A narrative review of the management of BRAF non-V600E mutated metastatic non-small cell lung cancer
Review Article

A narrative review of the management of BRAF non-V600E mutated metastatic non-small cell lung cancer

Inas Abuali1,2^, Chung-Shien Lee3,4^, Nagashree Seetharamu4^

1Division of Hematology and Oncology, Massachusetts General Hospital, Boston, MA, USA; 2Department of Medicine, Harvard Medical School, Boston, MA, USA; 3College of Pharmacy and Health Sciences, St. John’s University, New York, NY, USA; 4Division of Medical Oncology and Hematology, Northwell Health Cancer Institute, New York, NY, USA

Contributions: (I) Conception and design: All authors; (II) Administrative support: None; (III) Provision of study materials or patients: All authors; (IV) Collection and assembly of data: None; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

^ORCID: Chung-Shien Lee, 0000-0003-3505-6402; Inas Abuali, 0000-0001-9491-4716; Nagashree Seetharamu, 0000-0002-3282-7622.

Correspondence to: Nagashree Seetharamu, MD. Division of Medical Oncology and Hematology, Northwell Health Cancer Institute, New York, NY, USA. Email: nseetharamu@northwell.edu.

Background and Objective: V-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations occur in approximately 2–4% of patients with non-small cell lung cancer (NSCLC). BRAF non-V600E mutant NSCLC is a rare entity that has yet to be fully characterized. The treatment paradigm is evolving and is currently often extrapolated from data pertaining to V600E mutations. This article serves as a comprehensive review of the clinical characteristics, prognosis, current management and treatment algorthim for patients with NSCLC that harbors BRAF other than the common V600E mutation (non-V600E).

Methods: We performed a review of publications on EMBASE and MEDLINE/PubMed that described the prevalence and characteristic features of this patient subset of NSCLC, with a focus on the current treatment landscape, through October 2021. Non-English publications were excluded. We searched ClinicalTrials.gov for active and past trials pertaining to this patient subset.

Key Content and Findings: BRAF non-V600E mutant NSCLC occurs in females and smokers and is typically mutually exclusive with other driver mutations. Therapeutic choices are guided by extrapolating data from other malignancies and from BRAF-V600E mutant NSCLC. In the absence of any other driver mutations, NSCLC patients with BRAF non-V600E mutations should be treated with front line checkpoint immunotherapy with or without platinum-based chemotherapy. Early enrollment in clinical trials is recommended given the rare nature of this mutation without clear guidelines to steer clinical decisions. For patients who are unable to receive standard chemotherapy, or immunotherapy agents and are not able to participate in clinical trials, tyrosine kinase inhibitors of BRAF and MEK can be employed in some cases depending on the specific mutation and its position in the BRAF gene.

Conclusions: Given the rare nature of BRAF non-V600E mutant NSCLC, without clear guidelines, we offer this review with a proposed treatment algorithm to guide practicing clinicians in formulating evidence-based decisions.

Keywords: Non-small cell lung cancer (NSCLC); BRAF non-V600E mutations; targeted therapy; lung cancer

Received: 15 November 2021; Accepted: 12 April 2022; Published: 30 June 2022.

doi: 10.21037/pcm-21-49

Introduction

Lung cancer remains the leading cause of cancer-related deaths worldwide. In the United States, it accounts for a quarter of all deaths (1). The development of targeted therapy following the identification of the heterogenous molecular landscape of non-small cell lung cancer (NSCLC) has revolutionized the treatment paradigm over the past decade with the advent of precision medicine (2). For patients with metastatic NSCLC of the adenocarcinoma (ADC) subtype, molecular testing is performed to screen for actionable driver mutations, such as epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations, and Kirsten rat sarcoma viral oncogene (KRAS) and receptor tyrosine kinase (ROS1) translocations. Effective Food and Drug Administration (FDA) approved targeted therapies have dramatically prolonged the life expectancy of patients carrying those alterations. We present the following article in accordance with the Narrative Review reporting checklist (available at https://pcm.amegroups.com/article/view/10.21037/pcm-21-49/rc).

Methods

We searched EMBASE and MEDLINE/PubMed for English-language literature through October 2021 using the terms “non-small cell lung cancer”, “lung adenocarcinoma”, “BRAF-mutated”, “BRAF-V600E mutation”, “Non BRAF-V600E mutation”, “NSCLC”. All searches were conducted between August and October 2021.

