Phase III, Randomized Study of Atezolizumab Plus Bevacizumab and Chemotherapy in Patients With <i>EGFR</i>- or <i>ALK</i>-Mutated Non-Small-Cell Lung Cancer (ATTLAS, KCSG-LU19-04).

Abstract

In the treatment of non-small-cell lung cancer (NSCLC) with a driver mutation, the role of anti-PD-(L)1 antibody after tyrosine kinase inhibitor (TKI) remains unclear. This randomized, open-label, multicenter, phase III study evaluates the efficacy of atezolizumab plus bevacizumab, paclitaxel, and carboplatin (ABCP ) in <i>EGFR-</i> or <i>ALK</i>-mutated NSCLC that progressed before TKI therapy. We compared the clinical efficacy of ABCP followed by maintenance therapy with atezolizumab plus bevacizumab with pemetrexed plus carboplatin or cisplatin (PC) followed by pemetrexed maintenance. The primary end point was progression-free survival (PFS). A total of 228 patients with activating <i>EGFR</i> mutation (n = 215) or <i>ALK</i> translocation (n = 13) were enrolled from 16 sites in the Republic of Korea and randomly assigned at 2:1 ratio to either ABCP (n = 154) or PC arm (n = 74). The median follow-up duration was 26.1 months (95% CI, 24.7 to 28.2). Objective response rates (69.5% <i>v</i> 41.9%, <i>P</i> < .001) and median PFS (8.48 <i>v</i> 5.62 months, hazard ratio [HR], 0.62 [95% CI, 0.45 to 0.86]; <i>P</i> = .004) were significantly better in the ABCP than PC arm. PFS benefit increased as PD-L1 expression increased, with an HR of 0.47, 0.41, and 0.24 for PD-L1 ≥1%, ≥10%, and ≥50%, respectively. Overall survival was similar between ABCP and PC arm (20.63 <i>v</i> 20.27 months, HR, 1.01 [95% CI, 0.69 to 1.46]; <i>P</i> = .975). The safety profile of the ABCP arm was comparable with that previously reported, with no additional safety signals, but higher rates of treatment-related adverse events were observed compared with the PC arm. To our knowledge, this study is the first randomized phase III study to demonstrate the clinical benefit of anti-PD-L1 antibody in combination with bevacizumab and chemotherapy in patients with <i>EGFR-</i> or <i>ALK</i>-mutated NSCLC who have progressed on relevant targeted therapy.