Atezolizumab plus bevacizumab and chemotherapy in non-small-cell lung cancer (IMpower150): key subgroup analyses of patients with EGFR mutations or baseline liver metastases in a randomised, open-label phase 3 trial.

The IMpower150 trial showed significant improvements in progression-free and overall survival with atezolizumab plus bevacizumab plus carboplatin plus paclitaxel (ABCP) versus the standard-of-care bevacizumab plus carboplatin plus paclitaxel (BCP) in chemotherapy-naive patients with non-squamous non-small-cell lung cancer. Here, we report the efficacy of ABCP or atezolizumab plus carboplatin plus paclitaxel (ACP) versus BCP in key patient subgroups. IMpower150 was a randomised, open-label, phase 3 study done at 240 academic medical centres and community oncology practices across 26 countries worldwide. Patients with chemotherapy-naive metastatic non-small-cell lung cancer were randomly assigned (1:1:1) to receive ABCP, ACP, or BCP every three weeks. The co-primary endpoints were overall survival and investigator-assessed progression-free survival in intention-to-treat wild-type patients (patients with epidermal growth factor receptor [EGFR] or anaplastic lymphoma kinase [ALK] genetic alterations were excluded). Efficacy was assessed in key subgroups within the intention-to-treat population, including patients with EGFR mutations (both sensitising and non-sensitising; EGFR-positive) previously treated with one or more tyrosine kinase inhibitors and patients with baseline liver metastases. Overall survival in the intention-to-treat population was included among secondary efficacy endpoints. Exploratory endpoints included the proportion of patients achieving an objective response in the intention-to-treat population, including EGFR-positive patients and patients with baseline liver metastases. Data are reported as per the Jan 22, 2018, data cutoff date, at which the number of coprimary prespecified overall survival events was met in the ABCP versus BCP groups. This trial is registered with ClinicalTrials.gov, number NCT02366143, and is ongoing. Between March 31, 2015, and Dec 30, 2016, 1202 patients were enrolled. 400 patients were randomly assigned to ABCP, 402 to ACP, and 400 to BCP. In EGFR-positive patients (124 of 1202), median overall survival was not estimable (NE; 95% CI 17·0-NE) with ABCP (34 of 400) and 18·7 months (95% CI 13·4-NE) with BCP (45 of 400; hazard ratio [HR] 0·61 [95% CI 0·29-1·28]). Improved overall survival with ABCP versus BCP was observed in patients with sensitising EGFR mutations (median overall survival NE [95% CI NE-NE] with ABCP [26 of 400] vs 17·5 months [95% CI 11·7-NE] with BCP [32 of 400]; HR 0·31 [95% CI 0·11-0·83]) and in the intention-to-treat population (19·8 months [17·4-24·2] vs 14·9 months [13·4-17·1]; HR 0·76 [0·63-0·93]). Improved median overall survival with ABCP versus BCP was seen in patients with baseline liver metastases (13·3 months [11·6-NE] with ABCP [52 of 400] vs 9·4 months [7·9-11·7] with BCP [57 of 400]; HR 0·52 [0·33-0·82]). Median overall survival was 21·4 months (95% CI 13·8-NE) with ACP versus 18·7 months (95% CI 13·4-NE) with BCP in EGFR-positive patients (HR 0·93 [95% CI 0·51-1·68]). No overall survival benefit was seen with ACP versus BCP in patients with sensitising EGFR mutations (HR 0·90 [95% CI 0·47-1·74]), in the intention-to-treat population (HR 0·85 [0·71-1·03]), or in patients with baseline liver metastases (HR 0·87 [0·57-1·32]). In the intention-to-treat safety-evaluable population, grade 3-4 treatment-related events occurred in 223 (57%) patients in the ABCP group, in 172 (43%) in the ACP group, and in 191 (49%) in the BCP group; 11 (3%) grade 5 adverse events occurred in the ABCP group, as did four (1%) in the ACP group, and nine (2%) in the BCP group. Improved survival was noted for patients treated with ABCP compared with those given BCP in the intention-to-treat population, and in patients with baseline liver metastases. The overall survival signal in the subgroup of patients with EGFR sensitising mutations warrants further study. F. Hoffmann-La Roche, Genentech.

Reck M ，Mok TSK ，Nishio M ，Jotte RM ，Cappuzzo F ，Orlandi F ，Stroyakovskiy D ，Nogami N ，Rodríguez-Abreu D ，Moro-Sibilot D ，Thomas CA ，Barlesi F ，Finley G ，Lee A ，Coleman S ，Deng Y ，Kowanetz M ，Shankar G ，Lin W ，Socinski MA ，IMpower150 Study Group ... -  《-》

IMpower150 Final Exploratory Analyses for Atezolizumab Plus Bevacizumab and Chemotherapy in Key NSCLC Patient Subgroups With EGFR Mutations or Metastases in the Liver or Brain.

