Nivolumab with carboplatin, paclitaxel, and bevacizumab for first-line treatment of advanced nonsquamous non-small-cell lung cancer

Abstract

Background: This international, randomized, double-blind phase III study (ONO-4538-52/TASUKI-52) evaluated nivolumab with bevacizumab and cytotoxic chemotherapy as first-line treatment for nonsquamous non-small-cell lung cancer (NSCLC). Patients and methods: Between June 2017 and July 2019, this study enrolled treatment-naïve patients with stage IIIB/ IV or recurrent nonsquamous NSCLC without sensitizing EGFR, ALK, or ROS1 alterations. They were randomly assigned in a 1 : 1 ratio to receive nivolumab or placebo in combination with carboplatin, paclitaxel, and bevacizumab every 3 weeks for up to six cycles, followed by nivolumab/placebo with bevacizumab until progressive disease or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) assessed by an independent radiology review committee (IRRC). Results: Overall, 550 patients from Japan, Korea, and Taiwan were randomized; of these patients, 273 and 275 received the nivolumab and placebo combinations, respectively. In the present preplanned interim analysis with a median follow up of 13.7 months, the IRRC-assessed median PFS was significantly longer in the nivolumab arm than in the placebo arm (12.1 versus 8.1 months; hazard ratio 0.56; 96.4% confidence interval 0.43-0.71; P < 0.0001). The PFS benefit was observed across all patients with any programmed death-ligand 1 (PD-L1) expression levels including PD-L1negative patients. The IRRC-assessed objective response rates were 61.5% and 50.5% in the nivolumab and placebo arms, respectively. The incidence of treatment-related adverse events of grade 3 or 4 was comparable between the two arms; treatment-related adverse events leading to death were observed in five and four patients in the nivolumab and placebo arms, respectively. Conclusion:The TASUKI-52 regimen should be considered a viable new treatment strategy for treatment-naïve patients with advanced nonsquamous NSCLC.

Successful treatment of two patients with unresectable lung squamous cell carcinoma with tislelizumab regardless of programmed death-ligand 1 expression: a report of two cases

“…The patient in case 1 achieved a significant remission, although both PD-L1 and PD-1 were negative, which is consistent with the results of some studies [ 19 ]. The reason may include conflicting results between different detection antibodies, heterogeneity in PD-L1 expression within and across tumor sites, and temporally dynamic PD-L1 expression [ 20 ].…”

Current Immunotherapeutic Strategies Targeting the PD-1/PD-L1 Axis in Non-Small Cell Lung Cancer with Oncogenic Driver Mutations

“…For non-squamous NSCLC, four phase III trials showed a clinical benefit of PD-1/PD-L1 inhibitors in combination with platinum-based chemotherapy. Carboplatin (CBDCA)/Pemetrexed (PEM)/Pembrolizumab, CBDCA or CDDP/PEM/atezolizumab, CBDCA/nanoparticle albumin bound-Paclitaxel (nabPTX)/atezolizumab, CBDCA/PTX/bevacizumab (BEV)/atezolizumab and CBDCA/PTX/BEV/nivolumab are now standard treatment options for non-squamous NSCLC in a front-line setting [ 6 , 7 , 8 , 9 , 10 ]. With respect to squamous NSCLC, phase III trials comparing CBDCA/PTX or nabPTX/pembrolizumab to CBDCA/PTX or nabPTX showed a survival benefit [ 33 ].…”

“…However, the clinical trials of ICIs combined with chemotherapy have reshaped NSCLC therapy and to yield a variety of first-line treatment options for patients. The growing use of ICIs has dramatically improved patient outcome and the overall three-year survival rate of stage IV NSCLC has reached 40–50% [ 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 ]. The therapeutic effects of ICIs in these clinical trials have been associated with PD-L1 tumor proportion scores (TPS) or tumor mutational burden (TMB).…”

“…The therapeutic effects of ICIs in these clinical trials have been associated with PD-L1 tumor proportion scores (TPS) or tumor mutational burden (TMB). In general, PD-1 or PD-L1 inhibitors show excellent therapeutic effects against tumors that express high PD-L1 levels (TPS > 50%) and/or a high TMB [ 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ]; however, these indicators are not sufficient to predict response or outcome to ICI therapy [ 15 , 16 , 17 , 18 ]. Consequently, other biological approaches have been used to identify predictive biomarkers and identify mechanisms of cancer immune escape.…”

A Bayesian Network Meta-Analysis of First-Line Treatments for Non-Small Cell Lung Cancer with High Programmed Death Ligand-1 Expression

“…Randomized trials have revealed that anti-PD-1 mAbs (pembrolizumab and nivolumab) and anti-PD-L1 mAb (atezolizumab) provide additional benefits in both overall survival (OS) and progression-free survival (PFS) for patients with previously treated advanced NSCLC, compared with chemotherapy [ 7 , 8 , 9 , 10 , 11 ]. ICIs are also recommended as a first-line treatment for advanced or metastatic NSCLC, either as monotherapy or in combination with chemotherapy or other targeted agents, based on histology, genetic alterations, and level of PD-L1 expression [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ].…”