This search was independently conducted by the first author I.A. Non-English publications were excluded.

We searched ClinicalTrials.gov for a list of active trials involving patients with BRAF mutations. This search was independently conducted by the second author C.L. Further systematic procedures are outlined in Table 1.

Table 1

Systematic search strategy

Items Specification
Date of search (specified to date, month and year) October 1st, 2021/January 22, 2022
Databases and other sources searched PubMed/Medline, EMBASE, ClinicalTrials.gov
Search terms used (including MeSH and free text search terms and filters) “non-small cell lung cancer”, “lung adenocarcinoma”, “BRAF-mutated”, “BRAF-V600E mutation”, “Non BRAF-V600E mutation”, “NSCLC”
Timeframe January 1, 2000 to January 22, 2022
Inclusion and exclusion criteria (study type, language
restrictions etc.)		 Excluded non-English publications
Selection process (who conducted the selection, whether it was conducted independently, how consensus was obtained, etc.) IA independently reviewed and selected studies from PubMed/Medline and EMBASE; CSL independently reviewed and selected trials from ClinicalTrials.gov

BRAF mutations in NSCLC

The V-raf murine sarcoma viral oncogene homolog B1 (BRAF) proto-oncogene belongs to the group of serine-threonine kinases which carries an essential role in the mitogen-activated protein kinase (MAPK) pathway (3). The oncogenic BRAF mutations, located on chromosome 7, have been detected in various cancers including melanoma, colorectal, lung and papillary thyroid cancers. These mutations have long been known to portend poorer prognosis in various tumor types. In a systematic review by (4), BRAF mutations increased the risk of mortality by 2.25 times for patients with colorectal cancer HR =2.25 (95% CI: 1.82–2.83), and by 1.7 times for patients with melanoma (95% CI: 1.37–2.12). Due to its lower frequency in patients with NSCLC, the clinical characteristics and prognostic implications are less defined with conflicting results in the literature.

BRAF mutations occur in approximately 2–4% of patients with NSCLC (5,6). There is a variability in the reported incidence according to the detection methodology employed. Immunohistochemistry (IHC) can screen for BRAF V600E mutations but is limited by the heterogeneity in tumor cells and limited amount of available tissue. Sanger sequencing is the gold standard in precision oncology, but is limited by its ability to only identify alterations with a frequency of 15–20%. Next generation sequencing (NGS) techniques on tissue yield a high sensitivity and acceptable specificity as compared to PCR-based Sanger sequencing. NGS on plasma cell-free DNA is an emerging tool due to rapidity and cost-effectiveness (7). A retrospective series by Marchetti et al. (8), evaluated the presence of BRAF mutations in 1,046 NSCLC patients, 739 of which were ADCs and 307 were squamous cell carcinomas (SCCs) and noted the presence of these genomic alterations in 3.5% of the tumors and in 4.9% of lung ADCs.

BRAF mutations are typically exclusive from other driver mutations. They are typically classified into three classes: class 1 mutations signal as RAS-independent active monomers (e.g., V600E); class 2 mutations are constitutively active RAS-independent dimers; and class 3 mutations have low/absent kinase activity (9). The most common BRAF mutation involves a glutamate substitution for valine at codon 600 (V600E) accounting for approximately 55% of BRAF mutations. The incidence of V600E mutations in ADCs in the study by Marchetti et al. was 2.8% (8). They found this to be more prevalent in females (about 9% in females with ADCs), but independent of smoking history. Tumors with this mutation were more aggressive and associated with poorer prognosis.

Forty-five percent of BRAF mutations in NSCLC are non-V600E, one of the many reported such as G469A (35%) or D594G (10%) (10). In contrast to V600E, non-V600E mutations are primarily found in smokers, earlier stages and do not seem to carry a prognostic implication.

While the pathogenic role of BRAF V600E and its targetable nature have been clearly established in many cancers including NSCLC, the rarer non-V600E mutations are still being evaluated for their role in cancer and novel therapeutics are being tested for tumors harboring these mutations in pre-clinical and clinical trial settings. One estimate suggests that lung cancers with a non-V600 BRAF mutation account for approximately 40,000 annual deaths worldwide (11).

