Slide 1: FRAME: A phase I trial of VS-6766 and Defactinib in KRAS mutated NSCLC
FRAME: A phase I trial of the combination of the dual RAF- MEK inhibitor VS-6766 and the FAK inhibitor Defactinib; Evaluation of efficacy in KRAS mutated NSCLC. Matthew G. Krebs, Rajiv Shinde, Rozana Abdul Rahman, Rafael Grochot, Martin Little, Jenny King, Mark Van De Velde, Joseph Kitchin, Mona Par
Slide 2: Disclosure Information
Disclosure Information Dr Matthew Krebs I have the following financial relationships to disclose: Consultant for: Achilles Therapeutics, Bayer, Janssen, OM Pharma, Roche, Seattle Genetics Speaker’s Bureau for: Janssen, Roche Grant/Research support from: BerGenBio, Roche Travel expenses: BergenBio, I
Slide 3: High Unmet Need in Refractory KRAS M NSCLC
High Unmet Need in Refractory KRASM NSCLC Adenocarcinoma NSCLC Adenocarcinoma3 S 15 KRAS mutations represent 25% C of lung adenocarcinoma US Annual Incidence1,2: 92K R % of Patients 10 WW Annual Incidence1,2: 836K (EGFR 17%, ALK 7%)4 E E 5 N I 1 Globocan, 2018 2 https://www.ncbi.nlm.nih.gov/books/NB
Slide 4: Mechanism of action of VS-6766
Mechanism of action of VS-6766 • VS-6766 inhibits both MEK & RAF kinase activities • MEK inhibitors paradoxically induce MEK phosphorylation (pMEK) by relieving ERK-dependent feedback inhibition of RAF • By inhibiting RAF phosphorylation of MEK,VS-6766 has advantage of not VS-6766 PD0325901 inducing
Slide 5: Single Agent Activity of VS-6766
Single Agent Activity of VS-6766 Single agent activity seen across a spectrum of KRAS mutant tumours including KRAS G12V NSCLC Guo et al Lancet Oncology 2020, 21:1478-1488
Slide 6: Rationale for Combination of VS-6766 with a FAK Inhibitor
Rationale for Combination of VS-6766 with a FAK Inhibitor NSCLC cancer model H358 KRAS (G12C) mutant Tumor growth 600 Vehicle Trametinib 0.3 mg/kg QD Tumor volume (m m3 +/- SEM) 400 FAKi 50 mg/kg BID VS-6766 0.3 mg/kg QD 200 VS-6766 + FAKi 0 0 5 10 15 20 Days on treatment Pachter et al., RAS meeting
Slide 7: FRAME: Investigator-Sponsored Basket Trial of VS-6766 + Defactinib in KRAS M Cancers
FRAME: Investigator-Sponsored Basket Trial of VS-6766 + Defactinib in KRASM Cancers • 3+3 dose escalation trial design followed by tumour-specific or molecularly stratified dose expansion cohorts • Primary endpoint: determine the dose at which no more than one patient out of up to six patients exper
Slide 8: Demographics and Toxicity seen in patients with KRAS M NSCLC
Demographics and Toxicity seen in patients with KRASM NSCLC Treatment related adverse events Patient demographics All NSCLC Patients (n=20) Median Age 62 (22 - 73) (range) Gender Male 8 Female 12 Tumor types NSCLC 20 KRAS Mutation G12D 8 G12C 7 G12A 2 G12V 2 Q61H 1 Prior treatments All lines: median
Slide 9: Clinical activity in KRAS M NSCLC
Clinical activity in KRASM NSCLC Data cut off March 5, 2021 • ORR = 15% (3/20) • ORR in G12V mt = 100% (2/2) • DCR = 65% (13/20) • Median PFS = 16 weeks • 7 pts on treatment ≥ ~24 weeks *Continuing treatment # Unconfirmed PR 2 Evaluable patients were withdrawn prior to the second scan for disease pr
Slide 10: Response in a patient with KRAS G12V NSCLC
Response in a patient with KRASG12V NSCLC 72F - Diagnosed with NSCLC May 2019 June 2019- Sept 2019 treated with first line Carboplatin + Pemetrexed + Pembrolizumab Oct 2019- Progression, palliative RT to right hip Nov 2019- To present on treatment on FRAME study VS-6766 + Defactinib
Slide 11: Importance of CRAF in KRAS signaling
Importance of CRAF in KRAS signaling KRAS G12V signals mainly through RAF/MEK in CRAF, but not BRAF, ablation improves survival of mice with KRAS G12V contrast to other variants, such as KRAS G12D, which signal more through PI3K/AKT induced lung cancer in vivo KRAS G12V NSCLC models are especial
Slide 12: Summary & Conclusions
Summary & Conclusions • The combination of VS-6766 (RAF/MEKi) + defactinib (FAKi) with a novel, intermittent schedule exhibits a manageable safety profile, with no patients discontinuing for adverse events to date • VS-6766 as monotherapy and in combination with defactinib shows confirmed partial re
Slide 13: Acknowledgements
Acknowledgements Participating patients and their families. This study is sponsored by the Institute of Cancer Research, managed by the DDU’s Investigator Initiated Trial Team with statistical and database support from the Institute of Cancer Research Clinical Trials and Statistics Unit. Drug Develo