Clinical characteristics of the patient population

A schematic summary of this study is presented in Fig. 1. The baseline characteristics of OAK and POPLAR cohort, SH&WH cohort, and NCC cohort are shown in Additional file 1: Tables. S2-4. The ctDNA-adjusted bTMB were calculated for each patient. All patients received immunotherapy or chemotherapy.

Fig. 1
figure 1

Study schematic. Blood-based next-generation sequencing was performed before NSCLC patients receiving immune checkpoint inhibitors. OAK and POPLAR cohort, National Cancer Center (NCC) cohort, and Shanghai and Wuhan (SH&WH) cohort were used to assess the predictive value of ctDNA-adjusted bTMB

The association between ctDNA-adjusted bTMB and tumor burden

There was a small but significant positive spearman correlation between bTMB score and the sum of the longest diameters (Spearman r = 0.246, P < 0.001, Additional file 1: Fig. S2A) and the number of metastatic sites (P < 0.001, Additional file 1: Fig. S2B) in OAK and POPLAR cohort. However, no associations were observed between ctDNA-adjusted bTMB with the sum of longest diameters of target lesions at baseline (Spearman r = 0.005, P = 0.880, Additional file 1: Fig. S2C) or the number of metastatic sites (P = 0.107, Additional file 1: Fig. S2D). These results indicated that ctDNA-adjusted bTMB was independent of tumor burden.

The predictive role of ctDNA-adjusted bTMB in different cohorts

  1. (1)

    OAK and POPLAR cohort

The genomic mutational landscape and clinical characteristics of patients from OAK and POPLAR cohort are shown in Additional file 1: Fig. S3. The associations between bTMB, ctDNA-adjusted bTMB, and clinical outcomes were assessed. The RCS models showed non-linearly associations between the level of bTMB and HR for PFS and OS (Additional file 1: Fig. S4A left and S4B left). When the bTMB level was adjusted by ctDNA, it was linearly correlated with HR for PFS and OS (Additional file 1: Fig. S4A right and S4B right). The ROC curves were used to indicate the predictive ability of bTMB and ctDNA-adjusted bTMB for DCB. The ctDNA-adjusted bTMB showed better predictive performance than unadjusted bTMB (AUC: 0.63 vs 0.46, P = 0.013, Additional file 1: Fig. S5). The optimal cutoff value of ctDNA-adjusted bTMB for predicting DCB was 8 muts/Mb × ng (Additional file 1: Fig. S5). In patients receiving atezolizumab, high ctDNA-adjusted bTMB was significantly associated with improved DCB (P < 0.001, Fig. 2A) and ORR (P = 0.020, Fig. 2B). However, no significant associations of ctDNA-adjusted bTMB with DCB (P = 0.289, Fig. 2A) and ORR (P = 0.801, Fig. 2B) were observed in the docetaxel arm. Notably, the interaction P values for atezolizumab vs. docetaxel treatment were positive for OS (P = 0.016) and PFS (P = 0.002), which indicated that high ctDNA-adjusted bTMB might predict better outcomes with ICIs treatment (Fig. 2C and D).

Fig. 2
figure 2

Associations of ctDNA-adjusted bTMB in patients receiving atezolizumab vs. docetaxel treatment. Comparison of (A) durable clinical benefit (DCB) and (B) objective response rate (ORR) between patients with high and low ctDNA-adjusted bTMB in atezolizumab arm and docetaxel arm. Predictive capacity for (C) OS and (D) PFS is stratified by treatment with atezolizumab vs. docetaxel in patients with low and high ctDNA-adjusted bTMB in OAK and POPLAR cohort

In the patients with original low bTMB but high ctDNA-adjusted bTMB, significantly longer median OS was found in treatment arm of atezolizumab than docetaxel (HR = 0.67, 95% CI: 0.48-0.94, Fig. 3A), while the OS in patients with original high bTMB but low ctDNA-adjusted bTMB were comparable between different treatment arms (HR = 0.95, 95% CI: 0.54–1.67, Fig. 3B). Among the patients with atezolizumab treatment and original high bTMB, high ctDNA-adjusted bTMB was significantly associated with improved median OS and median PFS (OS, HR = 0.32, 95% CI: 0.20–0.52, Fig. 3C; PFS, HR = 0.40, 95% CI: 0.26–0.62, Fig. 3D). Then, our study explored the role of ctDNA-adjusted bTMB in patients with negative PD-L1 expression. Indeed, the interactions between ctDNA-adjusted bTMB and treatment arms were significant for OS (interaction P = 0.010, Fig. 3E) and PFS (interaction P = 0.001, Fig. 3F). Furthermore, we found that ctDNA-adjusted bTMB was predictive for OS in patients with serine/threonine kinase 11 (STK11) or Kelch-like ECH-associated protein 1 (KEAP1) mutation (Additional file 1: Table S5).

