FDA Grants Frontline Atezolizumab Priority Review for NSCLC

Sandra Horning, MD

The FDA has granted a priority review to a supplemental biologics license application (sBLA) for atezolizumab (Tecentriq) for use in combination with bevacizumab (Avastin), carboplatin, and paclitaxel for the first-line treatment of patients with metastatic nonsquamous non—small cell lung cancer (NSCLC).

The sBLA is a based on findings from the phase III IMpower150 trial, in which the atezolizumab regimen demonstrated a median progression-free survival (PFS) of 8.3 months compared with 6.8 months with bevacizumab and chemotherapy alone. The difference translated into a 38% reduction in the hazard for progression or death (HR, 0.62; 95% CI, 0.52-0.74; P <.0001).

The 12-month PFS rate was 37% with the atezolizumab-containing regimen and 18% with the bevacizumab plus chemotherapy regimen. The objective response rate was 64% versus 48%, respectively.

Genentech, the manufacturer of the PD-L1 inhibitor atezolizumab, reported in March 2018 that the atezolizumab regimen also significantly improved overall survival versus bevacizumab and chemotherapy alone. The company plans to present these data at an upcoming oncology meeting. The FDA is scheduled to make its decision on the sBLA by September 5, 2018.

“Our phase III results showed Tecentriq in combination with Avastin, paclitaxel, and carboplatin has the potential to provide a significant survival benefit in the initial treatment of metastatic nonsquamous non—small cell lung cancer,” Sandra Horning, MD, chief medical officer and head of Global Product Development, Genentech, said in a statement. “We are working closely with the FDA to bring this treatment regimen to people with this type of lung cancer as soon as possible.”

The IMpower150 study enrolled 1202 patients with stage IV nonsquamous NSCLC. Patients were randomized evenly to receive atezolizumab plus carboplatin and paclitaxel (arm A), atezolizumab with bevacizumab plus carboplatin and paclitaxel (arm B), or bevacizumab plus carboplatin and paclitaxel (arm C). Those with known EGFR or ALK alterations were excluded from the primary ITT analysis. Patients were also tested for a tumor T-effector gene expression signature.

The median age of patients in the trial was 63 years and 60% were previous smokers. Overall, most patients were male and the ECOG performance status was 0 for 39% of patients in arm B and for 43% in arm C. The minimum follow-up at the time of the analysis was 9.5 months. For the interim analysis, the study was only designed to compare arms B and C. Follow-up is continuing for patients in the atezolizumab/chemotherapy arm (arm A), and results will be reported at a later date.

Investigators evaluated multiple biomarker assays as potential ways to enrich for PFS, including the T-effector (Teff) gene signature and PD-L1 expression by the SP142 and SP263 assays. Patients also were screened for EGFR mutations and ALK rearrangements.

Overall the PFS benefit was virtually identical between the intention-to-treat group (HR, 0.62; n = 692) and biomarker-enriched population (HR, 0.62; n = 503). The hazard ratios reflected a consistent trend in favor of the atezolizumab arm across all subgroups:

• Teff-high (n = 284) — HR, 0.51; median PFS, 11.3 versus 6.8 months
• Teff-low (n = 374) — HR, 0.76; median PFS, 7.3 versus 7.0 months
• PD-L1-high (n = 135) — HR, 0.39; median PFS, 12.6 versus 6.8 months
• PD-L1-low (n = 224) — HR, 0.56; median PFS, 8.3 versus 6.6 months
• PD-L1 unknown (n = 338) — HR, 0.77; median PFS, 7.1 versus 6.9 months

The PD-L1—high subgroup had a 51% reduction in the hazard ratio with atezolizumab by the SP142 assay (median PFS, 11.1 vs 6.9 months; HR, 0.49; 95% CI, 0.30-0.79) and a 50% reduction by the SP263 assay (median PFS, 9.1 vs 6.2 months; HR, 0.50; 95% CI, 0.33-0.77).

For the PD-L1—low subgroup, the hazard ratio with atezolizumab was 0.53 (median PFS, 8.3 vs 6.1 months; 95% CI, 0.37-0.76) by the SP142 assay and 0.57 by the (median PFS, 9.7 vs 6.9 months; 95% CI, 0.38-0.84) by the SP263 assay.

The PD-L1—negative subgroup had a 23% reduction in the hazard by the SP142 assay (median PFS, 8.2 vs 7.0 months; HR, 0.77; 95% CI, 0.57-1.04) and 28% by the SP263 assay (median PFS, 7.2 vs 7.0 months; HR, 0.72; 95% CI, 0.53-0.97).

Patients with EGFR/ALK had a 41% reduction in the hazard with atezolizumab and median PFS of 8.7 months versus 6.1 months without atezolizumab. For patients with actionable EGFR mutations, the addition of atezolizumab led to a 59% reduction in the hazard ratio (median PFS, 10.2 vs 6.1 months). Patients with liver metastases had a 60% reduction in the hazard ratio when they received atezolizumab and a median PFS of 8.2 months versus 5.4 months without atezolizumab.

Each of the agents showed similar toxicity profiles as in previous trials. Serious treatment-related adverse events were observed in 25.4% of patients treated with the atezolizumab regimen compared with 19.3% of those in the control arm. There were no new safety signals or toxicity issues with this combination.

Atezolizumab is currently approved as a treatment for patients with metastatic NSCLC following progression on a platinum-containing regimen, and an FDA-approved targeted therapy for those patients harboring EGFR or ALK abnormalities.

Kowanetz M, Socinski MA, Zou W, et al. IMpower150: Efficacy of atezolizumab plus bevacizumab and chemotherapy in 1L metastatic nonsquamous NSCLC across key subgroups. Presented at: 2018 AACR Annual Meeting; April 14-18, 2018; Chicago, Illinois. Abstract CT076.

In the investigational arms, atezolizumab was administered at 1200 mg intravenously every 3 weeks and bevacizumab was given at 15 mg/kg. In each arm, carboplatin and paclitaxel were given on day 1 of each cycle for 4 to 6 cycles. In arm A, maintenance therapy was given with atezolizumab alone and in arm B patients received maintenance therapy with the combination of bevacizumab and atezolizumab. In arm C, maintenance was given with bevacizumab alone.