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RET Alteration as a Predictive Biomarker in Cancer Immunotherapy
26 Pages Posted: 7 Aug 2023
More...Abstract
Background: The alteration of RET, an oncogenic driver identified in numerous cancers, has become a critical element during decision-making giving targeted therapy demonstrates robust anti-tumor activities. However, its association with the efficacy of immune checkpoint inhibitors (ICIs) is unclear. Here, we aim to explore RET alteration as a predictive biomarker in immunotherapy and determine the optimal treatment option for patients with RET-altered lung cancer.
Methods: We examined the predictive value of RET alteration in 1406 patients with 6 types of tumors in the discovered cohort, and validated it in 1524 patients with 9 types of tumors. TCGA cohort was used to explore the molecular mechanisms underlying RET alteration. Based on 15 studies recruited 907 patients with RET-altered lung cancer, we conducted a meta-analysis to estimate the objective response rate (ORR), median OS (mOS) in patients treated with multi-kinase inhibitors (MKIs) and selective RET inhibitors (SRIs).
Results: In 2930 patients treated with ICIs, RET alteration was associated with favorable OS (HR=0.60; 95% CI, 0.48-0.75; P<0.001) compared with RET unalteration. This association remained significant after controlling for age, gender, therapy target, tumor mutation burden, and mutation in POLE, TP53, BRCA1/2 (HR=0.68; 95% CI, 0.49-0.93; P=0.01). Genomic and immunologic analysis suggested RET alteration enhanced both intrinsic and extrinsic immune activities. Additionally, the frequencies of mutational signature SBS7d, SBS10b, SBS31, SBS32, SBS42, SBS53, and SBS86, seven predictors for immunotherapy, changed significantly in RET-altered tumors. In RET-altered lung cancer, we estimated the efficacy of ICIs (ORR, 43%; mOS, 21 months), MKIs (ORR, 20%; mOS, 9 months), and SRIs (ORR, 66%). A nomogram and its calibration curves were also developed to calculate survival probabilities after the initiation of immunotherapy in lung cancer.
Conclusion: RET alteration was associated with favorable outcomes in cancer immunotherapy. For RET-altered lung cancer, ICIs might be considered before MKIs in therapeutic decision-making.
Funding Information: None.
Declaration of Interests: None.
Keywords: RET, immunotherapy, targeted therapy, lung cancer, biomarker
Suggested Citation: Suggested Citation