Dabrafenib, Alone or in Combination with Trametinib, in Pediatric Patients with BRAF V600 Mutation-Positive Langerhans Cell Histiocytosis

Introduction: Langerhans cell histiocytosis (LCH) is a rare proliferative disorder associated with varied clinical presentations. Patients (pts) with advanced disease have frequent recurrences despite standard chemotherapy and a significant proportion experience long-term complications, including orthopaedic, endocrine, auditory, or neurodegenerative complications. BRAF V600 mutations have been reported in over 50% of LCH cases. The BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib is approved for BRAF V600-mutation positive melanoma, NSCLC, and anaplastic thyroid cancer. Here we describe the pooled analysis of pts with LCH from two open-label phase I/II studies in pediatric pts with recurrent/refractory malignancies, treated with dabrafenib monotherapy (CDRB436A2102; NCT01677741) or dabrafenib plus trametinib (CTMT212X2101; NCT02124772). Results: At the data cut-off date of January 19, 2021, 13 pts with LCH had received dabrafenib monotherapy (n=2, escalation; n=11, expansion). Median age was 3 years (range, 1-11) and all pts had received prior chemotherapy (100%); one patient received prior immunoglobulin and prior anti-CD52 monoclonal antibody (8%). Median duration of exposure to dabrafenib was 51 months (range, 7-65); 7 pts continued treatment on a rollover study and 6 discontinued, due to adverse events (AE; n=2), investigator decision (n=3), or switch to combination therapy via compassionate use (n=1). All pts experienced AEs, regardless of relationship to treatment; 11 pts (85%) had grade ≥3 AEs. All pts experienced AEs, suspected to be related to treatment, most commonly vomiting (46%), increased creatinine (38%), dry skin, rash, and melanocytic naevus (each 30%). AEs led to treatment discontinuation in 2 pts (increased blood creatinine; Epstein-Barr virus associated lymphoma, not related to treatment); there were no on-treatment deaths. The overall response rate (ORR) was 77% (6 complete response [CR]; 4 regressive disease [RD]); median duration of response (DOR) was not reached (NR), the estimated 24-month DOR rate was 90% (95% CI, 40-100). Median PFS was NR; the estimated 24-month PFS rate was 90% (95% CI, 50-100). At the data cut-off date of February 10, 2021, 12 pts with LCH had received dabrafenib + trametinib combination (2, escalation; 10, expansion). Median age was 4 years (range, 2-13) and all pts had received prior chemotherapy (100%). Median duration of exposure to treatment was 22 months (range 1.8-35.9); 8 patients continued therapy on a rollover study and 4 discontinued, due to AEs (n=2), lack of efficacy (n=1), or long term CR (n=1). All pts experienced AEs; 9 pts (75%) had grade ≥3 AEs. All pts experienced AEs, suspected to be related to treatment, most commonly pyrexia (58%), diarrhoea, dry skin, decreased neutrophil count, and vomiting (each 42%). AEs led to treatment discontinuation in 2 pts (AST increased; ALT increased); there were no on-treatment deaths. The ORR was 58% (4 CR; 3 RD); median DOR was NR, the estimated 24-month DOR rate was 100% (95% CI, NR-NR). Median PFS was NR; the estimated 24-month PFS rate was 100% (95% CI, NR-NR). Conclusions: Dabrafenib, with or without trametinib, demonstrated durable efficacy in pediatric pts with relapsed/refractory BRAF V600E mutation-positive LCH, with 90-100% of responses ongoing at 24 months. Treatment was associated with acceptable tolerability and manageable toxicities; the safety profile was consistent with what has been seen in other pediatric indications and in adult studies. Disclosures Whitlock: Sobi Pharmaceuticals: Consultancy; Novartis: Research Funding; Amgen; Jazz Pharmaceuticals: Honoraria. Roughton: Novartis Pharma AG: Current Employment. Choi: Novartis Pharmaceuticals: Current Employment. Osterloh: Novartis Farmacéutica S.A. Spain: Current Employment. Russo: Novartis: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Hargrave: AstraZeneca; Bayer; DayOne; Janssen; Novartis; Roche: Consultancy; AstraZeneca: Research Funding; AstraZeneca; Bayer; Novartis; Roche: Honoraria; Bayer: Speakers Bureau. OffLabel Disclosure: Trametinib in combination with dabrafenib is approved for the treatment of unresectable/metastatic melanoma with BRAF V600E or V600K mutations; adjuvant treatment for melanoma with BRAF V600E or V600K mutations; metastatic non-small cell lung cancer with BRAF V600E mutation; locally advanced/metastatic anaplastic thyroid cancer with BRAF V600E mutation.