  1. (2)

    Shanghai and Wuhan (SH&WH) cohort

Fig. 3
figure 3

Kaplan–Meier estimates of OS in patients with (A) low original bTMB and high ctDNA-adjusted bTMB and (B) high original bTMB and low ctDNA-adjusted bTMB, according to treatment group. Kaplan–Meier curves of (C) OS and (D) PFS in patients with high original bTMB and different levels of ctDNA-adjusted bTMB in atezolizumab arm. Predictive capacity for (E) OS and (F) PFS is stratified by treatment with atezolizumab vs. docetaxel in patients with PD-L1 negative expression and different levels of ctDNA-adjusted bTMB

The general characteristics and top 20 gene alterations are shown in Additional file 1: Fig. S6. In the ROC curve, an optimal ctDNA-adjusted bTMB cutoff value of 6 muts/Mb × ng was used to obtain the maximum AUC of 0.683, with sensitivity of 66.7% and specificity of 70.0% (Additional file 1: Fig. S7) to predict DCB. The interactions between ctDNA-adjusted bTMB and treatment were marginally significant for OS (interaction P = 0.081, Fig. 4A) and PFS (interaction P = 0.062, Fig. 4B), suggesting the potential to use ctDNA-adjusted bTMB in predicting treatment benefits of ICIs.

  1. (3)

    National Cancer Center (NCC) cohort

Fig. 4
figure 4

The interactions between ctDNA-adjusted bTMB and treatment in SH&WH cohort. Predictive capacity for (A) OS and (B) PFS is stratified by high vs. low ctDNA-adjusted bTMB in patients receiving different treatments

The clinical and molecular features of NCC cohort are shown in Additional file 1: Fig. S8. We found that bTMB was higher in patients with four or more metastatic sites (P = 0.015, Additional file 1: Fig. S9A). No significant association was found between bTMB and OS in NCC cohort (HR = 0.72, 95% CI: 0.24–2.16, Fig. 5A). After ctDNA adjustment, no differences of ctDNA-adjusted bTMB levels were observed between patients with metastatic sites ≥4 and metastatic sites < 4 (P = 0.278, Additional file 1: Fig. S9B). The optimized cutoff value of ctDNA-adjusted bTMB for predicting DCB was 11 muts/Mb × ng by the ROC curve (Additional file 1: Fig. S10A). Higher DCB rate and ORR were found in those with ctDNA-adjusted bTMB above versus below 11 muts/Mb × ng (DCB, 61.5% vs. 26.5%, P = 0.041, Additional file 1: Fig. S10B; ORR, 46.2% vs. 17.6%, P = 0.065, Additional file 1: Fig. S10C). Compared with patients with low ctDNA-adjusted bTMB, patients with high ctDNA-adjusted bTMB demonstrated superior OS (28.5 vs. 13.0 months, HR = 0.21, 95% CI: 0.05–0.90, Fig. 5B) and were more likely to undergo tumor shrinkage (Additional file 1: Fig. S11).

Fig. 5
figure 5

Association between ctDNA-adjusted bTMB and OS or PFS in NCC cohort. A Kaplan-Meier survival curve of OS comparing patients treated with immunotherapy with bTMB of less than 6 muts/Mb×ng and bTMB of at least 6 muts/Mb×ng. B Kaplan-Meier survival curve of OS comparing patients treated with immunotherapy with ctDNA-adjusted bTMB of less than 11 muts/Mb×ng and bTMB of at least 11 muts/Mb×ng. Kaplan–Meier curves of (C) OS and (D) PFS in patients with high original bTMB and different levels of ctDNA-adjusted bTMB. Kaplan–Meier curves of (E) OS and (F) PFS in patients with PD-L1 negative expression and different levels of ctDNA-adjusted bTMB

Among patients with original high bTMB, high ctDNA-adjusted bTMB was significantly associated with prolonged median OS and median PFS after ICIs treatment (OS, HR = 0.11, 95% CI: 0.01–0.89, Fig. 5C; PFS, HR = 0.10, 95% CI: 0.03–0.38, Fig. 5D). We further explored the association between ctDNA-adjusted bTMB and clinical outcomes in NSCLC patients with PD-L1 negative expression. In this subgroup, patients with high ctDNA-adjusted bTMB had longer median OS and median PFS than those with low ctDNA-adjusted bTMB (Figs. 5).

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