Abstract
Simple SummaryMEK-inhibitor monotherapy has activity in advanced NRASQ61R/K/L mutant melanoma but is associated with dose-limiting cutaneous toxicity. The combination of a BRAF- with a MEK-inhibitor at their full dose (as in BRAFV600E/K mutant melanoma) has low cutaneous toxicity. We hypothesized that a low dose of the BRAF-inhibitor dabrafenib can mitigate the skin toxicity associated with a full dose of the MEK-inhibitor trametinib in patients with advanced NRASQ61R/K/L mutant melanoma who progressed after treatment with immune checkpoint inhibitors. The results of this two-stage phase 2 trial show that addition of a low dose of dabrafenib effectively mitigates the skin toxicity associated with trametinib. This combination is, however, insufficiently active in patients with advanced NRASQ61R/K/L mutant melanoma. The combination of low-dose dabrafenib plus full-dose trametinib can be of further interest for the treatment of MEK-inhibitor-sensitive tumors.Background: MEK-inhibitor monotherapy has activity in advanced NRASQ61R/K/L mutant melanoma but is associated with dose-limiting cutaneous toxicity. The combination of a BRAF- with a MEK-inhibitor at their full dose (as in BRAFV600E/K mutant melanoma) has low cutaneous toxicity. It is unknown whether a low dose of BRAF-inhibitor can mitigate the skin toxicity associated with full-dose MEK-inhibitor treatment in patients with advanced NRASQ61R/K/L mutant melanoma. Methods: This two-stage phase 2 clinical trial investigated trametinib 2 mg once daily in patients with advanced NRASQ61R/K/L mutant melanoma who were pretreated with immune checkpoint inhibitors. In case of trametinib-related cutaneous toxicity, low-dose dabrafenib (50 mg twice daily) was added to prevent recurrent cutaneous toxicity (pre-amendment). Following an amendment, trametinib was combined upfront with low-dose dabrafenib (post-amendment). Objective response rate (ORR) served as the primary endpoint. Results: All 6 patients enrolled pre-amendment developed trametinib-related cutaneous toxicity, necessitating treatment interruption. Combining trametinib with low-dose dabrafenib prevented recurrent skin toxicity thereafter. Trametinib-related skin toxicity was effectively mitigated in all 10 patients post-amendment. In all 16 included patients, the ORR and disease control rate was 6.3% (1 partial response) and 50.0%, respectively. The trial was halted after the first stage. Conclusions: Combining full-dose trametinib with low-dose dabrafenib can mitigate MEK-inhibitor-related skin toxicity but was insufficiently active in this patient population. This combination can be of further interest for the treatment of MEK-inhibitor-sensitive tumors.
Highlights
No therapy has shown to increase overall survival (OS) of patients with advanced BRAFV600 wild-type melanoma (50% of melanoma patients) who progress beyond treatment with programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) immune checkpoint inhibitors (ICI).NRASQ61R/K/L mutations, present in approximately half of patients with advanced BRAFV600 wild-type melanoma, are mutually exclusive with BRAFV600 mutations and activate the mitogen-activated protein kinase pathway (MAPK- or RAS-RAF-MEK-ERKpathway) through canonical activation of RAF, MEK and ERK [1,2,3]
Study Design and Patient Population. This single-center, two-stage, dual-stratum, open-label phase 2 clinical trial (NCT04059224) was conducted at the Universitair Ziekenhuis Brussel (Brussels, Belgium) and included adult patients with advanced BRAFV600 wild-type, NRASQ61R/K/L mutant melanoma who had confirmed progressive disease (PD) following or who were ineligible for treatment with PD-1 and/or CTLA-4 ICI
Among the first 6 patients, and subsequent 10 patients, respectively 6 (100.0%) and 6 (60.0%) patients were in need of interrupting trametinib treatment and respectively 2 (33.3%) and 5 (50.0%) patients required a trametinib dose reduction because of treatment-related AE (Figure 2)
Summary
No therapy has shown to increase overall survival (OS) of patients with advanced BRAFV600 wild-type melanoma (50% of melanoma patients) who progress beyond treatment with programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) immune checkpoint inhibitors (ICI).NRASQ61R/K/L mutations, present in approximately half of patients with advanced BRAFV600 wild-type melanoma, are mutually exclusive with BRAFV600 mutations and activate the mitogen-activated protein kinase pathway (MAPK- or RAS-RAF-MEK-ERKpathway) through canonical activation of RAF, MEK and ERK [1,2,3]. In the randomized phase 3 NEMO trial, comparing the MEK-inhibitor binimetinib to dacarbazine chemotherapy in patients with advanced NRASQ61R/K/L mutant melanoma, binimetinib treatment resulted in a significantly improved objective response rate (ORR, 15% versus 7%) and median progression-free survival (PFS, 2.8 versus 1.5 months, p < 0.001), but not OS (11.0 versus 10.1 months, p < 0.50) [5]. MEK-inhibitor monotherapy has activity in advanced NRASQ61R/K/L mutant melanoma but is associated with dose-limiting cutaneous toxicity. Conclusions: Combining full-dose trametinib with low-dose dabrafenib can mitigate MEK-inhibitor-related skin toxicity but was insufficiently active in this patient population. This combination can be of further interest for the treatment of MEK-inhibitor-sensitive tumors
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