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Table of Contents
REVIEW ARTICLE: BIOMARKER SERIES
Year : 2021  |  Volume : 4  |  Issue : 2  |  Page : 328-334

BRAF in lung cancer: A narrative review


1 Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India
2 Department of Molecular Diagnostics, Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India

Date of Submission08-May-2021
Date of Decision28-May-2021
Date of Acceptance13-Jun-2021
Date of Web Publication30-Jun-2021

Correspondence Address:
Ullas Batra
Sector 5 Rohini, Sir Chhotu Ram Marg, New Delhi - 110 085
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CRST.CRST_85_21

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  Abstract 


Testing for the presence of oncogenic driver mutations in non-small-cell lung cancer (NSCLC) is a therapeutic mandate, and hence, in-depth knowledge of all the targetable biomarkers is essential. Apart from the well-known driver mutations in epidermal growth factor receptor, anaplastic lymphoma kinase, and ROS1, mutations in BRAF comprise an important molecular subtype of NSCLC, which is amenable to targeted therapy. In this review, we have described the molecular biology, detection methods, and various treatment modalities available for patients with NSCLC harboring BRAF mutations. We searched the PubMed, Embase, Scopus, and My Cancer Genome databases using the keywords, “BRAF,” “NSCLC,” “vemurafenib,” “dabrafenib,” and “trametinib.” A total of 44 articles were included in the review. Although targeted therapies have been successfully used in the management of advanced NSCLCs with BRAF mutations, it is necessary for clinicians to be mindful of the nuances of BRAF testing and interpretation of the results. Judicious use of BRAF inhibitors, either in the first or second line, can lead to improved survival in this subgroup of patients. In addition, immunotherapeutic agents may have a role in BRAF-mutant NSCLCs, in contrast to other oncogene-addicted NSCLCs where they are contraindicated.

Keywords: BRAF, dabrafenib, MEK, trametinib, vemurafenib, molecular, driver


How to cite this article:
Sharma M, Nathany S, Batra U. BRAF in lung cancer: A narrative review. Cancer Res Stat Treat 2021;4:328-34

How to cite this URL:
Sharma M, Nathany S, Batra U. BRAF in lung cancer: A narrative review. Cancer Res Stat Treat [serial online] 2021 [cited 2021 Jul 24];4:328-34. Available from: https://www.crstonline.com/text.asp?2021/4/2/328/320159




  Introduction Top


The identification of driver oncogenes amenable to targeted therapies has improved the survival and quality of life of patients with non-small-cell lung cancer (NSCLC). Mutations in the canonical oncogenic drivers, such as the epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase, and ROS1, have been studied extensively and are observed in almost 40% of the Asian patients with NSCLC.[1] Other targetable mutations for which testing is advocated by the National Comprehensive Cancer Network (NCCN) include the BRAF V600E mutation and alterations in the ERBB2, MET, RET, and NTRK[2] Although, these genes are altered in a relatively small proportion of patients with NSCLC, the availability of targeted therapies and the resultant improvement in the survival outcomes render testing for these mutations essential. With the success of anti-BRAF therapy in cancers like melanoma,[3] hairy cell leukemia, and papillary thyroid carcinoma, BRAF-mutant NSCLC has now emerged as a druggable entity.[4] Mutations in BRAF are seen in 0.8%–5% of the cases of NSCLC,[5] depending on the ethnicity and smoking status.[6] The most commonly reported BRAF alteration is a transversion at nucleotide 1799 (1799 T > A) that occurs in exon 15, resulting in the substitution of valine for glutamic acid at codon 600 (V600E). The V600E mutation is seen in about 50% of the cases with BRAF mutations,[6] and currently, approved drugs are available only for this mutation. Besides the V600E mutation, other substitutions as well as BRAF fusions also occur in patients with NSCLC, but can only be detected using broad panel-based testing methods.

This narrative review is focused on the molecular biology, oncogenesis, frequency distribution, detection methods, and treatment strategies for BRAF-mutant NSCLC.


