Updated result from the phase 2 PHAROS study: has the sustained efficacy and tolerability of encorafenib plus binimetinib been demonstrated in patients with BRAF V600E-mutant metastatic non-small-cell lung cancer?

In non-small cell lung cancer (NSCLC), treatment is tailored to driver gene mutations, which are therapeutic targets (1,2). Activating mutations in the BRAF gene are generally mutually exclusive with epidermal growth factor receptor mutations and ALK rearrangements. BRAF V600E, the most frequent BRAF mutation, is found in 1–2% of lung adenocarcinomas (3,4). In clinical trials involving patients with advanced melanoma, the combination of BRAF and MEK inhibitors has demonstrated significantly superior antitumor effects compared with BRAF inhibitor monotherapy (5,6). In a phase II PHAROS study of the BRAF inhibitor encorafenib and the MEK inhibitor binimetinib in patients with BRAF V600E-mutant metastatic NSCLC, primary analysis reported a higher response rate than conventional chemotherapy (7). Specifically, the objective response rate (ORR) in an independent radiological review was 75% in treatment-naive patients (n=59), and 46% in previously treated patients (n=39) in the PHAROS study (7). The primary endpoint of ORR was met in both the treatment-naive and previously treated groups (7). However, at the data cutoff date of September 22, 2022, for the primary analysis, treatment was still ongoing in 25 (42%) treatment-naive patients and 8 (21%) previously treated patients. The median duration of response (DOR) was not estimable [not evaluable (NE); 95% confidence interval (CI): 23.1 months to NE] and 16.7 months (95% CI: 7.4 to NE), respectively (7). Furthermore, the median overall survival (OS) was NE in both groups (7). Riely et al. reported an updated analysis from the phase 2 PHAROS study that evaluated long-term efficacy, OS, and safety at 18 months after additional follow-up (8). Specifically, the median follow-up duration for progression-free survival (PFS) by independent radiology review extended from 18.2 months (95% CI: 16.4–22.3) to 33.3 months (95% CI: 30.4–41.3) for treatment-naive patients. In addition, it was from 12.8 months (95% CI: 9.0–19.8) to 14.0 months (95% CI: 11.3–44.2) for previously treated patients.

According to its design, the PHAROS trial (NCT03915951) is an ongoing, single-arm, open-label, multicenter phase II trial evaluating the activity of encorafenib plus binimetinib against tumors, as well as their safety in adult patients with BRAF V600E-mutant metastatic NSCLC who are either treatment-naive or previously treated (7,8). Patients received encorafenib (450 mg) orally once daily and binimetinib (45 mg) orally twice daily for 28-day cycles (7,8). The primary endpoint was confirmed as the ORR based on the Response Evaluation Criteria in Solid Tumors version 1.1, as assessed by an independent radiological review (7,8). Secondary endpoints included ORR confirmed by investigator assessment, DOR, disease control rate, PFS, OS, and safety (7,8).

The primary endpoint, confirmed ORR, has already been reported as achieved, with 75% (95% CI: 62–85%) in treatment-naive patients (n=59) and 46% (95% CI: 30–63%) in previously treated patients (n=39) (7). Notably, in the updated results, the median DOR was 40.0 months (95% CI: 23.1–NE) in treatment-naive patients and 16.7 months (95% CI: 7.4–NE) in previously treated patients. This confirmed the sustained efficacy of encorafenib plus binimetinib (8). Another combination therapy of BRAF and MEK inhibitors, dabrafenib plus trametinib, showed a response rate of 63.9% (95% CI: 46.2–79.2%) and median DOR of 10.2 months (95% CI: 8.3–15.2) in treatment-naive patients with BRAF V600E-mutant metastatic NSCLC (9). In pretreated patients in the study of dabrafenib plus trametinib, the response rate was 68.4% (95% CI: 54.8–80.1%) and median DOR was 9.8 months (95% CI: 6.9–18.3) (9). While the DOR for encorafenib plus binimetinib was numerically superior to that for dabrafenib plus trametinib, a cautious interpretation of these results is warranted, given the differences in study design, patient populations, small sample sizes, and wide 95% CIs. Specifically, the DOR and ORR results for encorafenib plus binimetinib were based on an independent radiological review, whereas those for dabrafenib plus trametinib were based on the investigator’s assessment.

