Efficacy of immune checkpoint inhibitors in advanced non-small cell lung cancer harboring BRAF mutations

Wang, Haowei; Cheng, Lei; Zhao, Chao; Zhou, Fei; Jiang, Tao; Guo, Haoyue; Shi, Jinpeng; Chen, Peixin; Tang, Zhonghai; Mao, Shiqi; Jia, Keyi; Ye, Lingyun; Cai, Chenlei; Li, Xuefei; Chen, Xiaoxia; Zhou, Cai-cun

doi:10.21037/tlcr-22-613

Cited by 6 publications

(4 citation statements)

References 43 publications

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“…In a phase 3 trial of treatment-naive patients with metastatic non-squamous NSCLC, the combination of pembrolizumab, pemetrexed, and a platinum resulted in significantly longer median PFS compared with chemotherapy alone (8.8 versus 4.9 months; HR = 0.52; P < 0.001) 81 . In a small retrospective study in China, immunotherapy plus chemotherapy ( n = 9) in treatment-naive patients with BRAF V600E -mutant advanced NSCLC resulted in a significantly longer median PFS compared with chemotherapy or targeted therapy ( n = 20; 18.5 versus 4.1 months; P = 0.0098) 82 . This efficacy benefit with immunochemotherapy was not observed in later lines.…”

Section: Treatment Landscapementioning

confidence: 97%

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BRAFV600E-mutant metastatic NSCLC: disease overview and treatment landscape

Planchard,

Sanborn,

Negrao

et al. 2024

npj Precis. Onc.

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In this review, we cover the current understanding of BRAF mutations and associated clinical characteristics in patients with metastatic NSCLC, approved and emerging treatment options, BRAF sequencing approaches, and unmet needs. The BRAFV600E mutation confers constitutive activity of the MAPK pathway, leading to enhanced growth, proliferation, and survival of tumor cells. Testing for BRAF mutations enables patients to be treated with therapies that directly target BRAFV600E and the MAPK pathway, but BRAF testing lags behind other oncogene testing in metastatic NSCLC. Additional therapies targeting BRAFV600E mutations provide options for patients with metastatic NSCLC. Emerging therapies and combinations under investigation could potentially overcome issues of resistance and target non-V600E mutations. Therefore, because targeted therapies with enhanced efficacy are on the horizon, being able to identify BRAF mutations in metastatic NSCLC may become even more important.

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Section: Treatment Landscapementioning

confidence: 97%

“…Median PFS was longer in the first line than in subsequent treatment lines in patients with WT (12.8 versus 5.6 months) and BRAF-mutant (11.2 versus 4.0 months) NSCLC. These studies suggest that immunotherapy-based treatments are an option for patients with BRAF V600E -mutant advanced NSCLC 82 , 83 .…”

Section: Treatment Landscapementioning

confidence: 97%

BRAFV600E-mutant metastatic NSCLC: disease overview and treatment landscape

Planchard,

Sanborn,

Negrao

et al. 2024

npj Precis. Onc.

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“…A similar combination of drugs was used to treat patients with advanced BRAF-mutant non-small cell lung cancer. Relapse-free survival in patients receiving a combination of an immune checkpoint inhibitor and targeted therapy was better than in those receiving targeted therapy alone (18.5 vs. 4.1 months, respectively) (Wang et al, 2023).…”

Section: Combining Immune Checkpoint Inhibitors With Targeted Therapymentioning

confidence: 94%

Biological mechanisms of resistance to immune checkpoint inhibitors and overcoming this resistance: Challenges in medical oncology

Moskalenko

2024

Regul. Mech. Biosyst.

