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

Abstract

Purpose: 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 EGFR- or ALK-mutated NSCLC that progressed before TKI therapy.

Materials and methods: 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).

Results: A total of 228 patients with activating EGFR mutation (n = 215) or ALK 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% v 41.9%, P < .001) and median PFS (8.48 v 5.62 months, hazard ratio [HR], 0.62 [95% CI, 0.45 to 0.86]; P = .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 v 20.27 months, HR, 1.01 [95% CI, 0.69 to 1.46]; P = .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.

Conclusion: 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 EGFR- or ALK-mutated NSCLC who have progressed on relevant targeted therapy.

Trial registration: ClinicalTrials.gov NCT03991403.

FIG 1.

CONSORT diagram. ABCP, atezolizumab plus bevacizumab, paclitaxel and carboplatin; ITT, intention-to-treat; PC, pemetrexed plus carboplatin or cisplatin.

FIG 2.

PFS, OS, and depth or response in the efficacy/safety evaluation population. (A) Objective response rate. (B) Kaplan-Meier curves for investigator-assessed progression-free survival and (C) OS; HR and P values were calculated using a stratified log-rank test using stratification factor (EGFR v ALK) and presence of brain metastases (yes v no). Waterfall plot for tumor response as per RECIST from the (D) ABCP arm (E) and PC arm. ABCP, atezolizumab plus bevacizumab, paclitaxel, and carboplatin; HR, hazard ratio; OS, overall survival; PC, pemetrexed plus carboplatin or cisplatin; PFS, progression-free survival; TKI, tyrosine kinase inhibitor.

FIG 3.

Forest plot on the basis of PFS. ABCP, atezolizumab plus bevacizumab, paclitaxel, and carboplatin; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; ITT, intention-to-treat; PC, pemetrexed plus carboplatin or cisplatin; PFS, progression-free survival.

FIG 4.

Exploratory analysis on the basis of the PD-L1 SP263 expression and Lunit SCOPE. Kaplan-Meier curves for PFS of patients with PD-L1 SP263 (A) <1%, (B) ≥1%, (C) ≥10%, (D) ≥50%, and Lunit SCOPE based inflamed score (E) <20% and (F) ≥20%. ABCP, atezolizumab plus bevacizumab, paclitaxel, and carboplatin; HR, hazard ratio; NA, not available; PC, pemetrexed plus carboplatin or cisplatin; PFS, progression-free survival.

FIG A1.

Kaplan-Meier curves for duration of response. ABCP, atezolizumab plus bevacizumab, paclitaxel, and carboplatin; HR, hazard ratio; PC, pemetrexed plus carboplatin or cisplatin; PFS, progression-free survival.

FIG A2.

PFS on the basis of the presence of brain metastases (A) Kaplan-Meier curves for patients with brain metastases and (B) without brain metastases. ABCP, atezolizumab plus bevacizumab, paclitaxel, and carboplatin; HR, hazard ratio; PC, pemetrexed plus carboplatin or cisplatin; PFS, progression-free survival.

FIG A3.

PFS on the basis of the initial EGFR mutation status. Kaplan-Meier curves for patients (A) with EGFR deletion 19 and (B) EGFR Leu858Arg mutation. ABCP, atezolizumab plus bevacizumab, paclitaxel, and carboplatin; HR, hazard ratio; PC, pemetrexed plus carboplatin or cisplatin; PFS, progression-free survival.

FIG A4.

PFS on the basis of acquired EGFR Thr790Met mutation status in EGFR-mutated population. (A) Kaplan-Meier curves for patients with acquired EGFR Thr790Met mutation and (B) without acquired EGFR Thr790Met mutation. PFS, progression-free survival.

FIG A5.

Forest plot of OS. ABCP, atezolizumab plus bevacizumab, paclitaxel, and carboplatin; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; ITT, intention-to-treat; OS, overall survival; PC, pemetrexed plus carboplatin or cisplatin; PFS, progression-free survival; TKI, tyrosine kinase inhibitor.

FIG A6.

Exploratory analysis on the basis of PD-L1 SP142 expression profile. Kaplan-Meier curves for patients with (A) TC0 and IC0 and (B) TC1/2/3 or IC1/2/3. ABCP, atezolizumab plus bevacizumab, paclitaxel, and carboplatin; HR, hazard ratio; PC, pemetrexed plus carboplatin or cisplatin; PFS, progression-free survival.

FIG A7.

(A) Forest plot of PFS (left) and OS (right) in each arm of ABCP and PC for inflamed score cutoff of 10%, 15%, 20%, and 33.3%. The cox proportional hazard model was used to calculate HR (dot) and 95% CI (error bar). (B) HR of PFS between ABCP and PC for all analyzable inflamed score cutoffs. The cox proportional hazard model was used to calculate hazard ratio (dot) and 95% CI (error bar). The interaction P for each inflamed score cutoff was displayed (red, P < .05; black, P ≥ .05). ABCP, atezolizumab plus bevacizumab, paclitaxel, and carboplatin; HR, hazard ratio; OS, overall survival; PC, pemetrexed plus carboplatin or cisplatin; PFS, progression-free survival.