Response to the Combination of Osimertinib, Dabrafenib, and Trametinib in Leptomeningitis From EGFR-Mutant NSCLC With Acquired BRAF V600E Mutation: A Case Report

Molecular sequencing after highly potent targeted gene inhibitors have suggested resistant tumors can display substantial heterogeneity. Among these various mechanisms of resistance, secondary mutations on targetable oncogenes have been identified. BRAF V600E, as a bypass mechanism on disease progression while receiving osimertinib therapy, has been reported in 3% of EGFR-mutated patients. Few case reports described the efficacy of the association of osimertinib and dabrafenib plus trametinib. Here, we report, for the first time, a case of a patient treated with this association, with a prolonged response on leptomeningeal metastasis. We also provide a comprehensive overview of the available literature on the efficacy and tolerance of this association.


Introduction
Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (TKI) active in the central nervous system and is the current standard of care for the first-line treatment of EGFR-mutant NSCLC. 1 Despite an improvement in progression-free survival (PFS) and overall survival in comparison with first-generation EGFR TKIs (median PFS of 18.9 mo), patients invariably experience disease progression characterized by heterogeneous mechanisms of resistance including 3% of BRAF V600E bypass mutations. The combination of the BRAF inhibitor dabrafenib and MEK inhibitor trametinib is a standard therapeutic option for patients with NSCLC harboring a primary BRAF V600E mutation. 2 Here, we report the case of a complete leptomeningeal response to the association of osimertinib, dabrafenib, and trametinib (OþDþT) in a patient with EGFR-mutant NSCLC harboring a BRAF V600E mutation as a resistance mechanism to osimertinib.

Case Presentation
A 67-year-old never-smoker man presented vertebral pain caused by a multisite metastatic lung adenocarcinoma (bone, liver, lymph nodes, and brain), harboring an EGFR exon 19 deletions (p.E746_A750del) with asymptomatic infratentorial brain metastases without clinical and radiologic signs of meningitis. Molecular results and panels performed at each time point are described in the Appendix (Supplementary data). He received erlotinib at 150 mg/day with a good initial response (Fig. 1A). After 26 months, he experienced vision alterations with metamorphopsia, which was found to be choroid metastases without any sign of leptomeningeal disease on brain magnetic resonance imaging (MRI). Bronchial and liquid biopsies identified an EGFR p.T790M mutation and the initial EGFR exon 19 deletion with no BRAF mutation, and the patient was subsequently treated with osimertinib leading to an almost complete response. After 3 years of osimertinib, he experienced progressive disease, and next-generation sequencing performed on a lymph node core needle  biopsy revealed an EGFR exon 19 deletion, the loss of T790M mutation, and the appearance of the BRAF V600E mutation with a high allelic fraction (21%). Chemotherapy with carboplatin and pemetrexed was initiated with a partial response; but 6 months later during maintenance therapy with pemetrexed, he experienced neurologic symptoms including confusion, walking disability, vomiting, neck stiffness, and diplopia, and a brain MRI confirmed the existence of carcinomatous meningitis. On the basis of the previous detection of the BRAF V600E mutation, after obtaining patient informed consent, a combination of OþDþT at full dose was initiated. An early and dramatic response was observed with complete regression of all clinical neurologic manifestations and the disappearance of signs of meningitis on the first brain MRI at 3 months (Fig. 1B), allowing the patient to regain full autonomy. No subsequent extracranial progression was observed, and response is still ongoing after 12 months of treatment. However, several treatment-related toxicities occurred (Fig. 2). First, grade 2 pyrexia was observed at day 5 after treatment initiation; dabrafenib was discontinued with prompt fever improvement, then reintroduced in a reduced dose at 100 mg twice a day. Recurrence of pyrexia after 4 months led to another temporary reduction in the dose of dabrafenib to 75 mg for 1 week, before reescalation to 100 mg twice a day. Grade 2 thrombocytopenia was also observed, leading to the discontinuation of the three TKIs for 2 weeks with gradual reintroduction. The platelet count then remained stable between 80 g/liter and 100 g/liter without hemorrhagic symptoms. Finally, grade 1 interstitial pneumonitis was detected on a computed tomography scan after 3 months of treatment.
Considering the clinical improvement of neurologic symptoms, the combination was not discontinued and prednisolone at a dose of 40 mg/day was introduced. A follow-up computed tomography scan did not reveal any improvement or worsening of the pneumonitis and the patient still receives prednisolone at the dose of 20 mg/ day without respiratory symptoms.

Discussion
Understanding the mechanisms of acquired resistance to osimertinib is still an area of active investigation. A large panel of on-target and bypass mechanisms have been described under osimertinib However, management of osimertinib postprogression remains unclear. The identification of targetable mechanisms of resistance has exposed combining TKIs as an interesting strategy. It has already been evaluated for patients harboring MET amplification as a mechanism of resistance with promising results and a favorable profile of tolerance. RET inhibition associated with osimertinib also revealed encouraging results in the case reports of patients with RET-fusion.  The BRAF V600E mutation as a resistance mechanism to osimertinib is present in 3% of patients. Previously reported cases revealed OþDþT efficacy, with some rapid and prolonged responses ( Table 1) but none of them presented leptomeningeal metastases. In our case, BRAF mutation was identified at disease progression with osimertinib, but because chemotherapy was the standard of care, the OþDþT combination was not immediately introduced after resistance to osimertinib. This treatment sequence may have modified the subclonal heterogeneity of the tumor and resensitized it to EGFR inhibition, by prompting the proliferation of the sensitive EGFR-mutated clone after removing the selective pressure from the EGFR TKI. 3 However, experience gained from patients rechallenged with first-generation EGFR TKIs reflects that, despite an interesting initial disease control rate (45%), the median PFS remains short (around 2.0 mo). 4 The relative long-term response (at least 1 y) achieved using OþDþT argues in favor of the efficacy of this treatment combination.
Another major consideration when combining TKIs is the management of toxicity. In previous reports, the combination of OþDþT has mainly been associated with expected grade 1 to 2 toxicities including pyrexia, fatigue, and gastrointestinal disorders (Table 1) with no major signs of additional toxicities. In our case, pyrexia led to treatment interruption and dose reduction. Pyrexia is one of the toxicities often observed with BRAF inhibitors (6% of grade 3), but its severity seems to be enhanced when combined with MEK inhibitors. It often occurs during the first month of treatment and prompt interruption of TKIs usually results in rapid resolution of symptoms. Most of the time, both drugs can be safely restarted at the same dose. 5 Thrombocytopenia has been reported with osimertinib monotherapy but not with dabrafenib-trametinib and could worsen with the combination of three TKIs. Finally, pneumonitis can be observed with both osimertinib and dabrafenibtrametinib and could be a major issue for their combination and should be strictly monitored.

Conclusion
The use of BRAF inhibitors combined with osimertinib for patients who experience disease progression with the BRAF V600 mutation seems to be feasible with interesting central nervous system efficacy even on leptomeningeal metastases. Acceptable overlapping toxicity was observed but close monitoring of symptoms of the patient is crucial especially pneumonitis-related symptoms. This case report also underscores the need for a repeated tumor or liquid biopsies to identify targetable mechanisms of resistance after progression with osimertinib.