Relationship between immune phenotype and treatment selection of Chemo-IO vs. IO-only in TPS-high NSCLC using hypothetical test-and-control group generation based on survival data extracted from phase III trials.

Abstract

e13569 Background: Immunotherapy has become the treatment of choice for the first-line treatment of unresectable NSCLC with high PD-L1 tumor proportion score (TPS). However, the optimal treatment regimen, particularly when to add chemotherapy, remains unclear. To evaluate whether an immune microenvironment biomarker could help guide the treatment regimen, we have explored computational hypothetical analysis applying historical proportion of inflamed immune phenotype (IIP) to published outcome data of clinical trials. Methods: R package “IPDfromKM” was used to reconstruct raw time-to-event outcomes from Kaplan-Meier (KM) curves. Data from KN-189 and KN-407 for anti-PD1 with chemotherapy (Chemo-IO), and KN-024 and KN-042 for anti-PD1 (IO-only) in the first-line treatment of NSCLC were included for analysis. Overall survival (OS) data were computed from KM of pts with PD-L1 TPS of ≧ 50% from these studies (KN-189 n=132, KN-407 n=73, KN-024 n=154, KN-042 n=299). It was assumed that Lunit SCOPE IO classified pts into IIP or non-IIP at a ratio of 57% vs. 43%, based on previous analysis. One hundred hypothetical sets of Chemo-IO and IO-only groups satisfying hazard ratio (HR) of IIP to non-IIP as 0.81 and 0.61 (± 0.025) while maintaining the proportion of IIP were randomly generated. A total of 10,000 (100 x 100) combinations of cohorts were analyzed to test our hypothesis of superiority of Chemo-IO over IO-only in non-IIP as well as non-superiority of Chemo-IO over IO-only in IIP. Results: Patient-level OS data for a total of 205 pts with Chemo-IO and 453 pts with IO-only were reconstructed. The median OS was favorable in Chemo-IO vs IO-only (HR 0.73, 95% confidence interval [CI] 0.54-0.99, p = 0.045). From 10,000 hypothetical combinations of cohorts, the median HR of Chemo-IO compared to IO-only was 0.61 (interquartile range [IQR] 0.60-0.63) in non-IIP group, whereas that was 0.86 (IQR 0.84-0.89) in IIP group (Table). The upper 95% bound of HR was < 1 for 8,611 combinations of non-IIP groups, but > 1 for all possible combinations of IIP groups. Given a non-superiority margin of 1.37(=1/0.73), 8,306 combinations were positive for the upper 95% bound of HR < 1.37. Overall, 6,917 matched combinations supported our hypothesis. Conclusions: From the computational analysis, 69.17% cases of hypothetical combinations support that Chemo-IO would be superior to IO-only in non-IIP group, whereas Chemo-IO would not be superior to IO-only in IIP group, implying a potential value of confirmatory biomarker analysis in providing evidence for regimen selection. [Table: see text]