Differences in the Biologic Activity of 2 Novel MEK Inhibitors Revealed by ¹⁸F-FDG PET: Analysis of Imaging Data from 2 Phase I Trials

Abstract

Two mitogen-activated protein kinase kinase (MAPK2, also known as MEK) inhibitors were assessed with 18 F-FDG PET in separate phase I clinical studies, clearly illustrating the potential of metabolic imaging for dose, dosing regimen, and compound selection in early-phase trials and utility for predicting nonresponding patients. Methods: 18 F-FDG PET data were collected during 2 independent, phase I, dose-escalation trials of 2 novel MEK inhibitors (RO5126766 and RO4987655). PET acquisition procedures were standardized between the 2 trials, and PET images were analyzed centrally. Imaging was performed at baseline; at cycle 1, day 15; and at cycle 3, day 1. A 10-mmdiameter region of interest was defined for up to 5 lesions, and peak standardized uptake values were determined for each lesion. The relationship between PET response and pharmacokinetic factors (dose and exposure), inhibition of extracellularsignal-regulated kinase (ERK) phosphorylation in peripheral blood mononuclear cells, and anatomic tumor response as measured by Response Evaluation Criteria in Solid Tumors was investigated for both compounds. Results: Seventy-six patients underwent PET, and 205 individual PET scans were analyzed. Strong evidence of biologic activity was seen as early as cycle 1, day 15, for both compounds. 18 F-FDG PET revealed striking differences between the 2 MEK inhibitors at their recommended dose for phase II investigation. The mean amplitude of the decrease in 18 F-FDG from baseline to cycle 1, day 15, was greater for patients receiving RO4987655 than for those receiving RO5126766 (47% vs. 16%, respectively; P 5 0.052). Furthermore, a more pronounced relationship was seen between the change in 18 F-FDG uptake and dose or exposure and phosphorylated ERK inhibition in peripheral blood mononuclear cells in patients receiving RO4987655. For both investigational drugs, PET responses tended to be greatest in patients with melanoma tumors. 18 F-FDG was able to identify early nonresponding patients with a 97% negative predictive value. Conclusion: These data exemplify the role of 18 F-FDG PET for guiding the selection of novel investigational drugs, choosing dose in early-phase clinical development, and predicting nonresponding patients early in treatment.

Phase I Expansion and Pharmacodynamic Study of the Oral MEK Inhibitor RO4987655 (CH4987655) in Selected Patients with Advanced Cancer with RAS–RAF Mutations

“…Evidence of pharmacodynamic drug effect was observed with a metabolic response in all four cohorts, with markedly larger effects in those in which objective tumor shrinkage was observed. Our study confirms the high negative predictive value of FDG for MEK inhibition and potential for FDG-PET to predict early nonresponders (27). We also noted a significant decrease of pERK phosphorylation in all cohorts, but an effect on proliferation (as measured by Ki67) was only observed in the two melanoma cohorts.…”

“…Our findings show that RO4987655 has clinical activity in patients with BRAF V600-mutated melanoma, BRAF wild-type melanoma, and KRAS-mutated NSCLC, but not (47) 13 (14) 5 (5) Infections Oral candidiasis, subcutaneous abscess, cellulitis 37 (40) 13 (14) 3 (3) Nervous system disorders Headache, dysgeusia 32 (34) 16 (17) 2 (2) Metabolism and nutrition disorders Decreased appetite, hypocalcaemia 26 (27) 14 (15) 2 (2) in KRAS-mutated colorectal cancer. The safety profile of RO4987655 was at the level predicted from the phase I/part 1 selection of the MTD with no new safety signals being identified.…”

[18 F]FDG-PET imaging is an early non-invasive pharmacodynamic biomarker for a first-in-class dual MEK/Raf inhibitor, RO5126766 (CH5126766), in preclinical xenograft models

“…The decrease in [ 18  F]FDG uptake was dose-dependent and increased with treatment exposure, therefore strongly paralleling and supporting the observations obtained with this class of compounds in patients [18,25]. The effect in [ 18  F]FDG uptake in vitro was more rapid in B - raf mutant cell line COLO205, reflecting the increased sensitivity of B - raf mutated tumors to MEK inhibition.…”

“…It suggests a new therapeutic approach for ras tumors by blocking feedback activation of ERK signalling [24]. RO5126766 has shown potent in vivo anti-tumor efficacy in diverse human tumor xenografts models and has recently been evaluated in a phase I dose-escalation study in humans in which [ 18  F]FDG-PET was included as one of the biomarker assessments [18,25]. Our results show that in vivo [ 18  F]FDG-PET imaging of preclinical tumor models can be used to successfully monitor therapeutic response to MEK inhibition.…”

Melanoma & Nuclear Medicine: New Insights & Advances

“…Nonetheless, FDG-PET/CT can play an important role for the evaluation of these innovative treatments, providing important information regarding early discrimination between responders and refractory disease and also enabling detection of immune-related toxicities prior to clinical manifestations [135,145,152,153]. …”