  Methods Top


As this is a narrative review of the literature, a meta-analysis or systematic analysis of the data was not performed. No specific inclusion or exclusion criteria were considered when selecting the articles to be included in this review. The PubMed, Embase, Scopus, and My Cancer Genome databases were searched using the keywords, “BRAF,” “NSCLC,” “vemurafenib,” “dabrafenib,” and “trametinib.” A total of 44 articles were included in the review.


  Molecular Biology Top


BRAF is a serine/threonine-protein kinase involved in the MAPK pathway, resulting in cell growth, proliferation, differentiation, and survival.[7] The gene maps to the long arm of chromosome 7 and has 18 exons coding for 766 amino acids.[8] The BRAF protein has three conserved domains, including the RAS-binding domain and the kinase domain, which is critical for targeted therapy. A critical step in BRAF signaling is the dimerization/heterodimerization of the BRAF protein.[9] Under normal physiological conditions, in the presence of a wild-type BRAF protein, the BRAF signaling cascade is inhibited by a negative feedback mechanism. However, in the mutant BRAF (V600E) protein, the inhibitory glycine-rich P-loop in the conserved domain is disrupted, leading to the constitutive activation of the BRAF protein, resulting in continuous downstream signaling independent of ligand binding. This in turn leads to an increase in cell growth, proliferation, migration, and survival, ultimately resulting in oncogenesis.[7] A simplified schema of the BRAF signaling pathway is depicted in [Figure 1].
Figure 1: Normal and abnormal BRAF signaling

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  Spectrum of BRAF Alterations in Cancer Top


Mutations

Single-nucleotide variations (SNVs) are the most common type of alterations found in BRAF. More than 200 SNVs have been identified in this gene across various tumor types. These SNVs are classified into three categories depending on the kinase activity, RAS-dependence, and dimerization status of the mutant protein.[10] [Table 1] describes the various classes of mutations along with the differences in the clinicopathologic characteristics of the V600E and non-V600E mutations. However, evidence regarding the actionable potential of the non-V600E mutations still remains elusive.
Table 1: Functional classes and characteristics of BRAF mutations

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Fusions

Although the V600E is the most common targetable mutation, many fusions involving BRAF have also been reported. In a study of 20,573 different tumors, including hematolymphoid malignancies, BRAF fusions were reported in 55 (0.3%) tumors, with 29 different fusion partners.[11] Currently, there are more than 60 known fusion partners of BRAF;[12] the commonly occurring ones include KIAA1549, AGAP3, TRIM24, and CCDC6. Although these genes participate in in-frame kinase fusions with BRAF, the activity of the BRAF kinase inhibitors against these fusions is not very well known, owing to the rarity of their occurrence. In the MSK-IMPACT study[13] on 374 patients, 7 patients harbored a BRAF fusion. In another study by Schrock et al.,[12] BRAF fusions were seen in 10 out of 3505 cases of NSCLC, with AGAP3 as the most common 5' fusion partner. The various fusion partners of BRAF are listed in [Table 2]. Due to their low incidence, they may not be amenable to MAPK inhibition, and hence, further research is warranted to ascertain the response.
Table 2: Fusion partners of the BRAF gene described in nonsmall-cell lung cancer

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Copy Number Alterations

BRAF amplification (copy number gains) has also been reported in BRAF-mutant cancers, as a secondary resistance mechanism to BRAF-directed therapies.[4]


  BRAF Alterations as a Mechanism of Resistance Top


Although BRAF has emerged as a driver oncogene in NSCLC, BRAF alterations have also been reported as mechanisms of both intrinsic and acquired resistance in EGFR-mutant NSCLCs.[4] The BRAF V600E mutation has been described as a resistance mechanism in addition to the canonical T790M resistance mutation in EGFR. Ohashi et al.,[14] in their study on 195 patients with NSCLC, reported that two patients developed BRAF mutations and did not respond to EGFR tyrosine kinase inhibitors (TKIs). More recently, the presence of a V600E mutation in the circulating tumor DNA has also been reported to confer resistance to EGFR-TKIs in patients with NSCLC. However, whether the same is applicable to other oncogene-addicted tumors remains to be determined.


