Promise in treatment-resistant advanced ovarian cancer 

A new combination of targeted drugs for a type of ovarian cancer has shown promising results in an early clinical trial, shrinking tumours in half of patients. The combination of drugs, which both work by blocking signals cancer cells need to grow, could offer a new treatment option for women with an uncommon type of ovarian cancer that rarely responds to chemotherapy or hormone therapy. 

The Phase I FRAME trial, led by a team at The Institute of Cancer Research, London and The Royal Marsden NHS Foundation Trust, tested the drugs called VS-6766 and defactinib  in 25 patients with low-grade serous ovarian cancer. Overall, 46% of patients saw their tumours shrink significantly in response to the treatment.  

Responses in patients who had a mutation in a gene called KRAS were even more promising. KRAS is one of the most commonly mutated genes in cancer, found in one quarter of all tumours. Until recently KRAS-driven tumours were extremely difficult to treat. 

64% of patients with a KRAS mutation saw their tumour shrink following treatment, suggesting that tumour profiling could be used to identify patients most likely to benefit from the new drug combination. Participants lived an average of 23 months before their cancer progressed. 

It is unusual to see such positive clinical responses in Phase I clinical trials, which set out to determine the safety of the treatment, and establish the dose that can be tolerated without unmanageable side effects. 

Researchers at the ICR and The Royal Marsden recently established that VS-6766 remains active in the body for extended periods and can be given in an unconventional, innovative, twice-weekly schedule to deliver its potent anti-tumour effects while minimising side effects. Patients also received defactinib twice daily. 

A Verastem-sponsored Phase II trial led globally by Dr Susana Banerjee from the ICR and The Royal Marsden is now recruiting to further test the effectiveness of the combination. 

Low-grade serous ovarian cancer is an uncommon form of cancer that tends to develop at an earlier age than other types of ovarian cancer. Less than 13% of patients respond to chemotherapy and less than 14% respond to hormone therapy.  

Recent advances have shown that MEK inhibitors, which block part of cancer’s RAS-RAF-MEK-ERK signalling growth pathway, can cause tumours to shrink in around one out of four people with this type of cancer, but they tend to stop working as tumours develop resistance to treatment. 

Researchers believe the resistance may be triggered by a molecule called p-FAK which is also involved in growth pathways. The current study tested whether using VS-6766, a dual RAF/MEK inhibitor, in combination with defactinib, a FAK inhibitor, could offer a new treatment option for patients and avoid drug resistance. The treatment continued to work in patients who had already received a MEK inhibitor prior to the study. 

In the US, the combination of VS6766 and defactinib has already received breakthrough therapy designation by regulators, which aims to accelerate the development and approval of highly promising drugs.  

Dr Susana Banerjee, Team Leader in Women’s Cancers at The Institute of Cancer Research, London, and Consultant Medical Oncologist and Research Lead for The Royal Marsden NHS Foundation Trust Gynaecology Unit, said: “If these findings are confirmed in larger trials, they’ll represent a significant advance in low-grade serous ovarian cancer treatment. I am delighted that this drug combination has worked so well in a group of patients who are in urgent need of new treatments including those who have previously been treated with a MEK inhibitor. We’re very hopeful that this could become the standard of care for women with low-grade serous ovarian cancer.” 

Professor Kristian Helin, Chief Executive of The Institute of Cancer Research, London said: “Overcoming cancer’s ability to evolve resistance to treatment is a huge challenge for cancer research. This study has turned a deep understanding of how cancer fuels its growth and develops resistance into a highly targeted treatment for patients who currently have few treatment options. Scientists have been working to develop treatments that can effectively target KRAS-driven cancers for decades. It’s fantastic that early trials indicate this treatment is highly effective for this patient group, and that a phase II trial has already begun.” 

Image credit: National Cancer Research

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