Global study explores MEK / FAK combination in recurrent low-grade serous ovarian cancer with or without KRAS mutations

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The ENGOT-ov60 / GOG3052 / RAMP 201 (NCT04625270) Phase 2 trial is currently enrolling patients with recurrent LGSOC at 26 sites in the US and UK. To be eligible for the study, patients must have a histologically proven LGSOC, a KRAS transfer or KRAS wild type if treated in the first part of the study, measurable disease according to RECIST v1.1, an ECOG performance index of 1 or less, and adequate organ function and recovery from previous toxicities.

In an interview with Targeted Oncology â„¢ following a study protocol presentation at the 2021 American Society of Clinical Oncology Annual Meeting, Susana K. Banerjee, PhD, Medical Oncology Consultant and Head of Research for the Royal Marsden NHS Foundation Trust Gynecology Unit, explained in detail the progression of ENGOT-ov60 / GOG3052 / RAMP 201.

TARGETED â„¢ ONCOLOGY: What does the treatment landscape look like for recurrent LGSOC today?

BANERJEE: This is a very rare type of gynecologic cancer and unfortunately the treatments currently approved for recurrent or advanced diseases are not as effective as we would like them to be. For example, chemotherapy, with response rates in this context is less than 10% and hormone therapy, for example, letrozole is around this mark or slightly higher. But there has been progress in the development of MEK inhibitors in this setting, and they have shown their effectiveness.

I was very happy to have been involved in recruiting patients for 2 different randomized trials as a site at the Royal Marsden in London UK. These trials included the MILO / ENGOT-ov11 trial of binimetinib [Mektovi] versus standard of care and the GOG-0281 trial of trametinib [Mekintist] compared to the standard of care. What is clear is that some patients may benefit more than without conventional treatments for MEK inhibitors.

Another important point, because we understand the biology of LGSOC much better, is that about 30% of these patients can harbor a mutation in the KRAS and up to about 70% may exhibit alterations in the RAS pathway. So that’s where we are at the moment.

Can you describe the mechanism of action of this VS-6766? What was the rationale for administering this agent in combination with defactinib to patients with recurrent LGSOC?

VS-6766 is a unique small molecule inhibitor, and it blocks MEK kinase activity and MEK RAF phosphorylation. This has the potential to eliminate any compensatory MEK activation. Defactinib is a reversible and competitive ATP inhibitor of FAK and has been shown to block certain compensatory parallel signaling seen in blockade of the RAS pathway. Thus, there is preclinical data which indicates that inhibition of FAK may induce tumor regression when combined with inhibitors of RAF / MEK in in vivo models of KRAS– mutated ovarian cancer.

What’s really exciting is that the combination of VS-6766 and defactinibis is currently being evaluated in the ongoing investigator-sponsored frame study. This is a first-phase academic study sponsored by the Institute of Cancer Research in the UK, and the first results have been reported. Responses have been noted in patients with recurrent LGSOC, particularly those with KRAS mutations. Activity was also observed in patients who had previously been treated with an MEK inhibitor, which is therefore very exciting. The response rates we presented [among] small numbers in an early phase study was 56% in KRAS– mutated patients, and in the overall population of patients with LGSO it was approximately 40%.

We plan to present an update of this study at a conference later this year.

A new phase 2 study is underway in this patient population. Can you discuss the design of the study?

Given these encouraging preclinical results observed so far, the ENGOT-ov60 / GOG3052 / RAMP 201 trial will be a phase 2 study investigating the combination in this context. It is an adaptive design and multicenter two-part study with parallel, randomized and open cohorts. The study is designed to assess both the efficacy and of course the safety of VS-6766 alone or in combination with defactinib.

What is important is that the cohorts are according to KRAS mutation status. This will be very important to assess upstream activity in patients with KRAS mutation or without. I think it’s a very exciting place we’re in right now.

What are the main objectives of this study?

The primary endpoint is the overall response rate, and that is by an independent blinded radiological examination. But there are very important secondary endpoints regarding safety, tolerability, other clinical outcomes such as progression free survival and overall survival. It is important to note that here we will be looking at pharmacokinetics and, of course, biomarkers of activity. The aim is to establish whether this combination has significant activity for patients in a context where currently approved therapies must be better.

We will also examine, as I said, for the first time upstream the activity according to KRAS mutation status, and the hope is that this combination will be useful in the future.

This trial is already open in the United States and in recruitment. We hope to open very soon in European countries such as UK, France, Spain, Belgium, Italy and Canada. I think what is important in terms of inclusion criteria is that patients must have had disease progression after at least 1 previous treatment containing platinum. It is important to note that patients who have previously received MEK inhibitor therapy are eligible to participate in this study.

Finally, the good news from this study is that the FDA breakthrough designation was granted in May to VS-6766 in combination with defactinib for the treatment of recurrent LGSOC after at least 1 prior treatment containing platinum. So I am excited about this collaboration and look forward to recruiting patients for this trial. I really hope this can help shape future treatments for women with LGSOC.

If this test is positive in the future, what impact do you think it will have?

There is great potential for targeted therapies and I sincerely hope that there will be more therapies approved by the FDA, EMA and around the world so that women with this rare malignant tumor have effective treatment options. .

I wrote about this trial in the recurring LGSOC. Of course, it would be great, in general, if effective treatments were provided earlier in the disease path at the time of diagnosis, and ultimately we would like to prevent this disease.

Reference:

Banerjee SN, Monk BJ, Nieuwenhuysen EV, et al. ENGOT-ov60 / GOG3052 / RAMP 201: Phase 2 study of VS-6766 (dual RAF / MEK inhibitor) alone and in combination with defactinib (FAK inhibitor) in low-grade serous ovarian cancer (LGSOC) recurrent. J Clin Oncol. 2021; 39 (suppl 15). doi: 10.1200 / JCO.2021.39.15_suppl.TPS5603

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