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

Abstract

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/m 2 ), 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.

Nivolumab in combination with anlotinib achieved remarkable efficacy in a patient with driver-negative lung squamous cell carcinoma and PS of 4

“…Anlotinib provide a potential for patients who unable to benefit from chemotherapy, immunotherapy and EGFR-mutation target agent (6). In the IMpower150 and TASUKI-52 trials, ICIs combined with angiogenic inhibitors and chemotherapy showed a significant PFS benefit in NSCLC patients compared to the combination of angiogenic inhibitors and chemotherapy (18,19). At the World Conference on Lung Cancer (WCLC) in 2019, a phase 1 trial with sintilimab (ICI) plus anlotinib as first-line treatment in advanced NSCLC patients without oncogenic driver mutations showed encouraging results (20).…”

The effect of smoking status on efficacy of immune checkpoint inhibitors in metastatic non-small cell lung cancer: A systematic review and meta-analysis

“…The risk of bias of included RCTs is summarized in Supplementary File: Figure S1. Two trials were judged as unclear risk of bias [22,26]. The remaining trials were rated with a low risk of bias.…”

The Effect of Asymptomatic and/or Treated Brain Metastases on Efficacy of Immune Checkpoint Inhibitors in Metastatic Non–Small Cell Lung Cancer: A Meta-Analysis

“…Finally, 17 eligible articles (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) reporting 15 RCTs (14 phase 3 and 1 phase 2 trials) with 10,358 patients (1,199 with and 9,159 without asymptomatic/treated BMs) were included in the meta-analysis. Most of the RCTs (3,(5)(6)(7)(8)(9)(11)(12)(13)(14)(15)(16)(17)(18) stated clearly that patients with meningeal metastasis were excluded, whereas the other three trials (4,10,19) did not provide information for whether patients with meningeal metastasis were excluded. The clinical and demographic characteristics of included studies are shown in Table 1 and Supplementary File: Table S3.…”

“…The risk of bias in included RCTs is summarized in Supplementary File, Figure S1. Only one trial (19) was judged as having an unclear risk of bias, as it had more than three domains for indicating them an unclear risk. The remaining trials were rated with a low risk of bias.…”

“…However, the majority of ICIs trials systematically excluded patients with untreated/unstable BMs. Some recent RCTs (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) have included a small number of patients with asymptomatic and/or treated BMs but with inconsistent results. In CheckMate-057 (9), -078 (10), and a pooled analysis of KEYNOTE-010 and -024 and -042 trials (20), patients with baseline asymptomatic or treated BMs had similar OS with ICIs or chemotherapy (CT).…”