725MO - Phase I study of the combination of the dual RAF/MEK inhibitor VS-6766 and the FAK inhibitor defactinib: Results of efficacy in low grade serous ovarian cancer

Background

Patients with low grade serous ovarian cancer (LGSOC) have limited response to conventional chemotherapy and hormonal therapy. Recently, MEK inhibitors have shown an overall response rate (ORR) 15-26%. Activation of p-FAK is a possible mechanism of resistance to MEK inhibitors and we hypothesised combination of a RAF/MEK inhibitor with a FAK inhibitor would overcome this.

Methods

We explored the safety, pharmacokinetics and pharmacodynamics in the dose escalation study and recommended a phase two dose of the combination of RAF/MEK inhibitor VS-6766 3.2 mg twice a week and the FAK inhibitor defactinib 200 mg twice daily, both administered 3 out of 4 weeks in 28 day cycles in a highly intermittent dosing schedule. We evaluated confirmed responses using RECIST 1.1. We present the efficacy of the combination in patients with LGSOC in this trial so far.

Results

Currently, 25 patients with LGSOC have been treated with 24 evaluated for response, median age 57 (range 31 to 75 years) and median previous lines of therapy 4 (range 1 to 9). Of the 24 evaluable patients, 11 (46%) had KRAS mutations and 10 (42%) received prior MEK inhibitor treatment. The most common adverse events were rash and CK elevation which were predominantly grade 1/2. The overall response rate in all patients was 46% (11/24, 95% CI: 28% to 65%), with ORR of 64% (7/11, 95% CI: 35% to 85%) in patients with KRAS mutations, and 44% (4/9, 95% CI: 19% to 73%) in patients with KRAS wildtype tumours. Four patients had undocumented KRAS status. Responses were observed in patients with and without prior MEK inhibitor treatment. The median progression free survival was 23 months for the whole cohort, 13/24 patients are still on study and updated results will be presented.

Conclusions

An intermittent dosing schedule of the combination of VS-6766 and defactinib has shown encouraging clinical activity in patients with recurrent LGSOC. These data support an ongoing registration-directed study of VS-6766 ± defactinib in patients with recurrent LGSOC (ENGOT-ov60/NCRI/GOG-3052; NCT04625270).

Clinical trial identification

NCT03875820.

Editorial acknowledgement

None

Legal entity responsible for the study

The Institute of Cancer Research and The Royal Marsden Hospital NHS Foundation Trust.

Funding

Verastem Oncology.

