ASCO 2018: First-Line Atezolizumab Improves Survival in Advanced NSCLC

Interim analysis of IMpower150 shows improved overall survival with atezolizumab combination in the ITT population and across all subgroups

The anti-PD-L1 antibody, atezolizumab administered together with bevacizumab, carboplatin, and paclitaxel reduced the risk of death by 22% compared with bevacizumab and chemotherapy in patients with advanced wild-type non-squamous non–small cell lung cancer (NSCLC), according to findings presented at the ASCO 2018 Annual Meeting, held 1 to 5 June in Chicago, USA. These phase III data from the IMpower150 (NCT02366143) trial were published simultaneously in the New England Journal of Medicine

Dr. Mark A. Socinski of the Florida Hospital Cancer Institute in Orlando, USA presented interim overall survival (OS) data from the phase III, open-label, global, randomised IMpower 150 study on behalf of an international team of investigators. 

IMpower150 enrolled 1202 patients with stage IV non-squamous NSCLC. Patients were equally randomised to receive atezolizumab, carboplatin, and paclitaxel (arm A; n = 349), atezolizumab plus bevacizumab and chemotherapy (arm B; n = 359), or bevacizumab and chemotherapy (arm C; n = 337). Across the cohorts, 104 patients were EGFR mutation positive and had an ALK rearrangement. Baseline liver metastases were present in 94 patients. 

In arms A and B, atezolizumab was administered at 1200 mg intravenously every 3 weeks and bevacizumab (arms B and C) was given at 15 mg/kg. In each arm, carboplatin and paclitaxel were administered at standard doses 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. 

The co-primary endpoints were investigator-assessed progression-free survival (PFS) and OS in the in the intent-to-treat (ITT) EGFR/ALK wild-type population and PFS in patients with a T-effector (T-eff) signature. 

OS was significantly improved with atezolizumab and chemotherapy over chemotherapy 

In the wild-type ITT population, analysis done after a median 13.5 months of follow-up demonstrated improved OS with the atezolizumab combination over chemotherapy alone (hazard ratio [HR] 0.78; 95% confidence interval [CI] 0.64, 0.96); p = 0.016). In arm A versus arm C, OS was similar (HR 0.88; p = 0.201). 

Comparison of arms B and C revealed median 18-month OS with atezolizumab in the ITT wild-type patients (n=696) was 19.2 months compared to 14.7 months in the bevacizumab/chemotherapy arm (HR 0.78; 95% CI 0.64, 0.96; p = 0.0164). 

In the overall ITT population (n=800), the median OS with atezolizumab/bevacizumab/chemotherapy was 19.8 months compared with 14.9 months for bevacizumab/chemotherapy (HR 0.76; 95% Cl 0.63, 0.93). An analysis of data from patients with EGFR/ALK alterations (n=104) showed OS was not reached (NE) compared to 17.5 in the respective arms (HR 0.54; 95% Cl 0.29, 1.03). 

Better than expected survival was also seen in patients with liver metastases, where median OS with atezolizumab/bevacizumab/chemotherapy was 13.2 months compared with 9.1 months for bevacizumab/chemotherapy (HR 0.54; 95% Cl 0.33, 0.88). 

There was a 46% reduction in the risk of death with atezolizumab/bevacizumab/chemotherapy compared with bevacizumab/chemotherapy for patients with liver metastases (HR 0.54; 95% CI 0.33, 0.88) and a 46% reduction in the risk of death for patients with EGFR/ALK-mutated NSCLC (HR 0.54; 95% CI 0.29,1.03). The risk of death was reduced by 15% (HR, 0.85; 95% CI 0.53, 1.36) and 18% (HR, 0.82; 95% CI 0.49,1.37) for patients with liver metastases and EGFR/ALK alterations, respectively. 