Targeting BRAF mutations

The BRAF gene encodes a serine/threonine-protein kinase, which is a key regulator of cell growth and proliferation. The enzymatic kinase domain or the p-loop is located within amino acid residues 457 through 717 of the B-Raf protein. Residues 596–600 is a section within the kinase domain which interacts with the phosphate-binding loop keeping the kinase in a locked position. Upon phosphorylation of this activating loop, mitogen-activated 2 kinase 1 and 2 (MAP2K 1/2) signaling pathway gets triggered which in turn activates other proteins and ultimately results in cell proliferation. L597 and V600 residues specifically interact with other amino acids within the kinase domain to keep it inactive until it gets phosphorylated.

In the study by Tissot et al., the median overall survival (OS) of patients with BRAF V600E mutant NSCLC was longer than that of patients with NSCLC harboring a BRAF non-V600E mutation (25 vs. 13 months, respectively, P=0.153) (12). The OS of stage IV V600E-mutated-patients was also longer than the non-V600E, but this was not statistically significant (16 vs. 7 months, P=0.272). Of note, in this study population concurrent KRAS mutations were found among five out of 38 patients carrying BRAF non-V600E mutations. This contrasts with BRAF-V600E mutations that were mutually exclusive of all other driver mutations. This has been hypothesized to lead to resistance to targeted therapies such as dabrafenib, since BRAF inhibition in this case can lead to a feedback loop that activates RAS (13,14).

For metastatic NSCLC with BRAF V600E mutations, targeted therapy is preferred as the first-line systemic option, as a combination of dabrafenib (RAF-inhibitor) and trametinib (MEK-inhibitor). An FDA approval and designation of those drugs as Orphan Drugs for the treatment of this specific subset of patients was granted in October 2015 based on the phase II study NCT01336634, for previously treated patients (3), and for treatment naïve patients (4). Subsequently the FDA in 2017 granted regular approval for Dabrafenib and Trametinib combination for metastatic NSCLC with BRAF V600E mutation (15,16). For those patients with PD-L1 >50%: immunotherapy vs targeted therapy vs immunotherapy and chemotherapy combination are all FDA-approved options. Expert opinion still favors that the initial treatment of BRAF V600E mutant NSCLC with high PDL1 expression is targeted therapy given durable efficacy and good response rates of immunotherapy in the second line (17).

There is less data to guide the management of BRAF non-V600E, however. Management decisions are often guided by extrapolating from studies that focused on other malignancies or studies that predominantly included V600E mutations with few non-V600E patients.

Targeted therapy

Theoretically, many non-V600 BRAF mutations are kinase-impaired and thus considered unattractive for RAF-targeted therapy. A study by Gautschi et al. examined 35 NSCLC BRAF mutant patients. Only six were non-V600E (G466V, G469A, G469L, G596V, V600K, and K601E) (18). One patient had a co-occurring driver mutation, which was KRAS V12 together with BRAF V600K. Another patient had concomitant HER2 amplification with BRAF V600E. No co-occurring alterations of EGFR, ALK, MET, RET, or ROS1 were reported. From the non-V600E group: only the patient with G596V had partial response with vemurafenib monotherapy.

However, a study by Noeparast et al., investigated a patient cohort of NSCLC and demonstrated that non-V600 BRAF mutations, resulting in either high or impaired kinase activity, confer sensitivity to combined dabrafenib and trametinib treatment (19).

In trying to understand the specific molecular pathways that compromise non-V600E mutations, consideration can be given to other TKIs not specifically targeting BRAF as an area for future research. For example, sorafenib, an agent with multiple targets that blocks the activation of C-RAF, B-RAF, c-KIT, FLT-3, RET, VEGFR-2, VEGFR-3 and platelet-derived growth factor receptor demonstrated a benefit in one patient A case report of a 56-year-old woman with NSCLC and the BRAF G469R mutation was reported by Sereno et al. (20). This patient was heavily pretreated with seven lines of therapy and demonstrated a rapid (within 10 days) and durable six months response to sorafenib. A somatic mutation, ARAF S214C, was expressed at high levels and was felt to be an indicator of a sorafenib response.

There is also translational data demonstrating a supportive mechanism of action for dasatinib in kinase-inactivating non-V600E BRAF mutations (21).

The role of checkpoint inhibitors

Dudnik et al. investigated the association between BRAF mutations and PD-L1 expression in 39 patients with NSCLC (22). In their population, a high rate of PD-L1 expression was noted in 42–50% without a statistically significant difference between BRAF V600E and non-V600E mutant patients. While utilization of immune checkpoint inhibitors (ICIs) is often controversial in patients with driver-mutations, ICI therapy in their study group was associated with an objective response rate (ORR) of 25% to 33% and a median progression free survival (PFS) of 3.7 to 4.1 months, which was comparable to results observed in NSCLC patients receiving ICI in the second line setting. It was noted that neither the BRAF mutation subtype nor the PD-L1 expression level affected OS. While the study had design limitation such as only 74% of patients underwent PD-L1 testing, 30% only were assessed for MSI status and TMB and only 56% were treated with ICIs, the authors concluded that BRAF mutant NSCLC is associated with a high level of PD-L1 expression, low/intermediate TMB and MS-stable status with ICIs carrying a favorable activating against both BRAF V600E and BRAF non-V600E mutant NSCLC.

In another study by Guisier et al., anti-PD-1 efficacy was assessed in 107 patients, of which 18 patients harbored a BRAF non-V600E mutation (23). This was utilized in the second line setting onwards for 94% of this patient cohort. Response rate was 35% and the duration of response was not reached. While limited by the small numbers of this retrospective study, it was noted that the patients with BRAF non-V600E are prone to respond slightly better to immune checkpoint inhibitors (ICIs) than the patients with BRAF V600E (35% response rate vs. 26% respectively) (23).

Further studies are warranted to further confirm these findings. It is hypothesized that the efficacy of ICI in BRAF-mutated NSCLC is likely due to smoking status which is associated with a higher PD-L1 expression and possibly higher mutational burdens.

The role of chemotherapy

Prior to the advent of targeted therapy, traditional platinum-based combination chemotherapy was employed for management of BRAF-mutated NSCLC. In the study by Cardarella et al. published in 2013, the median PFS of patients with BRAF-mutant advanced NSCLC treated with platinum-based combination chemotherapy was 5.2 months compared with 6.7 months for wild-type patients (P=0.622) (24). Within the BRAF cohort, the median PFS was shorter in patients with V600E mutations compared with non-V600E mutations but did not reach statistical significance (4.1 vs. 8.9 months; P=0.297).

In this era of personalized lung cancer therapies, chemotherapy is often reserved for the salvage setting following disease progression on targeted and immune therapies.

Future directions

A current area of research is identification of mechanisms of resistance to targeted therapies that eventually arise (2). For V600E-mutant NSCLC, two mechanisms have emerged: (I) loss of full-length BRAF V600E in concert with expression of a truncated form of the mutant protein or (II) enhanced EGFR signaling through autocrine activation induced through BRAF-independent c-Jun signaling. Second generation BRAF inhibitors such as PLX8394 or using a combination of BRAF and MEK inhibition have been shown to prevent resistance medication through expression of a BRAF V600E splice variant (11).

Mechanisms of resistance for BRAF non-V600E mutations are yet to be elucidated and further research is warranted to determine appropriate strategies to overcome development of resistance and to guide appropriate sequencing of therapy. Table 2 summarizes ongoing trials in this population (25-30).

Table 2

Ongoing and future clinical trials for BRAF non-V600 mutated tumors

Protocol name Phase Patient population Treatment regimen Target sample size (n) Primary outcomes Secondary outcomes
NCT02428712 (25) I/IIA Advanced solid tumors who are refractory to, relapsed after, or intolerant to standard therapy or for whom no standard therapy exists; cohort 2: BRAF non-V600 mutations PLX8394 100 PK, safety DOR, PFS, ORR
NCT03091257 (26) I MM patients who relapsed on ≥2 lines of therapy with a BRAF mutation, including non-V600 mutations Dabrafenib + trametinib 60 ORR Safety
NCT03843775 (27) I/II Metastatic or advanced solid tumor whom no standard therapy is considered to be appropriate confirmed histologically for a BRAF non-V600 mutation Binimetinib + encorafenib 38 Safety, ORR
NCT04488003 (28) II Locally advanced or metastatic malignancy that has progressed following systemic therapy for which the patient is not a candidate for further treatment; group 3 and 4: BRAF non-V600 mutations Ulixertinib 528 ORR, PFS DOR, OS, PK
NCT04249843 (29) I Advanced or metastatic solid tumor who have experienced disease progression on ≥1 prior systemic therapy; group 1: BRAF non-V600 mutations BGB-3245 69 Safety, ORR DOR, PFS, PK
NCT04439279 (MATCH Treatment Subprotocol R) (30) II Advanced refractory solid tumors, lymphomas, or MM with BRAF non-V600 mutations Trametinib 35 ORR PFS
NCT04566393 (31) EA Solid tumor with a MAPK pathway-alteration, including but not limited to KRAS, NRAS, HRAS, BRAF, MEK, and ERK mutations Ulixertinib (BVD-523) N/A N/A N/A
NCT03049618 (32) IIA Locally advanced or metastatic NSCLC or squamous cell carcinoma of the head and neck that has progressed ≥1 line of platinum-based chemotherapy Recombinant EphB4-HSA fusion protein + pembrolizumab 42 ORR DOR, Safety, OS, PFS
NCT03989115 (33) IB/II Relapsed or refractory solid tumors OR EGFR+ locally advanced or metastatic NSCLC RMC-4630 + cobimetinib OR RMC-4630 + osimertinib 168 Safety PK, ORR, DOR
NCT04913285 (34) I/IB Metastatic or advanced solid tumor with BRAF OR melanoma NRAS mutation KIN-2787 ± binimetinib 155 Safety, PK, ORR, DOR Additional PK
NCT03284502 (35) IB Locally advanced or metastatic solid tumors with RAS or RAF mutation HM95573 + cobimetinib or cetuximab 140 Safety PK
NCT02974725 (36) IB Advanced or metastatic KRAS or BRAF mutated NSCLC or NRAS mutated melanoma LXH254 + LTT462 or trametinib or ribociclib 331 Safety ORR, DOR, DCR, PFS, OS, PK
NCT02857270 (37) I Advanced or metastatic cancer with an activating MAPK pathway alteration: BRAF mutated metastatic melanoma refractory to or relapsed after treatment with RAF and/or MEK inhibitors OR
metastatic melanoma with a NRAS mutation OR BRAF mutated NSCLC		 LY3214996 245 Safety PK, ORR, DOR, PFS, DCR, OS
NCT04892017 (38) I Advanced or metastatic solid tumors with RAS or RAF mutations DCC-3116 ± trametinib 130 Safety, ORR DPR, PFS, PK
NCT03721120 (LIBELULE) (39) III Treatment naïve locally advanced or metastatic NSCLC Liquid biopsy mutational analysis 286 TTI Rate of treatment, PFS, QOL

DCR, disease control rate; DOR, duration of response; EA, expanded access; MM, multiple myeloma; NSCLC, non-small cell lung cancer; ORR, objective response rate; OS, overall survival; PK, pharmacodynamics; PFS, progression-free survival; QOL, quality of life; TTI, time-to-appropriate treatment initiation.

Most clinical trials are focused on BRAF V600E mutant NSCLC. Several phase I clinical trials, however, are open to include all forms of BRAF mutations in NSCLC and are investigating new targeted therapies.

Conclusions

BRAF non-V600E mutant NSCLC is a rare entity that has yet to be fully characterized. It often occurs in females and smokers and is typically mutually exclusive with other driver mutations.

In the absence of any other driver mutations, NSCLC patients with BRAF non-V600E mutations should be treated with front line checkpoint immunotherapy with or without platinum-based chemotherapy. Early enrollment in clinical trials is recommended given the rare nature of this mutation without clear guidelines to steer clinical decisions. For patients who are unable to receive standard chemotherapy, or immunotherapy agents and are not able to participate in clinical trials, tyrosine kinase inhibitors of BRAF and MEK can be employed in some cases depending on the specific mutation and its position in the BRAF gene.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://pcm.amegroups.com/article/view/10.21037/pcm-21-49/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://pcm.amegroups.com/article/view/10.21037/pcm-21-49/coif). NS serves as an unpaid editorial board member of Precision Cancer Medicine from September 2020 to August 2022. NS reports consulting fee from Boehringer Ingram. She has been on scientific advisory board for AstraZeneca, Amgen, Takeda, Genentech, Regeneron, and Pfizer within the last 36 months. None of these have any impact on the manuscript. The other authors have no conflicts of interest to declare.

Ethical Statement:The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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doi: 10.21037/pcm-21-49
Cite this article as: Abuali I, Lee CS, Seetharamu N. A narrative review of the management of BRAF non-V600E mutated metastatic non-small cell lung cancer. Precis Cancer Med 2022;5:13.

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