Abstract 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

Abstract

Background: Preclinical experiments in-vitro show MEK inhibitors can cause upregulation of p-FAK in KRASM cells. The combination of a MEK and FAK inhibitor could overcome this in-vitro and in-vivo. Methods: We are conducting an open label phase I dose escalation with expansion study (NCT03875820). Dose escalation evaluated a twice a week schedule (Mon/Thurs) CH5126766/VS-6766 (CH) 3 weeks out of 4 with a twice a day dosing schedule of defactinib (Def) administered 3 weeks out of 4. The dose levels explored were cohort 1 (CH 3.2 mg, 200 mg Def), cohort 2a (CH 4 mg Def 200 mg) and cohort 2b (CH 3.2 mg and Def 400 mg). Pharmacokinetic data were collected at cycle 1 d15 when both drugs were administered. In a subset of patients consenting to multiple biopsies, 3 biopsies were performed (baseline, after a single dose of CH run in and after 8-15 days of the combination therapy). At the recommended phase 2 dose (R2PD), expansion cohorts in patients with low grade ovarian cancer (LGSOC, n=20), KRASM non-small cell lung cancer (NSCLC, n=20) and KRASM colorectal cancer (CRC, n=10) will be treated. Results: Forty two patients have been treated on the trial so far. There were no dose limiting toxicities (DLTs) in the first 3 patients in cohort 1 and thus patients were recruited to cohort 2a and 2b. The cohort 2b dose level was deemed intolerable because of 2/3 patients experiencing DLTs of grade 2 rash not allowing dosing of 75% of the planned dose. No DLTs were seen in the first 6 patients treated on schedule 2a. However, given chronic grade 2 toxicities in patients on treatment > 6 months, the RP2D was deemed to be cohort 1. The most common side effects in the study were rash, CK elevation, AST elevation, hyperbilirubinemia and nausea, most of which were NCI CTC grade 1-2. All changes were reversible. The mean AUC of CH and Def at R2PD was 6179 ng*hr/ml and 2071 ng*hr/ml, respectively, which is in the range of what was seen in the single agent dose escalation studies. Sequential biopsies were obtained in 7 patients and 6/7 showed an increase in p-FAK following single agent CH which was reduced in 5/7 with combined CH and Def therapy. The response rate was 67% (4/6) or 50% (4/8) in KRASM LGSOC or all LGSOC patients treated to date, respectively. A range of KRASM were found in tumors of LGSOC patients who responded (G12V, G12A and G12D). Of the 4 patients with LGSOC who have responded to treatment, 3 have had a prior MEK inhibitor and are currently are on study for a median of 20.5 months (range 7-23 months). Expansion cohorts in LGSOC and KRASM NSCLC and CRC are ongoing and will be presented. Conclusion: We report a novel intermittent schedule of the combination of a RAF-MEK and FAK inhibitor with very promising clinical activity in patients with KRASM LGSOC including those who had been previously treated with a MEK inhibitor. Citation Format: Rajiv Shinde, Angelika Terbuch, Martin Little, Reece Caldwell, Roopa Kurup, Ruth Riisnaes, Mateus Crespo, Ruth Ruddle, Bora Gurel, Adam Stewart, Jenny King, Mona Parmar, Alison Turner, Florence Raynaud, Muneeb Mahmud, Christina Yap, Jonathan A. Pachter, Gordon B. Mills, Anna Minchom, Juanita Lopez, Susana N. Banerjee, Johann S. de Bono, Matthew Krebs, Udai Banerji. 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 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT143.

FAK Inhibitor-Based Combinations with MEK or PKC Inhibitors Trigger Synergistic Antitumor Effects in Uveal Melanoma

“…FAK inhibitors have been assessed in clinical trials alone or in combination with RAF/MEK inhibitors in multiple cancer types, including UM [ 25 , 26 ]. We are not aware of any trial in cancer patients associating a FAK inhibitor with a PKC inhibitor.…”

“…Recently, a combination of FAK and MEK inhibitors has been shown to synergize both on in vitro and in vivo UM models [ 17 ]. Following these observations, a clinical trial has been started to evaluate the potential effect of combinations of FAK and RAF/MEK inhibitors [ 25 , 26 ].…”

A focal adhesion kinase-YAP signaling axis drives drug tolerant persister cells and residual disease in lung cancer

“…Similarly, targeting FAK signaling has gained recent momentum, in particular as a combinatorial agent overcoming resistance-associated signaling in cancer therapy 49 . Amongst other contexts, the engagement of FAK signaling has been reported in KRAS-mutant patients treated with the dual RAF/MEK inhibitor VS-6766 in a phase I clinical trial (NCT03875820) [49][50][51] , with subsequent and current clinical studies testing the efficacy of combinatorial treatment with FAK and RAF/MEK inhibitors (NCT04620330, NCT04625270) 52,53 . Our findings provide evidence of FAK-YAP/TEAD signaling engagement in drug tolerance across EGFR-mutant, ALK fusion-positive, KRAS-mutant and NF1-mutant NSCLC more broadly and therefore offer rationale for combinatorial treatment approaches testing FAK inhibitors (e.g., VS-4718) and TEAD inhibitors (e.g., VT104) across several molecularly defined NSCLC subtypes to enhance treatment response to targeted inhibitors against these important oncogenic targets.…”

Targeting KRAS in NSCLC: Old Failures and New Options for “Non-G12c” Patients

“…Anyway, a stronger inhibitor of tumor growth requires more complex strategies. The combination of VS-6766 and the FAK inhibitor defactinib was shown to overcome FAK phosphorylation induced by MEK inhibition in in vivo models [ 90 , 91 ]. An open label phase I dose escalation with an expansion study (FRAME trial—NCT03875820) is recruiting patients with advanced, KRAS +, solid tumors to evaluate this combination.…”