Encorafenib and biNimetinib Followed by CEmiplimab and FiAnLimab in Patients With BRAF Mutant melanOma and Symptomatic Brain Metastases

1. RATIONAL Melanoma with Brain Metastasis Background Brain metastases in patients with advanced and metastatic melanoma are a frequent complication and a significant cause of morbidity and mortality in this patient population. As the incidence of brain metastases continues to increase in patients with metastatic melanoma, it is urgent that the investigators identify effective therapies. Recent data have shown an incidence of brain metastases in ≤ 50% of patients with metastatic melanoma (Chukwueke U et al 2016). Because this is typically a late complication of systemic disease, melanoma-related brain metastases have been associated with significant neurologic morbidity and a poor median overall survival, with treatment, of approximately 9 months (Ramanujam S et al 2015). Factors that predict survival include age, performance status, and the number of brain metastases, which are summarized as the melanoma-specific graded prognostic assessment (Sperduto PW et al 2010). Systemic Therapy for Melanoma Patients with Brain Metastases Patients with BRAF-mutated melanoma and symptomatic brain metastases (SBM) have a high unmet medical need. On one hand, treatment with ipilimumab and nivolumab yields the best results in patients with asymptomatic disease, according to CM204 and ABC studies (Tawbi HA et al 2021)(Long GV et al 2021), but it has worse outcomes for patients with symptomatic disease, according to CM204 study (Tawbi HA et al 2021). On the other hand, targeted therapy with dabrafenib and trametinib yields a high response rate that is independent of the symptomatic status (Davies MA et al 2017) although the durability of these responses is usually short termed, in contrast with immunotherapy (Davies MA et al 2017). A phase I clinical trial has demonstrated a promising maintained activity with the combination of cemiplimab and fianlimab in patients with unresectable or metastatic melanoma who were all naïve to anti-PD-1 therapy for advanced disease (n=98). The ORR was 61%, the median progression-free survival (PFS) was 15 months (Hamid O et al 2023). The combination is currently being investigated in patients with melanoma at diverse stages (Baramidze A et al 2023)(Panella TJ et al 2023). Additionally, the relativity clinical trial has demonstrated an improvement of PFS with the combination of nivolumab and relatlimab in comparison to nivolumab (Tawbi HA et al 2022), although patients with brain metastases were underrepresented. In addition, a previous communication suggests that the treatment with immunotherapy is not as efficacious for patients with BRAF-mutated melanoma and brain metastases previously treated and progressed to targeted therapy (Lau PKH et al 2021). The sandwich approach (starting with targeted therapy based in encorafenib and binimetinib followed by dual immune checkpoint blockade without waiting to progression) has been demonstrated that sequencing targeted and immunotherapy is a feasible strategy in the SECOMBIT clinical trial (Ascierto PA et al 2021). Recetly, the Spanish Melanoma Group (GEM) has published the results of the EBRAIN/GEM1802 clinical trial, evaluates the treatment with encorafenib and binimetinib (EB) followed by radiotherapy in symptomatic and asymtomatic patients with BRAF mutated melanoma and brain metastases, showing and intracranial objective response of 70.8% and complete response of 10.4%. This clinical trial also explores if radiotherapy after achieving an objective response or stable disease in the brain could improve the intracranial progression free survival (icPFS). Median icPFS and OS were 8.5 and 15.9 months, respectively (8.3 months for icPFS and 13.9 months OS for patients receiving radiotherapy). In conclusion, encorafenib plus binimetinib showed promising clinical benefit in terms of icRR and tolerable safety profile. Sequential radiotherapy is feasible but it does not seem to prolong response (Marquez-Rodas I et al 2024). 2. HYPOTHESIS For patients with BRAF-mutated melanoma and symptomatic brain metastases, an induction treatment with encorafenib and binimetinib (EB) for about two months (i.e. 8 weeks) followed by cemiplimab plus fianlimab (CF) would allow a 6 month icPFS rate of 40% in comparison to historical control of 20% based on CM204 symptomatic arm (Margolin KA et al 2021). 3. STUDY TREATMENTS Induction treatment with oral encorafenib 450 mg once daily (QD) + binimetinib 45 mg twice daily (BID)(combination: EB) for approximately two months (i.e. 8 weeks) followed by cemiplimab 350 mg + fianlimab 1600 mg combination every 3 weeks (Q3W)(Combination: CF) administered to patients intravenously (IV) for up to two years. Treatment may be discontinued due to death, PD or non-acceptable toxicity. Encorafenib plus binimetinib should be discontinued at least 72 hours prior to the first dose of cemiplimab plus fianlimab. Rechallenge with encorafenib 450mg QD + binimetinib 45 mg BID will be mandatory for those patients that progress under CF, with the exception of patients with intracranial response or stabilization and only extracranial PD in which case CF could be continued at the physician criteria. In the case of continuing treatment with CF, tumor assessment should be repeated after 8 weeks to confirm the progression and the benefit of CF to the brain. 