Pfizer Inc. (NYSE: PFE) today announced updated follow-up results from the single-arm Phase 2 PHAROS trial evaluating BRAFTOVI® (encorafenib) + MEKTOVI® (binimetinib) for the treatment of adults with metastatic non-small cell lung cancer (mNSCLC) with a BRAF V600E mutation. In treatment-naïve patients, the median overall survival (OS) was 47.6 months (95% confidence interval [CI], 31.3, not estimable) after a median follow-up of 52.3 months. In previously treated patients, the median OS was 22.7 months (95% CI, 14.1, 32.6), after a median follow-up of 48.2 months. The four-year OS rates were 49% (95% CI, 35, 62) and 31% (95% CI, 16, 47) for treatment-naïve and previously treated patients, respectively. These data, from pre-specified secondary trial endpoints, will be presented today in an oral presentation (1849MO) at the 2025 European Society for Medical Oncology (ESMO) Congress in Berlin, Germany, and have been simultaneously published in the Journal of Clinical Oncology.
"The PHAROS trial results set a new standard for NSCLC patients with the BRAF V600E mutation, with survival outcomes nearing four years-the longest survival we've seen in people with treatment-naïve metastatic NSCLC who harbor a BRAF V600E mutation," said Melissa Johnson, M.D., Director of Lung Cancer Research at Sarah Cannon Research Institute and PHAROS investigator. "These findings, which highlight the potential impact of encorafenib and binimetinib for newly diagnosed metastatic NSCLC patients with BRAF V600E, offer renewed optimism for their prognosis and treatment goals."
Lung cancer is the number one cause of cancer-related deaths around the world.1 NSCLC accounts for approximately 80-85% of lung cancers,2 with BRAF V600E mutations occurring in about 2% of patients with NSCLC.3 Prior to the development of targeted treatments, patients with BRAF V600E-mutant metastatic NSCLC had poor outcomes with standard chemotherapy.4
At the time of this analysis, the safety profile of BRAFTOVI + MEKTOVI was consistent with previous findings. The most common (≥30%) treatment-related adverse events were nausea (52%), diarrhea (44%), fatigue (33%), and vomiting (30%).
"These long-term survival results reinforce Pfizer's unwavering commitment to improving outcomes in lung cancer," said Jeff Legos, Chief Oncology Officer, Pfizer. "The findings provide hope for treatment-naïve BRAF V600E mNSCLC patients and their families and underscore the importance of advancing therapies that can provide a sustained impact for patients."
The Phase 2 PHAROS trial (NCT03915951) is an open-label, multicenter, single-arm study examining BRAFTOVI + MEKTOVI combination therapy in treatment-naïve and previously treated patients with BRAF V600E-mutant metastatic NSCLC. BRAFTOVI + MEKTOVI 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 objective response rate (ORR; the primary endpoint) and duration of response (secondary endpoint) results from the PHAROS trial. The ORR was 75% (95% CI: 62, 85) for treatment-naïve patients (n=59) and 46% (95% CI: 30, 63) for previously treated patients (n=39).
Pfizer is continuing its commitment to help non-scientists understand the latest findings with the development of abstract plain language summaries (APLS) for company-sponsored research being presented, which are written in non-technical language. Those interested in learning more can visit www.Pfizer.com/apls to access the summaries.
About BRAF V600E-mutant non-small cell lung cancer (NSCLC)
NSCLC treatment has dramatically evolved, enabling more individualized treatment options based on molecular profiles and immunologic status. BRAF mutations exemplify this precision medicine opportunity-while BRAF V600E mutations occur in only about 2% of NSCLC cases,3 they represent approximately half of all BRAF-mutant metastatic NSCLC.5 Targeting BRAF offers potential to inhibit tumor growth and proliferation driven by these specific mutations.6
Despite this evolution, unmet needs remain for advanced disease. Approximately one in six patients with advanced NSCLC have no biomarker testing results prior to first-line treatment.7 Among tested patients, many do not receive targeted therapy or have limited to no options available for targeted therapy.8-10
About BRAFTOVI® (encorafenib) + MEKTOVI® (binimetinib)
BRAFTOVI is an oral small molecule kinase inhibitor that targets BRAF V600E, and MEKTOVI is an oral small molecule MEK inhibitor, both of which target key proteins in the MAPK signaling pathway (RAS-RAF-MEK-ERK). Inappropriate activation of proteins in this pathway has been shown to occur in certain cancers, including melanoma, CRC, and NSCLC.
