Neoadjuvant treatment with a single-agent atezolizumab yielded in a phase II Lung Cancer Mutation Consortium 3 (LCMC3) study a 20% major pathological response (MPR) rate in patients with previously untreated, resectable, stage IB–III non-small cell lung cancer (NSCLC), with no new safety signals and encouraging survival. Biomarker analyses showed that pre-treatment peripheral blood immune cell profiles may predict MPR in patients with resectable NSCLC treated with atezolizumab. Although confirmatory and functional studies are needed, the insights from this analysis also suggest an important role for the innate immune system in the context of PD-(L)1 inhibition and the potential for new treatment regimens. The findings are published by Prof. David P. Carbone of The Ohio State University Comprehensive Cancer Center in Columbus, OH, US and colleagues on behalf of LCMC study investigators on 12 September 2022 in the Nature Medicine.
The authors wrote in the study background that survival of patients with resectable NSCLC has not substantially improved since the establishment of adjuvant chemotherapy as standard treatment more than 20 years ago. PD-(L)1 inhibitors are approved for the treatment of advanced NSCLC and resected stage II–III, PD-L1-expressing NSCLC. These agents have shown some benefit when given before surgery in small studies of patients with resectable NSCLC; however, the pathological response rates in these studies have wide confidence intervals (CIs) and predictive biomarkers of response remain unclear.
The phase II LCMC3 study was performed to evaluate the efficacy of neoadjuvant atezolizumab, a PD-L1 inhibitor, in a large population of treatment-naive patients with resectable, stage IB–IIIB NSCLC. To define the clinical and biological effects of neoadjuvant atezolizumab and to identify biomarkers predictive of response or lack thereof, the LCMC3 study evaluated prospectively the immune environment pre- and post-treatment with atezolizumab and correlated these changes with the primary efficacy measure of MPR.
In this ongoing, open-label, single-arm phase II study, 181 patients with untreated, resectable, stage IB–IIIB NSCLC received two doses of neoadjuvant atezolizumab monotherapy. The primary endpoint was MPR defined as ≤ 10% viable malignant cells in resected tumours without EGFR or ALK alterations. Of the 143 patients in the primary endpoint analysis, the MPR was 20% (95% CI 14–28%) with 6% of pathologic complete response.
Median disease-free survival (DFS) and overall survival (OS) were not reached. With a minimum duration of follow-up of 3 years, the 3-year OS rate of 80% was encouraging.
The most common adverse events during the neoadjuvant phase were fatigue (39%) and procedural pain (29%), along with expected immune-related toxicities; there were no unexpected safety signals. There was a low incidence of treatment-related grade ≥3 adverse events. There was only one treatment-related death (immune-mediated pneumonitis), the onset of which occurred 1 month after surgery; the patient died despite optimal medical management.
In exploratory analyses, MPR was predicted using the pre-treatment peripheral blood immunophenotype based on 14 immune cell subsets. Immune cell subsets predictive of MPR in the peripheral blood were also identified in the tumour microenvironment and were associated with MPR.
The authors commented that this study of neoadjuvant atezolizumab is the largest study of preoperative immune checkpoint inhibitor monotherapy in early-stage NSCLC to date and it met the primary endpoint. Neoadjuvant atezolizumab was well tolerated. The composite perioperative mortality rate in LCMC3 was equivalent to that of neoadjuvant chemotherapy and of surgery without chemotherapy. Overall, the safety profile was consistent with that observed in advanced disease. However, biomarkers predictive of drug toxicity remain an unmet need. Despite a high-risk population, including approximately half of patients with clinical stage III disease, 88% of patients had planned surgery. Median DFS and OS were not reached, with an encouraging 3-year OS rate of 80%.
LCMC3 is also the largest analysis of pre- and post-treatment samples in patients with NSCLC treated with single-agent immunotherapy, enabling the robust study of predictive biomarkers. Consistent with findings in the metastatic setting, MPR was associated with high PD-L1 TPS, but as PD-L1 status was unknown for 19% of patients, this outcome should be interpreted with caution. The study team showed in a rigorous training–testing analysis that multi-lineage immunophenotyping of a pre-treatment peripheral blood sample provides information that may predict the probability of pathological response.
The authors recognised that interpretation of predictive biomarker analyses is limited because of the single-arm design of this study. Additional studies are needed to validate the significantly associated cell subsets and further establish the role of peripheral NK cells and NK-like T cells, as well as dendritic cells in tumour tissue, in antitumour responses to immune checkpoint inhibitors in NSCLC. Following external validation, the value of these cell subsets in predicting outcomes in the clinical practice setting must be determined.
The authors also acknowledged as a limitation that MPR was assessed only on the primary tumour; data on the lymph nodes were exploratory.
Overall, the authors concluded that these data confirm that anti-PD-L1 monotherapy is effective in a subset of patients and begin to address two major unmet needs: understanding which biomarkers are predictive of immunotherapy response and identifying patients who may not need chemotherapy. Although confirmatory and functional studies are needed, the insights from this analysis also suggest an important role for the innate immune system in the context of PD-(L)1 inhibition and the potential for new treatment regimens involving agents that modulate ILT2/HLA-G and NKG2A/HLA-E.
The LCMC3 study was funded by Genentech.
Chaft JE, Oezkan F, Kris MG, et al. Neoadjuvant atezolizumab for resectable non-small cell lung cancer: an open-label, single-arm phase II trial. Nature Medicine; Published online 12 September 2022. DOI: https://doi.org/10.1038/s41591-022-01962-5