Abstract CT019: 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

Abstract

Background KRAS is a known oncogenic driver in non-small cell lung cancer (NSCLC), with KRAS G12C and G12V mutations occurring in ~13% and ~7% of the of NSCLC ( adenocarcinoma subtype). The dual RAF-MEK inhibitor VS-6766 has shown single agent activity against G12V KRAS mutated NSCLC (Guo C et al Lancet Oncology 2020, 21:1478-88). Based on pre-clinical data, we hypothesised that augmented focal adhesion kinase (FAK) signalling is a mechanism of resistance to MEK inhibition and devised the current clinical trial. We have previously reported the safety of an intermittent schedule of the combination of VS-6766 and the FAK inhibitor defactinib and its efficacy in low grade serous ovarian cancer (Shinde et al., AACR 2020). We now report the activity of the combination in KRAS mutated NSCLC. Methods Patients were treated with an intermittent dose of drugs VS-6766 at 3.2 - 4 mg twice a week and defactinib 200 mg twice daily in the dose escalation and expansion cohorts of the study. Both drugs were administered three weeks on/one week off in 28-day cycles. We aim to recruit 20 patients with KRAS mutated NSCLC in an expansion cohort. Results To date, 19 patients with KRAS mutated NSCLC have been treated in the dose escalation and expansion cohorts. All patients had been previously treatment with a PD-1 or PDL-1 targeting immune checkpoint inhibitor. The median age was 64 years (22 - 73), M/F ratio was 7/12, and the median prior lines of treatment was 3. Currently, 17 of 19 patients have had at least one re-staging assessment, 2/17 (12%) patients had a partial response and 10/17 (59%) had stable disease as their best response. Of note, 11/17 (65%) patients had a degree of reduction in size of their tumours and 5/17 (29%) have been treated for 6 months or more with 3 patients still on treatment. Interestingly, 2/2 (100%) of the KRAS G12V NSCLC patients showed a partial response. Conclusions Developing new treatments for non-G12C KRAS mutated NSCLC is an area of unmet need. The combination of VS-6766 and defactinib treatment in cohorts of patients with NSCLC pre-treated with chemotherapy and immunotherapy has shown anti-tumour activity in subsets of patients with KRAS mutated NSCLC, in particular those with tumours harbouring KRAS G12V mutations. A registration-directed study evaluating VS-6766 ± defactinib for treatment of recurrent NSCLC with KRAS G12V mutation (NCT04620330) has been initiated Citation Format: Matthew G. Krebs, Rajiv Shinde, Rozana Abdul Rahman, Rafael Grochot, Martin Little, Jenny King, Joseph Kitchin, Mona Parmar, Alison Turner, Muneeb Mahmud, Christina Yap, Nina Tunariu, Juanita Lopez, Johann S. De Bono, Udai Banerji, Anna Minchom. 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 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT019.

More to the RAS Story: KRASG12C Inhibition, Resistance Mechanisms, and Moving Beyond KRASG12C

“…91 Beyond MEK inhibition, negative clinical trial results have been observed from RAS-selected trials assessing inhibitors of the synthetic lethality target, CDK4. [92][93][94][95] However, some cause for optimism remains, with the recently reported early clinical success of defactinib and VS-6766 (a dual RAF/MEK inhibitor) in KRAS G12V NSCLC, 96 as well as a vastly improved understanding of the contextual signaling outputs (and consequent vulnerabilities) conferred by mutations affecting different RAS isoforms, codons, and amino acids. 97,98 Underpinning all of the above is the paradigm-shifting success of immune checkpoint inhibitors in NSCLC, whose presence in monotherapy and combination regimens now anchor stages III-IV treatment guidelines.…”

Epithelial-mesenchymal transition status is a remarkable biomarker for the combination treatment with avutometinib and defactinib in KRAS-mutated non-small cell lung cancer

“…Therefore, this combination therapy is promising and is currently being tested in clinical trials for patients with several cancers, including KRAS-mutated NSCLC and LGSOC. In this phase I/II trial, the objective response rate to combination therapy was 15.0% in patients with KRAS-mutated NSCLC and 44.8% in patients with LGSOC 17,18,46,47 . Additionally, two ongoing phase II trials aim to evaluate the effectiveness of avutometinib and defactinib combination therapy in patients with KRASmutated NSCLC and in those with LGSOC 17,19,48 , and a useful biomarker is urgently needed for this combination therapy in patients with KRAS-mutated NSCLC.…”

“…However, its e cacy is limited owing to its side effects 45 . In contrast, combination therapy with avutometinib and defactinib was generally well-tolerated in a phase I trial (NCT03875820) 17,46 . Therefore, this combination therapy is promising and is currently being tested in clinical trials for patients with several cancers, including KRAS-mutated NSCLC and LGSOC.…”

“…While avutometinib monotherapy displayed better e cacy than other MEK inhibitors in KRAS-mutated NSCLC, the development of effective combination strategies remains crucial. The combination of avutometinib and the FAK inhibitor defactinib has demonstrated clinical e cacy in both KRAS-mutated NSCLC and low-grade serous ovarian cancer (LGSOC) [17][18][19] .…”

Drugging KRAS: current perspectives and state-of-art review

“…Focal adhesion kinase (FAK) induction was identified as a potential resistance mechanism to VS-6766. Therefore, a combination phase I trial of VS-6766 and FAK inhibitor, defactinib, in NSCLC was performed, which resulted in an ORR of 15% and again showed activity in KRAS G12V-mutant NSCLC (2 out of 2 responses) [ 145 ]. Phase I and phase II studies involving VS-6766 in combinations with defactinib (NCT04620330 and NCT04625270), everolimus (NCT02407509), cetuximab (NCT05200442), adagrasib (NCT05375994), and sotorasib (NCT05074810) are planned or underway in multiple malignancies including lung, ovarian, and colorectal cancers.…”