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Early Data in Hand, Verastem Marches Ahead With RAF-MEK Inhibitor Program in KRAS-mutated Cancers

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NEW YORK – Some patients with advanced cancers harboring mutations in the RAS-RAF-MEK pathway — including those with difficult-to-target KRAS mutations — had durable responses while avoiding dose-limiting toxicities on Verastem Oncology's investigational VS-6766, the results of a recently published study showed.

These data give Verastem more confidence in its plan to advance VS-6766, a MEK and pan-RAF inhibitor, into two registration-enabling studies in lung and ovarian cancer by the end of the year.

Verastem licensed VS-6766 in early 2020 from Tokyo-based Chugai Pharmaceutical. The data from the Phase I dose-escalation and dose-expansion basket trial, published Wednesday in Lancet Oncology, showed that VS-6766 is safe and tolerable when administered in an intermittent, twice-weekly dosing schedule. Patients with various solid tumors harboring RAS-RAF-MEK pathway mutations, including patients with KRAS-mutated non-small cell lung cancer and low-grade serous ovarian cancer, responded to the drug.

Patients were eligible to enroll in Part II of the trial — which followed a safety assessment in Part I — if their cancers harbored mutations in BRAF, KRAS, NRAS, and other RAS-RAF-MEK pathway genes. The investigators were encouraged to find that those patients with KRAS mutations were among the most frequent responders.

"What is very unusual for this trial is the fact that we saw so many responses in KRAS-mutant cancers, which is something we've been trying for the last 20 or 30 years and have not achieved," Udai Banerji of the Royal Marsden NHS Foundation Trust in London, the study's lead investigator, said in an interview. "And what is really, really interesting is that the responses we saw are not in G12C [KRAS mutations.]"

KRAS, once thought to be an undruggable target, is a frequently mutated gene in cancer. "For decades, KRAS has been considered extremely challenging to drug, and there remains no effective targeted therapy against the majority of RAS-mutant cancers," wrote Banerji and co-authors in the Lancet Oncology paper.

Approximately 30 percent of lung cancer patients in Western countries have KRAS mutations, for example, and KRAS G12C mutations are the most common. As such, much of the recent drug development activity in this space has focused on tumors with KRAS G12C mutations. Amgen's investigational agent sotorasib demonstrated early activity in KRAS G12C-mutated NSCLC earlier this fall, and Mirati Therapeutics is also studying a drug in advanced solid tumors with this alteration.

But KRAS G12C mutations account for only 15 percent of KRAS-mutated tumors, leaving a significant unmet need. Researchers have had limited success trying to treat patients with other types of KRAS mutations, and when the rare patient has responded, the response has not been durable.

"If you scan the literature of Phase I studies, you might see an occasional patient with a KRAS-mutant cancer respond, but definitely not reproducibly, and definitely not for long periods of time," