Encorafenib plus binimetinib for BRAF V600E-mutant metastatic NSCLC: clinical implications of the phase 2 PHAROS study

Abstract

Drs. Ramalingam and Carlisle discuss the incidence and pathophysiology of BRAF V600E-mutant metastatic non-small cell lung cancer and current treatment options. The podcast provides an overview of the data from the recent Pfizer-sponsored phase 2 PHAROS (NCT03915951) study, which were the basis for the recent US Food and Drug Administration approval of encorafenib plus binimetinib for BRAF V600E-mutant metastatic non-small cell lung cancer.

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1. Podcast transcript

Welcome to the podcast. This podcast was supported by Pfizer, with editorial support provided by Caitlin Cash, PhD, of Nucleus Global and funded by Pfizer.

SR: Hello, my name is Suresh Ramalingam, and I'm the Executive Director of the Winship Cancer Institute of Emory University and also serve as the Roberto C. Goizueta Chair for Cancer Research.

JC: Hi, my name is Jennifer Carlisle. I'm an Assistant Professor in the Department of Hematology and Medical Oncology at the Winship Cancer Institute of Emory University.

In today's podcast, we will be discussing the incidence and pathophysiology of BRAF V600E-mutant metastatic non-small cell lung cancer and current treatment options. We will provide an overview of the efficacy and safety data from the phase 2 PHAROS study, which was the basis for the FDA approval of encorafenib plus binimetinib for patients diagnosed with BRAF V600E-mutant metastatic non-small cell lung cancer.

SR: Jennifer, can you provide us first with an overview of BRAF mutations?

JC: Sure. The BRAF gene encodes a protein involved in the mitogen-activated protein kinase or MAPK pathway, and dysregulation of this pathway leads to uncontrolled cell growth, dedifferentiation and proliferation [1,2]. BRAF mutations occur in several different solid tumors, including approximately 40% of melanomas, a third of thyroid cancers, 9% of colorectal cancers, and 2–4% of non-small cell lung cancers [3,4]. BRAF mutations are divided into three classes [2,5]. The most common BRAF mutation is class I in which the valine at codon 600 is substituted for glutamic acid, resulting in an approximately 500-fold increase in BRAF kinase activity. We call this mutation BRAF V600E, and it accounts for approximately 2% of all non-small cell lung cancer cases [3,5,6].

In contrast to other oncogenic drivers, BRAF mutations are not clearly associated with specific characteristics other than the high frequency of adenocarcinoma histology, which accounts for over 85% of the BRAF-mutant non-small cell lung cancers [4,6,7]. Smoking history can be associated with BRAF mutations, but a few studies have indicated that this association is less apparent with the BRAF V600E versus other BRAF mutations [4,8–10]. So, BRAF V600E is an actionable molecular biomarker for metastatic non-small cell lung cancer [11,12] with two FDA-approved combination regimens, including the most recently approved combination of encorafenib plus binimetinib [13,14]. Suresh, can you explain actionable biomarkers, and how they are important in determining optimal therapy for non-small cell lung cancer?

SR: An actionable biomarker is one that has a targeted treatment that has demonstrated improved outcomes in the patient population [4,7]. In non-small cell lung cancer, there is a growing number of genomic alterations that can be detected by biomarker testing. These include EGFR, ALK, BRAF, HER2, KRAS, MET, NTRK, RET and ROS1 [7,11]. There are also additional biomarkers, such as PD-L1 expression, which may identify patients that are likely to respond to immunotherapy [15,16]. The current guidelines recommend that all patients with advanced or metastatic non-small cell lung cancer undergo broad-based molecular testing for actionable biomarkers and also PD-L1 expression [11,17]. Biomarker testing and appropriate therapy guided by that are associated with improved patient outcomes [18,19]. So, we recommend that treatment not be initiated until biomarker test results are received to ensure that optimal therapy is selected in the first-line setting, except for rare situations where waiting for results is not an option. Now Jennifer, what are the current treatment options for patients with BRAF V600E-mutated metastatic non-small cell lung cancer?

JC: Well, BRAF inhibitor monotherapy, such as vemurafenib or dabrafenib, was initially studied, but the clinical benefit was limited by resistance from a reactivated MAPK pathway [13,20,21]. The combination of BRAF and MEK inhibitors provided synergistic antitumor activity by inhibiting two steps in the pathway; these combinations have prolonged clinical benefit compared to BRAF inhibitor monotherapy with a manageable safety profile [13,22–25]. The addition of the MEK inhibitor to a BRAF inhibitor has been shown to overcome or delay acquired resistance as well as reduce the occurrence of hyperproliferative cutaneous events, like squamous cell carcinoma [13,21,22,26,27]. Encorafenib plus binimetinib, as well as dabrafenib plus trametinib, are BRAF plus MEK inhibitor combinations approved for patients with BRAF V600E-mutant metastatic non-small cell lung cancer [13,14].

