410P - Phase I study of the investigational, oral pan-RAF kinase inhibitor TAK-580 (MLN2480) in patients with advanced solid tumors (ST) or melanoma (MEL)...

Date 11 September 2017
Event ESMO 2017 Congress
Session Poster display session
Topics Anti-Cancer Agents & Biologic Therapy
Drug Development
Melanoma and other Skin Tumours
Presenter Anthony Olszanski
Citation Annals of Oncology (2017) 28 (suppl_5): v122-v141. 10.1093/annonc/mdx367
Authors A.J. Olszanski1, R. Gonzalez2, P. Corrie3, A.C. Pavlick4, M. Middleton5, P. Lorigan6, R. Plummer7, S. Skaria8, C. Herbert9, M. Gore10, S. Agarwala11, A. Daud12, S. Zhang13, B. Bahamon14, L. Rangachari14, E. Hoberman15, M. Kneissl16, D. Rasco17
  • 1Department Of Medical Hematology/oncology, Fox Chase Cancer Center, 19111 - Philadelphia/US
  • 2Medical Oncology, University of Colorado Denver, Denver/US
  • 3Oncology, Cambridge University Hospitals NHS Foundation Trust - Addenbrooke's Hospital, CB2 0QQ - Cambridge/GB
  • 4Department Of Medicine, NYU Cancer Center, New York/US
  • 5Oncology, University of Oxford, Oxford/GB
  • 6Medical Oncology, The University of Manchester, Institute of Cancer Sciences and the Christie NHS Foundation Trust, Manchester/GB
  • 7Northern Institute For Cancer Research, Newcastle University, NE2 4HH - Newcastle-upon-Tyne/GB
  • 8Oncology, Mid Essex Hospital, Chelmsford/GB
  • 9Oncology, University Hospitals Bristol, Bristol/GB
  • 10Medicine, Royal Marsden Hospital, SW3 6JJ - London/GB
  • 11Medical Oncology And Hematology, St. Luke’s Cancer Center, Easton/US
  • 12Medicine (hematology/oncology), University of California San Francisco, 94143 - San Francisco/US
  • 13Medical Oncology, Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge/US
  • 14Translational & Biomarker Research, Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge/US
  • 15Research & Development, Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge/US
  • 16Oncology Clinical Research, Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge/US
  • 17Medical Oncology, South Texas Accelerated Research Therapeutics, 78229 - San Antonio/US

Abstract

Background

MAPK pathway mutations leading to signaling hyperactivation are common in many ST; as RAF kinases play a key role in MAPK signaling, they represent a valid target for therapy. As a pan-RAF inhibitor, TAK-580 is differentiated from approved BRAF-specific RAF inhibitors. Here we report the expanded cohort data from a single-agent, first-in-human study of TAK-580 (NCT01425008).

Methods

Patients with advanced ST or inoperable stage III/IV MEL received TAK-580 Q2D or QW in 28-d cycles. Primary objectives were safety and maximum tolerated doses [MTD] of TAK-580; secondary objectives included preliminary antitumor activity, PK and PD effects. Safety and PK were compared between 2 MTD regimens (200 mg Q2D vs 600 mg QW). Preliminary antitumor activity of TAK-580 Q2D vs QW was evaluated in NRAS-mutation positive (mut) MEL. Activity and efficacy (PFS) were assessed in BRAF-mut MEL. Plasma PK were assessed pre- and post-dose between d1 and d28 of cycle 1 (C1). Tumor biopsies were taken at screening and post-dose on d21 or 22 of C1. Disease assessments were performed at baseline and every 2 cycles thereafter.

Results

80 patients received TAK-580 200 mg Q2D (60 MEL + 20 PK-evaluable ST) and 19 MEL patients received 600 mg QW. DLTs observed were: periorbital edema and maculopapular rash (280 mg Q2D); rash and hyperbilirubinemia (800 mg QW). For Q2D and QW, 41% and 32% of patients, respectively, had Gr ≥ 3 drug-related adverse events (AE); 19% and 11% discontinued due to AEs. Total weekly exposure (AUC168h) after TAK-580 600 mg QW was comparable to 3-fold AUC48h after 200 mg Q2D. Of 14 NRAS-mut MEL Q2D patients, 1 achieved PR (1.5 mos). In comparison, none of 17 NRAS-mut MEL QW patients had an objective response. 50% of the 16 BRAF-mut MEL Q2D patients achieved a PR with a median PFS of 4.6 mos (range 1.0–40.8).

Conclusions

The safety and PK profiles of TAK-580 Q2D and QW at MTD were acceptable. QW dosing improved safety but not efficacy over Q2D dosing. PD results were consistent with the proposed mechanism of action of TAK-580 with observed RAF pathway inhibition. These data support the use of QW dosing in the assessment TAK-580 given in combination.

Clinical trial identification

NCT01425008

Legal entity responsible for the study

Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited

Funding

Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited

Disclosure

A.J. Olszanski: Consulting or advisory role: Merck, Takeda, BMS, Kyowa Hakko Kirin, G1 Therapuetics; Research funding: Takeda, Immunocore, EMD Serono, Amgen, Incyte, Kyowa Hakko Kirin, Lilly, Advaxis, Mirati Therapuetics, Ignyta, Novartis, Pfizer, BMS, Kura; Travel/accommodation/expenses: Takeda, Churchill Pharmaceuticals, Kyowa Hakko Kirin, G1 Therapuetics. R. Gonzalez: Consultant: Bristol-Myers Squibb, Novartis, Genentech. Research support: Merck, Novartis, Genentech, Bristol-Myers Squibb, Incyte, Syndax, Takeda. P. Corrie: Advisory boards; Novartis, Pierre Fabre, Bristol-Myers Squibb, MSD, Celgene. Research funding: Celgene. Speaker honoraria: MSD, Novartis. M. Middleton: Consulting or advisory role: GSK, BMS, Amgen, Merck, Roche (all compensated); Clovis, Immunocore (both uncompensated); Travel/accommodation/expenses: Roche, Merck; Corporate-sponsored research: GSK, AZ, Eisai, Clovis, BMS, Amgen, Roche, Merck, Vertex, Immunocore, Pfizer, Medimmune. P. Lorigan: Advisory board: GSK, Novartis, Roche, Bristol-Myers Squibb, Merck, Amgen. Travel/accommodation/expenses: Bristol-Myers Squibb, MSD. A. Daud: Stock ownership: OncoSec, Inc.; Advisory board or board of directors: Novartis, Merck, Pfizer, Genentech; Corporate-sponsored research: Merck, Pfizer, Genentech, BMS. S. Zhang, E. Hoberman: Employment: Millennium Pharmaceuticals. Inc. B. Bahamon, L. Rangachari, M. Kneissl: Employment: Millennium Pharmaceuticals, Inc. D. Rasco: Corporate-sponsored research: Takeda Oncology. All other authors have declared no conflicts of interest.