Frontline Atezolizumab Combo Emerges as Potential New Standard in NSCLC

Author(s):

The frontline regimen of atezolizumab (Tecentriq), bevacizumab (Avastin), carboplatin, and paclitaxel has emerged as a potential new standard of care for the treatment of patients with metastatic nonsquamous NSCLC.

Martin Reck, MD, PhD

At the 2018 European Lung Cancer Conference, Reck presented findings from the phase III IMpower150 trial showing that the atezolizumab combination delayed progression or death by 38% compared with bevacizumab and chemotherapy alone for patients with advanced nonsquamous NSCLC. The median progression-free survival (PFS) was 8.3 months versus 6.8 months, respectively (HR, 0.62; 95% CI, 0.52-0.74; P <.0001).

“IMpower150 is the first phase III immunotherapy-based combination study to demonstrate a statistically significant and clinically meaningful improvement in PFS in all-comer first-line metastatic nonsquamous NSCLC, providing a potential new standard of care for patients,” said Reck, lead investigator on IMpower150 and chief oncology physician, Department of Thoracic Oncology, Lung Clinic Grosshansdorf, Germany.

“The trial explored these combinations because atezolizumab’s T-cell mediated cancer cell killing may be enhanced through bevacizumab’s reversal of VEGF-mediated immunosuppression, while the chemotherapy of carboplatin plus paclitaxel may induce immune responses,” Reck, added.

Genentech (Roche), the manufacturer of atezolizumab and bevacizumab, reported in a press release in March 2018 that the atezolizumab combination had also been shown to improve overall survival (OS) in the study. The OS benefit was observed across predetermined patient subgroups, including cohorts with varying PD-L1 expression levels. Genentech plans to submit the IMpower150 OS data for presentation at an upcoming oncology meeting.

IMpower150 randomized 1202 patients with stage IV nonsquamous NSCLC cancer in a 1:1:1 ratio to receive atezolizumab with carboplatin and paclitaxel (arm A), atezolizumab with carboplatin and paclitaxel plus bevacizumab (arm B), or carboplatin and paclitaxel plus bevacizumab (arm C). Atezolizumab was administered at 1200 mg IV every 3 weeks and bevacizumab was given at 15 mg/kg. Patients in each arm received carboplatin and paclitaxel on day 1 of each cycle for 4 to 6 cycles. Maintenance therapy was administered in arm A with atezolizumab alone, and in arm B, patients received bevacizumab plus atezolizumab. Patients in arm C received maintenance therapy consisting of bevacizumab alone.

For the patients in arms B and C, 61% (n = 356) and 62% (n = 336) were men and the ECOG performance status was 0 for 39% and 43%, respectively. Overall, the median age of the patients was 63 years and 60% were previous smokers. The minimum and median follow-up was 9.5 and approximately 15 months, respectively for the interim analysis, which was designed to compare arms B and C.

The 6-month and 12-month PFS rates were 67% (95% CI, 0.22-0.72) versus 56% (95% CI, 0.51-0.62), and 37% (95% CI, 0.31-0.42) versus 18% (95% CI, 0.13-0.23), in arm B versus arm C, respectively. The objective response rate (ORR) for the atezolizumab arm was 64%, comprising a 4% complete response (CR) rate and 60% partial response (PR) rate. Among patients receiving bevacizumab plus chemotherapy alone the ORR was 48%, comprising a 1% CR and 47% PR. In the respective cohorts, the median duration of response was 9.0 months (range, 0.4-24.9) and 5.7 months (range, 0.0-22.1).

“IMpower150 provided the opportunity to evaluate multiple strategies to enrich for PFS, including the T-effector (Teff) gene signature expression and PD-L1 immunohistochemistry. The Teff gene signature is defined by mRNA expression of 3 genes, including PD-L1, CXCL9, and IFNγ, and is a surrogate for both PD-L1 expression and pre-existing immunity,” Reck explained. “In the OAK study, the Teff gene signature appeared to be a more sensitive biomarker of PFS benefit for monotherapy atezolizumab versus docetaxel than PD-L1 IHC expression.”

In IMpower150, Teff was detected in 177 (44%) of arm B and 166 (42%) of arm C patients. The trial met the second co-primary endpoint of PFS in the Teff-high cohort. A landmark median PFS was demonstrated of 11.3 months (95% CI, 9.1-13.0) with the atezolizumab combination, compared to 6.8 months (95% CI, 5.9-7.4) with bevacizumab and chemotherapy alone (HR, 0.505; 95% CI, 0.377- 0.676; P <.0001). In this subgroup, 6- and 12- month PFS rates were 72% and 46% with the atezolizumab combination versus 57% and 18% with chemotherapy/bevacizumab.

Patients with high Teff gene expression and wild-type EGFR in the atezolizumab cohort demonstrated an ORR of 69%, comprising a 4% CR rate and 65% PR rate, compared to a 54% ORR rate, comprising a 2% CR rate and 51% PR rate, with chemotherapy plus bevacizumab. The median duration of response was 11.2 months (range, 0.5-24.9) and 5.7 months (range, 0-22.1) months, respectively.

PD-L1 expression levels were comparable between arms B and C. In patients with high PD-L1 (TC3/IC3), the median PFS was 12.6 versus 6.8 months (HR, 0.39) in the atezolizumab group versus the chemotherapy/bevacizumab-alone arm. In addition, patients testing negative (TC0/IC0) for PD-L1 showed an improvement in PFS with atezolizumab (median PFS, 7.1 vs 6.9 months; HR, 0.77).

In another subgroup of patients with a biomarker of interest, patients with EGFR or ALK mutations demonstrated a median PFS of 9.7 versus 6.1 months with the respective treatments. Additionally, in the ITT EGFR wild-type population, investigator-assessed median PFS was 8.3 months (95% CI, 7.7- 9.8) with the atezolizumab combination compared to 6.8 months (95% CI, 6.0-7.1) with bevacizumab and chemotherapy alone (HR, 0.617; 95% CI, 0.517-0.737; P <.0001).

The incidence of adverse events (AEs), including serious AEs and immunological AEs, was similar between treatment arms.

The anti—PD-L1 agent atezolizumab is currently approved in the United States and European Union for the treatment of NSCLC regardless of PD-L1 expression in the second line and beyond.

Reck M, Socinski MA, Cappuzzo F, et al. Primary PFS and safety analyses of a randomized phase III study of carboplatin + paclitaxel +/− bevacizumab, with or without atezolizumab in 1L non-squamous metastatic NSCLC (IMpower150). Presented at: 2018 European Lung Cancer Conference; April 11-14, 2018; Geneva, Switzerland. Abstract 134PD.

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