Encorafenib and binimetinib as a new regimen for BRAF mutant non-small cell lung cancer

Introduction

Thanks to the development of molecular targeted therapy in recent years, the prognosis of non-small cell lung cancer (NSCLC) patients has significantly improved. V-raf murine sarcoma viral oncogene (RAF) homolog B1 (BRAF) gene mutant lung cancer (referred to as BRAF lung cancer) accounts for 1–2% frequency in NSCLC, with more than half of the cases being observed in smokers (1,2). Histopathological findings show that the majority are adenocarcinomas, often exhibiting papillary or micropapillary growth patterns, as reported (1). Since non-V600 mutations are predominant among BRAF gene mutations (3), the frequency of V600E mutations is extremely low, approximately 1%, in non-squamous NSCLC, significantly lower compared to the frequencies observed in malignant melanoma and papillary thyroid cancer (4,5). RAF is one of the serine/threonine kinases and is a component of the RAS/RAF/MEK/ERK pathway (MAPK pathway). There are three subtypes: ARAF, BRAF, and CRAF. These subtypes form homo- or hetero-dimers, activating downstream molecules and contributing to cell differentiation and proliferation (6). BRAF gene mutations frequently occur within the activation loop composed of codons 599–602 or the phosphate binding loop composed of codons 464–469. In 2005, the V600E mutation located in exon 15 of the activation loop was demonstrated to confer cell proliferation and tumorigenicity using immunodeficient mice (7). A BRAF protein with a V600E mutation in the kinase domain has an approximately 500-fold increase in kinase activity compared to the wild-type (8), phosphorylates and activates MEK as a monomer, and constitutively activates the MAPK pathway, resulting in sustained activation of the MAPK pathway and stimulation of aberrant cell proliferation (9). Combination therapy using the BRAF kinase inhibitor dabrafenib and the MEK inhibitor trametinib is currently available for this patient population with BRAF lung cancer (10). Recently, Riely et al. have presented the results of a single-arm phase II trial (PHAROS trial) involving the BRAF kinase inhibitor encorafenib and the MEK inhibitor binimetinib (11). According to their research findings, it is anticipated that the combination therapy of encorafenib plus binimetinib will become available for clinical use in the BRAF^V600E-mutant NSCLC patients. The choice between the combination therapy of dabrafenib plus trametinib or the combination therapy of encorafenib plus binimetinib is expected to become a significant clinical question with implications for treatment decisions.

Dabrafenib plus trametinib versus encorafenib plus binimetinib

The combination therapy of dabrafenib plus trametinib was initially developed for malignant melanoma and was investigated in two single-arm phase II trials targeting BRAF^V600E-mutant NSCLC patients (12,13). In the cohort targeting previously treated cases (n=57), the combination therapy of dabrafenib plus trametinib showed an overall response rate of 63.2% and a median progression-free survival (PFS) of 9.7 months [95% confidence interval (CI): 6.9 to 19.6 months] (12). In the cohort targeting treatment-naïve cases (n=36), the therapy showed an overall response rate of 64% and a median PFS of 10.9 months (95% CI: 7.0 to 16.6 months), indicating favorable outcomes (13). These phase II trials have established the effectiveness of this combination therapy in NSCLC patients with the BRAF^V600E gene mutation. In the report of previously treated cases, adverse events of any grade with dabrafenib plus trametinib combination therapy were observed in 98% of patients and adverse events of grade 3 or higher were observed in 49% of patients (12). The most frequently occurring adverse events of any grade included fever (46%), nausea (40%), vomiting (35%), diarrhea (33%), fatigue (32%), and decreased appetite (30%). Common adverse events of grade 3 or 4 were neutropenia (9%), hyponatremia (7%), and anemia (5%). In the reports of untreated cases, adverse events of any grade occurred in 100% of patients and adverse events of grade 3 or higher occurred in 69% of patients (13). Common adverse events of any grade were fever (64%), nausea (56%), diarrhea (36%), fatigue (36%), peripheral edema (36%), vomiting (33%), dry skin (33%) and decreased appetite (33%). Common adverse events of grade 3–4 were fever (11%), increased alanine aminotransferase (11%), hypertension (11%), and vomiting (8%).

A phase II study by Riely et al. demonstrated the efficacy of encorafenib plus binimetinib in a treatment-naïve (n=59) and previously treated cohort (n=39) of BRAF^V600E-mutant NSCLC (11). Patients who had prior treatment with a BRAF or MEK inhibitor, other driver alterations [e.g., epidermal growth factor receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK) rearrangement, or ROS proto-oncogene 1 (ROS1) rearrangement], untreated symptomatic brain metastasis, or leptomeningeal disease were excluded in this trial. Median treatment duration was 9.2 months for encorafenib and 8.4 months for binimetinib. The objective response rate (ORR) by independent radiology review was 75% (95% CI: 62% to 85%) in treatment-naïve patients and 46% (95% CI: 30% to 63%) in previously treated patients. The median duration of response (DOR) was not estimable (95% CI: 23.1 to NE) and 16.7 months (95% CI: 7.4 to NE), respectively. The disease control rate after 24 weeks was 64% in treatment-naïve patients and 41% in previously treated patients. Median PFS was NE (95% CI: 15.7 to NE) in treatment-naïve patients and 9.3 months in previously treated patients (95% CI: 6.2 to NE). The most common treatment-related adverse events (TRAEs) were nausea (50%), diarrhea (43%), and fatigue (32%). Taken together, the combination of encorafenib and binimetinib demonstrated clinical benefit with an acceptable safety profile.

