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    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

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    Authors
    Krebs, Matthew G
    Shinde, R.
    Rahman, Rozana A
    Grochot, R.
    Little, Martin
    King, J.
    Kitchin, J.
    Parmar, M.
    Turner, A.
    Mahmud, M.
    Yap, C.
    Tunariu, N.
    Lopez, J.
    De Bono, J. S.
    Banerji, U.
    Minchom, A.
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    Affiliation
    The Christie NHS Foundation Trust and The University of Manchester, Manchester
    Issue Date
    2021
    
    Metadata
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    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
    Krebs MG, Shinde R, Rahman RA, Grochot R, Little M, King J, et al. 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. In: Clinical Trials. American Association for Cancer Research; 2021.
    Journal
    Cancer Research
    URI
    http://hdl.handle.net/10541/624618
    DOI
    10.1158/1538-7445.AM2021-CT019
    Additional Links
    https://dx.doi.org/10.1158/1538-7445.AM2021-CT019
    Type
    Other
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1158/1538-7445.AM2021-CT019
    Scopus Count
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