Discussion
nausea, DLTs, tumor, diarrhea, toxicity, SD, vomiting, gastrointestinal toxicities, TRAEs
TUMOR, SOLID TUMORS, DRUG INTERACTION WITH, DRUG INTERACTION, TUMORIGENESIS
Aberration in the function or expression of ERBB receptor tyrosine kinases contributes to tumorigenesis. EGFR or HER2 targeting agents are widely used and have shown substantial clinical efficacy. However, drug resistance often arises from aberrant or compensatory mechanism from downstream signaling proteins. Neratinib and trametinib have demonstrated clinical benefits when used as monotherapy or in combination with chemotherapy [Here, we are the first to examine the safety, toxicity and preliminary anti-tumor efficacy in patients with advanced solid tumors treated with neratinib and trametinib. Unfortunately, continuous daily dosing of neratinib and trametinib was poorly tolerated. Two patients experienced DLTs of diarrhea at the initial dose level resulting in dose de-escalation to dose level minus 1 which was neratinib at a dose of 160 mg once daily in combination with trametinib at a dose of 1 mg once daily on a 5 days on and 2 days off schedule. This cohort was expanded to include a minimum of six patients treated and evaluable for DLT to further evaluate safety and tolerability. In total, 8 patients were DLT evaluable, and dose level minus one was determined to be the MTD. The TRAEs observed in this study are consistent with previous studies and were mainly gastrointestinal toxicities such as diarrhea, nausea and vomiting [In our PK cohort of 8 patients treated at dose level minus 1 (160 mg neratinib daily with 1 mg trametinib 5 days on and 2 days off), trametinib pharmacokinetics, when co-administered with neratinib, appears to have a much lower oral clearance (1.55 L/h) leading to higher exposure (AUCStudies of trametinib and neratinib have shown that each agent has different metabolism pathways. Neratinib is metabolized via cytochrome P450-3A4 (CYP3A4) pathway [We believe the observed drug–drug interaction from our PK analysis is due to combination therapy with neratinib and trametinib, with neratinib inhibiting the clearance of trametinib via the P-gp efflux pathway leading to a very high exposure of trametinib. There may be other factors such as saturation of deacetylation and glucuronidation enzyme pathways which may contribute to additional lowering of trametinib clearance resulting in increased total exposure. With trametinib as a substrate for P-gp, the use of P-gp strong inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, erythromycin, ritonavir, verapamil) or P-gp inducers (e.g.,: phenytoin, rifampin, St. John’s wort, corticosteroids, efavirenz, nevirapine) should be avoided whenever possible when taking trametinib [Limited anti-tumor efficacy was seen across all treated patients. The lack of meaningful response may be due to suboptimal dosing of both neratinib and trametinib. No partial responses were reported, and SD ≥ 4 months was seen in only 2 patients. Both patients were treated at dose level 1. No patients obtained SD ≥ 4 months or PR at dose level minus 1, the declared MTD.Interestingly, both patients with SD ≥ 4 months harbored 
There are several limitations to this study. First, we were unable to dose escalate to meaningful doses of either agent in combination due to overlapping toxicity resulting in poor patient tolerance. Second, there was heterogeneity in the molecular aberrations allowable for enrollment onto study. Five of 11 (45.5%) patients enrolled on dose level minus 1 had only activating In conclusion, neratinib and trametinib combination therapy was not tolerable at dose level 1. MTD was declared as dose level minus 1 (neratinib 160 mg daily with trametinib 1 mg, 5 days on and 2 days off) and had limited clinical activity. This may be due to suboptimal drug dosing of trametinib and neratinib. The increased plasma exposure of trametinib may have contributed to the toxicity observed. Based on the results from our PK cohort, there was significant drug–drug interaction with an increase in trametinib plasma concentrations and exposure due to a decrease in clearance of trametinib. We hypothesize that this could be due to neratinib-induced inhibition of trametinib clearance via P-gp efflux mechanisms. Further work is needed in determining the best dose and/or schedule for treating patients with both agents in combination to improve tolerability. Additionally, further work needs to be done to determine the appropriate tumor types and molecular aberrations for enrollment.