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

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.

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Publication Details

Journal
Signal Transduction and Targeted Therapy
Published
2024-12-16
DOI
https://doi.org/10.1038/s41392-024-02060-3
Citations
15
Primary Topic
Cancer Immunotherapy and Biomarkers
Type
article
Field-Weighted Citation Impact
4.24

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article

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

Shun Lü, Zhiyi He, Rongrong Chen, Xiang Yan et al.
15 citations
Signal Transduction and Targeted Therapy
Cancer Immunotherapy and Biomarkers
4.24
article

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

Shun Lü, Zhiyi He, Rongrong Chen, Xiang Yan, Jiexia Zhang, Bo Jia, Yuanyuan Xiong, Minglei Zhuo, Feng Jin, Hao Tang, Huan Yin, Chong Li, Junping Zhang, Zaiwen Fan, Xia Ma, Ziming Li, Jun Zhao, Xinghao Ai, Xiaotong Zhang, Wei Li, Zhe Wang
article en
15 citations

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.

Signal Transduction and Targeted TherapyVol. 9(1)
Guangxi Medical University (CN), Shanxi Medical University (CN), Shanghai Jiao Tong University (CN), Capital Medical University (CN), Chinese Academy of Medical Sciences & Peking Union Medical College (CN), Peking University (CN), Peking Union Medical College Hospital (CN), Shanghai Chest Hospital (CN), Soochow University (CN), Gene Therapy Laboratory (FR), Peking University Cancer Hospital (CN), First Affiliated Hospital of Guangzhou Medical University (CN), Shanghai Changzheng Hospital (CN), Qianjiang Central Hospital (CN), Peking University People's Hospital (CN), First Affiliated Hospital of GuangXi Medical University (CN), Second Affiliated Hospital of Xi'an Jiaotong University (CN), Air Force General Hospital PLA (CN), Beijing YouAn Hospital (CN), State Key Laboratory of Respiratory Disease (CN), Shanxi Academy of Medical Sciences (CN), Guangzhou Medical University (CN)
Natural Science Foundation of Shanghai, Beijing Xisike Clinical Oncology Research Foundation, National Natural Science Foundation of China, Shanghai Chest Hospital
Peace, Justice and strong institutions
Openalex Percentile: Top 4%
Cancer Immunotherapy and Biomarkers
4.24
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