After multiple clinical trials, atezolizumab was granted a priority review by the FDA. A decision is expected this fall.
After multiple clinical trials, the FDA granted priority review to atezolizumab, a PD-L1 inhibitor, for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who express PD-L1 and have progressed after a platinum-containing regimen, said Genentech, the manufacturer.
The phase 2 BIRCH study, one of the clinical trials on which the priority review is based, responses were observed in up to 27 percent of previously treated patients with NSCLC who had the highest levels of PD-L1 expression.
Under the expedited priority program, the FDA will issue a final decision on approval by Oct. 19, 2016. The FDA is also reviewing an application for a companion IHC test for detecting PD-L1 expression, which was developed by a division of Roche, the parent company of Genentech.
“In a study of atezolizumab in people with previously treated advanced lung cancer, PD-L1 expression correlated with how well they responded to the medicine,” said Sandra Horning, chief medical officer and head of Global Product Development at Genentech. “The goal of PD-L1 as a biomarker is to identify people most likely to benefit from atezolizumab alone.”
The open-label, single-arm phase 2 BIRCH study enrolled 667 patients with stage 3B/4 or recurrent NSCLC who did not have active CNS metastases. Patient characteristics were balanced across cohorts; the median age was 64 years, 35 percent were ECOG PS 0, 28 percent had squamous NSCLC, and 17 percent of patients were never-smokers. EGFR and KRAS mutations were identified in 327 and 177 patients overall, respectively.
All patients had disease that expressed PD-L1 as measured on tumor cells (TC) and tumor-infiltrating immune cells (IC) by Roche’s investigational IHC test. An IHC score of TC2/3 or IC2/3 was the inclusion criteria established by the trial design.
Atezolizumab was administered at 1200 mg IV at three-week intervals as frontline therapy to 142 patients (cohort one), as second-line to 271 patients who had progressed after one prior platinum therapy (cohort two), and to 254 patients who had undergone two or more prior chemotherapy regimens (cohort three).
Overall response rate (ORR) was the primary endpoint, with secondary outcome measures including duration of response, progression-free survival (PFS), Overall Survival (OS), and safety.
Among the 659 evaluable patients, the median treatment duration across all cohorts was 4.2 months. The ORR in cohort one was 19 percent and 17 percent in cohorts two and three in patients with TC2/3 or IC2/3 expression. Stronger response was seen in patients with higher expression; ORR rates were 26 percent, 24 percent and 27 percent in cohorts one, two and three in patients with PD-L1 expression of level TC3 or IC3.
At a median follow-up of 8.8, 7.9 and 8.6 months, median OS was 14 months, not reached (NR), and NR, across cohorts one, two and three, respectively. Six-month OS was achieved by 82 percent, 76 percent, and 71 percent of patients TC2/3 or IC2/3 expression levels in cohorts one, two and three, respectively, and by 79 percent, 80 percent and 75 percent of patients in cohorts one, two and three having TC3 or IC3 expression levels.
Six-month PFS rates were 46 percent, 29 percent and 31 percent at the PD-L1 expression level of TC2/3 and IC2/3 and 48 percent, 34 percent and 39 percent in patients with TC3 or IC3 expression levels in cohorts one, two and three, respectively.
The safety data for atezolizumab in BIRCH were similar to those observed in other trials. The most commonly reported adverse events (AEs) were fatigue (18 percent) and nausea (10 percent). Grade 3/4 treatment-related AEs occurred in 11 percent of patients overall and six percent of patients discontinued therapy due to a treatment-related AE. All-cause grade 3/4 AEs occurred in 38 percent of patients.
Results with atezolizumab in NSCLC from the phase 2 POPLAR trial were also previously reported. The study randomized 287 patients with previously treated NSCLC to receive atezolizumab (144 patients) or Taxotere (docetaxel) (143 patients). Intravenous atezolizumab was administered at 1200 mg every three weeks and docetaxel was used at 75 mg/m2 every three weeks.
In the overall study population, the results did not significantly favor atezolizumab; however, as in the BIRCH trial, PD-L1 expression was strongly associated with atezolizumab's efficacy in POPLAR.
In high PD-L1 expressing tumors (TC/IC 3), the median PFS was 7.8 versus 3.9 months, for atezolizumab and docetaxel, respectively . The ORR was 38 percent and 13 percent, respectively.
In patients without PD-L1 expression (TC/IC 0), a difference was not observed between the two groups. Across all expression levels, the ORR was 15 percent with both treatments. In this group, the median OS was 12.6 and 9.7 months and the median PFS was 2.7 and three months, for atezolizumab and Taxotere, respectively.
In the study, fewer grade 3 to 5 adverse events were experienced by patients treated with atezolizumab compared with Taxotere (44 percent vs 56 percent). There was a higher incidence of respiratory side effects with immunotherapy versus chemotherapy. Atezolizumab was associated with aspartate and alanine aminotransferase increases (4 percent each), colitis (1 percent), hepatitis (1 percent) and pneumonitis (2 percent).
Based on early-stage studies, atezolizumab previously received a breakthrough therapy designation from the FDA as a potential treatment for patients with PD-L1—positive NSCLC following progression on prior therapy, including chemotherapy and targeted therapies.
Atezolizumab also has an ongoing FDA priority preview for the treatment of patients with advanced bladder cancer. A decision on that indication is expected by Sept. 12, 2016.
Besse B, Johnson M, Jänne PA, et al. Phase II, single-arm trial (BIRCH) of atezolizumab as first-line or subsequent therapy for locally advanced or metastatic PD-L1-selected non-small cell lung cancer (NSCLC). Presented at: 2015 European Cancer Congress; September 25-29; Vienna, Austria. Abstract 16LBA.
Vansteenkiste J, Fehrenbacher L, Spira AI, et al. Atezolizumab monotherapy vs docetaxel in 2L/3L non-small cell lung cancer: Primary analyses for efficacy, safety and predictive biomarkers from a randomized phase II study (POPLAR). Presented at: 2015 European Cancer Congress; September 25-29; Vienna, Austria. Abstract 14LBA.
Spira AI, Park K, Mazières J, et al. Efficacy, safety and predictive biomarker results from a randomized phase II study comparing atezolizumab vs docetaxel in 2L/3L NSCLC (POPLAR). J Clin Oncol. 2015;(suppl; abstr 8010).