BRAF Fusion as Resistance Mechanism to Osimertinib in EGFR-Mutated NSCLC: A Case Report and Review of Literature

Osimertinib currently represents the standard first-line treatment of EGFR-mutated NSCLC, even though the treatment landscape is rapidly evolving. Despite the optimal response rate, osimertinib resistance inevitably occurs through both EGFR-dependent or -independent mechanisms.¹ Among the latter, BRAF mutations and rearrangements are two molecular mechanisms of acquired resistance and are reported in 1% to 3% of EGFR-mutant NSCLCs exposed to osimertinib.² Although dabrafenib and trametinib have been approved for the first-line treatment of patients with metastatic NSCLC harboring oncogenic BRAF V600E mutation, no targeted therapies are recommended in the case of acquired BRAF mutations or fusions, and clinical experience in this setting is still limited. Preclinical studies and a few case reports have revealed the antitumor potential of co-inhibition of both MAPK and EGFR pathway in case of BRAF rearrangements.³ Here, we describe the case of a patient with advanced EGFR-mutant NSCLC harboring CTNNA1-BRAF fusion treated with trametinib and osimertinib combination.

A 46-year-old ECOG PS 0 never-smoker female was diagnosed with advanced lung cancer with secondary lesions in the liver, mediastinal lymph nodes, bone, and brain, as assessed by total-body computed tomography and brain magnetic resonance imaging. The patient underwent computed-tomography-guided lung biopsy and received a diagnosis of lung adenocarcinoma (LUAD) with EGFR exon 19 deletion (ex19del, c.2235_2252delinsAAT p.E746_T751>I, variant allele frequency [VAF] 33.51%) by next-generation sequencing (NGS) (Fig. 1A). As per local clinical practice, the patient received frontline osimertinib obtaining early radiologic response and clinical benefit (Fig. 1B), followed by brain progression amenable to radiotherapy and further hepatic progression after 14 months from the start of treatment. A liver biopsy was performed to highlight potential resistance mechanisms (Fig. 1C) and NGS revealed retention of EGFR ex19del (VAF 29.5%), the appearance of CTNNA1-BRAF fusion, and TP53 mutation (VAF 20.4%). Off-label platinum-pemetrexed chemotherapy with osimertinib was delivered for four cycles followed by 12 pemetrexed maintenance cycles, achieving a partial response. After a further hepatic progression, as the only disease active site, the patient underwent left hepatic lobectomy with confirmation of LUAD, and NGS detected EGFR ex19del (VAF 20.4%), CTNNA1-BRAF fusion and TP53 mutation (VAF 14.6%) with contextual appearance of EGFR amplification. Pemetrexed and osimertinib treatment was continued for an additional 10 cycles until hepatic progression was not amenable to local treatment (Fig. 1D). At this time point, a new liver biopsy revealed localization of LUAD; because of the paucity of material, only an RNA fusion study on 55 genes was conducted and confirmed retention of CTNNA1-BRAF fusion.

Given the persistence of CTNNA1-BRAF fusion, the patient started off-label osimertinib (80 mg once daily) and trametinib (1 mg once daily) combination and obtained a partial response to the liver at first evaluation with 18F-Fluorodeoxyglucose positron emission tomography and stable disease at brain magnetic resonance imaging after 3 months (Fig. 1E). The treatment was overall well tolerated, with grade 1 peripheral edema. After 6 months from the beginning of the combination therapy, the patient experienced hepatic and brain progression (Fig. 1F). A liquid biopsy was performed and NGS analysis revealed the emergence of MET amplification (copy number variation score: 1.39) while retaining EGFR ex19del (VAF 20.4%). Therefore, the patient underwent whole brain radiotherapy, and off-label amivantamab treatment was started. The patient passed away after 3 cycles of amivantamab because of hepatic and peritoneal progression.

Discussion

To our knowledge, this represents the first case describing the efficacy of trametinib plus osimertinib combination in a patient with stage IV NSCLC harboring CTNNA1-BRAF fusion and EGFR mutation.

Fusion genes are recurrent oncogenic drivers as they frequently interfere with signaling pathways and represent potential targets for personalized therapy.⁴

Current evidence on the prevalence of BRAF fusions both in treatment-naive lung cancer and after EGFR–tyrosine kinase inhibitor treatment is presented in Table 1.^5–9 BRAF fusions are relatively uncommon in treatment-naive patients with lung cancer and are found almost exclusively in LUAD, with no BRAF fusion seen in squamous or SCLC.¹⁰ The most frequently reported partners of primary BRAF fusions in lung cancer are ARMC10, DOCK4, and TRIM24.⁷ Fusions involving the BRAF oncogene represent a different mechanism of BRAF activation and are mutually exclusive with other mutations involved in the MAPK pathway (e.g., BRAF V600E) because they induce the removal of the autoinhibitory N-terminal and lead to constitutive activation of the downstream signaling pathway.¹¹

Read more.