In contrast to class I BRAF mutations, class II and III result in dimers [2,5]. Current BRAF inhibitors are not effective for class II and III mutations due to paradoxical activation [2,28,29]. In this case, when the inhibitor binds to one monomer, it activates the second monomer in the dimer. So, targeted therapy for non-V600 BRAF mutations remains an unmet need and there are ongoing preclinical and clinical trials looking for novel drugs that inhibit dimers or disrupt dimerization [2,29–31]. Our current guidelines recommend that patients with BRAF V600E-mutant metastatic non-small cell lung cancer receive encorafenib plus binimetinib or dabrafenib plus trametinib as preferred first-line options or subsequent treatment when not prescribed in the first-line [11,17]. Immunotherapy, chemotherapy, or a combination of the two are also alternative options. So, Suresh, the FDA approval of encorafenib plus binimetinib for BRAF V600E-mutant metastatic non-small cell lung cancer was based on the phase 2 PHAROS study. Can you briefly describe the study design?

SR: Sure. PHAROS is an ongoing, single-arm, open-label, phase 2 trial. It evaluates the safety and efficacy of encorafenib plus binimetinib in patients with BRAF V600E-mutated non-small cell lung cancer metastatic disease [24]. Patients were required to have received either no or only one prior first-line treatment, which could not have been a BRAF or a MEK inhibitor [32]. Patients with symptomatic brain metastases, leptomeningeal disease or other active CNS metastases were excluded. Of the 98 patients enrolled, 59 were treatment-naive and 39 were previously treated [24]. Patients received encorafenib at a dose of 450 mg once daily and binimetinib at a dose of 45 mg twice daily, and the treatment was continued until disease progression or unacceptable toxicity. Overall, the median age was 70 years, 53% of the patients were women, 88% were White, 70% of the patients had a prior or current history of smoking and 8% of the patients had baseline brain metastases [24]. Of the previously treated patients, 62 and 46% had received prior immunotherapy and chemotherapy, respectively. Jennifer, can you review the results, specifically related to efficacy from the PHAROS trial for us?

JC: Yeah. The primary end point was objective response rate according to RECIST version 1.1 assessed by independent radiology review [24]. In treatment-naive patients, the objective response rate was 75%, with a median duration of response that was not estimable, and median time to response of 1.9 months. And this is based on a median duration of follow-up for PFS of 18.2 months. And here in these treatment-naive patients, median PFS and median OS were not reached.

In previously treated patients, the objective response rate was 46%, with median duration of response of 16.7 months, and time to response 1.7 months [24]. The median duration of follow-up in this group of patients was 12.8 months. And here in the previously treated patients, median PFS was 9.3 months, and median OS was not estimable. In previously treated patients, the objective response rate was 58% in the 24 who had received prior immunotherapy and 27% in the other 15 previously treated patients. In these previously treated patients, the objective response rate for their first-line therapy was 24% when it was immunotherapy and 22% when chemotherapy alone. What are the common adverse reactions observed in PHAROS, and what do you recommend for management?

SR: While the published PHAROS paper reported treatment-related adverse events, the FDA labels report all-causality adverse events or ARs [24,33,34]. So today, we will focus on ARs. The most frequent ARs were fatigue in 61% of the patients, nausea in 58%, diarrhea in 52% and musculoskeletal pain in 48% of patients [33,34]. Serious adverse reactions occurred in 38% of patients, with hemorrhage being the most common with 6%. Pyrexia was observed in 22% of the patients, with all of them being grade 1 or 2 [33].

The adverse reactions were generally managed with dose modifications [24,33,34]. With encorafenib, adverse reactions led to dose interruptions in 59% of the patients, and diarrhea was the most common reason at 17%; dose reduction was required in 30% of the patients, with diarrhea and nausea being the most common reasons at 8% each; permanent discontinuation of encorafenib was required in 16% of the patients, and the reasons were primarily diarrhea and musculoskeletal pain at 3% each [33]. With binimetinib, adverse reactions led to dose interruption in 62% of the patients, with diarrhea as the most common reason at 17%; dose reduction was required in 33% of the patients, with diarrhea accounting for 8% of those; and permanent discontinuation of binimetinib was required in 17% of the patients, with diarrhea being the most common reason at 3% [34].

The adverse reactions with encorafenib plus binimetinib can be generally managed with over-the-counter medications, lifestyle changes and proactive communication [35]. For instance, gastrointestinal disorders, such as nausea, diarrhea and vomiting, are some of the most commonly reported adverse reactions [33,34]. So, antiemetics, antidiarrheal medications and changes in eating habits may relieve discomfort for patients, and maintaining hydration can reduce the risk of further complications [35]. Recurrent or high-grade adverse reactions may require dose modifications, such as dose interruption or reduction [33,34]. Overall, proactive management of the adverse reactions may help patients from unnecessarily discontinuing treatment and enable patients to remain on treatment while deriving clinical benefit. Jennifer, having reviewed these results, how do you see them fitting into the current treatment landscape?

