Endocrine Abstracts

BackgroundBRAF/MEK inhibitors (BRAF/MEKi) dabrafenib + trametinib have revolutionized the treatment of BRAFm-ATC, but response is often short-lived. We previously reported that addition of an anti-PD-1 immune checkpoint inhibitor (ICI) to BRAF/MEKi prolongs overall survival (OS). Yet, some patients still develop resistance and progress. In BRAF ^V600E-mutated melanoma, OS is longer when BRAFi is continued beyond disease progression. Lenvatinib + pembrolizumab have shown promising efficacy in BRAF wild-type ATC. We aimed to study the efficacy of lenvatinib + continued BRAFi ± ICI after progression on BRAF/MEKi + ICI in metastatic BRAFm-ATC.

Methods: Retrospective study of BRAFm-ATC treated with lenvatinib + BRAFi ± ICI at progression on BRAF/MEKi + ICI. Primary outcome was median OS (mOS). Secondary outcomes were median progression free survival (mPFS) and disease control rate (DCR), defined as complete + partial response (PR) + stable disease (SD) as the best overall response (BoR). Survival was assessed by Kaplan-Meier method; BoR using RECISTv1.1.

Results: Thirteen patients with metastatic BRAFm-ATC, treated with lenvatinib + BRAFi ± ICI at progression on BRAF/MEKi + ICI between 3/1/14 and 10/15/23, were included. Data cut-off was 1/15/24. The table below highlights notable baseline characteristics. 10/12 (83%) evaluable specimens had a PD-L1 ≥ 1%. Mutational data at progression on BRAF/MEKi + ICI revealed acquired RAS mutations in 5/13 (38%) and PIK3CA mutation in 1/13 (8%). Median initial dose of lenvatinib was 10 mg (range, 10–20) and median duration of lenvatinib was 3 months (range, 0.7–13). Drugs combined with lenvatinib were: encorafenib (n = 1), dabrafenib (n = 1), encorafenib + pembrolizumab (n = 1), dabrafenib + atezolizumab (n = 1), and dabrafenib + pembrolizumab (n = 9). Median initial dose of dabrafenib with lenvatinib was 100 mg twice daily (range, 75 – 150). All patients were exposed to an ICI during their treatment course but in 2 patients, the ICI was stopped prior to initiating lenvatinib due to immune-related toxicity. mOS from start of lenvatinib was 3 months (95% CI, 2.1–3.9). On lenvatinib + BRAFi ± ICI, DCR was 46% (SD in 4/13, PR in 2/13). BoR was progressive disease in 4/13 (31%) and non-evaluable in 3/13 (23%). mPFS was 2 months (95% CI, 1.4–2.6). At data cut-off, 2/13 patients continued therapy.

Conclusions: In patients with metastatic BRAFm-ATC progressing on BRAF/MEKi + ICI, lenvatinib + BRAFi ± ICI offer limited additional survival benefits. Limitations of our study include retrospective review with selection bias and variability in previous therapies among patients. Continued research efforts to identify effective second line therapies for BRAFm-ATC are warranted.