443O - Pimasertib (Pim) and Sar245409 (Sar) - a Mek and Pi3K/Mtor Inhibitor Combination: a Phase Ib Trial with Expansions in Selected Genotype-Defined Solid Tumors

Abstract

ABSTRACT Aim: To investigate safety and efficacy in four expansion cohorts treated with the combination of PIM and SAR. Methods: The recommended phase 2 dose (RP2D) for the combination of PIM and SAR has previously been defined in a dose escalation part of the same trial as 60 mg and 70 mg QD, respectively. Inclusion criteria included ECOG PS 0-1, and in the expansion cohorts prior MEK and/or PI3K inhibitor therapy was not allowed (NCT01390818). With an extract date of 25 March 2014, we carried out preliminary analyses for safety and efficacy using standard criteria (NCI CTCAE v4.0 and RECIST v1.1). Results: At the RP2D, 4 disease- and genotype-specific cohorts were recruited: RAS mutated non-small cell lung cancer (NSCLC, n = 24), triple-negative breast cancer (TNBC, n = 26), BRAF inhibitor resistant malignant melanoma (MEL, n = 15) and dual KRAS and PIK3CA mutated colorectal cancer (CRC, n = 18). The most frequent (≥20%) all grade treatment-emergent adverse events were: diarrhea (77.1%), fatigue (54.2%), nausea (50.6%), vomiting (47.0%), dermatitis acneiform (37.3%), maculo-papular rash (30.1%), decreased appetite (30.1%), peripheral edema (25.3%), pyrexia (25.3%), stomatitis (24.1%), dizziness (24.1%), dyspnea (21.7%), skin rash (21.7%), increased creatinine phosphokinase levels (21.7%), abdominal pain (20.5%) and pruritus (20.5%). Serous retinal detachment, which is a class effect of MEK inhibitors, was reported in 34.9% of pts and all cases were resolved without serious damage to the eyesight. Confirmed responses were observed in 2 of 18 evaluable NSCLC patients and in 1 of 13 evaluable MEL pts. Conclusions: Toxicities were manageable and improved or resolved with drug interruptions and/or dose reductions. Clinical activity was observed and an updated response evaluation will be presented at the meeting. We plan to evaluate whether there is a specific subset of pts who are more likely to benefit from the combination treatment with PIM and SAR. Disclosure: R.S. Heist: Research funding (for clinical trials) going to the institution at which I work (MGH), from the following companies: Genentech, GSK, Pfizer, Debiopharm, Infinity, Exelixis, EMD Serono, Sanofi F. Campana: Frank Campana is a Sanofi employee; C. Egile: Coumaran EGILE is a Sanofi employee; V. Jego: I am currently working for Cytel Inc, a CRO contracted by Merck KGaA. I do not have any stock ownership or advisory board or board of director membership or other substantial relationship beyond employment; L. Damstrup: I am an employer of Merck Serono, no other conflict of interest. All other authors have declared no conflicts of interest.