Defactinib Plus RAF/MEK Inhibitor Combo Active in KRAS-Driven Cancers

Udai Banerji, MD

Findings from a phase 1 clinical trial (NCT03875820) demonstrated promising clinical activity with the combination of the RAF/MEK inhibitor VS-6766 (CH5126766) and the FAK inhibitor defactinib in patients with KRAS-mutant cancers, said senior author Udai Banerji.

"Overall, in solid tumors and possibly even in hematologic malignancies, [RAS-targeted therapy] is a large area of unmet need," said Banerji. "This trial was designed to introduce enough drug into the body to be able to inhibit the target for prolonged periods of time, while avoiding toxicity. We’re in early days, but there are many places where this treatment could be utilized."

The combination, which was given in an intermittent dosing schedule, showed particular promise for patients with low-grade serous ovarian cancer (LGSOC), non—small cell lung cancer (NSCLC), and colorectal cancer (CRC).

Notably, 4 patients with LGSOC (n = 8) responded to the combination. Of these responders, 3 had received a prior MEK inhibitor.

According to Banerji, the regimen could also have utility in patients with RAS-mutant pancreatic cancer and RAS-mutant multiple myeloma.

In an interview with OncLive, Banerji, the National Institute for Health Research Professor of Molecular Cancer Pharmacology, honorary consultant in medical oncology and deputy director of the Drug Development Unit at the Royal Marsden NHS Foundation Trust, discussed the rationale for the phase 1 trial, the potential implications of these data, and future studies in development.

OncLive: What was the rationale for this trial?

Banerji: I've been [investigating] RAS mutations in oncology for a while. Moreover, I've worked with [VS-6766 and defactinib].

VS-6766 is a unique compound in that it is not just a MEK inhibitor. It is a functional RAF inhibitor. I had been a part of the original trials with that [agent], and now I work on other trials with defactinib.

This study came out of some research that had been conducted in my lab regarding drug resistance. We found that when we exposed RAS-mutant cells to MEK inhibitors, there was a feedback loop of FAK activation [that worked] well.

Could you elaborate on some of the research you’ve done regarding RAS-mutant cancers?

Most of my research regarding RAS biology has to do with context specificity. One of the big challenges we have is that the low-hanging fruits, so to speak, in targeted therapy are now taken. There was a point where we thought if we inhibited the target that was active in 1 tumor type, it would be active across all tumors driven by the same mutation. While that has been true in some cases, such as HER2, my research in RAS signaling seems to suggest that RAS-driven lung cancers behave quite differently from RAS-driven colon cancers.

That has certainly been the case in BRAF-mutant cancers. For example, the BRAF inhibitor vemurafenib (Zelboraf) does wonders in melanoma, but not in colon cancer.

We're looking to explore RAS/RAF inhibitors, as well as combinations in multiple tumor types, and the only real way of doing that is through a clinical trial. Currently, approximately half of CRC is driven by RAS. Additionally, [RAS-driven cancer] accounts for about one-third of NSCLC, a [high percentage] of multiple myeloma—which is not well understood—and pancreatic cancer. The treatments in pancreatic cancer have not had much of an impact on patients, and 95% of those cancers are driven by a RAS mutation. It is a huge unmet need.

In the trial, we showed a real benefit in patients with LGSOC. Not much is known about LGSOC, and it doesn't respond well to chemotherapy. It's a rare subtype of ovarian cancer in which the treatment options are limited.

How was the trial designed?

Other MEK inhibitors have been investigated before, and in fact, MEK inhibitors have been around for a long time. Now, [VS-6766] is unusual in terms of its mechanism of action because it has MET inhibition and functional RAF inhibition. It’s unusual in the sense that it has a long half-life of more than 50 hours.

The tablet is given only twice a week, either Monday/Thursday or Tuesday/Friday. The FAK inhibitor is given on a standard schedule twice daily. [The combination] is given on a 3-weeks-on, 1-week-off schedule. We did that because we want the combination to be tolerable for long periods of time. In the past, we’ve run into problems with toxicity with RAF and MEK inhibitors, especially in combination studies.

Could you discuss the results presented at the 2020 AACR Virtual Annual Meeting I? What were some of the safety signals that were reported with the combination?

The trial went through different dose levels to find a safe and tolerable dose. We've confirmed a phase 2 dose, which is 3.2 mg of the VS-6766 compound given twice a week and 200 mg of defactinib given twice a day. Both of these drugs are given for 3 weeks with 1 week off.

With that [dosing schedule], we have seen some toxicities that are common to MEK inhibitors, such as skin rash. Rash is very tolerable and is seen with all MEK inhibitors. [The incidence] is less than what is seen with EGFR monoclonal antibodies, such as cetuximab (Erbitux). Some patients have been on the combination for more than 2 years, and we have seen that a little bit of makeup [can hide the rash].

In terms of biochemical abnormalities, we saw grade 1/2 creatine kinase elevation, which suggests the muscles are involved but is not serious. We've also seen bilirubin changes. However, those changes are not due to liver toxicities but rather due to glucuronidation of bilirubin, which happened with defactinib. We haven't had to take patients off treatment due to toxicity.