Final overall survival (OS) analyses are presented for EGFR mutations and liver or brain metastases subgroups in the phase 3 IMpower150 study (NCT02366143) evaluating atezolizumab plus bevacizumab plus carboplatin and paclitaxel (ABCP) or atezolizumab plus carboplatin and paclitaxel (ACP) versus bevacizumab plus carboplatin and paclitaxel (BCP). Overall, 1202 patients (intention-to-treat population) with chemotherapy-naive, metastatic, nonsquamous NSCLC were randomized to ABCP, ACP, or BCP. Patients with treated, stable brain metastases were permitted. OS was evaluated in EGFR mutations and baseline liver metastases subgroups; rate and time to development of new brain metastases were evaluated in the intention-to-treat patients. At data cutoff (September 13, 2019; median follow-up, 39.3 mo), OS improvements were sustained with ABCP versus BCP in sensitizing EGFR mutations (all: hazard ratio [HR] = 0.60; 95% confidence interval [CI]: 0.31-1.14; previous tyrosine kinase inhibitor [TKI]: HR = 0.74; 95% CI: 0.38-1.46) and baseline liver metastases (HR = 0.68; 95% CI: 0.45-1.02) subgroups. ACP did not have survival benefit versus BCP in sensitizing EGFR mutations (all: HR = 1.0; 95% CI: 0.57-1.74; previous TKI: HR = 1.22; 95% CI: 0.68-2.22) or liver metastases (HR = 1.01; 95% CI: 0.68-1.51) subgroups. Overall, 100 patients (8.3%) developed new brain metastases. Although not formally evaluated, an improvement toward delayed time to development was found with ABCP versus BCP (HR = 0.68; 95% CI: 0.39-1.19). This final exploratory analysis revealed OS benefits for ABCP versus BCP in patients with sensitizing EGFR mutations, including those with previous TKI failures, and with liver metastases, although these results should be interpreted with caution. The impact of ABCP on delaying the development of new brain lesions requires further investigation.

Nogami N ，Barlesi F ，Socinski MA ，Reck M ，Thomas CA ，Cappuzzo F ，Mok TSK ，Finley G ，Aerts JG ，Orlandi F ，Moro-Sibilot D ，Jotte RM ，Stroyakovskiy D ，Villaruz LC ，Rodríguez-Abreu D ，Wan-Teck Lim D ，Merritt D ，Coleman S ，Lee A ，Shankar G ，Yu W ，Bara I ，Nishio M ... -  《-》

Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC.

Socinski MA ，Jotte RM ，Cappuzzo F ，Orlandi F ，Stroyakovskiy D ，Nogami N ，Rodríguez-Abreu D ，Moro-Sibilot D ，Thomas CA ，Barlesi F ，Finley G ，Kelsch C ，Lee A ，Coleman S ，Deng Y ，Shen Y ，Kowanetz M ，Lopez-Chavez A ，Sandler A ，Reck M ，IMpower150 Study Group ... -  《-》

Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 tria

Atezolizumab (a monoclonal antibody against PD-L1), which restores anticancer immunity, improved overall survival in patients with previously treated non-small-cell lung cancer and also showed clinical benefit when combined with chemotherapy as first-line treatment of non-small-cell lung cancer. IMpower130 aimed to assess the efficacy and safety of atezolizumab plus chemotherapy versus chemotherapy alone as first-line therapy for non-squamous non-small-cell lung cancer. IMpower130 was a multicentre, randomised, open-label, phase 3 study done in 131 centres across eight countries (the USA, Canada, Belgium, France, Germany, Italy, Spain, and Israel). Eligible patients were aged 18 years or older, and had histologically or cytologically confirmed stage IV non-squamous non-small-cell lung cancer, an Eastern Cooperative Oncology Group performance status of 0 or 1, and received no previous chemotherapy for stage IV disease. Patients were randomly assigned (2:1; permuted block [block size of six] with an interactive voice or web response system) to receive atezolizumab (1200 mg intravenously every 3 weeks) plus chemotherapy (carboplatin [area under the curve 6 mg/mL per min every 3 weeks] plus nab-paclitaxel [100 mg/m2 intravenously every week]) or chemotherapy alone for four or six 21-day cycles followed by maintenance therapy. Stratification factors were sex, baseline liver metastases, and PD-L1 tumour expression. Co-primary endpoints were investigator-assessed progression-free survival and overall survival in the intention-to-treat wild-type (ie, EGFRwt and ALKwt) population. The safety population included patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02367781. Between April 16, 2015, and Feb 13, 2017, 724 patients were randomly assigned and 723 were included in the intention-to-treat population (one patient died before randomisation, but was assigned to a treatment group; this patient was excluded from the intention-to-treat population) of the atezolizumab plus chemotherapy group (483 patients in the intention-to-treat population and 451 patients in the intention-to-treat wild-type population) or the chemotherapy group (240 patients in the intention-to-treat population and 228 patients in the intention-to-treat wild-type population). Median follow-up in the intention-to-treat wild-type population was similar between groups (18·5 months [IQR 15·2-23·6] in the atezolizumab plus chemotherapy group and 19·2 months [15·4-23·0] in the chemotherapy group). In the intention-to-treat wild-type population, there were significant improvements in median overall survival (18·6 months [95% CI 16·0-21·2] in the atezolizumab plus chemotherapy group and 13·9 months [12·0-18·7] in the chemotherapy group; stratified hazard ratio [HR] 0·79 [95% CI 0·64-0·98]; p=0·033) and median progression-free survival (7·0 months [95% CI 6·2-7·3] in the atezolizumab plus chemotherapy group and 5·5 months [4·4-5·9] in the chemotherapy group; stratified HR 0·64 [95% CI 0·54-0·77]; p<0·0001]). The most common grade 3 or worse treatment-related adverse events were neutropenia (152 [32%] of 473 in the atezolizumab plus chemotherapy group vs 65 [28%] of 232 in the chemotherapy group), anaemia (138 [29%] vs 47 [20%]), and decreased neutrophil count (57 [12%] vs 19 [8%]). Treatment-related serious adverse events were reported in 112 (24%) of 473 patients in the atezolizumab plus chemotherapy group and 30 (13%) of 232 patients in the chemotherapy group. Treatment-related (any treatment) deaths occurred in eight (2%) of 473 patients in the atezolizumab plus chemotherapy group and one (<1%) of 232 patients in the chemotherapy group. IMpower130 showed a significant and clinically meaningful improvement in overall survival and a significant improvement in progression-free survival with atezolizumab plus chemotherapy versus chemotherapy as first-line treatment of patients with stage IV non-squamous non-small-cell lung cancer and no ALK or EGFR mutations. No new safety signals were identified. This study supports the benefit of atezolizumab, in combination with platinum-based chemotherapy, as first-line treatment of metastatic non-small-cell lung cancer. F. Hoffmann-La Roche.

West H ，McCleod M ，Hussein M ，Morabito A ，Rittmeyer A ，Conter HJ ，Kopp HG ，Daniel D ，McCune S ，Mekhail T ，Zer A ，Reinmuth N ，Sadiq A ，Sandler A ，Lin W ，Ochi Lohmann T ，Archer V ，Wang L ，Kowanetz M ，Cappuzzo F ... -  《-》

IMpower150 Final Overall Survival Analyses for Atezolizumab Plus Bevacizumab and Chemotherapy in First-Line Metastatic Nonsquamous NSCLC.

We report the final overall survival (OS) analyses of atezolizumab-carboplatin-paclitaxel (ACP [experimental arm]) and OS data with approximately 39.8 months of median follow-up with atezolizumab-bevacizumab-carboplatin-paclitaxel (ABCP) versus bevacizumab-carboplatin-paclitaxel (BCP) in chemotherapy-naive patients with metastatic nonsquamous NSCLC in the phase 3 IMpower150 study (NCT02366143). In this randomized, open-label study (N = 1202), coprimary end points included investigator-assessed progression-free survival and OS in intention-to-treat (ITT) wild-type (WT; no EGFR or ALK alterations) patients. Secondary and exploratory end points included OS in ITT and programmed death-ligand 1 (PD-L1) subgroups defined by the VENTANA SP142 and SP263 immunohistochemistry assays. At the final analysis with ACP versus BCP (data cutoff: September 13, 2019; minimum follow-up: 32.4 mo), ACP had numerical, but not statistically significant, improvements in OS (ITT-WT: median OS = 19.0 versus 14.7 mo; hazard ratio = 0.84; 95% confidence interval: 0.71-1.00). OS benefit was sustained with ABCP versus BCP (ITT-WT: 19.5 versus 14.7 mo; hazard ratio = 0.80; 95% confidence interval: 0.67-0.95). Exploratory analyses in the SP142-defined PD-L1 subgroups revealed longer median OS with ABCP and ACP versus BCP in PD-L1-high and PD-L1-positive subgroups; in the PD-L1-negative subgroups, median OS was similar with ACP and ABCP versus BCP. Safety was consistent with that in earlier analyses (data cutoff: January 22, 2018). At the final IMpower150 OS analysis, ACP had numerical, but not statistically significant, OS improvement versus BCP. Updated data with an additional 20 months of follow-up revealed continued OS improvement with ABCP versus BCP in all patients.

Socinski MA ，Nishio M ，Jotte RM ，Cappuzzo F ，Orlandi F ，Stroyakovskiy D ，Nogami N ，Rodríguez-Abreu D ，Moro-Sibilot D ，Thomas CA ，Barlesi F ，Finley G ，Kong S ，Lee A ，Coleman S ，Zou W ，McCleland M ，Shankar G ，Reck M ... -  《-》