Atezolizumab plus bevacizumab and chemotherapy in metastatic nonsquamous NSCLC: the randomized double-blind phase 3 IMpower151 trial

Abstract

After the global approval of atezolizumab plus bevacizumab and chemotherapy as first-line metastatic nonsquamous non-small-cell lung cancer (nsqNSCLC) treatment, the IMpower151 ( NCT04194203 ) trial was conducted in China to address regional differences. Chemotherapy-naive patients with metastatic nsqNSCLC (N = 305) were randomized 1:1 to receive either atezolizumab, bevacizumab, carboplatin and paclitaxel or pemetrexed (ABCPem/Pac; n = 152) or placebo plus bevacizumab, carboplatin and pemetrexed or paclitaxel (BCPem/Pac; n = 153). The primary endpoint was investigator-assessed progression-free survival (INV-PFS); secondary endpoints included subgroup analyses of INV-PFS, independent review facility-assessed PFS, overall survival, and investigator-assessed objective response rate and duration of response per RECIST v.1.1. Most patients (97%) received pemetrexed, and 53% had EGFR⁺ tumors. Median INV-PFS for ABCPem/Pac versus BCPem/Pac was 9.5 versus 7.1 months (stratified hazard ratio: 0.84; 95% confidence interval: 0.65, 1.09; P = 0.184). INV-PFS across subgroups and independent review facility-assessed PFS were consistent with INV-PFS in the intention-to-treat population. Median overall survival was 20.7 versus 18.7 months in the ABCPem/Pac versus BCPem/Pac arms, respectively (stratified hazard ratio: 0.93; 95% confidence interval: 0.67, 1.28). Confirmed objective response rate with ABCPem/Pac versus BCPem/Pac was 48% versus 50%, respectively; median duration of response was 11.3 versus 8.3 months. Adverse events of special interest for atezolizumab were observed in 68% (grades 3 and 4: 11%) and 71% (grades 3 and 4: 7%) of patients receiving ABCPem/Pac and BCPem/Pac, respectively. The most common adverse events of special interest for atezolizumab in the ABCPem/Pac and BCPem/Pac arms were hepatitis (driven by laboratory abnormalities; mostly low grade), hypothyroidism and rash. Overall, IMpower151 did not meet its primary endpoint (INV-PFS) in metastatic nsqNSCLC. ABCPem/Pac was generally well tolerated, with no new safety signals. Trial registration number: ClinicalTrials.gov, NCT02366143.

Fig. 1. IMpower151 CONSORT diagram.

Patient disposition. ABCPem/Pac, atezolizumab plus bevacizumab, carboplatin and pemetrexed or paclitaxel; BCPem/Pac, placebo plus bevacizumab, carboplatin and pemetrexed or paclitaxel.

Fig. 2. Investigator-assessed PFS.

a, Kaplan–Meier curves in the ITT population. b, Forest plot in key patient subgroups. Data markers in b represent HRs, with error bars indicating 95% CIs. ^aStratified log-rank. ^bUnstratified HR is reported. ^cIncludes patients with ALK WT tumors. ^dIncludes patients with sensitizing EGFR mutations exon 19 del (n = 96); L858R (n = 57); S768I, L861Q and G719X (n = 7); and ALK rearrangement (n = 5). ^ePrior lines were counted only when the reason for stopping was disease progression. ^fOne patient with EGFR mutation received EGFR TKI, but the reason for stopping was not disease progression. ^gOne patient was wrongly randomized as EGFR WT in the interactive voice- or web-based response system and had received no prior TKI treatment.

