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

Abstract

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. Disclosures Trudel: Celgene: Consultancy, Equity Ownership, Honoraria; Novartis: Consultancy, Honoraria; Glaxo Smith Kline: Honoraria, Research Funding; Oncoethix: Research Funding; BMS: Honoraria; Amgen: Honoraria. Bahlis:Amgen: Consultancy, Honoraria; BMS: Honoraria; Janssen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; Onyx: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau. Venner:Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria, Research Funding; J+J: Research Funding; Janssen: Honoraria. Hay:Amgen: Research Funding; Novartis: Research Funding; Janssen: Research Funding; Kite Pharmaceuticals: Research Funding.

A phase I, open-label, two-stage study to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of the oral AKT inhibitor GSK2141795 in patients with solid tumors

“…Preliminary results of a clinical trial of trametinib in relapsed/refractory multiple myeloma, which included the sequential addition of GSK2141795 at the time of disease progression, showed modest results. The results, however, suggest an improved overall response rate [16]. Currently, GSK2141795 is not in active development.…”

The Multiple Myeloma Drug Pipeline—2018: A Review of Small Molecules and Their Therapeutic Targets

“…114 Another Akt inhibitor uprosertib (GSK2141795) has been included with trametinib in an ongoing phase II trial (ClinicalTrials.gov identifier, NCT01951495) in which a modest ORR of 27% was reported. 115 In addition, the oral PI3K inhibitor alpelisib (BYL719) and the Pim inhibitor LGH447 currently are under study in a combined regimen (ClinicalTrials.gov identifier, NCT02144038). ONC 201, 116 described as a broadspectrum antitumor drug with efficacy against both solid tumors and hematologic malignancies by blocking both Akt and Erk, has been included in 2 early trials (ClinicalTrials.gov identifiers, NCT02863991 and NCT02609230) that include MM patients, although preliminary data have not yet been reported.…”

Lactic acidosis induces resistance to the pan-Akt inhibitor uprosertib in colon cancer cells

“…Clinical investigations combining uprosertib with the MEK inhibitor trametinib in several cancers types have been underway, however, similar studies in multiple myeloma, melanoma and cervical cancer have revealed no clinical benefits of this combination. [43][44][45][46] Although uprosertib treatment as a monotherapy has been well tolerated, 22,23 the adverse toxicity profile of phase II combination studies has been deemed unacceptable, thus, uprosertib is not currently under further development. 46 Since we have demonstrated that enhanced OXPHOS in the presence of lactic acid is related to uprosertib resistance, and previous reports highlight that resistance to MEK combination therapies also corresponds with enhanced OXPHOS, 41 this metabolic phenotype should be considered as a possible contributor to the lack of clinical efficacy observed during phase II trials with uprosertib.…”