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Upfront Atezolizumab Combination Pushes Ahead as Promising New Regimen in NSCLC

Tony Hagen
Published Online:2:43 PM, Fri April 13, 2018

Martin Reck, MD, PhD
According to findings presented by Martin Reck, MD, PhD, at the 2018 European Lung Cancer Conference, the frontline regimen of atezolizumab (Tecentriq), bevacizumab (Avastin), carboplatin, and paclitaxel has became a potential new standard of care for the treatment of patients with metastatic nonsquamous non–small cell lung cancer (NSCLC).

These findings from the phase III IMpower150 trial demonstrated that the atezolizumab combination delayed progression or death by 38% in comparison to bevacizumab and chemotherapy alone for patients with advanced nonsquamous NSCLC. The median progression-free survival (PFS) in patients 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 this trial and chief oncology physician for the Department of Thoracic Oncology at the Lung Clinic in 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.

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

A total of 1202 patients with stage IV nonsquamous NSCLC cancer were randomized in a 1:1:1 ratio to receive either atezolizumab with carboplatin and paclitaxel as arm A, atezolizumab with carboplatin and paclitaxel plus bevacizumab as arm B, or carboplatin and paclitaxel plus bevacizumab as arm C.

Atezolizumab was given to patients at a dose of 1200 mg via IV every 3 weeks while bevacizumab was given at 15 mg/kg. Patients in all arms received carboplatin and paclitaxel on day 1 of each cycle for 4 to 6 cycles. A maintenance therapy was given to patients 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.

Of 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% in arm B and 43% in arm C. The median age overall was 63 years and 60% of the patients were previous smokers. The minimum and median follow-up was 9.5 and approximately 15 months, respectively for the interim analysis, designed to compare arms B and C.

Six-month and 12-month PFS rates in arm B versus arm C 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), respectively. The objective response rate (ORR) for arm A was 64%, including a 4% complete response (CR) rate and a 60% partial response (PR) rate. In the patients receiving bevacizumab plus chemotherapy alone the ORR was 48%, comprising of 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. 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,” Reck explained.

Teff was detected in 177 (44%) of the patients in arm B and 166 (42%) in arm C. The trial met the second co-primary endpoint of PFS in the Teff-high cohort. A landmark median PFS was found at 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, respectively, 72% and 46% with the atezolizumab combination versus 57% and 18% with chemotherapy/bevacizumab.

In an anlysis of patients with high Teff gene expression and wild-type EGFR in the atezolizumab cohort, an ORR of 69% was demonstrated, 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. 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), there was a median PFS of 12.6 in the atezolizumab group versus the chemotherapy/bevacizumab-alone arm 6.8 months (HR, 0.39). Also, patients testing negative (TC0/IC0) for PD-L1 had 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. In the ITT EGFR wild-type population, the investigator-assessed median PFS was 8.3 months (95% CI, 7.7- 9.8) with the atezolizumab combination versus 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).

Adverse events (AEs) included serious AEs and immunological AEs and were similar between the treatment arms.

The anti–PD-L1 agent atezolizumab is currently approved in the United States and European Union for treatment of NSCLC, regardless of PD-L1 expression in the second-line or further beyond.
 
 
Reference:
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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