Biomarker Driven Phase II Clinical Trial of Trametinib in Relapsed/Refractory Multiple Myeloma with Sequential Addition of the AKT Inhibitor, GSK2141795 at Time of Disease Progression to Overcome Treatment Failure: A Trial of the Princess Margaret Phase II Consortium

Activating mutations of the MAPK pathway are reported in over half of myeloma tumors. Experience with MEK inhibitors in solid tumors suggest that although tumors harboring BRAF or RAS mutations are more likely to respond, response rates are low and duration of responses short. Potential explanations include the activation of alternative signaling pathways and in particular PI3K/AKT signaling. Studies of multiple myeloma (MM) tumors suggest that AKT activation is independent of oncogenic RAS and that combined inhibition of RAS and AKT enhances MM cell death. Based on these observations, we initiated a clinical trial to evaluate the activity of trametinib (TMTB) in MM patients (pts) with or without RAS/RAF mutations, as a single-agent and in combination with AKT inhibition for pts who fail to respond to TMTB alone.

Methods: Pts were independently recruited into biomarker positive (K/NRAS or BRAF mutated) or biomarker negative (K/NRAS, BRAF wild type) groups. All pts received TMTB, 2 mg/day on a 28 day cycle. In pts who developed progressive disease (PD) or achieved less than a partial response (PR) after 4 cycles of TMTB monotherapy, GSK2141795 (pan-AKT inhibitor) was added. TMTB combined with GSK2141795 was dosed at 1.5 mg/50 mg taken daily. The M-protein at the time of adding GSK2141795 was considered the new baseline for response assessment to the combination. The main objectives were to evaluate overall response rates (ORR; IMWG) to TMTB in the 2 groups and determine the clinical benefit of adding GSK2141795 to TMTB.

Results: At the data cutoff, 25 pts were enrolled: 12 in the mutated (MUT) and 13 in the wild type (WT) groups. Median age and prior lines of therapy were 65 years (range 42-76) and 4 (range 4-8) for the MUT group and 64 years (range 51-81) and 4 (range 2-8) for the WT group. 96%, 100%, 60% and 96% of pts had received prior proteasome inhibitor (PI), immunomodulatory drugs (IMiDs), pomalidomide or PI+IMiD therapy, respectively. The most common (>30%) adverse events (AEs) possibly related to study drugs were thrombocytopenia (40%) and diarrhea (32%) for TMTB monotherapy and nausea (72%), rash (63%), thrombocytopenia (36%) and anorexia (36%) with the addition of GSK2141795. The most frequent grade 3-4 AEs (>20%) were thrombocytopenia (24%) for TMTB monotherapy and thrombocytopenia (45%), anemia (45%), lymphopenia (36%), hyponatremia (27%), and neutropenia (27%) in combination with GSK2141795. One death occurred due to gastrointestinal bleed unrelated to study drugs.

Of 24 pts assessable for response, confirmed ORR was 8% (1 PR) for the MUT group (N=12), Further, 1 pt had an unconfirmed minimal response (MR) and 4 pts had stable disease (SD). For the WT group (N=12), we observed 2 MR (1unconfirmed) and 3 SD. For clinical benefit rate (CBR) of 17% in both groups. With the addition of GSK2141795 to TMTB (N=11), the ORR was 27% (3 PR, 1 unconfirmed) and 1 pt had an MR (CBR=36%). The median PFS is estimated to be 3.2 (range 0.9-3.8) and 1.8 (range 0.9-NR) months (p=0.91), for the MUT and WT groups, respectively.

Correlative studies are ongoing and are designed to identify predictors of response and resistance to TMTB. These include, assessment of pre- and post-treatment expression of phospho-ERK1/2, serial monitoring of clonal dynamics in bone marrow and cell-free DNA and pharmacogenomic studies. Analyses will be presented.

Conclusions: The MEK1/2 inhibitor, TMTB demonstrates clinical activity in MM pts with RAS mutated tumors. In addition, disease control was observed for pts with WT RAS/RAF tumors. However, single agent activity in heavily pre-treated pts is modest. The addition of GSK2141795 to block the alternative signaling pathway improved the ORR to 27% supporting further exploration of this treatment strategy for MM.