Frontline Atezolizumab Benefit in NSCLC Sustained Across Biomarker-Driven Subgroups

Mark A. Socinski, MD

Adding atezolizumab (Tecentriq) to chemotherapy and an angiogenesis inhibitor led to significant improvement in progression-free survival (PFS) for patients with untreated advanced nonsquamous non—small cell lung cancer (NSCLC), according to results from an ongoing trial presented at the 2018 AACR Annual Meeting.

A subgroup analysis showed that the benefit was independent of tumor PD-L1 expression status. Additionally, patients with EGFR or ALK aberrations derived significant benefit from the addition of atezolizumab, as did patients with liver metastases, which are associated with immune suppressive tumor environments and poor outcomes, said study coauthor Mark A. Socinski, MD.

“These data suggest that atezolizumab plus bevacizumab and chemotherapy provides a new treatment option for these key patient populations,” said Socinski, executive medical director of the Florida Hospital Cancer Institute. “This trial has recently demonstrated a significant overall survival benefit, and these data will be presented at an upcoming meeting.”

Still to be determined is the outcome of a third randomized arm of the trial, evaluating atezolizumab plus chemotherapy without bevacizumab.

Socinski reported initial results from IMpower150, a randomized, 3-arm trial evaluating performance characteristics in key subgroups and across multiple biomarker assays. The addition of bevacizumab reflected a desire to determine whether the immunomodulatory effects associated with the drug’s inhibition of VEGF might enhance atezolizumab’s T cell-mediated cancer-cell killing.

Eligible patients had stage IV or recurrent metastatic nonsquamous NSCLC, no prior exposure to chemotherapy, and tumor tissue available for biomarker testing. Otherwise-eligible patients with any PD-L1 expression status could participate.

Investigators randomly assigned 1202 patients to three treatment arms:

• Atezolizumab, carboplatin, and paclitaxel, followed by atezolizumab maintenance;
• Atezolizumab, bevacizumab, carboplatin, and paclitaxel, followed by maintenance with atezolizumab and bevacizumab;
• Bevacizumab, carboplatin, and paclitaxel, followed by bevacizumab maintenance.

The primary objective was PFS and focused on the effect of adding the PD-L1 inhibitor to the bevacizumab/chemotherapy regimen. Socinski reported findings from a prespecified analysis of clinical benefit in key biomarker and special-interest subgroups. Follow-up is continuing for patients in the atezolizumab/chemotherapy arm, 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. The Teff gene signature reflects mRNA expression of the PD-L1, CXCL9, and IFN-gamma genes and is a surrogate for both PD-L1 expression and preexisting immunity, said Socinski. Patients also were screened for EGFR mutations and ALK rearrangements.

A PFS benefit for the atezolizumab/bevacizumab/chemotherapy arm versus the bevacizumab/chemotherapy arm was announced late last year, and Socinski provided details of the benefit in specific subgroups of interest: PD-L1 expression as defined by the SP142 and SP263, EGFR/ALK aberrations, and patients with liver metastases.

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.

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 IMpower150 trial, patients who received the PD-L1 inhibitor along with bevacizumab (Avastin) and chemotherapy had a median PFS of 8.3 months compared with 6.8 months with bevacizumab and chemotherapy. 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).<<< 2018 AACR Annual Meeting