Fig. 3. Overall survival.

a, Kaplan–Meier curves in the ITT population. b, Forest plot of OS in key patient subgroups. Data markers in b represent HRs, with error bars indicating 95% CIs. ^aUnstratified HR is reported. ^bIncludes patients with ALK WT tumors. ^cIncludes patients with sensitizing EGFR mutations exon 19 del (n = 96); L858R (n = 57); S768I, L861Q and G719X (n = 7); and ALK rearrangement (n = 5). ^dPrior lines were counted only when the reason for stopping was disease progression. ^eOne patient with EGFR mutation received EGFR TKI, but the reason for stopping was not disease progression. ^fOne patient was wrongly randomized as EGFR WT in the interactive voice- or web-based response system and had received no prior TKI treatment.

Fig. 4. RNA sequencing comparison of the EGFR mutation subgroup versus the WT subgroup.

a, Volcano plot of differentially expressed genes. The log₂FC indicates the fold change in the expression level for each gene. Each dot represents one gene. |FC| of 2 and unadjusted P value of 0.01 were used to define genes that are differentially expressed at statistically significant levels. Genes that were significantly up or down regulated were labeled in red. b, Hallmark analysis of differentially expressed genes. The enriched gene sets in the EGFR mutation and WT subgroups were labeled in red and blue, respectively. Asterisks denote the level of statistical significance. c, Gene expression signature analysis. The gene signatures that are expressed at higher levels in the EGFR mutation and WT subgroups were labeled in red and blue, respectively. Asterisks denote the level of statistical significance. All P values reported are two sided. The CAMERA method was used to adjust P values in b and c to account for multiple hypothesis testing. CAF, cancer-associated fibroblast; cDC, conventional dendritic cell; DDR, DNA damage response; EMT, epithelial-to-mesenchymal transition; FC, fold change; MDSC, myeloid-derived suppressor cells; MHC, major histocompatibility complex; Mono_CD14, CD14⁺ monocytes; Mono_CD16, CD16⁺ monocytes; NES, normalized enrichment score; Pan_F_TBRS, pan-fibroblast TGF-β response signature; TAM, tumor-associated macrophages; T_eff, effector T cell; T_H1, T helper 1 cell; T_H2, T helper 2 cell; T_reg, regulatory T cell. Source data

Extended Data Fig. 1. Investigator-assessed PFS by EGFR mutation status.

Kaplan-Meier curves in patients with (a) EGFR mutation and (b) EGFR WT. EGFR mutation status was based on the presence of EGFR genomic alterations or ALK rearrangements. Sensitizing EGFR mutations include exon 19 del, L858R, S768I, L861Q, and G719X. (c) Investigator-assessed PFS in key patient subgroups of the EGFR mutation group. Data markers in (c) represent HRs, with error bars indicating 95% CIs. ^a Unstratified HR is reported. ^b Includes patients with sensitizing EGFR mutations S768I, L861Q and G719X (n = 7). ^c Two patients in the ABCPem/Pac arm had both sensitizing EGFR mutations exon19 del and L858R. ^d One patient was wrongly randomized as EGFR WT in the interactive voice- or web-based response system and had received no prior TKI treatment. ^e Prior lines were counted only when the reason for stopping was disease progression. ^f One patient with EGFR mutation received EGFR TKI but the reason for stopping was not disease progression. 1G, first generation; 2G, second generation; 3G, third generation; ABCPem/Pac, atezolizumab plus bevacizumab, carboplatin, and pemetrexed or paclitaxel; ALK, anaplastic large-cell lymphoma kinase; BCPem/Pac, placebo plus bevacizumab, carboplatin, and pemetrexed or paclitaxel; CI, confidence interval; EGFR, epidermal growth factor receptor; HR, hazard ratio; TKI, tyrosine kinase inhibitor; WT, wild type.

Extended Data Fig. 2. IRF-assessed PFS.

Kaplan-Meier curves in the intention-to-treat population. ABCPem/Pac, atezolizumab plus bevacizumab, carboplatin, and pemetrexed or paclitaxel; BCPem/Pac, placebo plus bevacizumab, carboplatin, and pemetrexed or paclitaxel; CI, confidence interval; HR, hazard ratio; IRF, independent review facility.

Extended Data Fig. 3. OS by EGFR mutation status.

