FDA Grants Atezolizumab Priority Review in Lung Cancer

Sandra Horning, MD

The FDA has granted a priority review to atezolizumab for the treatment of patients with locally advanced or metastatic non—small cell lung cancer (NSCLC) who express PD-L1 and have progressed after a platinum-containing regimen, according to Genentech, the manufacturer of the PD-L1 inhibitor.

The priority review is based on data from multiple clinical trials, including the phase II BIRCH study, in which responses were observed in up to 27% (P = .0001) of previously treated patients with NSCLC who had the highest levels of PD-L1 expression.¹

Under the expedited priority program, the FDA will issue a final decision on approval by October 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, MD, 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 II BIRCH study enrolled 667 patients with stage IIIB/IV or recurrent NSCLC who did not have active CNS metastases. Patient characteristics were balanced across cohorts; the median age was 64 years, 35% were ECOG PS 0, 28% had squamous NSCLC, and 17% 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 3-week intervals as frontline therapy to 142 patients (cohort 1), as second-line to 271 patients who had progressed after 1 prior platinum therapy (cohort 2), and to 254 patients who had undergone 2 or more prior chemotherapy regimens (cohort 3).

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 (range, 0-15). The ORR in cohort 1 was 19% and 17% in cohorts 2 and 3 in patients with TC2/3 or IC2/3 expression. Stronger response was seen in patients with higher expression; ORR rates were 26%, 24%, and 27% in cohorts 1, 2, and 3 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 1, 2, and 3, respectively. Six-month OS was achieved by 82%, 76%, and 71% of patients TC2/3 or IC2/3 expression levels in cohorts 1, 2, and 3, respectively, and by 79%, 80%, and 75% of patients in cohorts 1, 2, and 3 having TC3 or IC3 expression levels.

Six-month PFS rates were 46%, 29%, and 31% at the PD-L1 expression level of TC2/3 and IC2/3 and 48%, 34%, and 39% in patients with TC3 or IC3 expression levels in cohorts 1, 2, and 3, 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%) and nausea (10%). Grade 3/4 treatment-related AEs occurred in 11% of patients overall and 6% of patients discontinued therapy due to a treatment-related AE. All-cause grade 3/4 AEs occurred in 38% of patients.

Results with atezolizumab in NSCLC from the phase II POPLAR trial were also previously reported.^2,3 The study randomized 287 patients with previously treated NSCLC to receive atezolizumab (n = 144) or docetaxel (n = 143). Intravenous atezolizumab was administered at 1200 mg every 3 weeks and docetaxel was used at 75 mg/m2 every 3 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 (HR, 0.60; 95% CI, 0.31-1.16). The ORR was 38% and 13%, respectively.

In patients without PD-L1 expression (TC/IC 0), a difference was not observed between the 2 groups. Across all expression levels, the ORR was 15% with both treatments. In this group, the median OS was 12.6 and 9.7 months and the median PFS was 2.7 and 3.0 months, for atezolizumab and docetaxel, respectively.

In the study, fewer grade 3 to 5 adverse events were experienced by patients treated with atezolizumab compared with docetaxel (44% vs 56%). There was a higher incidence of respiratory side effects with immunotherapy versus chemotherapy. Atezolizumab was associated with aspartate and alanine aminotransferase increases (4% each), colitis (1%), hepatitis (1%), and pneumonitis (2%).

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 September 12, 2016.

References

1. 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.
2. 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.
3. 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).