Pfizer has exclusive rights to BRAFTOVI + MEKTOVI in the U.S., Canada, Latin America, Middle East, and Africa. Ono Pharmaceutical Co., Ltd. has exclusive rights to commercialize both products in Japan and South Korea, Medison has exclusive rights in Israel and Pierre Fabre Laboratories has exclusive rights in all other countries, including Europe and Asia (excluding Japan and South Korea). The PHAROS trial is conducted with support from Pierre Fabre.
INDICATION AND USAGE
WARNINGS AND PRECAUTIONS
New Primary Malignancies: New primary malignancies, cutaneous and non-cutaneous, can occur. In the PHAROS trial, cutaneous squamous cell carcinoma (cuSCC) and skin papilloma (SP), each occurred in 2% of patients. Perform dermatologic evaluations prior to initiating treatment, every 2 months during treatment, and for up to 6 months following discontinuation of treatment. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Dose modification is not recommended for new primary cutaneous malignancies. Based on its mechanism of action, BRAFTOVI may promote malignancies associated with activation of RAS through mutation or other mechanisms. Monitor patients receiving BRAFTOVI for signs and symptoms of non-cutaneous malignancies. Discontinue BRAFTOVI for RAS mutation-positive non-cutaneous malignancies. Monitor patients for new malignancies prior to initiation of treatment, while on treatment, and after discontinuation of treatment.
Tumor Promotion in BRAF Wild-Type Tumors: In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation using an FDA-approved test prior to initiating BRAFTOVI.
Cardiomyopathy: Cardiomyopathy manifesting as left ventricular dysfunction associated with symptomatic or asymptomatic decreases in ejection fraction, has been reported in patients. In the PHAROS trial, evidence of cardiomyopathy occurred in 11% and Grade 3 left ventricular dysfunction occurred in 1% of patients. Cardiomyopathy resolved in 82% of patients. Assess left ventricular ejection fraction (LVEF) by echocardiogram or multi-gated acquisition (MUGA) scan prior to initiating treatment, 1 month after initiating treatment, and then every 2 to 3 months during treatment. The safety has not been established in patients with a baseline ejection fraction that is either below 50% or below the institutional lower limit of normal (LLN). Patients with cardiovascular risk factors should be monitored closely. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.
Hepatotoxicity: Hepatotoxicity can occur when MEKTOVI is administered in combination with BRAFTOVI. In the PHAROS trial, the incidence of Grade 3 or 4 increases in liver function laboratory tests was 10% for aspartate aminotransferase (AST), 9% for alanine aminotransferase (ALT), and 3.2% for alkaline phosphatase. Monitor liver laboratory tests before initiation of BRAFTOVI and MEKTOVI, monthly during treatment, and as clinically indicated. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.
Rhabdomyolysis: Rhabdomyolysis can occur when MEKTOVI is administered in combination with BRAFTOVI. In the PHAROS trial, elevation of laboratory values of serum creatine kinase (CK) occurred in 41% of patients. No patient experienced rhabdomyolysis. Monitor CPK and creatinine levels prior to initiating MEKTOVI, periodically during treatment, and as clinically indicated. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.
Hemorrhage: Hemorrhage can occur when BRAFTOVI is administered in combination with MEKTOVI. In the PHAROS trial, hemorrhage occurred in 12% of patients, including fatal intracranial hemorrhage (1%); Grade 3 or 4 hemorrhage occurred in 4.1% of patients. The most frequent hemorrhagic events were anal hemorrhage and hemothorax (2% each). Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.
Venous Thromboembolism (VTE): In the PHAROS trial, VTE occurred in 7% of patients, including 1% of patients who developed pulmonary embolism. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.
Ocular Toxicities: In the PHAROS trial, serous retinopathy (retinal detachment) occurred in 2% of patients with no cases of blindness. Retinal vein occlusion (RVO) is a known class-related adverse reaction of MEK inhibitors and may occur in patients treated with MEKTOVI in combination with BRAFTOVI. The safety of MEKTOVI has not been established in patients with a history of RVO or current risk factors for RVO including uncontrolled glaucoma or a history of hyperviscosity or hypercoagulability syndromes. Perform ophthalmological evaluation for patient-reported acute vision loss or other visual disturbance within 24 hours. Permanently discontinue MEKTOVI in patients with documented RVO. Uveitis, including iritis and iridocyclitis, was reported in patients treated with MEKTOVI in combination with BRAFTOVI. In PHAROS, uveitis occurred in 1% of patients. Assess for visual symptoms at each visit. Perform an ophthalmological evaluation at regular intervals and for new or worsening visual disturbances, and to follow new or persistent ophthalmologic findings. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.