Kaplan-Meier curves in patients with (a) EGFR mutation and (b) EGFR WT. EGFR mutation status was based on the presence of EGFR genomic alterations or ALK rearrangements. Sensitizing EGFR mutations include exon 19 del, L858R, S768I, L861Q, and G719X. (c) OS in key patient subgroups of the EGFR mutation group. Data markers in (c) represent HRs, with error bars indicating 95% CIs. ^a Unstratified HR is reported. ^b Includes patients with sensitizing EGFR mutations S768I, L861Q and G719X (n = 7). ^c Two patients in the ABCPem/Pac arm had both sensitizing EGFR mutations exon19 del and L858R. ^d One patient was wrongly randomized as EGFR WT in the interactive voice- or web-based response system and had received no prior TKI treatment. ^e Prior lines were counted only when the reason for stopping was disease progression. ^f One patient with EGFR mutation received EGFR TKI but the reason for stopping was not disease progression. 1G, first generation; 2G, second generation; 3G, third generation; ABCPem/Pac, atezolizumab plus bevacizumab, carboplatin, and pemetrexed or paclitaxel; ALK, anaplastic large-cell lymphoma kinase; BCPem/Pac, placebo plus bevacizumab, carboplatin, and pemetrexed or paclitaxel; CI, confidence interval; EGFR, epidermal growth factor receptor; HR, hazard ratio; NE, not estimable; TKI, tyrosine kinase inhibitor; WT, wild type.

Extended Data Fig. 4. RNA sequencing comparison of patients with long PFS (≥ median) vs short PFS (< median) in the ITT population.

(a) Volcano plot of differentially expressed genes in the ABCPem/Pac arm. The log₂ FC indicates the fold change in the expression level for each gene. Each dot represents one gene. |FC| of 2 and unadjusted P value of 0.01 were used to define genes that are differentially expressed at statistically significant levels. Genes that were significantly up or down regulated were labeled in red. (b) Volcano plot of differentially expressed genes in the BCPem/Pac arm. The log₂ FC indicates the fold-change in the expression level for each gene. Each dot represents one gene. |FC| of 2 and unadjusted P value of 0.01 were used to define genes that are differentially expressed at statistically significant levels. Genes that were significantly up or down regulated were labeled in red. (c) Hallmark analysis of differential gene expression in the ABCPem/Pac and BCPem/Pac arms. The enriched gene sets in the long and short PFS subgroups were labeled in red and blue, respectively, for both the ABCPem/Pac and BCPem/Pac arms. Asterisks denote the level of statistical significance. (d) Gene expression signature analysis in the ABCPem/Pac and BCPem/Pac arms. The gene signatures that are expressed at higher levels in the long and short PFS subgroups were labeled in red and blue, respectively, for both the ABCPem/Pac and BCPem/Pac arms. Asterisks denote the level of statistical significance. All P values reported are 2 sided. The CAMERA method was used to adjust P values in (c) and (d) to account for multiple hypothesis testing. ABCPem/Pac, atezolizumab plus bevacizumab, carboplatin, and pemetrexed or paclitaxel; BCPem/Pac, placebo plus bevacizumab, carboplatin, and pemetrexed or paclitaxel; CAF, cancer-associated fibroblast; cDC, conventional dendritic cell; DDR, DNA damage response; EGFR, epidermal growth factor receptor; EMT, epithelial-to-mesenchymal transition; FC, fold change; ITT, intention to treat; MDSC, myeloid-derived suppressor cells; MHC, major histocompatibility complex; Mono_CD14, CD14⁺ monocytes; Mono_CD16, CD16⁺ monocytes; NES, normalized enrichment score; Pan_F_TBRS, pan-fibroblast TGF-β response signature; PFS, progression-free survival; TAM, tumor-associated macrophages; T_eff, effector T cell; T_H1, T helper 1 cell; T_H2, T helper 2 cell; T_reg, regulatory T cell; WT, wild type. Source data