Long-Term Data for PHAROS Show Half of Treatment-Naïve Patients Receiving Encorafenib Plus Binimetinib Alive at 4 Years

Targeted therapy continues to make waves in metastatic non–small cell lung cancer (NSCLC), as seen in Sunday’s oral session during the 50th European Society for Medical Oncology in Berlin, Germany, which highlighted both current therapies and those in the pipeline targeting ALK, EGFR, BRAF V600E, and ROS1.

Melissa L. Johnson, MD, director of lung cancer research at Sarah Cannon Research Institute in Nashville, Tennessee, presented long-term results from the phase 2 PHAROS study (NCT03915951),¹ which first showed the efficacy of combining a pair of targeted therapies, encorafenib (Braktovi; Pfizer) and binimetinib (Mektovi; Pfizer) by September 2022. The combination was approved in October 2023 for patients with BRAF V600E-mutated metastatic NSCLC.

Overall survival (OS) data, published simultaneously by the Journal of Clinical Oncology,² show the longest survival data ever seen in these patients, who typically were treated with chemotherapy before the use of targeted therapy. A different targeted therapy combination, dabrafenib and trametinib, was approved a decade prior.

Lung cancer is the second most common cancer in the United States and the top cause of cancer deaths, with NSCLC accounting for 80% or more of all lung cancers. Among those are BRAF V600E mutations occurring in about 2% of patients with NSCLC.³ These are so-called “driver mutations,” that lead to uncontrolled cell growth.

Johnson explained the study design, in which 98 patients (59 treatment naïve, 39 previously treated) received 450 mg of encorafenib twice daily and aminimum of 45 mg of binimetinib 45 mg twice daily. The primary end point was objective response rate (ORR), which was 75% in the treatment naïve group and 46% in the previously treated group. Johnson noted that the baseline characteristics were “consistent with what we expect for BRAF V600E mutated non-small cell lunger cancer—including 50/50 male and female, and two-thirds of patients current or former smokers.”

Among those previously treated, 60% had immunotherapy, she said. After a data cutoff of March 14, 2025, results were:

• Median follow-up for OS of 52.3 months in treatment-naïve patients, median OS was 47.6 months (95% CI; 31.3 to not estimable); 4-year OS probability was 49% (95% CI; 35 to 62).
• After median follow-up for OS of 48.2 months in previously treated patients, median OS was 22.7 months (95% CI; 14.1 to 32.6); 4-year OS probability was 31% (95% CI, 16 to 47).
• In the treatment-naïve and previously treated groups, 58% and 26% received at least 1 subsequent systemic treatment, respectively.
• No new safety signals were reported.

“These results support the [encorafenib-binimetinib] indication and support its use as a first line treatment for patients with BRAF V600E mutated non-small cell lung cancer,” Johnson said.

Promising Intracranial Responses With Olomorasib

Philippe Cassier, MD, a medical oncologist with Centre Léon Bérard in Lyon, France, presented phase 1/2 results for olomorasib (NCT04956640), a next-generation selective inhibitor that in September 2025 received breakthrough therapy designation to target KRAS G12C.⁴ Olomorasib is now being developed by Eli Lilly, and Cassier said it has been shown to be safe and efficacious “in multiple solid tumors with KRAS mutations.”

Cassier reported data on intracranial activity in patients with active brain metastases among patients with advanced NSCLC who were positive for KRAS G12C (tissue or plasma) who had not been previously treated with a KRAS G12C inhibitor. Patients received single agent olomorasib, 150 mg daily.⁵ Safety was assessed in all treated patients. Intracranial response was assessed by modified RECIST v1.1 in at least 1 measurable lesion (at least 5 mm), which was evaluated in patientswith at leas 1 post-baseline response assessment or who discontinued treatment before the first assessment.

As of January 15, 2025, 19 patients with a median age of 65 years were treated; 15 had prior systemic therapy, including 13 in the metastatic setting. Median number of intracranial lesions was 1 (range, 1-3). Common treatment-related adverse events were low-grade diarrhea, fatigue and nausea; no grade 3 or higher. Among the 18 evaluable patients, Cassier said during the session, “5 patients reached a complete intracranial response, while 4 additional patients had a partial response for an overall intracranial response rate of 43%.”

He pointed to an additional graph that indicated the durability, “with 100% of response still ongoing at the landmark of 6 months, and the median duration of response not reached after a median follow up of 8.1 months.”

Pointing again to the waterfall plot, Cassier said, “Some patients had major responses at the first assessment. We also saw in some patients a deepening of response over time.”

