Overall survival (OS) was substantially longer in chemotherapy-naive patients with metastatic non-small cell lung cancer (NSCLC) characterized by a high level of PD-L1 expression treated with the programmed cell death ligand 1 (PD-L1) inhibitor atezolizumab compared with platinum-based chemotherapy, according to results of an interim analysis of a randomized, open-label, phase 3 trial published in the New England Journal of Medicine.
While immune checkpoint inhibitor therapy, either as monotherapy or in combination with other agents, has emerged as a new standard of care for the first-line treatment of patients with EGFR and ALK wild-type advanced NSCLC, questions remain regarding which patient subgroups are most likely to benefit from such an approach.
In this study (IMpower110; ClinicalTrials.gov Identifier: NCT02409342), previously untreated patients with either squamous or nonsquamous metastatic NSCLC characterized by at least 1% PD-L1 expression on tumor cells or tumor-infiltrating immune cells according to immunohistochemical (IHC) analysis using the SP142 antibody were randomly assigned in a 1:1 ratio to receive first-line atezolizumab monotherapy or combination chemotherapy.
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The primary study endpoint was OS in the population of patients with at least 1% PD-L1 expression, with secondary study endpoints including OS in the prespecified subgroups defined according to PD-L1 expression level.
Of the 572 patients enrolled in the study, 277 patients with disease not characterized by a sensitizing alteration in EGFR or an ALK fusion oncogene were assigned to each study arm, which were well balanced with respect to age, sex, Eastern Cooperative Study Group (ECOG) performance status (0 vs 1), racial distribution, disease histology, and history of tobacco use. PD-L1 expression levels of at least 5% tumor/tumor-infiltrating immune cells and at least 50% tumor or at least 10% tumor-infiltrating immune cells were classified as intermediate/high and high, respectively.
A key study finding was that at a median follow-up of 15.7 months, the median OS in the subgroup of patients with disease characterized by a high level of PD-L1 expression receiving atezolizumab (107 individuals) and chemotherapy (98 individuals) was 20.2 months and 13.1 months, respectively (hazard ratio [HR], 0.59; 95% CI, 0.40-0.89; P =.01). Furthermore, the benefit of atezolizumab was observed in patients within this subgroup with disease characterized by both squamous and nonsquamous histology.
In contrast, in the subgroup of patients with metastatic NSCLC characterized by intermediate/high PD-L1 expression, the difference in median OS for those treated with atezolizumab (18.2 months; 166 individuals) and chemotherapy (14.9 months; 162 individuals) was less pronounced and did not meet prespecified criteria for significance (HR, 0.73; 95% CI, 0.52-0.99; P =.04).
Furthermore, for those with disease exhibiting at least 1% PD-L1 expression on either tumor or tumor-infiltrating immune cells, the difference in median OS between the 2 study arms was not significant (17.5 months [atezolizumab] vs 14.1 months [chemotherapy]; HR, 0.83; 95% CI, 0.65-1.07) at a median follow-up of 13.4 months, although a formal OS analysis was not conducted on this population of patients.
Of note, in all 3 subgroups defined by PD-L1 expression as previously described, the duration of response was significantly longer in the atezolizumab arm. For example, the confirmed response rate was 38.3% and 28.6% for those treated with atezoliumab and chemotherapy, respectively. At data cutoff, 68.3% of these responses were ongoing in the atezolizumab arm, with only 35.7% ongoing responses in the chemotherapy arm.
In the overall study population, no new safety signals were observed in patients receiving atezolizumab. The frequency of grade 3/4 adverse events was 30.1% and 52.6% for those treated with atezolizumab and chemotherapy, respectively, with considerably higher frequencies of grade 3/4 hematologic adverse events reported in the chemotherapy compared with the atezolizumab arm. In contrast, grade 3/4 immune-related AEs occurred in 6.6% patients treated with atezolizumab and 1.5% patients receiving chemotherapy.
Prespecified or exploratory assessments of OS data according to subgroups defined by blood-based tumor mutational burden and type of antibody used in IHC testing of PD-L1 expression were also reported.
This trial is ongoing, and a final analysis of OS is planned.
Disclosures: The original study was funded by Genentech, Inc. For a full list of disclosures, please refer to the primary study.
Reference
Herbst RS, Giaccone G, de Marinis F, et al. Atezolizumab for first-line treatment of PD-L1-selected patients with NSCLC. N Engl J Med. 2020;383:1328-1339. doi:10.1056/NEJMoa1917346
