SOC Encorafenib/Binimetinib Sets a Precedent for Therapeutic Improvements in BRAF V600E–Mutant NSCLC

Joseph C. Murray, MD, PhD

Within the past 3 years, the BRAF V600E–mutant NSCLC treatment arsenal has seen positive shifts toward improved standards of care [SOC] following the FDA approvals of dabrafenib plus trametinib and encorafenib plus binimetinib, according to Joseph C. Murray, MD, PhD, who added that uncertainty remains regarding optimal treatments following progression on these agents.

“There have been multiple strategies to manage BRAF V600E–altered NSCLC, primarily in the advanced metastatic stage. We’ve had an FDA approval in the first-line setting for dabrafenib plus trametinib, which is a MEK inhibitor required when we’re using a BRAF inhibitor,” Murray said in an interview with OncLive®. “More recently, we’ve had the FDA approval of encorafenib plus binimetinib.”

In June 2022, the FDA approved dabrafenib plus trametinib for the treatment of patients with unresectable or metastatic solid tumors with BRAF V600E mutations who experience disease progression after previous treatment and do not have adequate alternative treatment options.1 Furthermore, the FDA approved encorafenib plus binimetinib in October 2023 for the treatment of patients with metastatic NSCLC harboring a BRAF V600E mutation.2 The approval was based on data from the phase 2 PHAROS trial (NCT03915951).

During the interview, Murray highlighted efficacy data from the PHAROS trial, available alternative therapies for class II and III BRAF alterations, future treatment directions for BRAF V600E–mutated NSCLC, and approaches to address disease progression on standard treatments.

Murray is an assistant professor of oncology, co-director of the Lung Cancer Precision Medicine Center of Excellence, and director of the Upper Aerodigestive Cancer Division Immunotherapy Database at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, Maryland.

OncLive: What efficacy data have been reported from the PHAROS trial?

Murray: We saw updates [from this trial] at the 2024 ESMO Congress. In the PHAROS trial, investigators evaluated both progression-free survival [PFS] and overall survival [OS] outcomes. These were both secondary outcomes from this trial, which was a single-arm, open-label, multicenter study.

Of note, there was [a median] PFS [of 30.2 months with encorafenib plus binimetinib] in treatment-naive patients with [a median follow-up of] 33.3 months, which was an outstanding number compared with [those seen in] prior BRAF [inhibitor] studies. [There was also a] sustained median PFS of 9.3 months in previously treated patients.3 Those were the 2 main arms in this study. The PFS [outcomes] in the treatment-naive patients [were similar to] the OS findings, with a median OS that was not estimable yet; [the median OS was 22.7 months] in the previously treated patients.

What are alternative therapies for patients with class II and III BRAF alterations?

Class II and III alterations are not targetable using any BRAF and MEK inhibitor combination, at least from guideline-directed evidence. We should be considering clinical trials for patients with class II and class III alterations outside of the SOCs we can provide. These include using BRAF and MEK inhibitors for class I disease, and alternative therapies for class II and III disease.

For class II and III alterations, there’s a growing body of evidence [supporting the use of] pan-RAF inhibitors that are not specific to the V600 locus. Some other clinical trial agents can be considered beyond the SOC. In the setting of class II and III alterations, we often [consider] immunotherapy with or without chemotherapy based on other biomarkers, like PD-L1 status or other co-mutations that may be present. Those SOC options should always be available to patients, and they are also available to patients with class I mutations. The question remains: Do we use targeted therapy up front, or immunotherapy with or without chemotherapy across all patients with BRAF mutations?

What are some future directions for treatments in the BRAF V600E–mutant setting?

I’m excited to see studies that are more definitive about the mechanistic-to-translational research benefits of targeting BRAF upfront vs in the second-line setting, akin to how we may [consider the] sequencing of other BRAF-targeted agents in other diseases. In metastatic melanoma, we have the well-known phase 3 DREAMseq study [NCT02224781], which identified that the use of immunotherapy before BRAF V600–directed therapies was still beneficial to patients.

We don’t have that definitive study yet in [NSCLC]. Currently, our lab at Johns Hopkins is involved in retrospective research about the sequencing of [BRAF-directed] therapies in retrospective studies, asking: How did patients benefit, depending on the BRAF inhibitors [they received] up front for V600 alterations vs after immunotherapy, with or without chemotherapy? This is the most exciting place where we should see more data that can be gathered best in a clinical trial setting, perhaps via a registrational study that’s run by a cooperative group. It may also be the next study that drug companies can support to see how best to sequence these therapies for patient benefit.

How do you approach treatment following disease progression on standard treatments, such as dabrafenib and trametinib?

Many patients may [progress during treatment with] dabrafenib plus trametinib, and a consideration would be to switch to encorafenib plus binimetinib treatment. This is one of those situations that phase 2 studies have tried to answer. Is there a response in the second-line setting with encorafenib plus binimetinib based on [what therapies patients have received in] prior lines? It’s tricky to say. The sequencing of different treatment options is an area we need more research about. Do we opt for BRAF and MEK inhibition? Or do we use a different systemic therapy option, like immunotherapy with or without chemotherapy?

Even identifying BRAF mutations upfront is critical for patients. I’m a strong advocate for continued pathological review at the time of progression, including comprehensive molecular testing to assure ourselves that we’re targeting the same [mutation as before] and that there are no new resistance mechanisms we need to be aware of. This goes into play independent of what those resistance mechanisms may be. We should still use them to help our patients and guide our patients in making decisions about the next lines of therapy.

References

1. FDA grants accelerated approval to dabrafenib in combination with trametinib for unresectable or metastatic solid tumors with BRAF V600E mutation. FDA. Updated June 23, 2022. Accessed May 8, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-dabrafenib-combination-trametinib-unresectable-or-metastatic-solid
2. FDA approves encorafenib with binimetinib for metastatic non–small cell lung cancer with a BRAF V600E mutation. FDA. October 11, 2023. Accessed May 8, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-encorafenib-binimetinib-metastatic-non-small-cell-lung-cancer-braf-v600e-mutation
3. Riely GJ, Ahn MJ, Clarke J, et al. LBA56 Updated efficacy and safety from the phase II PHAROS study of encorafenib plus binimetinib in patients with BRAF V600E-mutant metastatic NSCLC (mNSCLC). Ann Oncol. 2024;35(suppl 2):S1246-S1247. doi:10.1016/j.annonc.2024.08.2298