QT Prolongation: BRAFTOVI is associated with dose-dependent QTc interval prolongation in some patients. In the PHAROS trial, an increase in QTcF to >500 ms was measured in 2.1% (2/95) of patients who received BRAFTOVI with MEKTOVI. Monitor patients who already have or who are at significant risk of developing QTc prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, severe or uncontrolled heart failure and those taking other medicinal products associated with QT prolongation. Correct hypokalemia and hypomagnesemia prior to and during BRAFTOVI administration. Withhold, reduce dose, or permanently discontinue for QTc >500 ms.
Interstitial Lung Disease (ILD): In the PHAROS trial, 1 patient (1%) receiving MEKTOVI with BRAFTOVI developed pneumonitis. Assess new or progressive unexplained pulmonary symptoms or findings for possible ILD. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.
Embryo-Fetal Toxicity: BRAFTOVI and MEKTOVI can cause fetal harm when administered to pregnant women. BRAFTOVI can render hormonal contraceptives ineffective. Effective, non-hormonal contraceptives should be used during treatment and for at least 30 days after the final dose for patients taking BRAFTOVI with MEKTOVI.
Risks Associated with BRAFTOVI as a Single Agent: There is an increased risk of certain adverse reactions compared to when BRAFTOVI is used in combination with MEKTOVI. If MEKTOVI is temporarily interrupted or permanently discontinued, reduce the dose of BRAFTOVI as recommended.
Risks Associated with Combination Treatment: BRAFTOVI is indicated for use as part of a regimen in combination with MEKTOVI. Refer to the prescribing information for BRAFTOVI and MEKTOVI for additional risk information.
Lactation: Advise women not to breastfeed during treatment with BRAFTOVI and MEKTOVI and for 2 weeks after the final dose.
Infertility: Advise males of reproductive potential that BRAFTOVI may impair fertility.
ADVERSE REACTIONS
The most common adverse reactions (≥25%, all grades, in the PHAROS trial) for BRAFTOVI with MEKTOVI were: fatigue (61%), nausea (58%), diarrhea (52%), musculoskeletal pain (48%), vomiting (37%), abdominal pain (32%), visual impairment (29%), constipation (27%), dyspnea (27%), rash (27%), and cough (26%).
Serious adverse reactions occurred in 38% of patients receiving BRAFTOVI with MEKTOVI. Serious adverse reactions (≥2% of patients in the PHAROS trial) were hemorrhage (6%), diarrhea (4.1%), anemia (3.1%), dyspnea (3.1%), pneumonia (3.1%), arrhythmia (2%), device related infection (2%), edema (2%), myocardial infarction (2%), and pleural effusion (2%). Fatal adverse reactions occurred in 2% of patients, including intracranial hemorrhage (1%) and myocardial infarction (1%).
Other clinically important adverse reactions occurring in <10% of patients who received BRAFTOVI with MEKTOVI in the PHAROS trial were peripheral neuropathy, dysgeusia, facial paresis, pancreatitis, hyperkeratosis, erythema, photosensitivity, and drug hypersensitivity.
In the PHAROS trial, the most common laboratory abnormalities (all grades) (≥20%) for BRAFTOVI and MEKTOVI included increased creatinine (91%), hyperglycemia (48%), anemia (47%), increased creatine kinase (41%), lipase increased (40%), increased ALT (34%), hypoalbuminemia (32%), increased alkaline phosphatase (31%), increased AST (31%), hyperkalemia (31%), hyponatremia (26%), lymphopenia (24%), serum amylase increased (22%), and thrombocytopenia (20%).
DRUG INTERACTIONS
Strong or moderate CYP3A4 inhibitors: Avoid coadministration of BRAFTOVI with strong or moderate CYP3A4 inhibitors, including grapefruit juice. If coadministration is unavoidable, reduce the BRAFTOVI dose.
Strong CYP3A4 inducers: Avoid coadministration of BRAFTOVI with strong CYP3A4 inducers.
Sensitive CYP3A4 substrates: Avoid the coadministration of BRAFTOVI with CYP3A4 substrates (including hormonal contraceptives) for which a decrease in plasma concentration may lead to reduced efficacy of the substrate. If the coadministration cannot be avoided, see the CYP3A4 substrate product labeling for recommendations.
Dose reductions of drugs that are substrates of OATP1B1, OATP1B3, or BCRP may be required when used concomitantly with BRAFTOVI.
Avoid coadministration of BRAFTOVI with drugs known to prolong QT/QTc interval.
The information above applies to the safety of the combination of BRAFTOVI and MEKTOVI unless otherwise noted. See full Prescribing Information for BRAFTOVI and for MEKTOVI for dose modifications for adverse reactions.
Please see full Prescribing Information for BRAFTOVI and full
