Impressive response to dabrafenib, trametinib, and osimertinib in a metastatic EGFR-mutant/BRAF V600E lung adenocarcinoma patient

Abstract

The survival outcomes of the FLAURA trial support osimertinib as the new standard of care for untreated patients harboring activating mutations in the epidermal growth factor receptor (EGFR). Despite the initial response, disease progression invariably occurs. Although uncommon, BRAF V600E mutation arises as a unique mechanism of resistance, and thus far, no prospective studies are available to support concurrent EGFR/BRAF blockade. We report a case of impressive radiological and ctDNA response under dabrafenib, trametinib, and osimertinib in an advanced EGFR-mutant lung adenocarcinoma patient who developed BRAF V600E as one of the acquired resistance mechanisms to second-line osimertinib. Moreover, the patient experienced remarkable clinical improvement and good tolerance to combination therapy. The present case suggests the importance of prospective studies evaluating both efficacy and safety of the combination in later line settings and points towards the potential of ctDNA to monitor resistance mechanisms and treatment benefit in clinical practice.

Fig. 1. Paired radiological and sequential blood-based ctDNA assessments throughout patient’s treatment demonstrating concordant results.

a Timeline displaying systemic and focal therapies since September 2016. b ctDNA levels in serial plasma samples based on fractional abundance of EGFR T790M, EGFR del19 (E746_A750 del), BRAF V600E, and PIK3CA E545K mutations. ^#2.4 CN results: EGFR del19 WT/RNAseP copy number ratio. c Paired 18F-FDG PET-CT scan maximum intensity projection (MIP) images displaying tumor burden variations. PD progression of disease, SBRT stereotatic body radiotherapy, Pembro pembrolizumab, CT chemotherapy, DTO dabrafenib, trametinib and osimertinib.

Fig. 2. 18F-FDG PET-CT scan imaging depicting impressive overall tumor response under dabrafenib, trametinib, and osimertinib in three timepoints.

a–d baseline imaging (January/2020) showing: hypermetabolic spiculated mass (orange circle) in the left-superior lobe measuring 4.4 × 3.3 cm (SUVmax: 9.4); multiple hilar, mediastinal, retroperitoneal, and iliac hypermetabolic lymph nodes (red arrow) measuring up to 2.7 cm (SUVmax: 12.8); several hypermetabolic bone lesions throughout axial and appendicular skeleton (yellow circle); a left iliac bone lesion with signs of periosteal reaction and adjacent soft-tissue infiltration (SUVmax: 11.4). e–h first response evaluation imaging (April/2020) showing considerable partial response in the lung mass, measuring 3.8 × 2.5 cm (SUVmax: 2.7), as well as in several bone lesions, especially in the left-iliac bone (SUVmax: 4.8); complete response in lymph nodes. i–l third response evaluation imaging showing disease progression in the left ischium (SUVmax: 12.5; previous SUVmax: 5.9) (October/2020). SUVmax maximum standard uptake value.