On the other hand, the efficacy trial results of dabrafenib plus trametinib and encorafenib plus binimetinib include significant potential biases due to factors such as the small number of patients, wide 95% confidence intervals in efficacy assessments, variations in follow-up periods across different trials, and the absence of a control arm (11-13). Furthermore, considering the dissociation half-lives and IC50 of dabrafenib, trametinib, encorafenib, and binimetinib, it is theoretically challenging to explain the differences in pharmacokinetics for the BRAF^V600E protein between the two regimens, as both dosing levels and intervals appear appropriate for both regimens (14-17). Moreover, in cohorts of previously treated patients, the nature of prior treatments (namely, immunotherapy, immunotherapy plus chemotherapy, and chemotherapy alone) is heterogeneous, thus complicating the analysis among cohorts. In fact, due to the recent approval of programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) inhibitors and their increasing use in first-line therapy, the PHAROS trial includes approximately 60% of patients previously treated with first-line immunotherapy (as opposed to only a few with dabrafenib plus trametinib). Moreover, in melanoma, decreased efficacy of combined BRAF and MEK inhibition has been reported in the post-PD-1 setting (18).

In this context, looking at adverse event incidence and tolerability, the most notable difference is the incidence of fever. Fever rate was 22% in adverse events of any grade with encorafenib plus binimetinib, significantly lower than with dabrafenib plus trametinib. Furthermore, regarding blurred vision, there is no mention of it in the combination therapy of dabrafenib plus trametinib. In the case of encorafenib plus binimetinib, it was observed in 17% of patients. Therefore, it is considered a specific adverse event of the latter and clinicians need to be cautious in monitoring adverse events. Adverse events of grade 3 or higher observed with encorafenib plus binimetinib occur at a rate of 41%, which is numerically lower than that observed with the combination of dabrafenib plus trametinib. However, these evaluations of dose tolerability were conducted in different patient populations at different time points. Thus, they may not necessarily apply to a broader patient population in routine clinical practice.

In the end, due to the uncertainties in comparing across trials, it’s not possible to determine whether one combination therapy has superior efficacy and safety over the other. However, in the phase II trial of dabrafenib plus trametinib, the ORR was similar between treatment-naïve patients and those with prior treatment (12,13). The similarity in response rates between first-line and second-line treatments differs from the observations in the PHAROS trial. The high ORR observed with encorafenib plus binimetinib combination therapy in the treatment-naïve group suggests that patients with BRAF V600-mutant metastatic NSCLC should consider this combination therapy as a first-line treatment (11) and that the treating physician should begin by searching for BRAF gene mutations before initiating a first-line therapy.

Considering the sample size of the PHAROS trial, the biomarker analyses conducted should be regarded as exploratory. In this study, the BRAF^V600E mutation was identified using a targeted Next-Generation Sequencing panel, concurrent mutations were identified, and predictive factors for the efficacy of encorafenib plus binimetinib were explored (11). Patients’ lung cancers concurrently harbored baseline mutations in several genes, with SETD2, TP53, and SMAD4 mutations being the most frequent. However, these mutations were not significantly correlated with treatment response. Given the rarity of BRAF^V600E-mutant NSCLC and the heterogeneity of concurrent mutations (19), further investigation into the role of concurrent mutations as biomarkers would require enrolling a larger patient cohort. Clinically, there are two treatment options for this patient group, and both should be considered as viable treatment choices at present. Due to the rarity of BRAF-mutated lung cancer and the difficulties of the study design, a phase III trial comparing the two combination therapies is unlikely to be conducted. In the future, we can hope for the implementation of large-scale registry studies. Furthermore, in the treatment-naïve cohort receiving encorafenib and binimetinib in the PHAROS trial, there is a potential for long-term DOR and PFS, which are currently not estimable (11). As these factors are crucial for clinicians to determine the treatment approach, it is advisable to await additional reports from long-term cohort follow-up to make informed decisions.

Future challenges for BRAF lung cancer

The potential application of BRAF inhibitors in the adjuvant setting or neo-adjuvant setting for BRAF^V600E-mutant NSCLC remains to be investigated. It is known that gatekeeper mutations, similar to those occurring with EGFR-TKIs or ALK inhibitors, are not observed as mechanisms of resistance to BRAF inhibitors. Given the remarkable efficacy demonstrated by osimertinib in the ADAURA trial and in consideration of this (20,21), it is deemed worthwhile to investigate. Due to the absence of gatekeeper mutations, the effectiveness of BRAF inhibitor rechallenge is also anticipated. Considering the sequence of immune checkpoint inhibitors’ usage, obtaining an answer regarding the most effective “timing” and “duration” for administering BRAF inhibitors is not straightforward at the current moment. Further investigation is needed in the future to address this question.

On the other hand, in lung cancer, non-V600 BRAF mutations occur more frequently than V600 BRAF mutations, underscoring the significance of targeted therapies aimed at these mutations as well. Existing BRAF inhibitors strongly target BRAF monomers with V600 mutations (Class I mutations), but they are unable to inhibit the dimerization of BRAF caused by non-V600 mutations (Class II/III mutations). Therefore, the development of novel agents with a new mechanism is anticipated.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

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