Two global registration studiesin first-line metastatic and early-stage NSCLC are ongoing.⁴

Zipalertinib Takes Aim at CNS Metastases in NSCLC With EGFR Exon 20 Insertion Mutations

In June 2025, data were reported ASCO for REZILIENT1 (NCT04036682) for zipalertinib, an irreversible EGFR tyrosine kinase inhibitor, in pretreated 244 patients with NSCLC harboring EGFR exon 20 insertion (ex20ins) mutations. The confirmed ORR was 35.2% (95% CI, 28.2 to 42.8); median DOR was 8.8 months (95% CI, 8.3 to 12.7). The most common grade 3 or higher treatment-related adverse events were anemia (7%), pneumonitis and rash (2.5% each.⁵

On Sunday, Helena A. Yu, MD, medical oncologist and drug development specialist at Memorial Sloan Kettering Cancer Center, offered preliminary results for REZILIENT2 (NCT5967689), also at 100 mg twice daily, in patients with these mutations and at least 1 active central nervous system (CNS) metastases and/or leptomeningeal disease (LMD).⁶

Besides ORR and DOR, this group was assessed for intracranial ORR (iORR), intracranial DOR (iDOR), and disease control rate (iDCR) by response assessment for brain metastases (RANO-BM), and safety. “CNS metastases in patients with NSCLC harbor and EGFR mutations are both common, happening in about 50% of patients and are associated with a poor prognosis,” Yu said, and patients have few treatment options.

She reported on cohort C from the ongoing phase 2b trial; these had active brain metastases, “so they needed to be newly diagnosed and or progressing…patients could have had leptomeningeal disease,” and prior lines of therapy were permitted. At data cutoff February 15, 2025, REZILIENT2 had enrolled 32 patients. The majority had ECOB status of 1 and 19% had LMD; more than half had EGFR with ex20ins; the remainder had uncommon single or compound EGFR mutations. Efficacy and safety data show:⁶

• 31.3% of those with measurable CNS disease had confirmed responses by RANO-BM.
• Of 5 confirmed responses, 2 of 5 had LMD, and 4 of 5 responses had not had prior CNS radiotherapy; median iDOR was 8.1 months.
• 27.6% had confirmed systemic response per RESIST with mDOR of 7.6 months.
• Safety profile of zipalteritnib at 100 mg twice daily was consistent with the prior study.

“In summary,” she said, “zipalertinib demonstrated clinically meaningful intracranial anti- tumor activity with a 31.3% intracranial response rate and a 68.8% intracranial disease control rate per RANO-BM in patients with non-small cell lung cancer with exon 20 insertions or other uncommon single or compound mutations, it also appears to be active in patients with leptomeningeal disease; the intracranial response rate was similar to the systemic response rate in the reported population.” Full reports will be forthcoming, Yu said.

Zipalertinib, which has received FDA breakthrough therapy desgination, is being developed by Taiho Pharmaceutical in collaboration with Cullinan Therapeutics.

References

1. Johnson ML, Smit EF, Felip E, et al. Updated overall survival analysis from the phase 2 PHAROS study of encoralfenib plus binimetinib in patients with BRAF V600E-mutant metastatic NSCLC (mNSCLC). Presented at: European Society for Medical Oncology 2025 Congress; October 17-21, 2025; Berlin, Germany; Abstract 1849MO.
2. Johnson ML, Smit EF, Felip E, et al. Updated overall survival analysis from the phase 2 PHAROS study of encorafenib plus binimetinib in patients with BRAF V600E-mutant metastatic non-small cell lung cancer. J Clin Oncol. Published online October 19, 2025.
3. Pfizer’s BRAFTOVI + MEKTOVI shows sustained long-term survival in patients with advanced lung cancer. News release. Pfizer. October 19, 2025. Accessed October 19, 2025. https://www.pfizer.com/news/press-release/press-release-detail/pfizers-braftovir-mektovir-shows-sustained-long-term
4. Cassier P, Schneider J, Italiano, A, et al. Intracranial efficacy of olomorasib, a second-generation KRAS G12C inhibitor in patients with KRAS G12C-mutant NSCLC who have active, untreated brain metastases. Presented at: European Society for Medical Oncology 2025 Congress; October 17-21, 2025; Berlin, Germany; Abstract 1846MO.
5. Piotrowska Z, Passaro A, Nguygen D, et al. Zipalertinib in patients with epidermal growth factor receptor exon 20 insertion-positive non-small cell lung cancer previously treated with platinum-based chemotherapy with or without amivantamab. J Clin Oncol. 2025;43(21);2387-2389. doi:10.1200/JCO-25-00763.
6. Activity of zipalertinib against active central nervous system (CNS) metastases in patients with non-small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion (ex20ins) /other uncommon mutations. Presented at: European Society for Medical Oncology 2025 Congress; October 17-21, 2025; Berlin, Germany; Abstract 1847MO.