Chapter 5 182 4.3 (95% CI: 1.4-5.7) months for the intermediate group and 9.1 (95% CI: 2.5-undefined) months for the sensitive group. OS for the resistant subgroup was significantly shorter than for the sensitive subgroup and numerically shorter than for the intermediate group (resistant vs sensitive: HR=0.34 (95% CI: 0.19-0.64), P<0.001; resistant vs intermediate: HR=0.63 (95% CI: 0.38-1.06), P=0.083. Median OS was 4.3 (95% CI: 2.0-7.9) months for the resistant subgroup, 10.4 (95% CI: 5.9-11.4) months for the intermediate group and 17.3 (95% CI: 8.5-undefined) months for the sensitive group. Test classification was also associated with response (P<0.001, see Supplemental Data: Results Supplementary Table 12). Eightyfive percent of patients classified as resistant experienced progressive disease as best response and only ten percent had a response (all partial). In the sensitive group, only 28% of patients had progressive disease as best response and 28% achieved a response (1 CR and 8 PRs as best response out of 32 patients). For differentiating patients with the worst outcome from the remainder of the cohort, we compared the resistant subgroup with the “not resistant” group, i.e., the combination of intermediate and sensitive subgroups, see Figures 2C and 2D. The resistant subgroup had significantly inferior OS and PFS than the other patients (HR=0.48 (95% CI:0.30-0.77), P=0.002 for OS and HR=0.46 (95% CI: 0.30-0.71), P<0.001 for PFS). These differences remained significant for PFS (P=0.015) and trended to significance for OS (P=0.062) in multivariate analysis when adjusted for other baseline characteristics, including performance status and PD-L1 expression. The patients with the best outcomes (sensitive subgroup) were compared with the “not sensitive” group, i.e., the remainder of the cohort (resistant+intermediate subgroups), Figures 2E and 2F. Patients classified as sensitive had significantly better OS and PFS than patients classified as not sensitive (HR=0.45; 95% CI: 0.25-0.79, P=0.006 for OS and HR=0.45; 95% CI: 0.27-0.76, P=0.003 for PFS). Median OS was 17.3 (95% CI: 8.5-undefined) months for the sensitive group, compared with 6.0 (95% CI: 4.3-9.2) months for the not sensitive group; median PFS was 9.1 (95% CI: 2.5-undefined) months for the sensitive group, compared with only 1.8 (95% CI: 1.4-2.7) months for the not sensitive group. In multivariate analyses, while the effect sizes for OS and PFS remained substantial (HR=0.60 and 0.63, respectively), classification sensitive vs not sensitive did not retain its independent significance as a predictive factor (Supplemental Data: Results Supplementary Tables 13 and 14). Baseline patient characteristics showed no association with test classification for P<0.05 (Supplemental Data: Results Supplementary Table 15). In particular, PD-L1 expression was not significantly correlated with test classification (P=0.387 for ternary classification vs. PD-L1+/PD-L1-/NA).
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