Phase I trial of MEK 1/2 inhibitor pimasertib combined with mTOR inhibitor temsirolimus in patients with advanced solid tumors

Abstract

Background Dual inhibition of activated MAPK and mTOR signaling pathways may enhance the antitumor efficacy of the MEK 1/2 inhibitor pimasertib and the mTOR inhibitor temsirolimus given in combination. Methods In this phase I study, patients with refractory advanced solid tumors (NCT01378377) received once-weekly temsirolimus plus once-daily oral pimasertib in 21-day cycles in a modified 3+3 dose-escalation design. The maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of pimasertib in combination with temsirolimus, safety and pharmacokinetics (PK) were investigated. Results Of 33 patients evaluated, all experienced ≥1 treatment-emergent adverse event (TEAE) and 31 had treatment-related TEAEs, most frequently stomatitis and thrombocytopenia. TEAEs were reversible. No deaths were attributed to treatment. Nine patients had dose-limiting toxicities (stomatitis, thrombocytopenia, serum creatinine phosphokinase increase, visual impairment) and the MTD was determined as 45 mg/day pimasertib plus 25 mg/week temsirolimus. However, due to overlapping toxicities no further investigations were performed and the RP2D was not defined. PK profiles of both agents were not adversely affected. Seventeen patients (17/26 patients) had a best response of stable disease; five had stable disease lasting >12 weeks. Conclusions The RP2D was not defined and the pimasertib plus temsirolimus combination investigated did not warrant further study.

Phase Ib Trial of the PI3K Inhibitor Copanlisib Combined with the Allosteric MEK Inhibitor Refametinib in Patients with Advanced Cancer

“…The incidence of hypertension (all-grade, 39.1%) was also consistent with reports of copanlisib monotherapy [ 7 , 8 , 21 ]. Increased creatine phosphokinase was the most common grade 4 TEAE (3.1%), consistent with reports of PI3K and MEK inhibitor combination therapies [ 15 , 24 – 26 ]. High rates of ophthalmologic toxicities have been associated with some MEK inhibitors (e.g., 19% incidence [all-cause] with trametinib and 27% incidence with RO4987655) [ 27 ], although were infrequent here (all-grade, 12.5%) and mostly mild in severity [ 18 ].…”

“…No objective responses were observed, consistent with the inadequate efficacy reported from studies with other PI3K and MEK inhibitor combinations [ 25 , 26 , 28 – 30 ]. This was unexpected based on preclinical evidence of such combinations being synergistic [ 3 , 4 ].…”

Oral stomatitis and mTOR inhibitors: A review of current evidence in 20,915 patients

“…(), Mita et al. () reported the incidence rates limited to grades 3 and 4 treatment‐related toxicities; for this reason, data about cases of stomatitis and stomatitis grades 1 and 2 are lower than real.…”

“…Pandya et al (2007),Armstrong et al (2013),Gandhi et al (2014),Mita et al (2017) reported the incidence rates limited to grades 3 and 4 treatmentrelated toxicities; for this reason, data about cases of stomatitis and stomatitis grades 1 and 2 are lower than real. Reports of all papers evaluating ridaforolimus and cases of stomatitis…”

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

“…In advanced solid tumors, a phase Ib clinical trial of combined MEK inhibitor (pimasertib) and PI3K/mTOR inhibitor (voxtalisib) had poor long-term tolerability and limited anti-tumor activity [262]. In a phase I trial of temsirolimus combined with pimasertib for patients with advanced solid tumors, there was unfavorable toxicity profile although some patients had some clinical benefit and stabilized disease [263]. A randomized phase II trial of the MEK inhibitor selumetinib in combination with temsirolimus for soft tissue sarcomas (STS) revealed that the combination treatment compared to selumetinib treatment alone did not improve progression-free survival in patients with advanced STS.…”