PD-L1-high status, determined via 3 separate immunohistochemistry assays, and blood tumor mutational burden strongly favored atezolizumab over platinum-based chemotherapy and supports the PD-L1 inhibitor as a first-line treatment option in patients with advanced non–small cell lung cancer.
Roy Herbst, MD, PhD
PD-L1—high status, determined via 3 separate immunohistochemistry (IHC) assays, and blood tumor mutational burden (bTMB) strongly favored atezolizumab (Tecentriq) over platinum-based chemotherapy and supports the PD-L1 inhibitor as a first-line treatment option in patients with advanced non–small cell lung cancer (NSCLC), according to an analysis of the phase III IMpower110 study presented at the 2019 ESMO Immuno-Oncology Congress.1
In patients with the highest PD-L1 expression level, defined as tumor cell (TC)3 or immune cell (IC)3 by Ventana SP142 IHC staining, the median overall survival (OS) was 20.2 months with atezolizumab versus 13.1 months with chemotherapy (HR, 0.59; 95% CI, 0.40-0.89).
“At the interim OS analysis, atezolizumab showed statistically significant and clinically meaningful OS improvements with atezolizumab versus platinum-based chemotherapy in the PD-L1 high by the SP142 antibody population,” said lead study investigator Roy S. Herbst MD, PhD, chief of Medical Oncology, professor of Medicine, Yale Cancer Center, Smilow Cancer Hospital.
OS was similar in patients with high PD-L1 status when PD-L1 was evaluated by Dako 22C3 staining (≥50% tumor proportion score [TPS]) at 20.2 months versus 11.0 months (HR, 0.60; 95% CI, 0.41-0.86) with atezolizumab versus chemotherapy, respectively, and also by SP263 staining (TC ≥50%), where the median OS was 19.5 months versus 16.1 months (HR 0.71; 95% CI, 0.50-1.00), respectively.
The analyses evaluated the efficacy of atezolizumab according to PD-L1 expression status and bTMB. Investigators used data from the phase III IMpower110 study, which met the primary endpoint of OS with atezolizumab in patients with advanced NSCLC who had ≥50% PD-L1 expression on TC3 or ≥10% expression on IC3 (HR, 0.59; 95% CI, 0.40-0.89; P  = .0106).2
The IMpower110 study enrolled 572 chemotherapy-naïve patients with stage IV NSCLC and measurable disease according to RECIST v1.1 criteria and an ECOG performance status of 0 to 1. To be eligible for enrollment, patients had wild-type disease that was EGFR/ALK-negative and PD-L1 expression status ≥1% on TC or IC per the Ventana SP142 assay. Patients were randomized 1:1 to be treated with atezolizumab at 1200 mg intravenously every 3 weeks or platinum-based chemotherapy in 4 to 6 21-day cycles.
The primary endpoint was hierarchically tested OS in wild-type patients, and an additional analysis included OS and progression-free survival in the SP263 PD-L1 positive (cutoffs ≥1% and ≥50% TC) and 22C3 PD-L1 positive (cutoffs ≥1% and ≥50 TPS) patients and in those with bTMB at cutoffs of ≥10, ≥16, and ≥20. A TMB score of 16 was equivalent to approximately 14.5 mutations per megabase.
The biomarker-evaluable population (BEP) in patients with TC1/2/3 or IC1/2/3 comprised 554 patients who were PD-L1 positive according to SP142, 534 patients who were PD-L1 positive by 22C3, 546 who were PD-L1 positive by SP263, and 389 patients with bTMB. The prevalence of PD-L1 expression according to SP263 was 77% (TC ≥1%) and 54% (TC ≥50%); by 22C3 was 78% (TPS ≥1%) and 49% (TPS ≥50%); and by SP142 was 100% (TC1/2/3 or IC1/2/3), 59% (TC2/3 or IC2/3), and 37% (TC3 or IC3).
In the cohort of patients having PD-L1 positivity, represented by TC1/2/3 or IC1/2/3 by SP142, the median OS was 17.5 months with atezolizumab versus 14.1 months with chemotherapy (HR, 0.83; 95% CI, 0.65-1.07). Similar results favoring atezolizumab were seen according to 22C3 staining (TPS ≥1%; HR, 0.73; 95% CI, 0.55-0.97) and SP263 staining (TC ≥1%; HR, 0.77; 95% CI, 0.58-1.02).
“PD-L1 immunohistochemistry and bTMB identified distinct populations of patients in the IMpower110 study,” said Herbst. “OS and PFS were consistently in favor of atezolizumab in PD-L1—high subgroups and this benefit was observed across bTMB subgroups.”
In patients with the lowest PD-L1 expression status, represented by TC1/2 or IC1/2 (SP142), TPS 1% to 49% (22C3), and TC 1% to 49% (SP263), OS began to favor chemotherapy over atezolizumab: HR, 1.04 (95% CI, 0.76-1.44); HR, 1.00 (95% CI, 0.63-1.58), and HR, 0.94 (95% CI, 0.58-1.53), respectively.
PFS also favored atezolizumab in a stepwise fashion according to PD-L1 expression. By SP142 staining patients with TC/IC3 had median PFS of 8.1 months with atezolizumab versus 5.0 months with chemotherapy (HR, 0.59; 95% CI, 0.43-0.82). In patients with PD-L1 status TC1/2/3 or /IC 1/2/3, the median PFS was 5.7 months and 5.5 months, respectively (HR, 0.77; 95% CI, 0.63-0.93). For TC1/2 and IC1/2, the median PFS was 5.5 months versus 5.6 months (HR, 0.90; 95% CI, 0.71-1.15) with atezolizumab versus chemotherapy, respectively.
bTMB was also supported as a prospective biomarker of atezolizumab efficacy. The median OS in patients with bTMB ≥10 receiving atezolizumab versus chemotherapy was 11.2 months versus 10.3 months (HR, 0.87; 95% CI, 0.58-1.30). Median OS with the respective treatments was 13.9 months versus 8.5 months (HR, 0.75; 95% CI, 0.41-1.35) at bTMB ≥16, and 17.2 months versus 10.5 months (HR, 0.77; 95% CI, 0.36-1.64) at bTMB ≥20.
Median PFS with atezolizumab versus chemotherapy, respectively, across the bTMB cutoff points was 5.5 months versus 4.3 months (HR, 0.74; 95% CI, 0.53-1.05), 6.8 months versus 4.4 months (HR, 0.55; 95% CI, 0.33-0.92), and 6.8 months versus 5.2 months (HR, 0.56; 95% CI, 0.30-1.06).
“These findings support atezolizumab as a first-line treatment option in patients with PD-L1—high NSCLC,” Herbst remarked, adding that bTMB appears to be a potential biomarker for checkpoint inhibitor monotherapy.