FDA Approves Encorafenib Plus Binimetinib for BRAF V600E+ Metastatic NSCLC

FDA

The FDA has approved encorafenib (Braftovi) plus binimetinib (Mektovi) for adult patients with metastatic non–small cell lung cancer harboring a BRAF V600E mutation, as detected by an FDA-approved test.

The regulatory decision was supported by data from the phase 2 PHAROS trial (NCT03915951) in which the doublet elicited 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%. In this group, the median duration of response (DOR) had not yet been reached (95% CI, 23.1-not evaluable [NE]). Seventy-five percent of patients had a DOR of at least 6 months and 59% had a DOR of at least 12 months.

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

A Deeper Dive Into PHAROS

The open-label, multicenter, single-arm study enrolled patients with a diagnosis of histologically confirmed metastatic NSCLC harboring a BRAF V600E mutation and measurable disease by RECIST v1.1 criteria. Patients could be naïve to treatment or have previously received 1 line of systemic therapy in the metastatic setting.

They were required to be at least 18 years of age and have an ECOG performance status of 0 or 1. They could not have previously been exposed to BRAF or MEK inhibitors.

Study participants were administered encorafenib at a once-daily dose of 450 mg paired with binimetinib at a twice-daily dose of 45 mg. Treatment continued 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.

A total of 98 patients were enrolled to the trial; 59 patients were treatment naïve and 39 were previously treated. The median age in the total population was 70 years (range, 47-86), and approximately half (53%) were female.

Most patients were White (88%) and not Hispanic or Latino (99%). Thirteen percent of patients were current smokers and 57% were former smokers. Moreover, more than half of patients had an ECOG performance status of 1 (73%) and the majority had adenocarcinoma (97%). All patients had metastatic disease but only 8% had baseline brain metastases.

The median duration of treatment with encorafenib was 9.2 months and 8.4 months for binimetinib. 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) resulted in dose interruptions of encorafenib in 59% of patients; the most common of these included 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%).

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

Serious adverse reactions were observed in 38% of patients who received the doublet. These effects 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 who received encorafenib at a once daily dose of 450 mg plus binimetinib, and this included intracranial hemorrhage (1%) and myocardial infarction (1%).

References

1. FDA approves encorafenib with binimetinib for metastatic non-small cell lung cancer with a BRAF V600E mutation. FDA. October 11, 2023. Accessed October 11, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-encorafenib-binimetinib-metastatic-non-small-cell-lung-cancer-braf-v600e-mutation
2. Encorafenib (Braftovi); Prescribing information. Pfizer Inc. Updated October 2023. Accessed October 11, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/210496s014lbl.pdf