JC: As you know, due to differences in study design, analyses, and patient populations, comparisons across trials have significant limitations. The objective response rate with dabrafenib plus trametinib was 64% in the treatment-naive patients and 63% in previously treated patients [22,23]. Median PFS was 10.9 and 9.7 months, respectively. From a safety perspective, pyrexia is a common challenge for patients receiving dabrafenib plus trametinib, with pyrexia observed in 55% of patients, including 5% with grade 3/4 events [36].

Studies evaluating immunotherapy and chemotherapy for BRAF V600E-mutant advanced non-small cell lung cancer are limited by small patient numbers, retrospective analyses, and conflicting results [6,16,37–39]. While immunotherapy, chemotherapy, and combinations are not specifically FDA approved for patients with BRAF V600E-mutant metastatic non-small cell lung cancer, they are approved in the metastatic setting in patients with non-small cell lung cancer without oncogenic drivers [40,41]. There are retrospective studies with small patient numbers that evaluated the efficacy of immunotherapy monotherapy regardless of line of treatment for patients with BRAF V600E mutations. And here the objective response rate ranged from 25 to 38%, and median PFS ranged from 1.8 to 10.5 months [37,42,43]. In other retrospective studies with small numbers looking at chemotherapy plus immunotherapy regardless of line of treatment in the BRAF V600E mutation setting, objective response rates ranged from 44 to 63%, median PFS ranged from 11.0 to 12.6 months [44,45]. And median PFS was longer when immunotherapy and chemotherapy were used in the first versus later lines with a median PFS of 18.5 months in the front-line setting compared to 1.9 months in later lines [44]. So, Suresh, what approach should be taken if a patient with high PD-L1 expression and a history of smoking also has a BRAF V600E mutation?

SR: High PD-L1 expression, which is defined as tumor proportion score of ≥50%, is a potential indicator of immunotherapy response; in patients with advanced stage non-small cell lung cancer, high PD-L1 co-expression with BRAF V600E mutations occurs in approximately 42–48% of the cases [16,37]. Analyses of patients with a BRAF V600E mutation and high PD-L1 expression are further limited by smaller patient populations and retrospective studies with inconsistent data [16,37]. One study compared the efficacy of immunotherapy in six patients with that of dabrafenib plus trametinib in four patients [37]. With immunotherapy, two patients had tumors shrink, and three patients had tumors grow. With dabrafenib plus trametinib, all four patients had tumor shrinkage. Based on the current evidence and guideline recommendations, patients with a BRAF V600E mutation and PD-L1 expression should receive a BRAF plus MEK inhibitor combination in the front-line setting [11].

JC: Thank you, Suresh. As we conclude our discussion, what are three takeaways for listeners?

SR: First, all patients with advanced or metastatic non-small cell lung cancer should be tested for actionable biomarkers as this is critical to selecting the optimal first and subsequent treatments for the patient [11,18,19]. Then, patients with an actionable biomarker should receive targeted therapy for their identified mutation [19]. Targeted therapies are changing the outcomes of patients with lung cancer very favorably. With the approval of encorafenib plus binimetinib, we have an additional option with a manageable safety profile for patients with BRAF V600E-mutated metastatic non-small cell lung cancer [14]. Thank you for listening.

Funding Statement

S Ramalingam reports a consulting or advisory role with GlaxoSmithKline; research funding to institution from AbbVie, Bristol Myers Squibb, Pfizer, Merck, AstraZeneca/MedImmune, Vertex, Takeda, EMD Serono, Genmab, Advaxis and Amgen; and travel and accommodation expenses from AstraZeneca and AbbVie.

Supplemental material

Supplemental data for this article can be accessed at https://doi.org/10.1080/14796694.2024.2391270

Author contributions

All authors contributed to all stages of this podcast and approved the final version prior to publication.

Financial disclosure

S Ramalingam reports a consulting or advisory role with GlaxoSmithKline; research funding to institution from AbbVie, Bristol Myers Squibb, Pfizer, Merck, AstraZeneca/MedImmune, Vertex, Takeda, EMD Serono, Genmab, Advaxis and Amgen; and travel and accommodation expenses from AstraZeneca and AbbVie.

J Carlisle reports personal fees for advisory board from Sanofi, Amgen, and Novocure and research funding to institution from AstraZeneca, Amgen, Hutchmed and Parexel. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

Medical writing support was provided by Caitlin Cash, PhD, of Nucleus Global and was funded by Pfizer.