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A real world analysis of secondary BRAF variations after targeted therapy resistance in driver gene positive NSCLC
DuJiang Liu1,2, KaiBo Ding1,2, KaiLai Yin2,3
1Department of Medical Thoracic Oncology, Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer(IBMC), Chinese Academy of Sciences, No.1 East Banshan Road, Gongshu District, Hangzhou, 310022, Zhejiang, China.
Abstract:
Secondary BRAF variations have been identified as a mechanism of resistance to tyrosine kinase inhibitors (TKIs) in patients with driver gene-positive NSCLC. Nevertheless, there is still a lack of consensus regarding the characteristics and subsequent treatment strategies for these patients. We retrospectively reviewed the medical records of patients with driver gene-positive NSCLC who received TKIs therapy at Zhejiang Cancer Hospital between May 2016 and December 2023. The clinical and genetic characteristics of these patients were assessed, along with the impact of various treatment strategies on survival. This study enrolled 27 patients with advanced NSCLC, in whom BRAF variations occurred at a median time of 28 months after the initiation of targeted therapy. The multivariate accelerated failure time (AFT) model revealed that, compared to chemotherapy-based regimens group, the combined targeted therapy group (p < 0.001) and the combined local treatment group for oligo-progression (p < 0.001) significantly extended patient survival. In contrast, continuing the original signaling pathway's targeted monotherapy was associated with shorter survival (p = 0.034). The median global OS for each treatment group was as follows: chemotherapy-based regimens group, 45 months; combined targeted therapy group, 59 months; combined local treatment group for patients with oligo-progression, 46 months; and targeted monotherapy group, 36 months. Study results indicate that the combination targeted therapy group (including TKIs, BRAF inhibitors, and/or MEK inhibitors) and the localized treatment group are more effective than traditional chemotherapy-based regimens in improving survival. Additionally, continuing targeted monotherapy along the original signaling pathway proves less effective than chemotherapy-based regimens.
Insights
Secondary BRAF alterations cause resistance to tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). Combined targeted therapy or local treatment for oligo-progression significantly improves survival compared to chemotherapy or continuing single-pathway TKIs.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Secondary BRAF variations are a known resistance mechanism to tyrosine kinase inhibitors (TKIs) in driver gene-positive non-small cell lung cancer (NSCLC).
- Optimal treatment strategies for NSCLC patients with secondary BRAF alterations remain unclear, lacking established consensus.
- Understanding clinical and genetic profiles is crucial for guiding therapy in this resistant NSCLC population.
Purpose of the Study:
- To investigate the clinical and genetic characteristics of NSCLC patients developing secondary BRAF variations during TKI therapy.
- To evaluate the impact of different treatment strategies on survival outcomes in this patient cohort.
- To identify effective therapeutic approaches beyond standard chemotherapy for TKI-resistant NSCLC.
Main Methods:
- Retrospective review of medical records for 27 advanced NSCLC patients treated with TKIs at Zhejiang Cancer Hospital (May 2016 - Dec 2023).
- Assessment of clinical and genetic profiles, focusing on the timing and nature of BRAF alterations.
- Multivariate accelerated failure time (AFT) model analysis to compare survival across treatment groups (chemotherapy, combined targeted therapy, local treatment, targeted monotherapy).
Main Results:
- Secondary BRAF variations emerged at a median of 28 months post-TKI initiation.
- Combined targeted therapy (TKIs, BRAF/MEK inhibitors) and local treatment for oligo-progression significantly improved overall survival (OS) compared to chemotherapy (p<0.001).
- Continuing targeted monotherapy along the original signaling pathway was associated with shorter OS (p=0.034) and was less effective than chemotherapy (median OS: 36 vs 45 months).
Conclusions:
- Combined targeted therapy and localized treatment strategies offer superior survival benefits over traditional chemotherapy for TKI-resistant NSCLC with secondary BRAF alterations.
- Continuing single-pathway targeted monotherapy should be avoided due to its diminished efficacy.
- These findings support personalized treatment approaches for NSCLC patients with acquired resistance mechanisms.
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