Abstract CT057: Phase 1/2 trial of trametinib + ceritinib in patients with unresectable melanoma
Authors: Eroglu Zeynep , Yin Vivien , Markowitz Joseph , Brohl Andrew , Tarhini Ahmad A. , Fan Wenyi , De Aquino Deanryan , Chen Ann , Rix Uwe , Khushalani Nikhil I. , Smalley Keiran 
Published: April 2024

Abstract
Background: In advanced melanoma, treatment options after progression on immunotherapy are limited, particularly for patients with BRAF-WT tumors. MEK-inhibitors have been explored, with limited clinical efficacy. Our pre-clinical data demonstrated efficacy of the tyrosine kinase inhibitor ceritinib in NRAS-mutant and BRAF-mutant melanoma cells lines. There was synergy observed combining the MEK inhibitor trametinib with ceritinib (compared to trametinib alone) in BRAF-WT melanoma xenografts, with dual suppression of MAPK and mTOR signaling (Verduzco et al, Mol Cancer Ther 2018) Further, in our anti-PD-1 resistant mouse melanoma models, combination of ceritinib and trametinib was highly effective when administered subsequent to anti-PD1. (Phadke et al, Cancer Immunol Res 2021)
Methods: We conducted a phase 1/2 trial of ceritinib monotherapy and then combination of trametinib with ceritinib in patients with advanced melanoma after failure of anti-PD-1 (and prior BRAF/MEK inhibitors if eligible.) Primary objective was to identify the maximum tolerated dose (MTD) of this combination, with secondary objectives of tumor response (RECIST 1.1) and progression-free (PFS) and overall survival (OS). In the initial phase 2 portion to explore single-agent activity, patients received oral ceritinib monotherapy at 450 mg daily (QD). In the subsequent phase 1 portion, patients started at dose level (DL)1 of 300 mg PO QD ceritinib + 2mg PO QD trametinib, with a BOIN design to guide dose escalation in cohort sizes of 3. DL 2 was 450 mg + 2 mg QD, while DL -1 was 300 mg + 1.5 mg QD of the combination. Tumor biopsies and blood samples were obtained on day 1 and day 15.
Results: We enrolled 28 patients with unresectable/metastatic melanoma. Median age was 66, 10 female, 26 stage IV, 11 NRAS-mutant, 4 BRAF V600-mutant, with median 3 prior lines of prior therapy. There was no objective response observed to ceritinib monotherapy in 11 patients; prolonged stable disease of 6 and 8 months was seen in 2 pts. Median PFS was 2.1 months (95% CI 1.91, NA); median OS was 7.3 months (95% CI 2.4, NA). Two patients had grade 3 AST/ALT elevation; there were no unexpected toxicities. Of the 17 patients on the combination regimen, 12 received DL1. Dose-limiting toxicities of grade 3 rash and grade 2 glaucoma led to de-escalating to DL -1 for other patients. Overall, most frequent grade 3/4 toxicities were grade 3 rash (n=3), grade 3 hypertension (n=2), and grade 3 ALT/AST elevation (n=2). MTD was determined at DL -1 of 1.5 mg trametinib + 300 mg ceritinib QD. Two patients had partial response (12%), both NRAS-mutant; 6 had SD (3 lasting ≥6 months). Median PFS was 3.1 months (95% CI 1.94, 6.18) with median OS of 7.8 months (95% CI 5.1, 13.2). Overall, patients with immediate prior line of anti-PD-1 before trial treatment had a trend toward improved OS (10.2 months vs 5.1 months; p=0.21); no differences were seen based on NRAS or BRAF-status.
Conclusions: Ceritinib does not appear to have meaningful single agent activity in treatment-refractory advanced melanoma. Efficacy of the combination with trametinib is modest, and the inability to dose-escalate the combination due to overlapping toxicities such as rash may have contributed. Analyses from baseline and on-treatment tumor biopsies, including immunohistochemistry and single cell RNA seq to explore drug effect on mTOR and MAPK pathways as well as immune infiltration, are ongoing and will be presented.
Citation Format: Zeynep Eroglu, Vivien Yin, Joseph Markowitz, Andrew Brohl, Ahmad A. Tarhini, Wenyi Fan, Deanryan De Aquino, Ann Chen, Uwe Rix, Nikhil I. Khushalani, Keiran Smalley. Phase 1/2 trial of trametinib + ceritinib in patients with unresectable melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT057.