We did a pharmacokinetic analysis which suggested that there is not much [toxicity] interaction [between the 2 drugs]. Granted, it's not a detailed pharmacokinetic study, but we've looked at both drugs individually within the combination and compared them to historical single-agent data. It's not very different.

We also did triple biopsies in a lot of patients. The preclinical hypothesis [stated that patients would have] increasing phosphorylation of FAK. That hypothesis panned out. There is an increase in FAK phosphorylation about 24 hours after [patients received] the RAF/MEK inhibitor, which goes down with the combination; that's exciting.

We've shown reduction in regulatory T cells, confirming 1 of our hypotheses.

Could you shed light on the clinical activity of the combination?

On the clinical side, we're extremely excited regarding what we've seen so far. We've seen the most striking results in patients with LGSOC. Six patients had KRAS-mutant LGSOC, 4 of which responded [to the combination]. The whole population [included] 8 patients, so [the response rate] was either 67% or 50%, [depending on which patients are included in the calculation].

A number of patients who responded [to the combination] had previously received a MEK inhibitor. This seems to suggest that we can [overcome] [MEK-mediated] resistance. We've also presented data in a huge population of patients with KRAS-mutant NSCLC. Lung cancer is a large cause of morbidity and mortality around the world. About one-third of those patients have a KRAS mutation. We saw 1 response which we presented, and we have seen 1 response after that. Some patients got to the 24-week cutoff, which is approximately 6 months. That is very meaningful. Additionally, the majority of patients got past the 12-week cutoff, which could be a sign of the drug’s activity.

The only way to go on to a registration trial, and possibly a randomized trial is [to enroll] more patients on study. We are looking at other exciting opportunities in KRAS-mutant CRC, as well as opportunities in KRAS-mutant pancreatic cancer, which continues to be a huge area of unmet need.

How did the combination compare with historical treatments in patients with LGSOC?

LGSOC is a subset of ovarian cancer which does not respond to chemotherapy. More than 50% of these patients have RAS/RAF mutations. Currently, the standard of care is chemotherapy, but it demonstrates response rates less than 10%. The other treatments are hormonal treatments, including letrozole, which have a response rate of about 13%.

In the limited number of patients with LGSOC in the trial, we showed a response rate greater than 50%. These data we presented may change the standard of care [for these patients] in the future.

What could the clinical implications of this regimen be?

The implications are huge, and we've seen some very good starting signals. In low-grade ovarian cancer, there is another drug, trametinib (Tafinlar) which has an overall survival benefit. However, patients on this combination have responded even after being on previous MEK inhibitors. Therefore, even in the MEK inhibitors space, it is likely that this combination will be effective.

Once the registration trial is done, [the combination] could even be used in the first-line setting versus chemotherapy because it's very likely to be better than chemotherapy. That's a huge change in what we have for patients with low-grade ovarian cancer.

In lung cancer, which is an even bigger population, there has been a lot of excitement in the RAS-mutant world regarding new inhibitors which are specific to KRAS G12C mutations. That's exciting because we've been looking for treatment for patients with RAS mutations for the last 30 years, and this is the first time that's happened.

Of course, what has been very exciting for these patients with RAS mutations is this combination. With RAF/MEK inhibitor monotherapy, we started to see signals [of activity], certainly KRAS-mutant responses [that don’t have] the G12C [mutation]. More than 50% of lung cancers that harbor RAS have G12V and D12 mutations, [so the combination] could be a game changer in lung cancer.

The signal [with the combination] is not as strong as in ovarian cancer, so you have to [accrue] a large number of patients to a trial.

Additionally, 40% to 50% of CRC cases harbor a KRAS mutation. That's another place we can go. We haven't looked into pancreatic cancer, but we are looking for support to do an expansion [study in these patients]. There are other possible places we can go such as multiple myeloma, which is a largely unexplored area [despite the fact that a lot of patients with myeloma harbor] RAS mutations.

Could these drugs be explored in combination with immunotherapy or chemotherapy?

We spoke about [the reduction in] regulatory T cells with the use of defactinib in this combination. There are a lot of cancers where the stroma is really important. This is particularly true in pancreatic cancer where, at least in preclinical models, it looks like you can kill the cancer cells. However, there's evidence that the stromal cells either stop the treatment from getting to the cancer cells or they secrete things that cause the cells to become resistant. Therefore, targeting the stroma is important.

Defactinib itself could have utility with different combinations apart from a RAF/MEK inhibitor, such as with immunotherapy and chemotherapy.

There is a body of evidence to suggest that VS-6766 in combinations with PI3K inhibitors, mTOR inhibitors, or other agents, may be very effective in certain types of RAS-mutated cancers. Those are further steps that should be taken because we've definitely seen the first tangible effects on RAS-mutant cancer.

Shinde R, Terbuch A, Little M, et al. 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. Presented at: the 2020 AACR Virtual Annual Meeting I; April 27-28, 2020. Abstract CT143. bit.ly/2WroZzs.