Prevalence of BRAF V600 in primary gliomas: a systematic review

Aims Glioma is a fatal disease that causes significant years of life lost to an individual. Mutations in the driver gene BRAF, such as the V600 alteration, may contribute to gliomagenesis in adults and children through abnormal signaling causing uncontrolled cell proliferation. The use of BRAF-inhibitor drugs including Vemurafenib and Dabrafenib have shown a favorable response in 48% and 50% of melanoma patients with BRAF V600 mutations respectively. BRAF inhibitors and MEK inhibitors have shown efficacy in certain paediatric gliomas in the recurrent setting. Despite the potential benefit of BRAF inhibitors, the prevalence of BRAF V600 within primary gliomas is not fully discovered. Some studies identify the prevalence to be over 50%, while others find the prevalence to be around 1%. We performed a comprehensive systematic review to determine the prevalence of BRAF V600 within the adult and paediatric glioma population in different diagnostic groups. Method A systematic literature search was performed using Ovid MEDLINE and Embase from genesis to the 22nd October 2020. Studies were not restricted by language. Studies were eligible if patients were histologically diagnosed according to WHO guidelines as a primary glioma evaluating the prevalence of BRAF V600 and included ≥ 10 primary glioma patients. The review protocol was registered in PROSPERO (CRD42019127704). Search results were managed using Endnote. Two independent reviewers assessed the eligibility of the publications using Rayyan, conflicts were evaluated by a third reviewer. Included articles were extracted by one reviewer and confirmed by a second reviewer. Risk of bias assessments were conducted using Hoy et al’s risk of bias tool. Results were synthesized using “metaprop” in R. The meta-analysis was carried out in R which produced forest plots. Results Our cohort included 182 studies with a total of 13669 adult and paediatric glioma patients classified diagnostically according to WHO guidelines. Among 48 glioma entities, BRAF V600 was identified most commonly in epithelioid glioblastoma with a prevalence of 69% (95% confidence interval (CI): 45-89%), followed by pleomorphic xanthoastrocytoma with a prevalence of 56% (95% CI: 48-64%), anaplastic pleomorphic xanthoastrocytoma with a prevalence of 38% (95% CI: 23-54%), ganglioglioma with a prevalence of 40% (95% CI: 33-46%), and anaplastic ganglioglioma with a prevalence of 46% (95% CI: 18-76%). Other glioma entities were found to have a prevalence of BRAF V600, these include astroblastoma (24%), desmoplastic infantile astrocytoma (16%), subependymal giant cell astrocytoma (8%), dysembryoplastic neuroepithelial tumour (3%), diffuse astrocytoma (3%), and pilocytic astrocytoma (3%). Conclusion To our knowledge, this is the largest systematic review examining the prevalence of BRAF V600 in adult and paediatric glioma classified according to diagnostic WHO criteria. However, there were some limitations in this review. The sample sizes of some studies were very small, and the method of mutational analysis for BRAF V600 varied between papers. We found BRAF V600 in a significant prevalence of epithelioid glioblastoma, pleomorphic xanthoastrocytoma, anaplastic pleomorphic xanthoastrocytoma, ganglioglioma, and anaplastic ganglioglioma. Of interest, BRAF V600 mutation was found in a lower prevalence of astroblastoma, desmoplastic infantile astrocytoma, subependymal giant cell astrocytoma, dysembryoplastic neuroepithelial tumour, diffuse astrocytoma, and pilocytic astrocytoma. Consideration of assessment of BRAF V600 mutation may enable further treatment options with BRAF and/or MEK inhibitors in these particular diagnostic entities.

Targeting BRAF Activation as Acquired Resistance Mechanism to EGFR Tyrosine Kinase Inhibitors in EGFR-Mutant Non-Small-Cell Lung Cancer

Osimertinib has become a standard of care in the first-line treatment of advanced-stage non-small-cell lung cancer (NSCLC) harboring exon 19 and 21 activating mutations in the EGFR gene. Nevertheless, the 18.9-month median progression-free survival emphasizes the fact that resistance to osimertinib therapy is inevitable. Acquired resistance mechanisms to osimertinib in EGFR-driven NSCLC include MET amplification, EGFR C797S mutation, neuroendocrine differentiation, small-cell lung carcinoma histologic transformation, PD-L1 and KRAS amplifications and ESR1-AKAP12 and MKRN1-BRAF translocations, as well as BRAF V600 mutation. This last one represents 3% of the acquired resistance mechanisms to osimertinib. In this review, we discuss the rationale for EGFR/BRAF/MEK co-inhibition in the light of a clinical case of EGFR-mutant NSCLC developing a BRAF V600 mutation as an acquired resistance mechanism to osimertinib and responding to the association of osimertinib plus dabrafenib and trametinib. Additionally, we discuss the acquired resistance mechanisms to osimertinib plus dabrafenib and trametinib combination in that context.

