1136P Regorafenib combined with BRAF-/MEK-inhibitors for the treatment of refractory melanoma brain metastases

• DOI: 10.1016/j.annonc.2023.09.2270
• Publication Date: 2023-10-20T12:49:50Z
• Authors: I. Dirven; A-S. Vander Mijns...; J. Tijtgat; M. Vounckx; B. Neyns
• Keywords: Regorafenib; Refractory (planetary science)

Background There are no active treatment options for patients (pts) with progressive melanoma brain metastases (MBM) who have failed treatment with immune checkpoint blockade (ICB) and BRAF-/MEK-inhibitors (BRAF/MEKi). Regorafenib (REGO), an oral multi-target kinase inhibitor (incl. inhibition of RAF-dimers), has single-agent activity in pretreated melanoma (VD Mijnsbrugge et al. SMR 2022). Methods We report our single center retrospective review of prospectively registered pts with refractory MBM treated with REGO and BRAF/MEKi. Results 17 pts with stage IV-M1d melanoma were included (8F; med age 54y [33-75]; WHO PS: 0/1/2/3 resp. n=3/6/6/2 pts; 13 pts BRAFmt (12 BRAF V600mt, 1 BRAF fusion), 4 pts NRAS Q61mt). All pts previously progressed on ICB, BRAF/MEKi (all BRAFmt pts), chemotherapy (4 pts), T-VEC (2 pts), REGO mono (3 pts), and REGO + ICB (2 pts). At baseline, 15 pts had active MBM (8 pts were on steroids); 4 pts had intracranial evaluable disease only. BRAFmt pts were treated with REGO (40-80 mg QD) combined with BRAF/MEKi, NRASmt pts with REGO + MEKi (+ low-dose BRAFi to mitigate skin toxicity). There were no grade >4 TRAE. Grade 3 TRAE included arterial hypertension (n=4), and hepatotoxicity (n=2). None of the 2 pts without active MBM at baseline progressed intra-cranially. The best objective intracranial response (according to RANO-BM) in 17 response evaluable pts was: PR in 5 pts (29%; incl. 4 BRAFmt pts), and SD in 5 pts (29%; incl. 4 BRAFmt pts). In 5 pts intra- and extracranial disease control (PR, SD) were concordant. 3 pts with PR intra- had SD extra-cranially; 2 pts with SD intra- had PD extra-cranially. Assuming a potential clinical benefit of therapy beyond first PD, 10 out of 16 progressive pts continued treatment and remained clinically stable for an additional 3-48 weeks (w) (median 7w). Median time on REGO+BRAF/MEKi in BRAFmt pts was 13w [range 3-62], and 27.5w [range 3-56] on REGO + MEKi in NRASmt pts. In 3 pts treatment is ongoing (9-62w after initiation). Median PFS and OS is resp.8.4w and 24.6w in BRAFmt pts; 8.6w and 10.1w in NRASmt pts. Conclusions In heavily pretreated patients with refractory MBM, REGO combined with BRAF/MEKi demonstrated promising anti-tumor activity. Further investigation in a prospective trial is warranted.