Clinical trial updates and treatments targeting BRAF V600E in metastatic non-small lung: Written recap

In this Managed Healthcare Executive Between the Lines series, Ibiayi Dagogo-Jack, M.D., and Julia Rotow, M.D., discuss the results of a trial that could reshape treatment decisions for patients newly diagnosed with BRAF V600E-mutant non-small cell lung cancer (NSCLC). Dagogo-Jack is a fellow at Brigham and Women’s Hospital and Dana-Farber Cancer Institute and an assistant professor of medicine at Harvard Medical School, all in Boston. Rotow is clinical director of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute and assistant professor of medicine at Harvard Medical School.

The two investigators talked about the updated follow-up results of the phase 2 PHAROS trial, which is evaluating Braftovi (encorafenib) plus Mektovi (binimetinib) in patients with BRAF V600E-mutant metastatic NSCLC. The findings, which were published in October 2025 in the Journal of Clinical Oncology, provide support for the use of the combination in treatment-naive patients with NSCLC with a BRAF V600E mutation.

“This [mutation] is a true oncogenic driver whose biology lends itself to targeted intervention,” Rotow said. “It’s an interesting driver in that it is a little less associated with nonsmoking status than some of our other actionable drivers. When we think about driver-positive lung cancer, we often think about things such as EGFR, ALK and ROS1, which we know are pretty heavily involved in younger or nonsmoking patient populations.”

Importance of testing

Dagogo-Jack and Rotow emphasized that comprehensive molecular testing is essential for identifying BRAF V600E mutations. BRAF V600E mutations occur in approximately 1% to 2% of NSCLC cases and about half of all BRAF-mutant metastatic NSCLC cases. Unlike some other lung cancer driver mutations that predominantly affect specific demographics, BRAF V600E mutations occur across diverse patient populations, affecting both smokers and never-smokers and younger and older individuals.

Rotow said next-generation sequencing is required for comprehensive biomarker profiling in all patients at their diagnosis. “While that's a simple topic on the surface, of course, it's very complicated when we consider some of the realities of access to adequate tissue for testing, variability among testing platforms and sensitivity or breadth of coverage and, of course, the variability in how patients present.”

When appropriately identified, she said, patients can derive substantial and durable benefit from BRAF-MEK inhibition. The combination of Braftovi and Mektovi is already approved and is marketed by Pfizer to treat adult patients with several metastatic or unresectable cancers with a BRAF V600E mutation, including melanoma, colorectal cancer and NSCLC.

The combination of Braftovi and Mektovi is able to target two different kinases. A BRAF V600E mutation can drive the growth of cancer cells, and Braftovi blocks the mutation of the BRAF V600E protein. Mektovi works by blocking the activity of MEK proteins, which are part of the signaling pathway that regulates cell growth and survival. The combination of Braftovi and Mektovi yields greater anticancer effects than either alone and can also delay development of resistance to treatment.

“Historical studies have shown that the BRAF plus MEK targeted approach has a slightly better tolerability than, for instance, a MEK inhibitor alone,” Dagogo-Jack said. “One other thing to think about is V600E has a unique mechanism of activation of the protein in the context and really lends itself to this targeted approach.”

Results from PHAROS trial

The phase 2 PHAROS trial is an open-label, single-arm study that enrolled two cohorts: 59 treatment-naive patients and 39 patients who had received one prior line of therapy, most commonly chemotherapy, immunotherapy or a combination. All participants had confirmed BRAF V600E mutations and received standard doses of both drugs until disease progression. The data reported in October 2025 are updated results as of the data cutoff date of March 14, 2025.

In treatment-naive patients, the median overall survival (OS) was 47.6 months after a median follow-up of 52.3 months. In previously treated patients, the median OS was 22.7 months, after a median follow-up of 48.2 months. The four-year OS rates were 49% for treatment-naive patients and 31% for treated patients.

The safety profile of the Braftovi and Mektovi combination was consistent with previous findings. The most common (affecting 30% of study participants or more ) treatment-related adverse events were nausea (52%), diarrhea (44%), fatigue (33%), and vomiting (30%). Liver enzyme elevations affected approximately 20% of patients. One-third required dose reductions, and 15% discontinued due to toxicity, with rates considered manageable.

The findings are prompting reconsideration of first-line treatment strategies. Although BRAF-mutant tumors show some immunotherapy sensitivity, emerging evidence suggests starting with targeted therapy may be optimal, reserving immunotherapy combinations for later treatment lines.

Rotow points out, however, that the PHAROS study had relatively few participants and that participants were not randomly assigned to treatment groups. She also noted that there are no comparisons with other BRAF-directed therapies or immunotherapies and that the study did not include patients with non-V600E mutations. “There are certainly changes in the evolving standard of care, in what patients are receiving in the front-line setting, in the previously treated populations, for example, and in what patients are receiving next line, as the field of lung cancer continues to improve.”

She says a randomized study that compared BRAF-directed therapies versus chemotherapy plus immunotherapy would be the gold standard for evidence.

The lack of data about patients with non-V600E mutations is especially concerning, says Dagogo-Jack. “I do worry that there will be people who receive encorafenib/binimetinib in the first-line setting who have these non-V600E mutations,” she says. “That might discourage some people about the true efficacy in a real-world population. This discussion really pertains to V600E alone.”

Still, Dagogo-Jack and Rotow say the study adds to growing evidence that precision medicine approaches, when properly applied, can deliver substantial benefits even in relatively rare cancer subtypes. For the estimated thousands of patients diagnosed annually with BRAF V600E-mutant lung cancer, these findings offer hope for extended survival with improved tolerability, a combination that could meaningfully impact both length and quality of life.

Rotow says in her practice she has switched some patients to the Braftovi and Mektovi combination based on the PHAROS data initially because patients experience fewer fevers with this treatment regimen. The combination demonstrated a pyrexia (fever) rate of just 8%, a nearly tenfold reduction, making it more tolerable for long-term use.

“But now with the updated survival data, this would be a good option,” Rotow says. “This is a little under the radar in general for clinicians practicing in this space, but a PFS [progression-free survival] of 30 months, those are really good numbers. Across the board, not just for BRAF, there’s a lot of progress in getting better survival outcomes for patients, not just with our initial generations of targeted drugs, but with the ongoing development of novel regimens.”

This increased survival of targeted therapies, she says, highlights how important it is to test for these mutations. “They really matter for patients. It’s 2.5 years of extra time on a targeted pill. We don’t want any patient to miss out on that possible outcome.”

This summary was written with the assistance of artificial intelligence.