Overall Survival Increased in NSCLC With First-Line Atezolizumab Combination

Mark Socinski, MD

Mark Socinski, MD

According to findings presented at the 2018 ASCO Annual Meeting, overall survival (OS) improved with the combination of atezolizumab (Tecentriq), bevacizumab (Avastin), carboplatin, and paclitaxel (collectively ABCP) versus a treatment regimen of bevacizumab and chemotherapy (BCP) alone in patients with advanced wild-type nonsquamous non—small cell lung cancer (NSCLC).¹The results of the phase III IMpower150 trial were also published in theNew England Journal of Medicine.²

The median OS with the addition of the PD-L1 inhibitor was 19.2 months (95% CI, 17.0-23.8) versus 14.7 months (95% CI, 13.3-16.9) in the BCP arm, amounting to a 22% reduction in the risk of death&nbsp;(HR, 0.78; 95% CI, 0.64-0.96;P= .0164). There was also a 24-month OS rate of 43% with atezolizumab and 34% for BCP. Additonally, ABCP 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 withEGFR/ALK-mutated NSCLC from the co-primary endpoints of OS and PFS. Approximately 13% of the trials participants wereEGFR-orALK-positive. Prior to study entry, these patients had received at least 1 prior EGFR TKI.

When patients withEGFR/ALKalterations 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 theEGFR/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 withEGFR/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 andEGFR/ALKalterations, 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&ndash;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. &ldquo;The highest response rate was near 70% and the longest duration of response was nearly 2 years.&rdquo;

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) &plusmn; 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.

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 wereEGFRmutation positive and 2% to 5% of patients had anALKrearrangement. Liver metastases were present at baseline for 13% of patients.