A phase II PHAROS study represents the first clinical trial of encorafenib plus binimetinib in patients with BRAFV600E-mutated metastatic non-small cell lung cancer (NSCLC); the combination treatment showed substantial antitumour activity in this population. The protocol-defined primary endpoint was met, with an objective response rate (ORR) of 75% in treatment-naïve and 46% in previously treated patients. Objective responses were durable.
Safety profile is consistent with that seen in the approved indication in melanoma. The findings are reported at 2023 ASCO Annual Meeting on 4 June in Chicago, IL, US along with a simultaneous publication in the Journal of Clinical Oncology by Dr. Gregory J. Riely of the Memorial Sloan Kettering Cancer Center in New York, NY, US, and colleagues.
Somatic activating mutations in BRAF occur in approximately 3-5% of patients with NSCLC. BRAFV600E mutation accounts for 50% of all BRAF mutations in lung cancer. BRAFV600 mutations are class I RAS-independent mutations that confer sensitivity to BRAF inhibition. BRAF mutations also occur in patients with other solid tumours, including melanoma, colorectal cancer, papillary thyroid cancer, diffuse gliomas, and cholangiocarcinoma.
Encorafenib is an oral, selective, reversible small-molecule RAF kinase inhibitor, with a long dissociation half-life of >30 hours. Binimetinib is an oral, ATP-uncompetitive, reversible inhibitor of MEK1 and MEK2 activation. In patients with BRAFV600E/K-mutated metastatic melanoma, encorafenib in combination with binimetinib demonstrated clinical benefit with an acceptable safety profile.
Currently, dabrafenib plus trametinib is the only approved targeted therapy available for patients with BRAFV600-mutated metastatic NSCLC. The approvals were based on the results of a single-arm phase II study, in which treatment with dabrafenib plus trametinib led to meaningful antitumour activity and a manageable safety profile in this patient population. ORR by independent review committee was 64% in treatment-naïve patients and 63% in previously treated patients; median progression-free survival (PFS) was 14.6 and 8.6 months.
The authors wrote in the background that given the observed efficacy and safety profile of encorafenib plus binimetinib in patients with BRAFV600-mutated metastatic melanoma, this combination was assessed in the phase II PHAROS study in patients with BRAFV600E-mutated metastatic NSCLC. The PHAROS is an ongoing, open-label, single-arm, phase II study, in which the patients with BRAFV600E-mutated metastatic NSCLC received oral encorafenib 450 mg once daily plus binimetinib 45 mg twice daily in 28-day cycles. The primary endpoint was confirmed ORR by independent radiology review (IRR). Secondary endpoints included duration of response (DoR), disease control rate (DCR), PFS, overall survival (OS), time to response, and safety.
At data cut-off, 98 patients of whom 59 treatment-naïve and 39 previously treated with BRAFV600E-mutated metastatic NSCLC received encorafenib plus binimetinib. Median duration of treatment was 9.2 months with encorafenib and 8.4 months with binimetinib. ORR by IRR was 75% (95% confidence interval [CI] 62 to 85) in treatment-naïve and 46% (95% CI 30 to 63) in previously treated patients.
Median DoR was not estimable (NE; 95% CI 23.1 to NE) and 16.7 months (95% CI 7.4 to NE). DCR after 24 weeks was 64% in treatment-naïve and 41% in previously treated patients. Median PFS was NE (95% CI 15.7 to NE) in treatment-naïve and 9.3 months (95% CI 6.2 to NE) in previously treated patients.
Although the sample size was small, encorafenib plus binimetinib showed antitumour activity in 4 of 8 patients with baseline brain metastases; all 4 of the treatment-naïve patients and none of the previously treated patients had an objective response. The authors commented that it is the first study to show intracranial activity with BRAF plus MEK inhibitors in patients with BRAFV600E-mutated metastatic NSCLC.
In the 5-year update of the phase II study of dabrafenib plus trametinib, investigator-assessed ORRs were similar between treatment-naïve patients and previously treated patients. The similarity in response rates for first-line and second-line therapy differs from observations in the PHAROS study. The high ORR observed with encorafenib plus binimetinib in the treatment-naïve group suggests that patients with BRAFV600-mutated metastatic NSCLC should receive targeted therapies as their initial therapy.
The authors wrote that in the PHAROS study, they used a targeted NGS panel to confirm BRAFV600E mutations, identify the most common concurrent alterations, and explore whether pretreatment molecular alterations could identify patients either more or less likely to benefit from encorafenib plus binimetinib. Although patients commonly had concurrent baseline mutations in several genes, with those in SETD2, TP53, and SMAD4 occurring most frequently, these alterations were not significantly associated with response to treatment. They commented as larger data sets become available, it will be important to assess whether these lower-frequency alterations are associated with patient outcomes.
Although the patient numbers were small and 95% CIs are overlapping, the ORRs appear to be lower for current smokers in the PHAROS study. Smoking can induce CYP1A2 isoform, which has been shown to lower the exposure to binimetinib and may explain the lower response in this study. Patients with smoking history often have more co-mutations; in the current study, co-mutations were not associated with patient outcomes. Additional data are needed to assess the impact of smoking on response to encorafenib plus binimetinib and determine the optimal treatment for patients with BRAF mutations with smoking history.
The most frequent treatment-related adverse events (TRAEs) were nausea (50%), diarrhoea (43%), and fatigue (32%). TRAEs led to dose reductions in 24 patients and permanent discontinuation of encorafenib plus binimetinib in 15 patients. One grade 5 TRAE of intracranial haemorrhage was reported.
In an accompanied editorial article, Dr. Thomas E. Stinchcombe of the Division of Medical Oncology, Duke Cancer Institute in Durham, NC, US wrote that the efficacy results from the studies of dabrafenib and trametinib, as well as encorafenib and binimetinib, are based on small number of patients, the 95% CI of the efficacy assessments are wide, and the duration follow-up differs among the studies. Given the uncertainty of cross-trial comparison, it is not possible to determine if one combination has superior efficacy. Consequently, attention will focus on the rate of AEs and tolerability. The most notable difference is in the rate of pyrexia. The rate of all grade pyrexia with encorafenib and binimetinib was 22%, and with dabrefenib and trametinib in the previously untreated patients, the rate of grade 1 or 2 and grade 3 were 53% and 11%.
The editorialist also wrote that given the rarity of BRAFV600E-mutated NSCLC and the incidence of each of the concurrent mutations, a registry would be the best method of developing a larger cohort of patients to further investigate the role of concurrent mutations. Dr. Stinchcombe further commented that it is unlikely there will be a phase III study comparing the two combinations, given the rarity of the BRAFV600E mutations and wide availability of the two combinations. Importantly, the better outcomes with both combinations observed in the untreated patients indicate that these agents should be used as first-line treatment. It also emphasises the importance of molecular testing for BRAF mutations at the time of diagnosis and having the results available before selecting a first-line treatment.
The PHAROS study was supported by Pfizer.
