PD-1T TILs as precision biomarker in NSCLC 37 2 To validate our findings, we next assessed the frequency of PD-1T TILs per mm2 in the validation set (n=77). The median number of PD-1T TILs per mm2 was 150 (IQR: 89-231) in patients with DC 6m versus 49 (IQR: 15-152) with PD (p<0.01) (Fig. 1F). The AUC of the ROC curve was 0.72 (CI: 0.60-0.84), indicating a similar performance as in the training set (Fig. 1G). The biomarker also reached a comparable sensitivity (77%) and NPV (88%), but somewhat lower specificity (67%) (Table 1). Importantly, we still observed a substantial enrichment of non-responding patients in the PD-1T low group (Fig. 1H). Assessment of secondary endpoints: DC at 12 months and survival Since approximately 60-70% of patients treated in 2nd line with PD-(L)1 blockade progress within 6 months, and an additional 10-20% progress within 12 months3,5,6, we also assessed the value of PD-1T TILs to predict DC at 12 months (DC 12m). Two patients in the training and eight patients in the validation set experienced disease progression between 6 and 12 months, and were therefore included the PD group in this analysis (Fig. 1A). Median PD-1T TIL numbers were comparable to the DC 6m analysis (training set, DC 12m: 282 (IQR: 192-363), PD 44 (IQR: 27-83), P<0.0001; validation set, DC 12m: 202 (IQR: 114-312), PD: 49 (IQR: 17-160) P<0.001, Fig. S2A,B). Using the same cut-off of 90 PD-1T TILs per mm2 the ROC curve yielded a high AUC in both data sets of 0.89 (CI: 0.73-1.00) (Fig. 2A, training set) and 0.78 (CI: 0.68-0.88) (Fig. 2B, validation set). Importantly, in the DC 12m analysis our predefined cut-off reached the intended criteria with a sensitivity of 92% and an NPV of 96% in the training set, and of 93% and 98%, respectively, in the validation set. In both cohorts a specificity of >50% was maintained (84% in the training set, 65% in the validation set) (Table 1). Notably, in both data sets only 1/43 (2%) and 1/77 (1%) samples from patients with DC 12m showed a low frequency of PD-1T TILs <90 per mm2, suggesting a reliable identification of a patient group with no long-term benefit from PD-1 blockade (Fig. 2C,D). As additional secondary endpoints, we assessed progression-free survival (PFS) and overall survival (OS) for patients with more or less than 90 PD-1T TILs per mm2. Since this cut-off was trained for prediction of DC at 6 months, PFS was significantly longer in PD-1T high patients in the training set (HR 0.30; 95% CI: 0.16-0.58, P<0.001) (Fig. S2C). Notably, PFS was also significantly increased in the validation set (HR 0.39; 95% CI: 0.24-0.63, P<0.0001) in PD-1T high patients (Fig. 2E). Likewise, OS was significantly longer in both the training (HR 0.27; 95% CI: 0.14-0.53, P<0.0001) (Fig. S2D) and validation set (HR 0.46; 95% CI: 0.28-0.76, P< 0.01) (Fig. 2F).
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