Subgroup analysis of Japanese patients in a Phase 3 study of atezolizumab in advanced triple-negative breast cancer (IMpassion130).

In the randomised Phase 3 IMpassion130 trial, atezolizumab combined with nab-paclitaxel (atezo + nab-P) in 902 patients with triple-negative breast cancer (TNBC) showed prolonged progression-free survival (PFS) in both the intention-to-treat (ITT) population and programmed death-ligand 1 (PD-L1)-positive subgroup compared with placebo plus nab-P (plac + nab-P). This study assessed the efficacy and safety of atezo + nab-P in the IMpassion130 Japanese subpopulation. Eligible patients had unresectable locally advanced or metastatic TNBC previously untreated with chemotherapy for metastatic disease. Patients were randomised 1:1 to receive either atezo + nab-P or plac + nab-P. Co-primary endpoints were investigator-assessed PFS and overall survival (ITT population and PD-L1-positive subgroup). These were also assessed in the Japanese subpopulation. There were 65 Japanese patients (34 atezo + nab-P; 31 plac + nab-P). The PD-L1-positive subgroup included 25 patients (12 atezo + nab-P; 13 plac + nab-P). Median PFS was 7.4 months (atezo + nab-P) versus 4.6 months (plac + nab-P; hazard ratio [HR], 0.47; 95% CI, 0.25-0.90). In the PD-L1-positive subgroup, median PFS was 10.8 months (atezo + nab-P) versus 3.8 months (plac + nab-P; HR, 0.04; 95% CI, <0.01-0.35). Safety results in the Japanese subgroup were consistent with those in the overall population. The Japanese subgroup had a lower incidence of adverse events leading to treatment withdrawal than the overall population. More patients in the atezo + nab-P arm had neutrophil count decreases and stomatitis than patients in the plac + nab-P arm. Atezo + nab-P efficacy in Japanese patients was consistent with the overall IMpassion130 population. No new safety signals were observed, and tolerability was consistent with that of the overall population.

Iwata H ，Inoue K ，Kaneko K ，Ito Y ，Tsugawa K ，Hasegawa A ，Nakagawa S ，Kuratomi H ，Tamura K ... -  《-》

Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial.

Immunotherapy in combination with chemotherapy has shown promising efficacy across many different tumour types. We report the prespecified second interim overall survival analysis of the phase 3 IMpassion130 study assessing the efficacy and safety of atezolizumab plus nab-paclitaxel in patients with unresectable, locally advanced or metastatic triple-negative breast cancer. In this randomised, placebo-controlled, double-blind, phase 3 trial, done in 246 academic centres and community oncology practices in 41 countries, patients aged 18 years or older, with previously untreated, histologically documented, locally advanced or metastatic triple-negative breast cancer, and Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomly assigned (1:1) using a permuted block method (block size of four) and an interactive voice-web response system. Randomisation was stratified by previous taxane use, liver metastases, and PD-L1 expression on tumour-infiltrating immune cells. Patients received atezolizumab 840 mg or matching placebo intravenously on day 1 and day 15 of every 28-day cycle and nab-paclitaxel 100 mg/m2 of body surface area intravenously on days 1, 8, and 15 until progression or unacceptable toxicity. Investigators, patients, and the funder were masked to treatment assignment. Coprimary endpoints were investigator-assessed progression-free survival per Response Evaluation Criteria in Solid Tumors version 1.1 and overall survival, assessed in the intention-to-treat population and in patients with PD-L1 immune cell-positive tumours (tumours with ≥1% PD-L1 expression). The final progression-free survival results were previously reported at the first interim overall survival analysis. The prespecified statistical testing hierarchy meant that overall survival in the subgroup of PD-L1 immune cell-positive patients could only be formally tested if overall survival was significantly different between the treatment groups in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02425891. Between June 23, 2015, and May 24, 2017, 902 patients were enrolled, of whom 451 were randomly assigned to receive atezolizumab plus nab-paclitaxel and 451 were assigned to receive placebo plus nab-paclitaxel (the intention-to-treat population). Six patients from each group did not receive treatment. At the second interim analysis (data cutoff Jan 2, 2019), median follow-up was 18·5 months (IQR 9·6-22·8) in the atezolizumab group and 17·5 months (8·4-22·4) in the placebo group. Median overall survival in the intention-to-treat patients was 21·0 months (95% CI 19·0-22·6) with atezolizumab and 18·7 months (16·9-20·3) with placebo (stratified hazard ratio [HR] 0·86, 95% CI 0·72-1·02, p=0·078). In the exploratory overall survival analysis in patients with PD-L1 immune cell-positive tumours, median overall survival was 25·0 months (95% CI 19·6-30·7) with atezolizumab versus 18·0 months (13·6-20·1) with placebo (stratified HR 0·71, 0·54-0·94]). As of Sept 3, 2018 (the date up to which updated safety data were available), the most common grade 3-4 adverse events were neutropenia (38 [8%] of 453 patients in the atezolizumab group vs 36 [8%] of 437 patients in the placebo group), peripheral neuropathy (25 [6%] vs 12 [3%]), decreased neutrophil count (22 [5%] vs 16 [4%]), and fatigue (17 [4%] vs 15 [3%]). Treatment-related deaths occurred in two (<1%) patients in the atezolizumab group (autoimmune hepatitis related to atezolizumab [n=1] and septic shock related to nab-paclitaxel [n=1]) and one (<1%) patient in the placebo group (hepatic failure). No new treatment-related deaths have been reported since the primary clinical data cutoff date (April 17, 2018). Consistent with the first interim analysis, this second interim overall survival analysis of IMpassion130 indicates no significant difference in overall survival between the treatment groups in the intention-to-treat population but suggests a clinically meaningful overall survival benefit with atezolizumab plus nab-paclitaxel in patients with PD-L1 immune cell-positive disease. However, this positive result could not be formally tested due to the prespecified statistical testing hierarchy. For patients with PD-L1 immune cell-positive metastatic triple-negative breast cancer, atezolizumab plus nab-paclitaxel is an important therapeutic option in a disease with high unmet need. F Hoffmann-La Roche and Genentech.

