Encorafenib plus binimetinib in patients with BRAF(V)(600)-mutant non-small cell lung cancer: Phase II PHAROS study design

BRAF(V600) oncogenic driver mutations occur in 1-2% of non-small cell lung cancers (NSCLCs) and have been shown to be a clinically relevant target. Preclinical/clinical evidence support the efficacy and safety of BRAF and MEK inhibitor combinations in patients with NSCLC with these mutations. We describe the design of PHAROS, an ongoing, open-label, single-arm, Phase II trial evaluating the BRAF inhibitor encorafenib plus the MEK inhibitor binimetinib in patients with metastatic BRAF(V600) -mutant NSCLC, as first- or second-line treatment. The primary endpoint is objective response rate, based on independent radiologic review (per RECIST v1.1); secondary objectives evaluated additional efficacy endpoints and safety. Results from PHAROS will describe the antitumor activity/safety of encorafenib plus binimetinib in patients with metastatic BRAF(V600)-mutant NSCLC.Lay abstract: Some people with non-small cell lung cancer (NSCLC) have changes in a gene called BRAF (known as 'gene mutations'). One common BRAF mutation is called 'V600'. Combinations of medicines that block proteins encoded by mutant BRAF and another gene called MEK can shrink tumors and slow their progression. We describe the design of PHAROS, a clinical trial investigating encorafenib (mutant BRAF inhibitor) combined with binimetinib (MEK inhibitor) in people with BRAF(V600)-mutant NSCLC that had spread to other parts of the body ('metastatic disease'). People are monitored for side effects and to see if their tumor shrunk. PHAROS includes people treated with encorafenib plus binimetinib as their first treatment for metastatic disease, and people whose cancer progressed after previous anticancer therapy.Pathogenesis and treatment of chronic pulmonary disease

Phase II, open-label study of encorafenib plus binimetinib in patients with BRAFV600-mutant metastatic non-small-cell lung cancer

PURPOSE The combination of encorafenib (BRAF inhibitor) plus binimetinib (MEK inhibitor) has demonstrated clinical efficacy with an acceptable safety profile in patients with BRAF(V600E/K)-mutant metastatic melanoma. We evaluated the efficacy and safety of encorafenib plus binimetinib in patients with BRAF(V600E)-mutant metastatic non-small-cell lung cancer (NSCLC).METHODS In this ongoing, open-label, single-arm, phase II study, patients with BRAF(V600E)-mutant metastatic NSCLC received oral encorafenib 450 mg once daily plus binimetinib 45 mg twice daily in 28-day cycles. The primary end point was confirmed objective response rate (ORR) by independent radiology review (IRR). Secondary end points included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival, time to response, and safety.RESULTS At data cutoff, 98 patients (59 treatment-naive and 39 previously treated) with BRAF(V600E)-mutant 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% CI, 62 to 85) in treatment-naive 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), respectively. DCR after 24 weeks was 64% in treatment-naive and 41% in previously treated patients. Median PFS was NE (95% CI, 15.7 to NE) in treatment-naive and 9.3 months (95% CI, 6.2 to NE) in previously treated patients. The most frequent treatment-related adverse events (TRAEs) were nausea (50%), diarrhea (43%), and fatigue (32%). TRAEs led to dose reductions in 24 (24%) and permanent discontinuation of encorafenib plus binimetinib in 15 (15%) patients. One grade 5 TRAE of intracranial hemorrhage was reported. Interactive visualization of the data presented in this article is available at the PHAROS dashboard ().CONCLUSION For patients with treatment-naive and previously treated BRAF(V600E)-mutant metastatic NSCLC, encorafenib plus binimetinib showed a meaningful clinical benefit with a safety profile consistent with that observed in the approved indication in melanoma.Pathogenesis and treatment of chronic pulmonary disease

Epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of non-small-cell lung cancer: results and open issues

The medical treatment of non-small-cell lung cancer (NSCLC) has progressively changed since the introduction of “targeted therapy”. The development of one of these molecular drug categories, e. g., the epidermal growth factor receptor (EGFR) tyrosine-kinase (TK) selective inhibitors, such as the orally active gefitinib and erlotinib, offers an interesting new opportunity. The clinical response rates obtained with their employment in unselected patient populations only account for approximately 10%. Because of this, over the last two years numerous studies have been performed in order to identify the patient subsets that could better benefit from these agents. Not only patient characteristics and clinical-pathological features, such as never-smoking status, female gender, East Asian origin, adenocarcinoma histology, bronchioloalveolar subtype, but also molecular findings, such as somatic mutations in the EGFR gene, emerge as potentially useful prognostic and predictive factors in advanced NSCLC. Further, specifically designed clinical trials are still needed to completely clarify these and other open issues that are reviewed in this paper, in order to clarify all the interesting findings available in the clinical practice