Frontline Atezolizumab Regimen Improves Survival for NSCLC

Mark Socinski, MD

The combination of atezolizumab (Tecentriq), bevacizumab (Avastin), carboplatin, and paclitaxel (ABCP) reduced the risk of death by 22% compared with bevacizumab and chemotherapy (BCP) in patients with advanced wild-type non-squamous non—small cell lung cancer (NSCLC), according to phase III data from the IMpower150 trial presented at the 2018 ASCO Congress and published in the New England Journal of Medicine.^1,2

The median overall survival (OS) with the addition of the PD-L1 inhibitor atezolizumab was 19.2 months (95% CI, 17.0-23.8) compared with 14.7 months (95% CI, 13.3-16.9) in the BCP arm (HR, 0.78; 95% CI, 0.64-0.96; P = .0164). The 24-month OS rate with atezolizumab was 43% compared with 34% for BCP. ABCP also improved median progression-free survival (PFS) by 1.5 months compared with BCP (8.3 vs 6.8 months; HR, 0.59; 95% CI, 0.50-0.70; P <.0001).

"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 and chemotherapy alone in the first-line nonsquamous NSCLC setting, across all PD-L1 subgroups," said lead investigator Mark A. Socinski, MD, executive medical director of the Florida Hospital Cancer Institute. "In the landmark analysis, you see an approximate doubling in median PFS and a tripling in the 18-month progression-free rate."

The trial was designed to exclude data for patients with EGFR/ALK-mutated NSCLC from the co-primary endpoints of OS and PFS. Approximately 13% of the trials participants were EGFR or ALK-positive. Prior to study entry, these patients had received at least 1 prior EGFR TKI.

When patients with EGFR/ALK alterations were included in the intent-to-treat population, the median OS with ABCP jumped to 19.8 months compared with 14.9 months for BCP (HR, 0.76; 95% Cl, 0.63-0.93). Better than expected survival was also seen in patients with liver metastases.

Added efficacy for both groups correlated with the addition of the VEGF inhibitor bevacizumab and atezolizumab. In a separate cohort of the study looking at atezolizumab plus carboplatin and paclitaxel (ACP) there was a less pronounced improvement compared with BCP. In the EGFR/ALK-positive group, the objective response rate (ORR) was 56% with ABCP compared with 40% with ACP and 41% with BCP.

There was a 46% reduction in the risk of death with ABCP compared with BCP 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.

"This suggests that the interplay between anti-VEGF and anti—PD-L1 is important in this subgroup of patients," Socinski said. "These data demonstrate that the combination of atezolizumab plus bevacizumab and chemotherapy provides a new standard of care, particularly for a key patient population in this trial."

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.

In the wild-type intent-to-treat population, the 18-month PFS rate was 27% with ABCP and 8% for BCP. The 18-month OS rate was 53% with ABCP compared with 41% for BCP. The ORR with ABCP was 63.5% compared with 48% for BCP, with complete response rates of 3.7% and 1.2%, respectively.

In patients with liver metastases in the wild-type analysis, the median OS with ABCP was 13.2 month compared with 9.1 months with BCP (HR, 0.54). Patients without liver metastases had a median OS of 19.8 versus 16.7 months for ABCP and BCP, respectively (HR, 0.83). The median OS in patients with EGFR/ALK mutations only was not evaluable with ABCP versus 17.5 months for BCP (HR, 0.54).

Favorable efficacy was seen with the ABCP combination compared with BCP across PD-L1 expression levels. In those with PD-L1 high expression (tumor cells [TC] 3 or immune cells [IC] 3; n = 136), the median OS was 25.2 months with ABCP compared with 15.0 months for BCP (HR, 0.70; 95% CI, 0.43-1.13). The ORR in this group was 69% with ABCP compared with 62% with ACP and 49% with BCP. The duration of response with ABCP in this group was 22.1 months compared with 12.2 months with ACP and 7.0 months for BCP.

In the PD-L1—low group (TC1/2 or IC1/2; n = 226), the median OS was 20.3 versus 16.4 months for ABCP and BCP, respectively (HR, 0.80; 95% CI, 0.55-1.15). In the PD-L1–negative group (TC0/IC0; n = 339), the median OS was 17.1 versus 14.1 months for ABCP and BCP, respectively (HR, 0.82; 95% CI, 0.62-1.08).

"The survival benefit was observed across all PD-L1 patient populations in the intent-to-treat wild-type population," Socinski said. “The highest response rate was near 70% and the longest duration of response was nearly 2 years.”

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

"When you look at the 2 arms that contained atezolizumab, there's really no substantial difference in these immune-related adverse events," said Socinski. "This suggests that addition of anti—PD-L1 therapy to anti-VEGF therapy does not increase the risk of immune-related events."

Based on data from the IMpower150 trial, the FDA is currently reviewing a supplemental new drug application for the ABCP regimen in nonsquamous metastatic NSCLC. The FDA is scheduled to make its decision on the sBLA by September 5, 2018.

References:

1. Socinski MA, Jotte R, 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. 2018;36 (suppl; abstr 9002).
2. Socinski MA, Jotte R, Cappuzzo F, et al. Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC. N Engl J Med. Published online June 4, 2018. DOI: 10.1056/NEJMoa1716948.

<<< 2018 ASCO Annual Meeting

The IMpower150 study enrolled 1202 patients with stage IV non-squamous NSCLC. Patients were randomized evenly to receive ACP (arm A; n = 402), ABCP (arm B; n = 400), or BCP (arm C; n = 400). Approximately 10% of patients were EGFR mutation positive and 2% to 5% of patients had an ALK rearrangement. Liver metastases were present at baseline for 13% of patients.