Celebrating a breakthrough: FDA endorses encorafenib plus binimetinib alongside two companion diagnostics for BRAV600E mutant metastatic non-small cell lung cancer
Authors: Haleema Qayyum Abbasi, Malik Olatunde Oduoye, Aman Goyal
Journal: International Journal of Surgery (2024)

Lung cancer, one of the most prevalent types of cancer and the leading cause of oncological fatalities not only in the United States but also worldwide, claimed over 150 000 lives in the United States in 20181. It is categorized into two types: small-cell lung cancer and non-small cell lung cancer. Non-small cell lung cancer (NSCLC) constitutes 85% of all lung cancer cases and is classified as adenocarcinoma, squamous cell carcinoma, or large cell carcinoma2. More than half of patients with NSCLC usually present at an advanced stage when the disease has already progressed beyond the lungs (distant metastasis). The chances of surviving stage IVA metastatic NSCLC over a 5-year period are ~10%, while for stage IVB, the survival rate is less than 1%, making it a significant global health concern1. The aim of this article is to improve the knowledge of the general public on the recently endorsed encorafenib plus binimetinib, along two companion diagnostics, for BRAFV600E mutant metastatic NSCLC. Although rare (only 2–4%), NSCLC patients have mutations in the BRAF gene, most commonly a point mutation in codon 6003. Approximately half of these mutations are BRAFV600E. More common in females, those with a history of smoking, and in adenocarcinoma cases, activating mutations in BRAF result in sustained signaling in the MAK pathway, which is normally suppressed by negative feedback, leading to unregulated cell division and oncogenesis4. BRAFV600E mutated metastatic NSCLC is not only associated with poor prognosis but is also less responsive to chemotherapy and radiotherapy. Nonetheless, platinum-based chemotherapy was the treatment of choice until the encouraging results of the phase II trial (NCT01336634) led to the approval of dabrafenib in combination with trametinib as the standard of care for these patients5,6. Although this combination therapy is widely endorsed, it poses challenges, including short dissociation half-life (2 h for dabrafenib) and serious side effects, of which pyrexia is the most common, followed by hypertension and disturbed hepatic enzyme levels, necessitating the review of current treatment modalities and efforts for novel approaches offering improved results7. On 11 October, the United States Food and Drug Administration (FDA) approved encorafenib plus binimetinib as a first-line treatment for adult patients with metastatic NSCLC harboring BRAFV600E mutations, making a major leap in the treatment of the disease8. Encorafenib is a second-generation oral rapidly accelerated fibrosarcoma (RAF) kinase inhibitor with enhanced properties, such as high bioavailability and the ability to maintain prolonged inhibition of mutant BRAFV600E due to its extended dissociation half-life (>30 h), setting it apart from other BRAF inhibitors such as dabrafenib that dissociate rapidly. This extended duration results in enhanced target inhibition and greater potency. Binimetinib is an oral selective mitogen-activated protein kinase (MEK) inhibitor6. When administered in combination, these drugs inhibit the action of proteins encoded by mutant genes and halt the growth and proliferation of cancer cells. FDA approval came shortly after this drug combination displayed promising results in a phase II multicenter PHAROS trial in terms of both efficacy and safety, with only minimal adverse effects in this patient population6. In this trial, encorafenib plus binimetinib demonstrated a robust 75% overall response rate (ORR) in the previously untreated group, and the median duration of response (DoR) and progression-free survival (PFS) were not estimable. In the previously treated group, the drug combination exhibited a 46% ORR, with a substantial median DoR of 16.7 months and a noteworthy median PFS of 9.3 months. Gastrointestinal disturbances and fatigue were the most common adverse effects6. Recently, the FDA granted approval to two companion diagnostics, FoundationOne CDx and FoundationOne Liquid CDx, to help in the identification and stratification of patients with metastatic BRAFV600E mutant NSCLC who may benefit from this treatment9. FoundationOne CDx is an advanced diagnostic tool that uses next-generation sequencing. It identifies substitutions, deletions, copy number alterations (CNAs) in more than 300 genes, gene rearrangements, microsatellite instability (MSI), and tumor mutational burden (TMB) using DNA from a tumor tissue sample9,10. FoundationOne Liquid CDx is a minimally invasive blood-based test that analyzes genomic changes using a blood sample and is an easy alternative for patients who are not eligible for the former9. The FDA approval of encorafenib plus binimetinib along with companion diagnostics marks a significant milestone for these patients, who, for the very first time, not only have pharmacotherapy but also two companion diagnostics tailored to their specific condition, a need previously unmet. It is a significant breakthrough in the field of oncology and is likely to pave the way for research on advanced and targeted treatment modalities and revolutionize treatment approaches, in addition to substantially reducing the global disease burden. Despite the significant anticancer activity and acceptable safety profile, caution should be exercised when administering this combination therapy, particularly in pregnant women, as the drug has shown abortifacient effects in animals11. However, there is a lack of clinical data regarding its use in pregnant women. Therefore, women with reproductive potential should be educated by physicians, especially obstetricians and gynecologists, about the harmful effects of this therapy and advised to use contraceptive methods before starting the treatment. Moreover, immunization with live vaccines should be withheld during and 12 months following the treatment, as a weakened immune system might result in decreased vaccine effectiveness and limited protection, leaving patients vulnerable to severe infections12. The current body of information on the safety of this combination therapy is inadequate, and broadening it could facilitate more comprehensive updates to management guidelines, potentially enhancing patient outcomes. Large-scale prospective studies, multicenter randomized trials, systematic reviews, and meta-analyses are required to validate the safety and efficacy of this treatment regimen. Ethics approval It is not applicable to this letter to the editor. Consent It is not applicable to this letter to the editor. Sources of funding No funding was received for this letter to the editor. Author contribution H.Q.A.: conceptualization of ideas and data curation; H.Q.A., M.O.O., and A.G.: writing the initial draft, critical review, and comments; M.O.O.: writing, reviewing, editing, supervision, and funding acquisition. Conflicts of interest disclosure The authors have no conflicting interests to declare that are relevant to the content of this article. Research registration unique identifying number (UIN) Not applicable. Guarantor Malik Olatunde Oduoye, https://orcid.org/0000-0001-9635-9891. Data availability statement Not applicable to this work. Provenance and peer review Not commissioned, externally peer-reviewed.