Patients with PD-L1 expression and the T-eff gene signature demonstrated improved OS 

Favorable efficacy was seen with the atezolizumab/bevacizumab/chemotherapy combination compared with bevacizumab/chemotherapy across PD-L1 expression levels. In those with PD-L1 expression (tumour cells [TC] 1, 2, 3 or immune cells [IC] 1, 2, 3; n = 357), the median OS was 22.5 months with atezolizumab/bevacizumab/chemotherapy compared with 16.4 months for bevacizumab/chemotherapy (HR 0.77; 95% CI 0.58, 1.04). In the PD-L1–negative group (TC0/IC0; n = 339), the median OS was 17.1 versus 14.1 months for atezolizumab/bevacizumab/chemotherapy and bevacizumab/chemotherapy, respectively (HR 0.82; 95% CI 0.62,1.08). 

T-eff gene signature high patients (n=285) showed greatly improved OS, which was 25.0 versus 16.7 months for atezolizumab/bevacizumab/chemotherapy and bevacizumab/chemotherapy, respectively (HR 0.83; 95% CI 0.59, 1.17). The T-eff low subgroup (n=377) had OS of 17.6 versus 14.3 months for atezolizumab/bevacizumab/chemotherapy and bevacizumab/chemotherapy, respectively (HR 0.78; 95% CI 0.60, 1.02). 

No new safety signals raised with atezolizumab added to chemotherapy 

Treatment-related grade 3 or 4 adverse event (AEs) occurred in 43% of patients in the atezolizumab/chemotherapy group and in 57% and 49% of those in the atezolizumab/bevacizumab/chemotherapy and bevacizumab/chemotherapy arms, respectively. Serious adverse events occurred in 39%, 44%, and 34% of patients in the atezolizumab/chemotherapy, atezolizumab/bevacizumab/chemotherapy, and bevacizumab/chemotherapy groups. The most common grade 3/4 immune-related AEs were rash (3% with atezolizumab/chemotherapy, 2% with atezolizumab/bevacizumab/chemotherapy, and 1% with bevacizumab/chemotherapy) and hepatitis (3% with atezolizumab/chemotherapy, 5% with atezolizumab/bevacizumab/chemotherapy, and 1% with bevacizumab/chemotherapy). 

Results from the phase III IMpower 150 trial may be practice changing 

Based on data from the IMpower150 trial, the FDA is currently reviewing a supplemental new drug application for the atezolizumab plus chemotherapy regimen in the first-line setting for patients with non-squamous metastatic NSCLC. The FDA is scheduled to make its decision by 5 September 2018. 

Conclusions 

The authors concluded that the IMpower150 trial met its co-primary PFS and OS endpoints and demonstrated a statistically significant and clinically meaningful benefit with atezolizumab plus bevacizumab and chemotherapy versus bevacizumab plus chemotherapy in the first-line non-squamous NSCLC, across all PD-L1 subgroups. 

Clinical benefit was observed in key subgroups of patients with EGFR/ALK genomic alterations and liver metastases at baseline, with the addition of bevacizumab to atezolizumab plus chemotherapy. 

The efficacy boundary has yet not been crossed for atezolizumab plus chemotherapy versus bevacizumab plus chemotherapy and will be tested again at the time of the final analysis. 

They also concluded that the IMpower150 trial provided findings that support the addition of atezolizumab to standard chemotherapy plus bevacizumab and provides a new option for frontline standard of care treatment, particularly for key patient populations studied in this trial. 

Disclosure 

This trial was sponsored by F. Hoffmann-La Roche/Genentech. 

References

Socinski MA, Jotte R, Cappuzzo F, et al. Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC. N Engl J Med, Published online 4 June 2018. DOI: 10.1056/NEJMoa1716948. 

Socinski M, Jotte RM, Cappuzzo F, et al. Overall survival (OS) analysis of IMpower150, a randomized Ph 3 study of atezolizumab (atezo) + chemotherapy (chemo) ± bevacizumab (bev) vs chemo + bev in 1L nonsquamous (NSQ) NSCLC. J Clin Oncol 36, 2018 (suppl; abstr 9002).