Clinical outcomes of tumor-agnostic targeting of BRAF, tumor mutation burden-high, and RET

IF 7.1 2区医学 Q1 ONCOLOGY

ESMO Open Pub Date : 2025-06-01 DOI:10.1016/j.esmoop.2025.105061

A. Ronaghy , E. Crimini , V.R. Holla , K.R. Mills Shaw , A.M. Doefler , E. Campbell , R.K. Yang , J.B. Iorgulescu , K.P. Patel , D.D. McPherson , J. Ning , F. Meric-Bernstam , D.D. Karp

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引用次数: 0

Abstract

Background

We report the BRAF p.V600E (BRAF V600E) mutations, high tumor mutational burden (TMB-H), and RET fusions frequency/outcomes with genomically matched therapies (GMTs). To raise awareness about GMTs providing data from a real-world scenario, the KISMET project was created. In this article we report the characteristics and the outcomes of patients with advanced cancer harboring three different classes of molecular alterations: BRAF V600E mutations, TMB-H, and RET fusions.

Patients and methods

We retrospectively assessed the prevalence of the three aforementioned agnostic targets among 10 893 patients who underwent next-generation sequencing (NGS) from February 2020 to May 2022. We evaluated the objective response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS) for GMT versus non-GMT in the three cohorts of patients with each specific alteration.

Results

BRAF V600E occurred in 6.5% (662/10 158) of patients, TMB-H in 11.2% (265/2369), and RET fusions in 0.6% (42/7105). GMT was given to 115 (72.3%) out of the 159 patients who started a new line of treatment after NGS testing: 65 of 85 with BRAF V600E mutations, 42 of 65 for TMB-H, and 8 of 9 for RET fusions. The ORR of GMT versus non-GMT was 55.6% versus 12.8% for all patients (P < 0.0001), 51% versus 17.6% for the BRAF V600E (P = 0.016), 57.6% versus 9.5% for the TMB-H (P = 0.004), and 75% versus 0% for RET fusions (P = 0.30). The mPFS for GMT versus non-GMT was 9.6 versus 3.7 months (P = 0.001), 9.2 versus 4.2 months (P = 0.08) for BRAF V600E, and 7.9 versus 3.7 months (P = 0.04) for TMB-H, respectively. For the eight patients with RET fusions who received RET inhibitors, the mPFS was 15.0 months.

Conclusions

BRAF V600E, TMB-H, and RET fusion were found in a wide variety of advanced cancers. Improved oncological outcomes with tumor type-agnostic GMT support the value of integrating comprehensive NGS testing and GMT administration for the aforementioned targets.

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肿瘤不可知靶向BRAF、肿瘤突变负担高和RET的临床结果

我们报道了BRAF p.V600E （BRAF V600E）突变、高肿瘤突变负担（TMB-H）和基因组匹配治疗（GMTs）的RET融合频率/结果。为了提高人们对从真实场景中提供数据的gmt的认识，创建了KISMET项目。在这篇文章中，我们报道了三种不同类型分子改变的晚期癌症患者的特征和结果：BRAF V600E突变、TMB-H和RET融合。患者和方法我们回顾性评估了2020年2月至2022年5月接受下一代测序（NGS）的10893例患者中上述三种不可知性靶点的患病率。我们评估了GMT与非GMT患者的客观缓解率（ORR）、中位无进展生存期（mPFS）和中位总生存期（mOS）。结果braf V600E发生率为6.5% (662/10 158)，TMB-H发生率为11.2% (265/2369)，RET融合发生率为0.6%（42/7105）。在接受NGS检测后开始新治疗的159名患者中，115名（72.3%）接受了GMT治疗：85名BRAF V600E突变患者中有65名，65名TMB-H患者中有42名，9名RET融合患者中有8名。在所有患者中，GMT和非GMT的ORR分别为55.6%和12.8% (P <；0.0001)， BRAF V600E为51%对17.6% (P = 0.016)， TMB-H为57.6%对9.5% (P = 0.004)， RET融合为75%对0% （P = 0.30）。GMT和非GMT的mPFS分别为9.6和3.7个月（P = 0.001）， BRAF V600E为9.2和4.2个月（P = 0.08）， TMB-H为7.9和3.7个月（P = 0.04）。对于接受RET抑制剂治疗的8例RET融合患者，mPFS为15.0个月。结论braf V600E、TMB-H和RET融合存在于多种晚期癌症中。与肿瘤类型无关的GMT改善了肿瘤预后，支持将综合NGS检测和GMT管理整合到上述目标的价值。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ESMO Open Medicine-Oncology

CiteScore

11.70

自引率

2.70%

发文量

255

审稿时长

10 weeks

期刊介绍： ESMO Open is the online-only, open access journal of the European Society for Medical Oncology (ESMO). It is a peer-reviewed publication dedicated to sharing high-quality medical research and educational materials from various fields of oncology. The journal specifically focuses on showcasing innovative clinical and translational cancer research. ESMO Open aims to publish a wide range of research articles covering all aspects of oncology, including experimental studies, translational research, diagnostic advancements, and therapeutic approaches. The content of the journal includes original research articles, insightful reviews, thought-provoking editorials, and correspondence. Moreover, the journal warmly welcomes the submission of phase I trials and meta-analyses. It also showcases reviews from significant ESMO conferences and meetings, as well as publishes important position statements on behalf of ESMO. Overall, ESMO Open offers a platform for scientists, clinicians, and researchers in the field of oncology to share their valuable insights and contribute to advancing the understanding and treatment of cancer. The journal serves as a source of up-to-date information and fosters collaboration within the oncology community.