Pfizer Inc. announced longer-term follow-up results from the Phase 2 single-arm PHAROS clinical trial evaluating the efficacy and safety of encoradenib in combination with binimetinib for patients with BRAF V600E-mutant metastatic non-small cell lung cancer (NSCLC).

After an additional 18 months of follow-up, the objective response rate (ORR) and the median duration of response (DoR) as assessed by independent radiology review were 75% and 40 months in treatment-naïve patients and 46% and 16.7 months in previously treated patients, respectively.

In addition, after approximately three years of follow-up in treatment-naïve patients, the median progression-free survival (PFS) with encoradenib + binimetinib was 30.2 months (95% confidence interval [CI], 15.7-not estimable [NE]), while median overall survival (OS) was not yet reached (95% CI, 31.3-NE).

These data will be presented today during a late-breaking oral session (Abstract LBA56) at the European Society for Medical Oncology (ESMO) Congress 2024 in Barcelona, Spain.

“BRAF V600E-mutant metastatic non-small cell lung cancer tends to be aggressive, and effective targeted first-line treatment options with manageable safety profiles are critical for the thousands of people who are diagnosed globally each year,” said Gregory Riely, M.D., Ph.D., Vice Chair, Clinical Research in the Department of Medicine at Memorial Sloan Kettering Cancer Center (MSK) and PHAROS investigator.

“The longer-term follow-up results from the PHAROS trial represent an important step forward in the treatment of BRAF V600E-mutant metastatic NSCLC, especially for treatment-naïve patients. These compelling results support the encoradenib + binimetinib combination as a standard of care option for these patients.”

Lung cancer is the number one cause of cancer-related death around the world.

NSCLC accounts for approximately 80-85% of lung cancers, with BRAF V600E mutations occurring in about 2% of patients with NSCLC.

Understanding the role of the mitogen-activated protein within the pathway including BRAF V600E-mutant metastatic NSCLC.

The Phase 2 PHAROS trial (NCT03915951) is an open-label, multicenter, single arm study examining encoradenib + binimetinib combination therapy in treatment-naïve and previously treated patients with BRAF V600E-mutant metastatic NSCLC. Notably, upon longer-term follow-up in previously treated patients, encoradenib + binimetinib showed a median PFS of 9.3 months (95% CI, 6.2-24.8) and a median OS of 22.7 months (95% CI, 14.1-32.2), with a safety profile that was consistent with previous findings; no new safety concerns were identified.

In this analysis, treatment-related adverse events (AEs) led to dose reduction in 26% of patients, and to permanent discontinuation in 16% of patients.

Nausea, diarrhea, and fatigue remained the most common treatment-related AEs.

“These potentially practice-changing results from the PHAROS trial show that the combination of encoradenib + binimetinib is providing long-term compelling efficacy for patients, and although no definitive conclusions can be made across trials, the duration of response and progression-free survival in treatment naïve patients appear to be the longest observed for BRAF V600E–mutant metastatic NSCLC compared with historical outcomes,” said Roger Dansey, M.D., Chief Development Officer, Oncology, Pfizer.

“These latest data reflect our deep understanding of the science behind biomarker-driven cancers and add to our legacy in developing innovative targeted treatments in NSCLC. We are continuing to build upon this strong foundation with a pipeline of targeted medicines and combinations across our tumour areas of focus, including the ongoing investigation of encoradenib in earlier settings of metastatic colorectal cancer, and the exploration of a next-generation brain-penetrant BRAF inhibitor.”

Encoradenib + binimetinib was approved by the U.S. Food and Drug Administration (FDA) in October 2023, and by the European Commission in August 2024, for the treatment of BRAF V600E-mutant metastatic NSCLC based on the initial ORR (the primary endpoint) and DoR (key secondary endpoint) results from the PHAROS clinical trial.

In addition to PHAROS, safety lead-in data from the ongoing Phase 3 BREAKWATER study investigating encoradenib in combination with cetuximab and FOLFIRI chemotherapy in previously untreated BRAF V600E-mutant metastatic colorectal cancer (CRC) will also be presented as a mini-oral session at ESMO (Abstract 515MO).

Encoradenib in combination with cetuximab and FOLFIRI was found to be generally tolerable in this patient population, with no new safety concerns identified.

These findings support the ongoing investigation of this combination regimen as a potential treatment option for BRAF V600E-mutant metastatic CRC.

The Phase 3 BREAKWATER trial is ongoing, with updated data expected in 2025.

BRAF mutations can occur in a number of tumour types, including metastatic melanoma, metastatic CRC and metastatic NSCLC.

Among different types of BRAF mutations, the BRAF V600E mutation is particularly important as it occurs in approximately half of patients with BRAF-mutant metastatic NSCLC.

Further, this mutation represents up to 90% of BRAF mutations in melanoma5 and more than doubles the risk of mortality for patients with CRC.

In addition to our continued investigation of encoradenib + binimetinib for BRAF-mutant cancers, Pfizer is also exploring a next-generation BRAF inhibitor designed to selectively inhibit mutant BRAF monomers and mutant BRAF-containing dimers and be brain penetrant.

The investigational drug is currently being evaluated in a Phase 1 clinical study.

Source: Pfizer Inc.