Dr. Udai Banerji, MD The Institute of Cancer Research and The Royal Marsden

KRAS Mutant Cancers: Phase I study RAF-MEK inhibitor and FAK inhibitor defactinib in an intermittent dosing schedule

MedicalResearch.com Interview with:

Dr. Udai Banerji, MD The Institute of Cancer Research and The Royal Marsden

Dr. Banerji

Dr. Udai Banerji, MD
The Institute of Cancer Research and The Royal Marsden

MedicalResearch.com: What is the background for this study?

Response: Not only have I been working in the RAS mutations oncology world for a while, but I also have prior preclinical experience working with VS-6766 (RAF/MEK inhibitor) and defactinib (FAK inhibitor), the two drugs in the Phase 1 study that was presented at the American Association for Cancer Research (AACR) annual medical meeting on April 27th.

It is important to know that there is a great significant medical need for novel treatments for KRAS mutant tumors, which are difficult to treat, aggressive, and quite common across advanced solid tumors, including low-grade serous ovarian cancer (LGSOC), non-small cell lung cancer (NSCLC) and colorectal cancer (CRC), resulting in the need for novel treatments in an area of significant medical need.

I felt that early signals in preclinical research warranted a clinical trial; so that, combined with my RAS experience, made pursuing the Phase 1 study a clear fit. A clinical trial setting allowed us to explore RAF and RAS inhibitor combinations in multiple tumor trials, which was our aim.

The data presented at AACR convey safety and dose response results from the dose-escalation portion and expansion cohorts from an open-label, investigator-initiated Phase 1 study evaluating the combination of VS-6766 (RAF/MEK inhibitor) and defactinib (FAK inhibitor) therapy in patients with LGSOC and KRAS mutant NSCLC. The introductory data described in the study suggest that a novel intermittent dosing schedule of RAF/MEK and FAK inhibitor combination therapy has promising clinical activity in patients with KRAS mutant LGSOC and KRASG12V mutant NSCLC, including patients formerly treated with a MEK inhibitor. Expansion cohorts remain ongoing. 

MedicalResearch.com: What are the main findings?

Response: In studies, MEK inhibitors, particularly in combination, have historically experienced issues with toxicities.

The Phase 1 study was thus designed such that it enabled us to give patients enough of the drug in an intermittent schedule to be able to inhibit the target for periods of time without resulting in high toxicity in patients observed to date. The trial went through different dose levels to find a tolerable dose, and it landed on a Phase 2 dose as follows:

VS-6766 was administered using a twice-weekly dose escalation schedule and was administered 3 out of every 4 weeks. Defactinib was administered using a twice-daily dose escalation schedule, also 3 out of every 4 weeks. Dose levels were assessed in 3 cohorts: cohort 1 (VS-6766 3.2mg, defactinib 200mg); cohort 2a (VS-6766 4mg, defactinib 200mg); and cohort 2b (VS-6766 3.2mg, defactinib 400mg).

  • In the 8 patients with LGSOC, the ORR was 50% (4 patients). Among the 6 patients with KRAS mutant LGSOC, the ORR was 67% (4 patients). Of the 4 patients who have responded, 3 had a prior MEK inhibitor and as of November 2019 had been on study for a median of 20.5 months (range 7-23 months).
  • In the 10 patients with NSCLC, all of which had KRAS mutations, 1 patient achieved a partial response. Additionally, 1 patient with KRASG12Dmutant NSCLC achieved a 22% tumor reduction and was still on treatment as of November 2019. Median time on treatment for this cohort was approximately 18 weeks. Median time on treatment for this cohort was approximately 18 weeks.

The initial data reported in the study suggest that a novel intermittent dosing schedule of RAF/MEK and FAK inhibitor combination therapy has promising clinical activity in patients with KRAS mutant LGSOC and KRASG12V mutant NSCLC, including patients with LGSOC previously treated with a MEK inhibitor. Expansion cohorts remain ongoing in areas of high unmet clinical need in oncology. 

MedicalResearch.com: What should readers take away from your report?

Response: More than 50% of patients with LGSOC, a subset of ovarian cancer, have RAS or RAF mutations. Currently, the standard of care for LGSOC is chemotherapy, and response rates are quite low, less than about 10%. Other treatments are hormonal treatments which have a response rate of about 13%. Data were presented at ESMO last year with an MEK inhibitor alone which had a response rate of about 26%.

The Phase 1 data has potential implications for these patients living with LGSOC. What we observed with the Phase 1 study is, in the 8 patients we treated with LGSOC, we observed an overall response rate of 50% (4 patients), and among the 6 patients with KRAS mutant LGSOC, we observed an overall response rate of 67% (4 patients). Overall, the combination of VS-6766 and defactinib in LGSOC was well tolerated by the patients in the trial and shows promising clinical activity, including durable response that is associated with clinically meaningful benefit, which is encouraging to see.

The Phase 1 regimen with the combination of the two therapies may also have wider implications for other cancers. Given that the RAS gene is mutated in about 30% of cancers, it is encouraging to see that, for KRAS proven cancers, this combination regimen was well tolerated in patients observed to date and demonstrated clinical activity. The research sets us up to evaluate the potential of this combination and regimen in patients with other cancer subsets.

MedicalResearch.com: What recommendations do you have for future research as a result of this work?

Response: There is a lot of excitement for compounds that target specific KRAS mutations as we have been looking for treatment for RAS in lung cancer for the last 30 years. As we are starting to see signals of KRAS mutant response, we are looking at a potential game changer in the treatment landscape. The data for lung cancer are currently not as strong as in ovarian cancer but there are positive signals that need to be explored in additional clinical studies with a larger number of patients.

We are also hoping to do an expansion study in KRAS driven solid tumours. 

Disclosures: U. Banerji: ; Boehringer-Ingelheim. ; Janssen. ; Astellas. ; Karus Therapeutics. ; Novartis. ; Phoenix Solutions. ; Onyx Pharmaceuticals. ; BTG International. ; Verastem. ; Chugai/Roche. ; AstraZeneca. ; Employee of The Institute of Cancer Research, which is involved in the development of PI3K, HSP90, HDAC, AKT, ROCK, RAF, CHK1 and HSF1 inhibitors.; The Institute of Cancer Research. 

Citation:

Phase I study of the combination of a RAF-MEK inhibitor CH5126766 and FAK inhibitor defactinib in an intermittent dosing schedule with expansions in KRAS mutant cancers

Abstract presented at the 2020 AACR meeting

https://www.aacr.org/

 

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May 13, 2020 @ 12:14 am

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