Slide 1: Phase I study of RAF-MEK inhibitor CH5126766 and FAK inhibitor defactinib
#CT143 Phase I study of the combination of a RAF-MEK inhibitor CH5126766 and FAK inhibitor defactinib in an intermittent dosing schedule with expansions in KRAS mutant cancers Rajiv Shinde, Angelika Terbuch, Martin Little, Reece Caldwell, Roopa Kurup, Ruth Riisnaes, Mateus Crespo, Ruth Ruddle, Bora
Slide 2: Conflict of Interest
Conflict of Interest Personal financial interests - honoraria received: Astellas, Novartis, Karus Therapeutics, Phoenix Solutions, Eli Lilly, Astex, Vernalis, Boehringer-Ingelheim, Janssen Institutional financial interests – funding for Phase I investigator-initiated trials: Onyx Pharmaceuticals, BT
Slide 3: Rationale for study
Rationale for study Rewiring of signal transduction FAK inhibition Preclinical following MEK inhibition reduces T reg experimental models populations show regression Serrels A Cell 2015, 163:160-173
Slide 4: Design and Safety
Design Safety Post R2PD Expansions in LGSOC (20), KRAS Recommended phase 2 dose is CH5126766 3.2 mg mutated NSCLC (20), KRAS mutated CRC (10) twice a week (Mon-Thu) + 200 mg of defactinib twice a day, both given 3 weeks out of 4 in 28 day cycles.
Slide 5: Pharmacokinetics and Pharmacodynamics
Pharmacokinetics Pharmacodynamics CH5126766 Dose AUC0-24h Cmax Cohort (mg) N Subject (h*ng/mL) (ng/mL) p-FAK CD4/FOXP3 cells/mm2 3.2 Mean 6179 354 150 30 1 3 Pre dose Pre dose (with 200mg VS) CV% 32.1 30.4 4 Mean 5353 289 Post CH5126766 Post CH5126766 2a 5 (with 200mg VS) CV% 15.8 16.0 100 Post comb
Slide 6: Efficacy – Low Grade Serous Ovarian Cancer
Efficacy – Low Grade Serous Ovarian Cancer No mutation detected No mutation detected FRA101001 KRAS G12D KRAS G12D KRAS G12V KRAS G12A KRAS G12D KRAS G12V FRA101002 10 FRA101009 0 Best Response % change -10 FRA101014 * from baseline -20 FRA101019 -30 Continuing on * -40 treatment FRA101007 -50 -60 *
Slide 7: Efficacy KRAS mutant NSCLC and Conclusions
Efficacy KRASM NSCLC Conclusions • The recommended dose of CH5126766 FRA102002 G12D Q61H 40 Best Response % change from baseline FRA102006 30 is 3.2 mg Mon-Thu in combination with FRA102007 20 defactinib 200 mg BD, both drugs G12C G12A G12D G12D G12C G12V G12D G12D FRA102008 10 delivered 3 weeks out