Treatment for advanced NSCLC includes platinum (plat)-based doublet chemotherapy (chemo), bevacizumab (bev), targeted agents for ALK+ or EGFR-mutant tumors and cancer immunotherapy targeting the PD-L1/PD-1 pathway. Atezolizumab (atezo; MPDL3280A) targets PD-L1 and inhibits binding to PD-1 and B7.1. A Ph Ib study (NCT01633970) of atezo + chemo as 1L therapy showed a manageable safety profile with promising clinical activity (ORRs 60%-75%; Liu, ASCO 2015) at all PD-L1 expression levels. Further, bev may enhance atezo antitumor responses by inhibiting VEGF-related immunosuppressive effects. Thus, 3 Ph III, multicenter, randomized open-label studies will evaluate atezo in combination with plat-based chemo (IMpower 130, 131, 150) Â± bev (IMpower 150) as 1L therapy in chemo-naive patients (pts) with advanced NSCLC.
These trials will enroll pts with previously untreated stage IV NSCLC (ECOG PS 0-1 and measurable disease per RECIST v1.1; Table). All pts must provide an archival tumor or biopsy sample at screening. Pts with untreated CNS metastases, autoimmune disease or prior immunotherapy are excluded. Stratification factors include sex, presence of liver metastases and PD-L1 expression. Per trial, pts will be randomized to receive atezo (1200 mg) with standard plat-based chemo Â± bev (bev for IMpower 150 only). Induction treatment is 4 or 6 21-day cycles followed by maintenance with atezo Â± bev (IMpower 150) or best supportive care. See table for primary efficacy endpoints. Secondary endpoints include ORR and duration of response per RECIST v1.1, PFS per independent review facility (RECIST v1.1), OS, safety/tolerability, pharmacokinetics and health-related quality of life. Mandatory tumor biopsies will be obtained at progression to distinguish pseudoprogression/tumor-immune infiltration from true progression and to assess biomarkers associated with response and immune escape.
Phase III Atezo Trials
|Study||Histology||N||Random- ization||Experimental Arm||Comparator Arm||Co-Primary Endpoints (RECIST v1.1)||Clinical Trials.gov Identifier|
|IMpower 130||Non-squamous||550||2:1||Atezo + Carboplatin + nab-Paclitaxel||Carboplatin + nab-Paclitaxel||1. PFS for ITT 2. PFS for PD-L1–selected||NCT02367781|
|IMpower 131||Squamous||1200||1:1:1||1. Atezo + Carboplatin + Paclitaxel 2. Atezo + Carboplatin + nab-Paclitaxel||Carboplatin + nab-Paclitaxel||1. PFS for ITT 2. PFS for PD-L1–selected||NCT02367794|
|IMpower 150||Non-squamous||1200||1:1:1||1. Atezo + Carboplatin + Paclitaxel 2. Atezo + Carboplatin + Paclitaxel + Bev||Carboplatin + Paclitaxel + Bev||1. PFS for ITT 2. PFS for PD-L1–selected||NCT02366143|
Clinical trial identification
IMpower 130: GO29537; IMpower 131: GO29437; IMpower 150: GO29436
F. Cappuzzo: served on Advisory Boards for Roche, BMS and Pfizer. A. Sandler, D. Waterkamp, W. Verret, Y. Shen: employee of Genentech, Inc. All other authors have declared no conflicts of interest.