  Detection Methods Top


Several techniques have been developed and optimized for the detection of alterations in BRAF, especially the V600E mutation. Many platforms have been approved by the Food and Drug Administration (FDA) and designated as companion diagnostic tests for the detection of BRAF alterations. [Table 3] describes the various techniques that can be used for the detection of BRAF alterations, along with their approval status, indications, and test attributes.
Table 3: Comparison between the various diagnostic techniques available with their approval status for the detection of BRAF alterations

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  Clinical Aspects of BRAF-Mutant Tumors Top


Various retrospective studies have reported the clinicopathological characteristics of patients with the V600E and non-V600E mutations, as well as the differences between them. BRAF mutations are predominantly seen in smokers (former or current),[17] with the V600E mutation being more common among non-smoker women.[5] However, a study on Indian patients with lung cancers reported a female predilection for BRAF mutations irrespective of their type; all the patients were never-smokers with adenocarcinoma histology.[18] BRAF V600E mutations have also been associated with shorter median disease-free survival and overall survival (OS) in patients with radically resected NSCLC and those with a predominant aggressive micropapillary component.[19],[20] Other studies have reported lower response rates and shorter progression-free survival (PFS) with platinum-based chemotherapy in patients with advanced NSCLC harboring the V600E mutation compared to those harboring non-V600E mutations; however, the differences were not statistically significant.[21] In addition, patients with the V600E mutation tend to have worse survival than those with non-V600E mutations if targeted therapy is not used.[4],[21]


  BRAF Inhibitors Top


Several studies have evaluated the role of BRAF inhibitors, as single agents or in combination with MEK inhibitors, in the first-line setting and beyond.[4] Given the rarity of the mutation, randomized trials are not practically feasible, and most of the data have been derived from single-arm studies. An overview of BRAF inhibitors and their response outcomes is depicted in [Table 4].
Table 4: BRAF inhibitors and their survival outcomes and response rates

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  Vemurafenib Top


This is a potent BRAF inhibitor[23] approved for the treatment of V600E-mutant melanoma in 2011 based on the results of the BRIM-3 trial.[27] In a basket trial on 20 patients with NSCLC (NCT01524978),[22] an objective response rate of 42% and a median PFS of 7.2 months were reported. In yet another study by Mazieres et al.[23] in 100 patients with NSCLC, the objective response rate was 44.9% and median PFS and OS were 5.2 months and 9.3 months, respectively.


  Dabrafenib Top


This is a selective oral BRAF inhibitor, tested as a single agent in a Phase II multi-center trial on 84 patients with metastatic NSCLC (78 pretreated and 6 untreated).[24] An objective response rate of 33% was observed in the pretreated group, with a median PFS of 5.5 months. Some serious adverse events of Grade 3–5 were noted, but dabrafenib showed promise and was granted FDA approval on November 21, 2013, for use in V600E-mutant NSCLC in patients who have received at least one prior line of platinum-based chemotherapy. The most commonly reported adverse reactions include hyperkeratosis, headache, pyrexia, and joint pain.


  Combination of BRAF and MEK Inhibitors Top


The addition of a MEK inhibitor to a BRAF inhibitor prevents/delays the development of resistance to BRAF inhibitors by blocking the downstream ERK signaling, and also prevents the paradoxical MAPK activation in cells with wild-type BRAF, thus decreasing the incidence of drug-related cutaneous squamous cell carcinoma.[28] The superiority of the combination over single-agent BRAF inhibitors has already been proven in Phase III trials in advanced malignant melanomas.[29]

Planchard et al.[24] evaluated the role of dabrafenib plus trametinib in cohort B of a Phase II, non-randomized study on patients with pretreated metastatic BRAF V600E–mutant NSCLC. The objective response rate was 63.2%, and the investigator-assessed disease control rate was 78.9%. The investigator-assessed response was observed in 68.4% of the patients who had received 1 prior line of therapy and 52.6% in those who had received 2–3 prior lines of therapy. The median PFS was 9.7 months; 7 (12%) patients needed treatment discontinuation, 35 (61%) needed dose interruption/delay, and 20 (35%) subsequently needed a dose reduction due to adverse events. Cutaneous squamous cell carcinoma was observed in 2 (4%) patients. In an updated analysis reported in 2020,[25] after a median follow-up of 16.6 months, the median OS was 18.2 months. Durable responses were seen, with ongoing responses in half of the patients with confirmed responses at initial data cut-off, and nearly 33% of the patients had a 36-month OS at the time of final analysis.

The combination was also assessed in the first-line setting in the 36 patients from cohort C.[26] At a median follow-up of 15.9 months, the objective response rate was 64% and 2 (6%) patients achieved a complete response. The median duration of response was 10.4 months, and the median PFS was 10.9 months. The updated analysis showed a median OS of 17.3 months, with nearly 40% of the patients being alive at 36 months.

Although data regarding intracranial efficacy are scarce, case reports suggest some clinical benefits with the combination.[30],[31] Both the cohorts described above included only three patients with asymptomatic/treated stable brain metastases, which did not show intracranial progression during the treatment. Given the definite intracranial activity of the combination in patients with melanoma,[32] this appears to be an attractive option for brain metastases in BRAF-mutant NSCLCs as well. The commonly reported adverse events were pyrexia (Grade 3 in 11%), nausea, fatigue, diarrhea, and dry skin.


  Encorafenib and Binimetinib Top


Encorafenib is a newer generation BRAF inhibitor which acts on some key enzymes of the MAPK pathway and results in the downregulation of ERK phosphorylation. The efficacy of this drug is established in BRAF-mutant melanoma and metastatic colorectal cancer. An open-label, non-randomized, Phase II study is ongoing to define the role of encorafenib in combination with binimetinib in patients with BRAF-V600E-mutant metastatic NSCLC either in the first line or beyond. Notably, patients who have received first-line treatment with immunotherapy alone or in combination will also be included (NCT03915951).[33] The ENCO-BRAF trial is comparing the combination against docetaxel in the comparator arm (NCT04526782).[34]


  Lifirafenib Top


This is a reversible BRAF V600E inhibitor, that also inhibits ARAF and CRAF. Lifirafenib was studied in a Phase I, open-label trial on patients with RAS-mutant solid tumors, and demonstrated duration of response of 31.7 months. An ongoing Phase I/II study (NCT03905148)[35] of lifirafenib in combination with mirdametinib (MEK inhibitor) is aimed at exploring the effectiveness and safety of this combination in refractory/advanced solid tumors.


  Present Recommendations for Management Top


The NCCN[2] and other guidelines[36] recommend testing for the BRAF V600E mutation at the time of diagnosis in all patients with NSCLC with non-squamous or mixed histology. Dabrafenib and trametinib were approved by the FDA in June 2017 for use in advanced BRAF-V600E-mutant NSCLC. In view of the similar objective response rate, PFS, and OS, the combination can be given either in the first-line setting or later. These drugs are currently not recommended in patients with non-V600E mutations in light of the evidence showing no efficacy in this group.[37]