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Immune checkpoint inhibitors have opened up new possibilities in clinical oncology. Monoclonal antibodies have shown their high clinical efficiency. They block CTLA-4, PD-1, and PD-L1 receptors and activate the immune response. Many patients have stable and even complete responses. However, some patients have primary or acquired resistance. Therefore, the treatment results in this category of patients are not predictable. Mechanisms of resistance to immune checkpoint inhibitors have not been definitively studied. Many theories try to explain the mechanisms of this phenomenon. Our study aimed to structure and combine the data into groups depending on the etiological factor that reduces the immune response. In addition, based on understanding the mechanisms of resistance and the results of recent clinical studies, we aimed to identify the main ways to overcome it. Therefore, mechanisms that lead to resistance may be associated with tumor properties, tumor microenvironment, or patient characteristics. Tumor properties that reduce the immune response include a) low tumor mutation burden and loss of tumor neoantigens, b) changes in the processing or presentation of neoantigens, and c) changes in signaling pathways of tumor development and epigenetic modifications in genes. The tumor microenvironment is represented by stromal and immune cells, extracellular matrix, cytokines, and blood vessels. Each structure can enhance or reduce the immune response and contribute to the acquired resistance to immune checkpoint inhibitors. The effectiveness of the treatment depends not only on the cells in the tumor microenvironment but also on the metabolic background. In addition, the basic characteristics of the patient ( gender, gut microbiota, HLA-I genotype) can modify the immune response. Based on knowledge about the mechanisms of resistance to immune checkpoint inhibitors, several therapeutic strategies aimed at activating antitumor activity have been evaluated. All of them are based on combining immune checkpoint inhibitors with other drugs. One of the most common options is a combination of PD-1/PD-L1 and CTLA-4 inhibitors. Alternative immune checkpoints are TIM-3, LAG-3, TIGIT and VISTA. Combining immunotherapy with chemotherapy, targeted therapy, neoangiogenesis inhibitors, epigenetic modifiers, PARP or TGF-β inhibitors enhances antitumor response by preventing depletion of effector T cells, enhancing T cell infiltration in the tumor, changes on the tumor microenvironment, and decreasing the accumulation of immunosuppressive cells. This review explores the biological mechanisms of resistance and potential ways of solving this problem.

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“…In contrast, Gibson et al observed higher PD-L1 expression in V600E (60% of cases) than in non-V600E (39% of cases), but again with no statistical significance (p = 0.27) [39]. Independently from PD-L1 expression, recent reports have underlined the important use of immune checkpoint inhibitors in BRAF-mutated NCSLCs, with a limited distinction between V600E and non-V600E [40].…”

mentioning

confidence: 92%

Clinicopathological Features of Non-Small Cell Lung Carcinoma with BRAF Mutation

Ambrosini-Spaltro,

Rengucci,

Capelli

et al. 2023

Current Oncology

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(1) Background: BRAF mutations affect 4–5% of lung adenocarcinomas. This study aimed to analyze the clinicopathological features of lung carcinomas with BRAF mutations, focusing on V600E vs. non-V600E and the presence of co-mutations. (2) Methods: All BRAF-mutated lung carcinomas were retrieved from a molecular diagnostic unit (the reference unit for four different hospitals). The samples were analyzed using next-generation sequencing. Statistical analyses included log-rank tests for overall survival (OS) and progression-free survival (PFS). (3) Results: In total, 60 BRAF-mutated lung carcinomas were retrieved: 24 (40.0%) with V600E and 36 (60.0%) with non-V600E mutations, and 21 (35.0%) with other co-mutations and 39 (65.0%) with only BRAF mutations. Survival data were available for 54/60 (90.0%) cases. Targeted therapy was documented in 11 cases. Patients with V600E mutations exhibited a better prognosis than patients with non-V600E mutations (p = 0.008 for OS, p = 0.018 for PFS); this was confirmed in PFS (p = 0.036) when considering only patients who received no targeted therapy. Patients with co-mutations displayed no prognostic difference compared to patients carrying only BRAF mutations (p = 0.590 for OS, p = 0.938 for PFS). (4) Conclusions: BRAF-mutated lung carcinomas with V600E (40.0%) had a better prognosis than those without V600E. Concomitant co-mutations (35.0%) did not affect the prognosis.

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Efficacy of immune checkpoint inhibitors in advanced non-small cell lung cancer harboring BRAF mutations

Cited by 6 publications

References 43 publications

BRAFV600E-mutant metastatic NSCLC: disease overview and treatment landscape

BRAFV600E-mutant metastatic NSCLC: disease overview and treatment landscape

Biological mechanisms of resistance to immune checkpoint inhibitors and overcoming this resistance: Challenges in medical oncology

Clinicopathological Features of Non-Small Cell Lung Carcinoma with BRAF Mutation

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