding (institution): Pfizer; Honoraria (self), Research grant/Funding (institution): MSD; Honoraria (self), Research grant/Funding (institution): Takeda Pharmaceutical Co., Ltd.; Research grant/Funding (institution): Ignyta; Research grant/Funding (institution): Merck Serono; Research grant/Funding (institution): Eisai; Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): Daiichi Sankyo; Research grant/Funding (institution): Astellas; Research grant/Funding (institution): Janssen Pharmaceutical; Honoraria (self), Research grant/Funding (institution): AstraZeneca. K.H. Lee: Research grant/Funding (institution): Ono Pharmaceutical. T. Yoshida: Research grant/Funding (institution): Ono Pharmaceutical; Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self), Research grant/Funding (institution): Bristol-Myers Squibb; Research grant/Funding (institution): Takeda; Honoraria (self): Chugai; Honoraria (self): Novartis; Research grant/Funding (institution): MSD; Research grant/Funding (institution): AbbVie. H. Tanaka: Honoraria (self), Research grant/Funding (institution): Ono Pharmaceutical; Honoraria (self), Research grant/Funding (institution): Bristol-Myers Squibb; Honoraria (self), Research grant/Funding (institution): Eli Lilly; Honoraria (self), Research grant/Funding (institution): MSD; Honoraria (self), Research grant/Funding (institution): Taiho Pharmaceutical; Honoraria (self): Pfizer; Honoraria (self): Novartis; Honoraria (self), Research grant/Funding (institution): Chugai pharmaceutical; Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self), Travel/Accommodation/Expenses: Boehringer Ingelheim. C.T. Yang: Honoraria (self): Ono Pharmaceutical; Honoraria (self): MSD; Honoraria (self): Pfizer; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Roche; Honoraria (self): Chugai. M. Nishio: Honoraria (self), Research grant/Funding (institution): Ono Pharmaceutical; Honoraria (self), Research grant/Funding (institution): Bristol Myers Squibb; Honoraria (self), Research grant/Funding (institution): Pfizer; Honoraria (self), Research grant/Funding (institution): Chugai Pharmaceutical; Honoraria (self), Research grant/Funding (institution): Eli Lilly; Honoraria (self), Research grant/Funding (institution): Taiho Pharmaceutical; Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self): Boehringer-Ingelheim; Honoraria (self), Research grant/Funding (institution): MSD; Honoraria (self), Research grant/Funding (institution): Novartis; Honoraria (self): Merck Biopharma; Honoraria (self), Research grant/Funding (institution): Daiichi Sankyo; Honoraria (self), Research grant/Funding (institution): Takeda Pharmaceutical Company Limited; Honoraria (self): Teijin Pharma Limited.; Honoraria (self): AbbVie. Y. Ohe: Honoraria (self), Research grant/Funding (institution): Ono Pharmaceutical; Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self), Research grant/Funding (institution): Bristol-Myers Squibb; Honoraria (self), Research grant/Funding (institution): MSD; Honoraria (self): Boehringer Ingelheim; Honoraria (self), Research grant/Funding (institution): Chugai; Honoraria (self), Research grant/Funding (institution): Eli Lilly; Honoraria (self), Research grant/Funding (institution): Taiho; Honoraria (self), Research grant/Funding (institution): Takeda; Honoraria (self), Research grant/Funding (institution): Nippon Kayaku; Honoraria (self), Research grant/Funding (institution): Kyorin; Honoraria (self), Research grant/Funding (institution): Novartis; Honoraria (self), Research grant/Funding (institution): Janssen; Honoraria (self): Pfizer; Research grant/Funding (institution): Ignyta; Research grant/Funding (institution): Kyowa Hakko Kirin; Honoraria (self): Celtrion; Honoraria (self): Amgen. T. Tamura: Research grant/Funding (institution): Ono Pharmaceutical; Honoraria (self): Chugai Pharmaceutical; Honoraria (self): Lilly. N. Yamamoto: Honoraria (self), Research grant/Funding (institution): Ono Pharmaceutical; Research grant/Funding (institution): AstraZeneca; Honoraria (self), Research grant/Funding (institution): MSD; Honoraria (self): Thermo Fisher Scientific; Honoraria (self), Research grant/Funding (institution): Daiichi-Sankyo; Honoraria (self), Research grant/Funding (institution): Taiho; Honoraria (self): Takeda; Honoraria (self), Research grant/Funding (institution): Chugai; Honoraria (self), Research grant/Funding (institution): Eli Lilly Japan; Honoraria (self), Research grant/Funding (institution): Boehringer-Ingelheim; Honoraria (self), Research grant/Funding (institution): Pfizer; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Novartis; Honoraria (self): Nipponkayaku; Research grant/Funding (institution): Shionogi; Research grant/Funding (institution): Tsumura; Research grant/Funding (institution): Astellas; Research grant/Funding (institution): Terumo; Research grant/Funding (institution): Tosoh; Research grant/Funding (institution): Toppan Printing. C-J. Yu: Research grant/Funding (institution): Ono Pharmaceutical. H. Akamatsu: Honoraria (self): Ono Pharmaceutical; Honoraria (self), Research grant/Funding (institution): MSD; Honoraria (self), Research grant/Funding (institution): Chugai Pharmatheutical; Honoraria (self): Astrazeneca; Honoraria (self): Bristol-Myers Squibb. Y. Namba: Full/Part-time employment: Ono Pharmaceutical. N. Sumiyoshi: Full/Part-time employment: Ono Pharmaceutical. K. Nakagawa: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Ono Pharmaceutical Co., Ltd.; Honoraria (self), Research grant/Funding (institution): Astellas Pharma Inc.; Honoraria (self), Research grant/Funding (institution): MSD K.K.; Honoraria (self), Research grant/Funding (institution): Nippon Boehringer Ingelheim Co., Ltd.; Honoraria (self), Research grant/Funding (institution): Novartis Pharma K.K.; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Pfizer Japan Inc.; Honoraria (self), Research grant/Funding (institution): Bristol Myers Squibb Company; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Eli Lilly Japan K.K.; Honoraria (self), Research grant/Funding (institution): Chugai Pharmaceutical Co., Ltd.; Honoraria (self), Research grant/Funding (institution): Daiichi Sankyo Co., Ltd.; Honoraria (self), Research grant/Funding (institution): Merck Serono Co., Ltd./ Merck Biopharma Co., Ltd.; Honoraria (self): Clinical Trial Co., Ltd.; Honoraria (self): Medicus Shuppan, Publishers Co., Ltd.; Honoraria (self): Care Net, Inc; Honoraria (self): Reno. Medical K.K.; Honoraria (self), Advisory/Consultancy: Kyorin Pharmaceutical Co., Ltd.; Honoraria (self): Medical Review Co., Ltd.; Honoraria (self): Roche Diagnostics K.K.; Honoraria (self), Research grant/Funding (institution): Bayer Yakuhin, Ltd; Honoraria (self): Medical Mobile Communications Co., Ltd; Honoraria (self): 3H Clinical Trial Inc.; Honoraria (self): Nichi-Iko Pharmaceutical Co., Ltd.; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Takeda Pharmaceutical Co., Ltd.; Honoraria (self), Research grant/Funding (institution): Taiho Pharmaceutical Co., Ltd.; Honoraria (self), Research grant/Funding (institution): SymBio Pharmaceuticals Limited; Honoraria (self): Nanzando Co., Ltd.; Honoraria (self): Yodosha Co., Ltd.; Honoraria (self): Nikkei Business Publications, Inc; Honoraria (self): Thermo Fisher Scientific K.K.; Honoraria (self): Yomiuri Telecasting Corporation; Honoraria (self): Nippon Kayaku Co., Ltd.; Honoraria (self), Research grant/Funding (institution): AbbVie Inc.; Research grant/Funding (institution): inVentiv Health Japan; Research grant/Funding (institution): Icon Japan K.K.; Research grant/Funding (institution): Gritsone Oncology.Inc; Research grant/Funding (institution): PAREXEL International Corp.; Research grant/Funding (institution): Kissei Pharmaceutical Co., Ltd.; Research grant/Funding (institution): EPS Corporation.; Research grant/Funding (institution): Syneos Health; Research grant/Funding (institution): Pfizer R&D Japan G.K.; Research grant/Funding (institution): A2 Healthcare Corp.; Research grant/Funding (institution): Quintiles Inc. / IQVIA Services Japan K.K.; Research grant/Funding (institution): EP-CRSU Co., Ltd.; Research grant/Funding (institution): Linical Co.,Ltd.; Research grant/Funding (institution): Eisai Co., Ltd.; Research grant/Funding (institution): CMIC Shift Zero K.K.; Research grant/Funding (institution): Kyowa Hakko Kirin Co.,Ltd; Research grant/Funding (institution): EPS International Co., Ltd.; Research grant/Funding (institution): Otsuka Pharmaceutical Co., Ltd.; Honoraria (self), Research grant/Funding (institution): AstraZeneca K.K.