Disclosure

S. Banerjee: Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Clovis; Financial Interests, Personal, Advisory Board: GSK; Financial Interests, Personal, Advisory Board: Genmab; Financial Interests, Personal, Advisory Board: Immunogen; Financial Interests, Personal, Advisory Board: Mersana; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: Sereno; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Oncxerna; Financial Interests, Personal, Advisory Board: Epsilogen; Financial Interests, Personal, Advisory Board: Tesaro; Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Institutional, Funding: GSK; Financial Interests, Institutional, Funding: Tesaro; Financial Interests, Institutional, Principal Investigator: Verastem. M. Krebs: Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Janssen; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Advisory Board: Seattle Genetics; Financial Interests, Personal, Advisory Board: OM Pharma; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Speaker’s Bureau: Janssen; Financial Interests, Personal, Other, travel expenses: BerGenBio; Financial Interests, Personal, Other, travel expenses: Immutep; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Institutional, Research Grant: BerGenBio; Financial Interests, Personal, Advisory Board: Achilles Therapeutics; Financial Interests, Institutional, Principal Investigator: Carrick; Financial Interests, Institutional, Principal Investigator: Turning Point Therapeutics; Financial Interests, Institutional, Principal Investigator: Janssen; Financial Interests, Institutional, Principal Investigator: Roche; Financial Interests, Institutional, Principal Investigator: AstraZeneca; Financial Interests, Institutional, Principal Investigator: Blueprint; Financial Interests, Institutional, Principal Investigator: BerGenBio; Financial Interests, Institutional, Principal Investigator: Immutep; Financial Interests, Institutional, Principal Investigator: Astellas; Financial Interests, Institutional, Principal Investigator: Seattle Genetics. M. Little: Financial Interests, Personal, Speaker’s Bureau: Pfizer. C. Yap: Financial Interests, Personal, Advisory Role: Faron Pharmaceuticals; Financial Interests, Personal, Other: Celgene. A. Minchom: Financial Interests, Institutional, Invited Speaker: Chugai Pharmaceuticals; Financial Interests, Personal, Advisory Board: Janssen Pharmaceuticals; Financial Interests, Institutional, Other: Amgen Pharmaceuticals; Financial Interests, Personal, Advisory Board: Merck Pharmaceuticals; Financial Interests, Institutional, Invited Speaker: Novartis Oncology; Financial Interests, Personal, Advisory Role: Faron Pharmaceuticals; Financial Interests, Institutional, Invited Speaker: Bayer Pharmaceuticals; Financial Interests, Institutional, Other: Loxo Oncology. J. Lopez: Financial Interests, Institutional, Research Grant: Roche-Genentech; Financial Interests, Institutional, Research Grant: Basilea ; Financial Interests, Institutional, Research Grant: Genmab; Financial Interests, Personal, Advisory Board: Basilea. J. de Bono: Financial Interests, Personal, Advisory Role: Amgen; Financial Interests, Personal, Other, Honoraria & Travel expenses, including accommodations: Amgen; Financial Interests, Personal, Advisory Role: Astellas; Financial Interests, Personal, Other, Honoraria & Travel expenses, including accommodations: Astellas; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Other, Honoraria & Travel expenses, including accommodations: AstraZeneca; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Other, Honoraria & Travel expenses, including accommodations: Bayer; Financial Interests, Personal, Advisory Role: Bioxcel Therapeutics; Financial Interests, Personal, Other, Honoraria & Travel expenses, including accommodations: Bioxcel Therapeutics; Financial Interests, Personal, Advisory Role: Boehringer Ingelheim; Financial Interests, Personal, Other, Honoraria & Travel expenses, including accommodations: Boehringer Ingelheim; Financial Interests, Personal, Advisory Role: Cellcentric; Financial Interests, Personal, Other, Honoraria & Travel expenses, including accommodations: Cellcentric; Financial Interests, Personal, Advisory Role: Daiichi; Financial Interests, Personal, Other, Honoraria & Travel expenses, including accommodations: Daiichi; Financial Interests, Personal, Advisory Role: Eisai; Financial Interests, Personal, Other, Honoraria & Travel expenses, including accommodations: Eisai; Financial Interests, Personal, Advisory Role: Genentech Roche; Financial Interests, Personal, Other, Honoraria & Travel expenses, including accommodations: Genentech Roche; Financial Interests, Personal, Advisory Role: Genmab; Financial Interests, Personal, Other, Honoraria & Travel expenses, including accommodations: Genmab; Financial Interests, Personal, Advisory Role: GlaxoSmithKline; Financial Interests, Personal, Other, Honoraria & Travel expenses, including accommodations: GlaxoSmithKline; Financial Interests, Personal, Advisory Role: Harpoon; Financial Interests, Personal, Other, Honoraria & Travel expenses, including accommodations: Harpoon; Financial Interests, Personal, Advisory Role: Janssen; Financial Interests, Personal, Other, Honoraria & Travel expenses, including accommodations: Janssen; Financial Interests, Personal, Advisory Role: Menarini Silicon Biosystems; Financial Interests, Personal, Other, Honoraria & Travel expenses, including accommodations: Menarini Silicon Biosystems; Financial Interests, Personal, Advisory Role: Merck Serono; Financial Interests, Personal, Other, Honoraria & Travel expenses, including accommodations: Merck Serono; Financial Interests, Personal, Advisory Role: Merck Sharp & Dohme; Financial Interests, Personal, Other, Honoraria & Travel expenses, including accommodations: Merck Sharp & Dohme; Financial Interests, Personal, Advisory Role: Orion Pharma; Financial Interests, Personal, Other, Honoraria & Travel expenses, including accommodations: Orion Pharma; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Other, Honoraria & Travel expenses, including accommodations: Pfizer; Financial Interests, Personal, Advisory Role: Qiagen; Financial Interests, Personal, Other, Honoraria & Travel expenses, including accommodations: Qiagen; Financial Interests, Personal, Advisory Role: Sanofi Aventis; Financial Interests, Personal, Other, Honoraria & Travel expenses, including accommodations: Sanofi Aventis; Financial Interests, Personal, Advisory Role: Sierra Oncology; Financial Interests, Personal, Other, Honoraria & Travel expenses, including accommodations: Sierra Oncology; Financial Interests, Personal, Advisory Role: Taiho; Financial Interests, Personal, Other, Honoraria & Travel expenses, including accommodations: Taiho; Financial Interests, Personal, Advisory Role: Terumo; Financial Interests, Personal, Other, Honoraria & Travel expenses, including accommodations: Terumo; Financial Interests, Personal, Advisory Role: Vertex Pharmaceuticals; Financial Interests, Personal, Other, Honoraria & Travel expenses, including accommodations: Vertex Pharmaceuticals; Financial Interests, Institutional, Research Grant: Astellas; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Bayer; Financial Interests, Institutional, Research Grant: Cellcentric; Financial Interests, Institutional, Research Grant: Daiichi; Financial Interests, Institutional, Research Grant: Genentech Roche; Financial Interests, Institutional, Research Grant: Genmab; Financial Interests, Institutional, Research Grant: GlaxoSmithKline; Financial Interests, Institutional, Research Grant: Harpoon; Financial Interests, Institutional, Research Grant: Janssen; Financial Interests, Institutional, Research Grant: Merck Serono; Financial Interests, Institutional, Research Grant: Merck Sharp & Dohme; Financial Interests, Institutional, Research Grant: Orion Pharma; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: Sanofi Aventis; Financial Interests, Institutional, Research Grant: Sierra Oncology; Financial Interests, Institutional, Research Grant: Taiho; Financial Interests, Institutional, Research Grant: Vertex Pharmaceuticals; Financial Interests, Personal and Institutional, Licensing Fees, DNA damage repair inhibitors for treatment of cancer (patent no. WO 2005 053662; licensee: AstraZeneca) – no personal income: AstraZeneca; Financial Interests, Personal and Institutional, Licensing Fees, 17-substituted steroids useful in cancer treatment (patent no. US5604213; licensee: Janssen) – no personal income: Janssen). U. Banerji: Financial Interests, Institutional, Research Grant: Verastem; Financial Interests, Institutional, Full or part-time Employment: The Institute of Cancer Research; Financial Interests, Personal, Advisory Role: Phoenix Solutions; Financial Interests, Personal, Advisory Role: Janssen; Financial Interests, Personal, Advisory Role: Boehringer Ingelheim; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Sierra Oncology; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Bayer; Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Institutional, Funding: Onyx; Financial Interests, Institutional, Funding: Chugai Pharma; Financial Interests, Institutional, Funding: BTG. All other authors have declared no conflicts of interest.