Noninvasive early identification of durable clinical benefit from immune checkpoint inhibition: a prospective multicenter study (NCT04566432)

Abstract

Immune checkpoint inhibitors (ICIs) have changed the treatment landscape for patients with non-small cell lung cancer (NSCLC). In spite of durable responses in some patients, many patients develop early disease progression during the ICI treatment. Thus, early identification of patients with no durable benefit would facilitate the clinical decision for these patients. In this prospective, multicenter study, 101 non-EGFR/ALK patients who received ICI treatment were enrolled after screening 328 stage III-IV NSCLC patients. At the date of cutoff, 83 patients were eligible for ICI efficacy evaluation, with 56 patients having progress-free survival (PFS) over 6 months, which was defined as durable clinical benefit (DCB). A multimodal model was established by integrating normalized bTMB, early dynamic of ctDNA and the first RECIST response. This model could robustly predict DCB with area under the curve (AUC) of 0.878, sensitivity of 79.2% at 86.4% specificity (accuracy = 80.0%). This model was further validated in the independent cohort of the DIREct-On study with AUC of 0.887, sensitivity of 94.7% at 85.3% specificity (accuracy = 90.3%). Patients with higher predict scores had substantially longer PFS than those with lower scores (training cohort: median PFS 13.6 vs 4.2 months, P < 0.001, HR = 0.24; validation cohort: median PFS 11.0 vs 2.2 months, P < 0.001, HR = 0.17). Taken together, these results demonstrate that integrating early changes of ctDNA, normalized bTMB, and the first RECIST response can provide accurate, noninvasive, and early prediction of durable benefits for NSCLC patients treated with ICIs. Further prospective studies are warranted to validate these findings and guide clinical decision-making for optimal immunotherapy in NSCLC patients.

Fig. 1

Overview of the study design. A total of 328 NSCLC patients were screened and 101 patients were enrolled in this study. However, 6 patients discontinued ICI treatment before PD mainly due to side effects, 2 patients died due to non-cancer reasons, 6 patients failed to collect sufficient blood samples at preset time and 4 patients were lost to follow-up. Finally, 83 NSCLC patients were included for further analysis

Fig. 2

Pre-treatment features associated with DCB. a The top 20 genes detected by liquid biopsy pre- and early on-treatment were shown for the 83 patients. The prevalence of alterations in each gene is listed on the right. Mutation counts for each sample are shown at the top, followed by rows indicating the benefit of treatment and ctDNA molecular response. Patients who achieved DCB had lower ctDNA concentration (b) but higher bTMB level (c) than those who achieved NDB. d Patients who achieved DCB had higher normalized bTMB level compared to those achieved NDB. e Patients with high bTMB had longer PFS than those with low bTMB (median 11.5 months versus 6.3 months). f Patients with high normalized bTMB had longer PFS compared to patients with low normalized bTMB (median 11.7 months versus 8.8 months). PFS: progression-free survival; HR hazard ratios, CI confidence intervals, bTMB blood-based TMB, DCB durable clinical benefit, NDB no durable benefit. The red horizontal bar in the (b–d) represents the mean and error bar represent ± SD; P < 0.05 represents statistical significance

Fig. 3

Early on-treatment ctDNA dynamics predicts response to ICI. a Swimmer plots display the timing of RECIST response assessment, molecular response and PFS for each patient. b Compared with DCB cohort, the ΔctDNA was significantly lower in the DCB group. The red horizontal bar represents the mean and error bar represent ±SD. c Patients with increased ctDNA had shorter PFS than those with decreased and persistently negative ctDNA (median 4.0 months versus 11.2 months versus 25.7 months). d The ΔctDNA had good sensitivity and specificity to identify patients with DCB. e Patients who achived a molecular response had longer PFS than those of non-molecular responders (median 11.5 months versus 4.0 months). DCB durable clinical benefit, Chemo chemotherapy, ICI immune checkpoint inhibitor, PR partial response, SD stable disease, PD disease progression, PFS progression-free survival. P < 0.05 represents statistical significance

Fig. 4

Early imaging RECIST evaluation predicts response to ICI. a Patients with RECIST responder (PR) had longer PFS than those with RECIST non-responder (SD + PD, median unreached versus 8.8 months). b Early RECIST response had good specificity, but low sensitivity to predict DCB. c Patients classified as molecular responders had longer PFS than nonmolecular responders in the cohort which RECIST were defined as SD (median 9.8 months versus 5.8 months). RECIST The response evaluation criteria in solid tumors, PR partial response, SD stable disease, PD disease progression, PFS progression-free survival, DCB durable clinical benefit. P < 0.05 represents statistical significance

Fig. 5

Multimodal model enables fully noninvasive outcome classification. a Two parameters (normalized bTMB and ΔctDNA) were used to build a model for predicting DCB in our discovery cohort, with a sensitivity of 75.0% and a specificity of 88.9%. Stacked column chart showed the proportion of patients predicted to achieve DCB (Pred-DCB) or NDB (Pred-NDB) by the model. Patients with higher predict scores had significantly longer PFS than those with lower scores (median 13.6 months versus 4.3 months). b Performance of the two parameters model in DIREct-On validation cohort, achieving a sensitivity of 80.5% and a specificity of 67.6%. Stacked column chart showing the proportion of patients with Pred-DCB or Pred-NDB. Patients with higher predict scores had longer PFS than those with lower scores (median 8.5 months versus 2.5 months). c Three parameters (normalized bTMB, ΔctDNA and the first RECIST response) were used to build a model for predicting DCB in our discovery cohort, with a sensitivity of 79.2% and a specificity of 86.4%. Stacked column chart showing the proportion of patients with Pred-DCB or Pred-NDB. Patients with higher predict scores had significantly longer PFS than those with lower scores (median 13.5 months versus 4.2 months). d Performance of the three parameters model in DIREct-On validation cohort, achieving a sensitivity of 94.7% and a specificity of 85.3%. Stacked column chart showing the proportion of patients with Pred-DCB or Pred-NDB. Patients with higher predict scores had longer PFS than those with lower scores (median undefined versus 2.2 months). bTMB blood-based TMB, DCB durable clinical benefit, NDB no durable benefit, RECIST The response evaluation criteria in solid tumors, PFS progression-free survival; P < 0.05 represents statistical significance