Regorafenib Combined with BRAF/MEK Inhibitors for the Treatment of Refractory Melanoma Brain Metastases

Abstract

Background: There are no active treatment options for patients with progressive melanoma brain metastases (MBM) failing immune checkpoint blockade (ICB) and BRAF/MEK inhibitors (BRAF/MEKi). Regorafenib (REGO), an oral multi-kinase inhibitor (incl. RAF-dimer inhibition), can overcome adaptive resistance to BRAF/MEKi in preclinical models.

Methods: This is a single-center retrospective case series of patients with refractory MBM treated with REGO plus BRAF/MEKi (compassionate use).

Results: A total of 22 patients were identified (18 BRAF-mutant, 4 NRAS^Q61-mutant; 19 with progressive MBM; 11 on corticosteroids). Thirteen BRAF^V600-mutant patients were progressing on BRAF/MEKi at the time of REGO association. BRAF-mutant patients received REGO (40-80 mg once daily) combined with BRAF/MEKi, NRAS-mutant patients were treated with REGO + MEKi (+low-dose BRAFi to mitigate skin-toxicity). Grade 3 TRAE included arterial hypertension (n = 4) and maculopapular rash (n = 3). There were no G4/5 TRAE. In BRAF-mutant patients, overall and intracranial objective response rates (overall ORR and IC-ORR) were 11 and 29%, and overall and intracranial disease control rates (overall DCR and IC-DCR) were 44 and 59%, respectively. In NRAS-mutant patients overall ORR and IC-ORR were 0 and 25% and overall DCR and IC-DCR were 25 and 50%, respectively. The median PFS and OS were, respectively, 7.1 and 16.4 weeks in BRAF-mutant and 8.6 and 10.1 weeks in NRAS-mutant patients.

Conclusions: In heavily pretreated patients with refractory MBM, REGO combined with BRAF/MEKi demonstrated promising anti-tumor activity with an acceptable safety profile. In BRAF^V600-mutant melanoma patients, responses cannot solely be attributed to BRAF/MEKi rechallenge. Further investigation in a prospective trial is ongoing to increase understanding of the efficacy.

Keywords: BRAF; BRAF/MEK inhibitors; NRAS; RAF dimer inhibitor; brain metastases; class II RAF inhibitor; regorafenib; stage IV-M1d melanoma; targeted therapy.

Figure 1

General overview of treatment disposition and triple-targeted therapy combinations used. Abbreviations: REGO—regorafenib; OD—once daily; DAB—dabrafenib; TRAM—trametinib; ENCO—encorafenib; BINI—binimetinib.

Figure 2

Responses to triple-targeted therapy. (A). Swimmer plots of all BRAF- and NRAS-mutant patients representing extracranial, intracranial, and overall responses, respectively, from top to bottom. The best objective responses (BORs) and moments of extracranial, intracranial, and overall progression are marked on the respective bars. The duration of survival after treatment interruption is shown as a striped bar. The gray circles on the Y-axis depict patients in whom REGO was associated following progression on BRAF/MEKi. (B). Waterfall plots of the maximal change in sum of target lesion diameters from baseline in the intracranial (left) and extracranial (right) target lesions in patients in whom the target lesions were evaluable for response and which changed in size. The color stands for the best objective response intracranially (left) and extracranially (right): red = progressive disease (PD); orange = stable disease (SD); and green = partial response (PR). The horizontal lines depict a change in size of the target lesions of at least +20% (PD) and −30% (PR) compared to baseline.

Figure 3

Kaplan–Meier curves for overall progression-free survival (PFS), intracranial PFS, extracranial PFS, and overall survival (OS) for BRAF (green)- and NRAS (orange)-mutant patients. Censored patients are shown as a vertical tick-mark. Abbreviations: 95% CI—95% confidence interval; N°—number.

Figure 3

Kaplan–Meier curves for overall progression-free survival (PFS), intracranial PFS, extracranial PFS, and overall survival (OS) for BRAF (green)- and NRAS (orange)-mutant patients. Censored patients are shown as a vertical tick-mark. Abbreviations: 95% CI—95% confidence interval; N°—number.

Figure 4

Case illustration. Axial slides of gadolinium-enhanced brain MRI. The orange arrow follows one brain metastasis in the brain stem. (A). Baseline, before triple-targeted therapy initiation. (B). After 4 weeks of triple-targeted therapy. (C). At 7 weeks after baseline MRI and 2 weeks after treatment interruption. (D). At 13 weeks after baseline scan and 6 weeks after triple-targeted therapy reinitiation. Doses are in mg. Abbreviations: BID—twice a day; DAB—dabrafenib; G—grade; ir-hepatitis—immune-related hepatitis; METHYLPRED—methylprednisolone; OD—once daily; REGO—regorafenib; TRAM—trametinib; W—week.