Encorafenib plus binimetinib showed prolonged survival, with a median OS of NE (95% CI: 31.3 months to NE) in treatment-naive patients, and 22.7 months (95% CI: 14.1–32.2) in previously treated patients (8). In patients with metastatic NSCLC treated with immune checkpoint inhibitors (ICIs) and platinum-based chemotherapy (PBC), OS ranges from 17 to 22 months (10-13). No trials have directly compared ICI plus PBC therapy with encorafenib plus binimetinib therapy as a first-line treatment for BRAF V600E-mutant NSCLC. However, an indirect comparison was reported for the effectiveness of dabrafenib plus trametinib, another BRAF and MEK inhibitor combination, based on data from a previously reported clinical trial, versus real-world ICI plus PBC using a de-identified, electronic health record-derived database (14). For first-line treatment, the median OS was 17.3 months (95% CI: 12.3–40.2) for dabrafenib plus trametinib (n=36) versus 17.7 months (95% CI: 5.4–21.3) for PBC (n=34). In the weighted analysis, the hazard ratio for death was 0.56 (95% CI: 0.29–1.1), and the risk reduction with dabrafenib plus trametinib did not reach statistical significance (P=0.13) (14). Despite the limitations of the small sample size and limited observation period for PBC, dabrafenib plus trametinib may provide a prolongation of OS, comparable to that achieved with PBC therapy. Consistently, real-world data from other groups have also reported a tendency toward improved OS with dabrafenib plus trametinib compared with ICI-based therapy in the first-line setting of BRAF V600E-mutant NSCLC (15). Considering these reports and the favorable outcomes observed with encorafenib plus binimetinib therapy in the PHAROS trial, it may be reasonable to consider encorafenib plus binimetinib as a first-line treatment and ICI plus PBC as a second-line option.

In clinical practice, BRAF V600E mutations may be detected after treatment with other drugs, including ICI-based regimens. Although slightly inferior to the first-line outcomes in the PHAROS trial, encorafenib plus binimetinib therapy demonstrated favorable results in pretreated patients. Moreover, it is regarded as the preferred treatment option for second-line therapy and beyond (8).

The safety profile in this updated analysis was consistent with that reported in the primary analysis, and no new safety concerns were identified (8). The most frequently observed treatment-related adverse events were nausea (52%), diarrhea (44%), fatigue (33%), and vomiting (30%). However, the incidence of grade 3/4 events was less than 3%, indicating mild severity (8). The safety profile of encorafenib plus binimetinib is similar to that of dabrafenib plus trametinib, except for the risk of pyrexia (8,9). In a phase 2 trial of dabrafenib plus trametinib, any grade of pyrexia occurred in 56% of patients and grade 3 pyrexia in 6% of patients (9). Dose reduction was reported in 12% of cases due to pyrexia and discontinuation in 2% of cases (9). In contrast, with encorafenib plus binimetinib, pyrexia occurred in 12% of treatment-naive patients at any grade, with no grade 3 cases. Among previously treated patients, pyrexia occurred in 3% and no grade 3 cases occurred (8). This difference in pyrexia as a treatment-related adverse event may be an important consideration in the treatment of patients with BRAF V600E-mutant NSCLC. Furthermore, compared to ICIs plus PBC, encorafenib plus binimetinib exhibits mild toxicity (8,10-13). Given the favorable outcomes of encorafenib plus binimetinib, its use as first-line therapy for BRAF V600E-mutant NSCLC in clinical practice may be more beneficial than ICIs plus PBC.

An updated analysis of the PHAROS trial has confirmed that encorafenib plus binimetinib treatment resulted in durable responses and prolonged survival. The updated safety data did not reveal any new concerns. Pyrexia occurred less frequently and was milder than that observed with the other BRAF and MEK inhibitor regimens. Further research is required to establish the comparative effectiveness of encorafenib plus binimetinib as first-line treatment versus ICIs plus chemotherapy.

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