Discussion
NSCLC, intercurrent illness
ONCOLOGY, DISEASE PROGRESSION, NSCLC
Our results demonstrate the tolerability, safety, and feasibility of adding full-dose atezolizumab to SABR in a frail, medically inoperable, early-stage NSCLC patient population. This study was not powered for robust estimates of PFS or OS, and our eligibility criteria were more liberal than most trials in this space, so a direct comparison of treatment outcomes to other trials is inappropriate. However, in our patient population with extensive comorbidities and high-risk factors, the observed median PFS of almost 26 months is encouraging in patients generally not suitable for systemic chemotherapy. Most patients expired from intercurrent illness without evidence of disease progression, limiting the utility of PFS. Thus, FFP was also analyzed post hoc to better evaluate progression. Evaluation of FFP needs to be interpreted with caution as this analysis was post-hoc and did not use a competing risks approach introducing potential biases into the KM estimatesICIs have become a standard-of-care front-line treatment for metastatic and locally advanced NSCLC following randomized phase III trials demonstrating survival benefits as compared to chemotherapy alonePreclinical studies demonstrate synergy between radiotherapy and ICI, and some studies find that synergy is suboptimal if ICI is initiated after the completion of radiotherapyOur study incorporated robust translational studies in a hypothesis-generating manner to identify potential biomarkers for future clinical trials. A limitation of our correlative analyses was the small patient numbers in this phase I trial, which limits the conclusions that can be drawn. These potential biomarkers and mechanistic findings require validation in larger phase III trials that are underway. PD-L1 expression in the TME is a highly validated predictive biomarker for ICI efficacy in advanced-stage NSCLC. Likewise, the presence of dormant/dysfunctional T cells in the TME can predict ICI response in advanced stage NSCLCThere is a lack of reliable peripheral blood biomarkers predictive of ICI response. We found differing pre-treatment levels of circulating T cell subsets and transcriptomic signatures of T cell activation between patients who progress versus those free from progression (Figs. To further explore these findings, we tested T-cell functionality after ex-vivo stimulation. After one cycle of ICI, stimulated T cell functionality increased in non-progressors and decreased in progressors compared to pre-treatment values (Fig. This study regimen has been adapted into the phase III randomized SWOG/NRG Oncology S1914 trial, currently active to accrual (NCT04214262). S1914 randomizes patients between standard-of-care SABR and SABR with a total of 8 cycles of neoadjuvant, concurrent, and adjuvant atezolizumab. A total of 480 patients are planned to be randomized, with a primary endpoint of OS. This study will also test the correlative biomarkers reported here, and the presence of a control arm will allow the determination of whether these biomarkers are prognostic for early-stage NSCLC in general or predictive of response to atezolizumab. Two other ongoing randomized phase 3 trials are also testing the integration of ICI and SABR for medically inoperable, early-stage NSCLC, PACIFIC-4 (NCT03833154), and KEYNOTE-867 (NCT03924869).