PD-1T TILs as precision biomarker in NSCLC 39 2 ◀ Figure 1. PD-1T TILs as biomarker for clinical outcome to PD-1 blockade in NSCLC. (A) Study design for analysis of PD-1T TILs in pretreatment samples from two retrospective stage IV NSCLC patient cohorts treated with PD-1 blockade. The training (n=43) and validation set (n=77) consisted each of 30% of patients with disease control at 6 months (DC 6m) of treatment. Researchers were blinded for clinical outcome. (B) Representative PD-1 IHC and digital mark-ups showing PD-1T TILs (brown) in a PD-1T TIL high and PD-1T TIL low tumor sample, respectively. (C) PD-1T TILs per mm2 in pretreatment samples from patients with DC 6m (n=14) and progressive disease (PD) (n=29) in the training set (n=43). Dashed line indicates a cut-off of 90 PD-1T TILs per mm2. Medians, interquartile ranges and minimum/maximum shown in boxplots, **P<0.01 by Mann Whitney U-test. (D) Receiver operating characteristic (ROC) curve for predictive value of PD-1T TILs for DC 6m (AUC 0.79; 95% CI: 0.61-0.98) in the training set (n=43). (E) Percentage of patients with PD-1T high (≥90 per mm2) (n=16) and PD-1T low (<90 per mm2) (n=27) pretreatment samples showing DC 6m or PD. (F-G) Same plots as shown in C and D for patients with DC 6m (n=22) and PD (n=55) in the validation set, ** P<0.01 (AUC: 0.72; 95% CI: 0.60-0.84). (H) Same plot as shown in E for patients with PD-1T high (n=35) and PD-1T low (n=42) pretreatment samples in the validation set (n=77). Differences between lesion-specific and overall response While the presence of <90 PD-1T TILs per mm2 was strongly associated with lack of benefit to PD-1 blockade, the PD-1T high group was more heterogeneous with 27/51 patients showing progressive disease within 12 months. It is known that progression can occur heterogeneously across metastases upon PD-1 blockade24. In addition, response assessment by RECIST criteria is based on the change in the sum of target lesion(s) and the development of new lesions25. Thus, patients can be classified as PD based on the progression of some lesions while other lesions are stable or regress. To explore whether such mixed responses occur in PD-1T high patients with PD, we assessed responses to PD-1 blockade in a lesion-specific manner. To this end, the percent increase or decrease in diameter of the biopsied lesion during treatment was determined using RECIST criteria. All patients showing PD within 12 months, and with at least two CT response assessments in which the biopsied lesion could be measured, were included in this analysis. In total, 11 PD patients in the PD-1T high group and 14 PD patients in the PD-1T low group could be evaluated. Interestingly, we observed that only 27% (3/11) of the biopsied lesions in the PD-1T high group showed confirmed progression of the biopsied lesion (defined as ≥20% growth compared to smallest diameter during treatment) compared to 71% (10/14) in the PD-1T low group. This indicates that the PD-1T TIL biomarker correlates better with lesion-specific response than with overall radiological response according to RECIST, and that this could account for at least part of the PD-1T high patients with PD (Fig. 3A). For comparison we also performed the same analysis in patients with DC at 12 months and found that 92% of the evaluable lesions (11/12) in the PD-1T high group showed a durable response after a follow-up of 12 months.
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