FDA Approves Encorafenib Plus Binimetinib Combination for Non-Small Cell Lung Cancer


Encorafenib (Braftovi; Pfizer Inc) and binimetinib (Mektovi; Pfizer Inc) approved for the treatment of patients with metastatic non-small cell lung cancer who harbor a BRAF V600E mutation.

The FDA has approved the combination of encorafenib (Braftovi; Pfizer Inc) and binimetinib (Mektovi; Pfizer Inc) for the treatment of adults with metastatic non-small cell lung cancer (NSCLC) who have a BRAF V600E mutation, as detected by an FDA-approved test.

“Today’s approval builds on our long-standing commitment to deliver innovative, personalized medicines to patients with lung cancer. By pursuing precision medicines that target a patient’s specific type of cancer, we are leveraging our deep understanding of tumor biology to help address the underlying cause of disease,” said Chris Boshoff, MD, PhD, chief oncology research and development officer and executive vice president at Pfizer, in a press release. “Since its initial FDA approval in 2018, Braftovi plus Mektovi combination therapy has helped thousands of people living with BRAF V600E- or V600K-mutant unresectable or metastatic melanoma. We look forward to helping even more patients with our Braftovi plus Mektovi targeted combination therapy.”

The FDA based the approval on data from the open-label, multicenter, single-arm, phase 2 PHAROS trial (NCT03915951), which enrolled patients with a diagnosis of histologically confirmed metastatic NSCLC who are harboring a BRAF V600E mutation and measurable disease by RECIST v1.1 criteria. Patients could be treatment naïve or have been previously administered 1 line of systemic therapy in the metastatic setting. Patients were also required to be at least 18 years of age, have an ECOG performance status of 0 or 1, and no prior exposure to BRAF or MEK inhibitors.

The trial enrolled 98 patients, 59 of whom were treatment naïve and 39 were previously treated, with a median age of 70 years (range, 47-86), and approximately half (53%) were female. Among the total population, 88% were White, 13% were current smokers, and 57% were former smokers. More than half of patients in the trial had an ECOG performance status of 1 (73%), 97% had adenocarcinoma (97%). All of the enrolled patients had metastatic disease, whereas only 8% had baseline brain metastases.

Encorafenib was administered at a once-daily dose of 450 mg paired with binimetinib at a twice-daily dose of 45 mg, with treatment continuing until progressive disease or unacceptable toxicity.

The key efficacy outcome measures included ORR by RECIST v1.1 criteria and DOR per independent review committee assessment. The median duration of treatment with encorafenib was 9.2 months and for binimetinib was 8.4 months.

In the trial, the combination produced an objective response rate (ORR) of 75% (95% CI, 62%-85%) per RECIST v1.1 criteria in treatment-naïve patients (n = 59), which was comprised of a complete response (CR) rate of 15% and a partial response (PR) rate of 59%. Among treatment-naïve patients, median duration of response (DOR) had not yet been reached (95% CI, 23.1-not evaluable [NE]), while 75% of patients had a DOR that lasted at least 6 months and 59% had a DOR of at least 12 months.

Among previously treated patients (n = 39), the combination produced an ORR of 46% (95% CI, 30%-63%), comprised of a CR rate of 10% and a PR rate of 36%. In this patient cohort, the median DOR was 16.7 months (95% CI, 7.4-NE), as 67% and 33% of patients experienced a DOR that lasted for at least 6 months or 12 months, respectively.

The most common toxicities occurring in at least 25% of patients included fatigue (all grade, 61%; grade 3/4, 8%), nausea (58%; 3.1%), diarrhea (52%; 7%), musculoskeletal pain (48%; 4.1%), vomiting (37%; 1%), abdominal pain (32%; 1%), visual impairment (29%; 2%), constipation (27%; 0%), dyspnea (27%; 8%), rash (27%; 3.1%), and cough (26%; 0%).

Adverse effects (AEs) caused dose interruptions in 59% of patients administered encorafenib, with the most common AEs including diarrhea (17%), nausea (13%), musculoskeletal pain (8%), fatigue (8%), increased aspartate aminotransferase (AST; 7%), increased alanine aminotransferase (6%), anemia (6%), hemorrhage (6%), vomiting (6%), and acute kidney injury (5%).

In patients administered encorafenib, AEs resulted in dose reductions among 30% of patients, with the most common being diarrhea (8%), nausea (8%), increased AST (5%), and fatigue (5%). Further, 16% of patients administered encorafenib experienced an AE that led to permanent treatment discontinuation.

Serious AEs occurred in 38% of patients administered the combination, which included 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 toxicities occurred in 2% of patients administered the once-daily dose of 450 mg of encorafenib plus binimetinib, which included intracranial hemorrhage (1%) and myocardial infarction (1%).

Lung cancer is the second most common type of cancer and the number 1 cause of cancer-related death globally. In 2023, the American Cancer Society estimates that there will be approximately 238,340 new cases of lung cancer diagnosed in the United States, and NSCLC accounts for between 80% and 85% of all lung cancers.

Some lung cancers are associated with acquired genetic abnormalities. For example, a BRAF V600E mutation occurs in approximately 2% of NSCLC cases and stimulates tumor cell growth and proliferation by altering the MAP kinase signaling pathway. Targeting components of this pathway could potentially inhibit unchecked tumor growth and proliferation caused by BRAF mutations, according to Pfizer.

Precision medicine is increasingly targeting patients with NSCLC and genetic changes, such as BRAF mutations, which can be detected using biomarker tests. Advances in targeted therapy have been associated with significant improvements in population-level NSCLC mortality in recent years.

“BRAF V600E mutations identify a unique subtype of metastatic non-small cell lung cancer that presents an actionable biomarker that precision medicines like Braftovi plus Mektovi combination therapy can help address,” said Gregory Riely, MD, PhD, vice chair, Clinical Research in the Department of Medicine at Memorial Sloan Kettering Cancer Center (MSK) and PHAROS investigator. “The PHAROS trial demonstrated that these patients could benefit from Braftovi plus Mektovi targeted therapy regardless of their prior treatment history. Given the specific efficacy and safety profile, patients and providers now have another option to help personalize treatment plans based on individual risk factors and preferences.”


U.S. FDA Approves Pfizer’s BRAFTOVI® + MEKTOVI® for BRAF V600E-Mutant Metastatic Non-Small Cell Lung Cancer. Pfizer. News release. https://www.pfizer.com/news/press-release/press-release-detail/us-fda-approves-pfizers-braftovir-mektovir-braf-v600e. October 12, 2023.

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