Neoadjuvant chemotherapy was provisionally administered to manage the disease. Research has demonstrated that neoadjuvant chemotherapy has a positive impact on the overall survival (OS) of patients compared to surgery alone(7). Despite the ongoing enhancements to standardized neoadjuvant chemotherapy regimens, the rate of recurrence in early-stage NSCLC continues to be high. Consequently, it is crucial to conduct further assessments of treatments such as targeted therapy and immunotherapy and implement them in the neoadjuvant setting. Trials focusing on prevalent NSCLC driver genes, including EGFR and ALK, have produced preliminary findings. Neoadjuvant-targeted therapy with EGFR-TKI(8) and ALK-TKI(9) has shown satisfactory efficacy in patients with resectable NSCLC.
Following the multiple-gene test, the patient was found to have a mutation in the BRAF gene. The open-label phase II trial BRF113928 indicated that dabrafenib plus trametinib therapy was found to have substantial and durable clinical benefit, with a manageable safety profile, in NSCLC patients with the BRAF V600E mutation, regardless of previous treatment(5, 10). While targeted therapy has demonstrated satisfactory efficacy in treating advanced NSCLC with the BRAF V600E mutation, there exists limited data concerning neoadjuvant targeted therapy for BRAF-mutated NSCLC, owing to the rare incidence of BRAF mutation. Liu et al. reported favorable responses to neoadjuvant targeted therapy in NSCLC patients with the BRAF V600E mutation, resulting in a major pathological response following surgery(6). This indicates the possibility of neoadjuvant targeted therapy for NSCLC patients with the BRAF V600E mutation. Consequently, our patient underwent neoadjuvant targeted therapy with dabrafenib and trametinib. In addition, the patient had concurrent mutations of TP53, FUS, KDM5C, and XPO1, with clinical significance yet to be determined. A study demonstrated that patients with EGFR-mutated NSCLC who had TP53-positive status and underwent targeted therapy showed a considerably lower disease control rate (DCR) compared to those with TP53-negative status(11). TP53 mutation may reduce the efficacy of targeted therapy. Thus, we decided to provide the patient with a four-week course of chemotherapy with the expectation of achieving a more favorable therapeutic outcome when combined with targeted therapy. After a single cycle of chemotherapy alone, the CT revealed that the right lung hilum tumor resembled the previous one. After commencing targeted therapy in combination with chemotherapy, the CT revealed that the right lung hilum tumor had decreased in size. In this patient, the combination of targeted therapy and chemotherapy demonstrated superior efficacy to chemotherapy alone. Despite the patient not achieving major pathologic response after neoadjuvant therapy, imaging revealed a considerable reduction in tumor size, and the patient underwent a surgery with good postoperative recovery. There are currently no clinical trials confirming the efficacy of neoadjuvant chemotherapy in combination with targeted therapy for NSCLC patients with the BRAF V600E mutation. However, our case demonstrates that the combination of neoadjuvant targeted therapy and chemotherapy presents the possibility of extending survival for NSCLC patients with the BRAF V600E mutation.
Immunotherapy typically excludes NSCLC patients with EGFR and ALK mutations due to their low levels of PD-L1 expression and poor efficacy(12). However, BRAF positivity is often linked to high levels of PD-L1 expression(13). BRAF-positive NSCLC patients are not typically excluded from immunotherapy, and it is viewed as one of the feasible treatment choices for such patients. However, the efficacy of immunotherapy in NSCLC patients with the BRAF mutation is also unsatisfactory, despite having high levels of PD-L1 expression. The study indicates that the objective response rate (ORR) of immune checkpoint inhibitors (ICIs) in BRAF-mutated patients is only 24%, which is less effective than targeted therapy(14). Therefore, immunotherapy should not be considered a viable option for BRAF-mutated patients. We have adopted neoadjuvant therapy that combines chemotherapy and targeted therapy for NSCLC patients with the BRAF V600E mutation. Furthermore, targeted therapy has demonstrated superior efficacy to immunotherapy in NSCLC patients with other rare mutations. In patients with advanced RET fusion-positive NSCLC, a trial revealed that the progression-free survival (PFS) with targeted therapy (selpercatinib) was significantly longer than platinum-based chemotherapy in combination with or without pembrolizumab(15). Excluding patients with rare mutation-positive NSCLC (e.g. BRAF and RET fusion) as well as common mutations (EGFR and ALK), could become a prospective approach in immunotherapy.