4. OBJECTIVES Primary Objectives To evaluate the 6 month intracranial progression-free survival (icPFS) proportion of Encorafenib plus Binimetinib followed by Cemiplimab plus Fianlimab in patients with BRAF-mutated melanoma and symptomatic brain metastases. Secondary Efficacy Objectives To assess the following efficacy endpoints: * 12 month icPFS rate * Intracraneal PFS (icPFS) * Extracraneal PFS (ecPFS) * Global PFS (PFS) * Overall survival (OS) * Intracranial objective response rate (icORR) at 2 and 6 months * Extracraneal ORR (ecORR) at 2 and 6 months * Basal Quality of Life (QoL), at 2 and 6 months * Basal systemic steroids decrease at 2 and 6 months * Modified Barthel index improvement at 2 and 6 months Secondary Safety Objectives To assess the following the safety profile of the combination through continuous assessment of Adverse events (AE) and Treatment-related AEs (TRAEs). Secondary Exploratory Objectives To evaluate the correlation between biomarkers and the clinical outcomes of treatment with encorafenib plus binimetinib followed by cemiplimab plus fianlimab in patients with BRAF-mutated melanoma and symptomatic brain metastases. 5. ENDPOINTS The primary endpoint for ENCEFALO is the 6 month intracranial progression-free survival (icPFS), defined as the proportion of patients alive and free of icPFS according to modified RECIST criteria at 6 month evaluation (week 24 +/- 3 weeks) after the start of study treatment. The icPFS will be assessed locally by investigators. Secondary Efficacy Endpoints * 12-months icPFS: Percentage of patients free of icPFS according to modified RECIST criteria at 12 month evaluation (week 48 +/- 3 weeks). * icPFS locally assessed according to modified RECIST criteria, median and global curve estimated by kaplan meier method * ecPFS locally assessed according to modified RECIST criteria, median and global curve estimated by kaplan meier method * PFS locally assessed according to modified RECIST criteria, median and global curve estimated by kaplan meier method * OS locally assessed, median and global curve estimated by kaplan meier method * Change in patient reported outcomes in Health-related quality of life (HRQoL), assessed through the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) version 3. * Changes in Barthel score from baseline. * Change in systemic steroids usage from baseline. Secondary Safety Endpoints Type, incidence, frequency, severity and relation to the treatment of reported adverse events, physical examinations and laboratory tests: * Frequency and severity of adverse events assessed by NCI CTCAE v5.0. * Frequency of treatment-related adverse events (TRAEs) assessed by NCI CTCAE v5.0. * Frequency of AEs leading to treatment discontinuation. Secondary Exploratory Endpoints * Expression of circulating tumor DNA (ctDNA) in blood samples at several time points throughout the study treatment. * Presence of peripheral blood mononuclear cells (PMDCs) in blood samples at several time points throughout the study treatment. 6. STUDY DESIGN The trial will enroll competitively up to 33 patients. The study will enroll the first 18 patients and monitor for progression at 6 months (24-weeks assessment). If there are 4 or less patients free of progression at the 6-months tumor assessment the accrual will be closed. Otherwise, a minimum of 15 additional patients will be accrued for a total of 33 evaluable patients. All patients will have a histologically confirmed diagnosis of unresectable metastatic BRAF-mutated melanoma, with one or more brain metastases with a diameter of 5 to 50 mm and symptomatology associated with the disease, defined as symptom related with intracranial hypertension or cognitive impairment. all patients will be ≥ 18 years and ECOG PS 0-2 (See Section 8 for further detail on eligibility). The design includes a screening phase in which patient eligibility is addressed, a treatment phase, and a follow-up phase. Study treatment will begin as soon as possible after signing the informed consent and inclusion will be completed as is indicated in protocol. All enrolled patients will receive an induction treatment with oral encorafenib 450 mg once daily (QD) + binimetinib 45 mg twice daily (BID)(combination: EB) for approximately two months (i.e. 8 weeks) followed by cemiplimab 350 mg + fianlimab 1600 mg combination every 3 weeks (Q3W)(Combination: CF) administered to patients intravenously (IV) for up to 2 years. Treatment may be discontinued due to death, PD or non-acceptable toxicity . Rechallenge with encorafenib 450mg QD + binimetinib 45 mg BID will be mandatory for those patients that progress under CF, with the exception of patients with intracranial response or stabilization and only extracranial PD in which case CF could be continued at the physician criteria. In the case of continuing treatment with CF, tumor assessment should be repeated after 8 weeks, and no longer, to confirm the progression and the brain benefit. The primary endpoint is efficacy determined by the 6-month icPFS proportion. All patients will undergo periodic mandatory tumor assessments by CT or MRI scan every 8 weeks ± 7 days for the first year from the start of study treatment and recommended every 12 weeks ± 7 days afterwards until progression or patient withdrawal. Further CT/MRI scans could be performed upon suspicion of disease progression according to standard clinical practice and physician criteria. Safety will be assessed at every visit through continuous monitoring of signs and symptoms and periodic laboratory analysis. 7. SAMPLE SIZE Using Simon's two-stage Minimax design (Simon R 1989), assuming the null hypothesis as the rate of patients not progressing in the brain at 6 months (defined as a success) is about 20% (Tawbi et al. 2021), will be tested against a one-sided alternative (40%). In the first stage Simon's two-stage minimax design, 18 patients will be accrued. If there are ≤4 successes (defined as patients not progressing at 6 months) in these 18 patients, the study will be stopped. Otherwise, a minimum of 15 additional patients will be accrued for a total of 33 evaluable patients.