  Immunotherapy in BRAF-Mutant Non-Small Cell Lung Cancer Top


Dudnik et al.[38] assessed the programmed death-ligand 1 (PD-L1) expression in 39 patients with BRAF-mutant NSCLC. They reported higher levels of PD-L1 expression in patients with BRAF-mutant NSCLCs compared to the overall population of patients with NSCLCs, for both V600E and non-V600E mutations (tumor proportion score 50% and greater for both). A tumor mutational burden (TMB) of 20 muts/Mb was seen in 18% of the tumors, which was similar to that seen in unselected patients with NSCLC. No significant differences between the study groups in terms of TMB and microsatellite instability status were observed. Nearly 55% of the patients received immune checkpoint inhibitors (ICIs) at some point during the treatment and showed an improved OS as compared to those who did not receive immunotherapy. However, patients in the ICI group had better performance status, higher PD-L1 expression, and had received more lines of therapy. Neither the type of BRAF mutation nor the PD-L1 expression level affected the OS. A more recent study on 72 patients with BRAF-mutant NSCLC (31 patients with V600E mutation) also reported a response rate of 28.6% with ICIs.[39] The IMAD-2 study retrospectively evaluated the efficacy and safety of ICIs in 44 patients with BRAF-mutant NSCLC (26 patients with V600E and 18 with non-V600 mutations) and reported a response rate of 26% in those with V600E and 35% in those with non-V600E mutations. Only four patients had received immunotherapy in the first-line setting.[39] These data are in stark contrast with those for other oncogene-addicted lung cancers, where single-agent immunotherapy has a very limited role. Although these studies show some promise with respect to the activity of ICIs in BRAF-mutant lung cancers, their numbers are quite small, and the association between the smoking status, number of lines of therapy given, and type of BRAF mutation is yet to be determined.

Data regarding the sequence of immunotherapy in BRAF-mutant lung cancers are scarce. However, at present, the guidelines recommend the use of a BRAF inhibitor or systemic therapy including immunotherapy in the first line.[2] Indirect evidence, however, suggests better outcomes in patients who receive targeted therapy first.[38] These differences can be attributed to the differences in the immune microenvironment. However, more prospective data in larger patient populations and ongoing trials may shed more light on this.


  Resistance to BRAF Inhibitors Top


Despite the success of BRAF inhibitors such as vemurafenib, dabrafenib, and trametinib, with an objective response rate of almost 60%, about 50% of the patients develop disease progression which can be attributed to resistance mechanisms. Different mechanisms of resistance to BRAF inhibitors have been reported, including the expression of CRAF kinases by Montagut et al.[40] The majority of the resistance mechanisms have been reported from various studies conducted in patients with melanoma. These mechanisms include reactivation of ERK, which may result from BRAF amplifications seen in almost 13% of the cases, and BRAF splice alterations which have been reported in about 16% of the cases.[41] Secondary mutations in other molecules of the MAPK pathway, such as KRAS or NRAS, have also been reported to confer resistance in 20% of the cases. The activation of pathways that bypass MAPK has also been reported. Alterations may occur in the PI3K/AKT/PTEN pathway, leading to the bypass of MAPK, resulting in ineffective BRAF inhibition. Rudin et al.[42] reported a case of BRAF-mutant NSCLC, that progressed on dabrafenib, with new-onset KRAS, TP53, and CDKN2A mutations. Importantly, the mechanism of dual inhibitor therapy is more complex as compared to the mechanism of single agents. Although all these mechanisms have been described in anecdotal reports and preclinical studies, real-world evidence is still lacking because of the lack of routine clinical testing for BRAF alterations. The various resistance mechanisms to BRAF inhibitors are shown in [Figure 2].
Figure 2: Simplified schematic diagram showing potential resistance mechanisms to BRAF inhibitors (mechanisms are in lavender colored boxes)

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  Conclusion Top


This review highlights the progress made in the treatment of NSCLC due to the availability and usage of next-generation sequencing. BRAF-mutant NSCLC, although rare, is another entity where targeted therapies have been successfully incorporated in the management of advanced NSCLC. Clinicians should however be aware of the nuances of BRAF testing and the interpretation of results. Judicious use of BRAF inhibitors, either in the first or second line, can lead to improved survival in this subgroup of patients. In addition, immunotherapeutic agents may have a role in BRAF-mutant NSCLCs, in contrast to other oncogene-addicted NSCLCs where they are contraindicated.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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