Encorafenib in Combination With Binimetinib (Braftovi and Mektovi)

CADTH reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class. The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada's federal, provincial, and territorial governments, with the exception of Quebec. This review assesses encorafenib (Braftovi), 75 mg oral capsules in combination with binimetinib (Mektovi), 15 mg oral tablets. Indications: Braftovi (encorafenib) is indicated, in combination with binimetinib, for the treatment of patients with unresectable metastatic melanoma with a BRAF V600 mutation, as detected by a validated test. Mektovi (binimetinib) is indicated, in combination with encorafenib, for the treatment of patients with unresectable metastatic melanoma with a BRAF V600 mutation, as detected by a validated test.

Target Enrichment Enhances the Sensitivity of Sanger Sequencing for BRAF V600 Mutation Detection

BRAF is a serine/threonine protein kinase whose mutations lead to unregulated cell growth and cause different types of cancers. Since V600E is a major BRAF mutation and V600E detection as a companion diagnostic test (CDx) is stipulated in the labeling of the BRAF V600 inhibitors. Traditional Sanger sequencing cannot accurately detect mutations lower than 15% variant allele frequency (VAF) due to its limited sensitivity. Here we applied our patented XNA molecular clamping technology to modify Sanger sequencing template preparation by enriching the mutation population. We found that the use of our mutation-enriched template enhanced the analytical sensitivity of Sanger sequencing to 0.04% VAF. The method is verified to detect V600E, V600K, and V600R mutants and is validated for the known BRAF mutation status in clinical samples. Our streamlined protocol can be used for easy validation of the highly sensitive target-enrichment method for detecting BRAF V600 mutations using Sanger sequencing in clinical labs. In addition to BRAF V600 mutations, this method can be extended to the detection of other clinically important actionable mutations for cancer diagnostics.

Encorafenib (Braftovi) in Combination With Binimetinib (Mektovi)

CADTH recommends that Braftovi in combination with Mektovi should be reimbursed by public drug plans for the treatment of unresectable or metastatic melanoma with a BRAF V600 mutation if certain conditions are met. Braftovi and Mektovi should only be reimbursed if used in combination and prescribed and monitored by clinicians with expertise in diagnosis and management of melanoma who are familiar with the toxicity profile associated with the Braftovi with Mektovi regimen and if it does not cost more than the least costly BRAF inhibitor and MEK inhibitor (BRAFi/MEKi) combination treatment. Braftovi with Mektovi should only be covered to treat adult patients with advanced or metastatic melanoma who have a BRAF V600 gene mutation that has been identified through a validated test. Patients who have not received previous treatment and patients whose disease has progressed after first-line immunotherapy are eligible for coverage.

Cost-Effectiveness Analysis of Dabrafenib Plus Trametinib and Vemurafenib as First-Line Treatment in Patients with BRAF V600 Mutation-Positive Unresectable or Metastatic Melanoma in China

Objective: To evaluate the cost-effectiveness of dabrafenib plus trametinib combination therapy versus vemurafenib as first-line treatment in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma from a healthcare system perspective in China. Methods: This study employed a partitioned survival model with three health states (progression-free survival, post-progression survival and dead) to parameterize the data derived from Combi-v trial and extrapolated to 30 years. Health states’ utilities were measured by EQ-5D-3L, also sourced from the Combi-v trial. Costs including drug acquisition costs, disease management costs and adverse event costs were based on the Chinese Drug Bidding Database and physician survey in China. The primary outcomes of the model were lifetime costs, life-years (LYs), quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratio (ICER). Deterministic and probabilistic sensitivity analyses were conducted, respectively. Result: Dabrafenib plus trametinib is projected to increase a patient’s life expectancy by 0.95 life-years over vemurafenib (3.03 vs. 2.08) and 1.09 QALY gains (2.48 vs. 1.39) with an incremental cost of $3833. The incremental cost-effectiveness ratio (ICER) was $3511 per QALY. In the probabilistic sensitivity analyses, at a threshold of $33,357 per QALY (three times the gross domestic product (GDP) per capita in China in 2020), the probability of dabrafenib plus trametinib being cost-effective was 90%. In the deterministic sensitivity analyses, the results were most sensitive to the dabrafenib plus trametinib drug costs, vemurafenib drug costs and discount rate of cost. Conclusion: Dabrafenib plus trametinib therapy yields more clinical benefits than vemurafenib. Using a threshold of $33,357 per QALY, dabrafenib plus trametinib is very cost-effective as compared with vemurafenib in China.