Schmid P ，Rugo HS ，Adams S ，Schneeweiss A ，Barrios CH ，Iwata H ，Diéras V ，Henschel V ，Molinero L ，Chui SY ，Maiya V ，Husain A ，Winer EP ，Loi S ，Emens LA ，IMpassion130 Investigators ... -  《-》

Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer.

Schmid P ，Adams S ，Rugo HS ，Schneeweiss A ，Barrios CH ，Iwata H ，Diéras V ，Hegg R ，Im SA ，Shaw Wright G ，Henschel V ，Molinero L ，Chui SY ，Funke R ，Husain A ，Winer EP ，Loi S ，Emens LA ，IMpassion130 Trial Investigators ... -  《-》

Atezolizumab (in Combination with Nab-Paclitaxel): A Review in Advanced Triple-Negative Breast Cancer.

Kang C ，Syed YY 《-》

Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer.

In the phase III IMpassion130 trial, combining atezolizumab with first-line nanoparticle albumin-bound-paclitaxel for advanced triple-negative breast cancer (aTNBC) showed a statistically significant progression-free survival (PFS) benefit in the intention-to-treat (ITT) and programmed death-ligand 1 (PD-L1)-positive populations, and a clinically meaningful overall survival (OS) effect in PD-L1-positive aTNBC. The phase III KEYNOTE-355 trial adding pembrolizumab to chemotherapy for aTNBC showed similar PFS effects. IMpassion131 evaluated first-line atezolizumab-paclitaxel in aTNBC. Eligible patients [no prior systemic therapy or ≥12 months since (neo)adjuvant chemotherapy] were randomised 2:1 to atezolizumab 840 mg or placebo (days 1, 15), both with paclitaxel 90 mg/m2 (days 1, 8, 15), every 28 days until disease progression or unacceptable toxicity. Stratification factors were tumour PD-L1 status, prior taxane, liver metastases and geographical region. The primary endpoint was investigator-assessed PFS, tested hierarchically first in the PD-L1-positive [immune cell expression ≥1%, VENTANA PD-L1 (SP142) assay] population, and then in the ITT population. OS was a secondary endpoint. Of 651 randomised patients, 45% had PD-L1-positive aTNBC. At the primary PFS analysis, adding atezolizumab to paclitaxel did not improve investigator-assessed PFS in the PD-L1-positive population [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.60-1.12; P = 0.20; median PFS 6.0 months with atezolizumab-paclitaxel versus 5.7 months with placebo-paclitaxel]. In the PD-L1-positive population, atezolizumab-paclitaxel was associated with more favourable unconfirmed best overall response rate (63% versus 55% with placebo-paclitaxel) and median duration of response (7.2 versus 5.5 months, respectively). Final OS results showed no difference between arms (HR 1.11, 95% CI 0.76-1.64; median 22.1 months with atezolizumab-paclitaxel versus 28.3 months with placebo-paclitaxel in the PD-L1-positive population). Results in the ITT population were consistent with the PD-L1-positive population. The safety profile was consistent with known effects of each study drug. Combining atezolizumab with paclitaxel did not improve PFS or OS versus paclitaxel alone. CLINICALTRIALS.GOV: NCT03125902.

Miles D ，Gligorov J ，André F ，Cameron D ，Schneeweiss A ，Barrios C ，Xu B ，Wardley A ，Kaen D ，Andrade L ，Semiglazov V ，Reinisch M ，Patel S ，Patre M ，Morales L ，Patel SL ，Kaul M ，Barata T ，O'Shaughnessy J ，IMpassion131 investigators ... -  《-》