This phase Ib study evaluated the safety, maximum-tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary efficacy of pimasertib (MSC1936369B), a MEK1/2 inhibitor, in combination with voxtalisib (SAR245409), a pan-PI3K and mTORC1/mTORC2 inhibitor, in patients with advanced solid tumours.
This study included a dose escalation and expansion in patients with select tumour types and alterations in the MAPK or PI3K pathways. A 3 + 3 design was used to determine MTD. Patients were evaluated for adverse events and tumour response.
146 patients were treated, including 63 in dose escalation and 83 in expansion. The MTD was pimasertib 90 mg and voxtalisib 70 mg daily. Based on the safety profile, the recommended phase 2 dose (RP2D) was pimasertib 60 mg and voxtalisib 70 mg. The most frequent treatment-emergent adverse events (TEAEs) were diarrhoea (75%), fatigue (57%), and nausea (50%). Responses included a complete response in one patient (1%), partial response in five (5%), and stable disease in 51 (46%). At the RP2D, 74 patients required dose interruption (73%), 20 required dose reduction (20%), and 26 discontinued treatment due to TEAEs (26%).
The combination of pimasertib and voxtalisib showed poor long-term tolerability and limited anti-tumour activity in patients with advanced solid tumours.
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We thank all the patients, their families and investigators who participated in this study.
L.G.: Research Fuding: Merck. Advisory Role: Merck, Genentech/Roche, Pfizer, Ignyta, Syndax, AbbVie, AstraZeneca, Bristol-Myers Squibb; L.D.: Employee of Merck KGaA; F.C.: Employee of Sanofi; D.M.H.: Research Funding: NIH R01 CA204749, AstraZeneca, Puma Biotechnology, Loxo Oncology. Consulting or Advisory Role: AstraZeneca, Atara Biotherapeutics, Chugai Pharma, CytomX Therapeutics, Boehringer Ingelheim, Pfizer, Genetech, Bayer, Debiopharm, ArQule; R.S.H.: Consulting: Boehringer Ingelheim. Research funding (to institution): Novartis, Celgene, Corvus, Genentech/Roche, Millenium, Mirati, ABBVie, Incyte, Exelixis, Daichi, Agios.
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All patients signed an informed consent prior to participation in the study. Ethical approval was given by the Institutional Review Boards at all participating institutions. The study was conducted according to the Declaration of Helsinki.
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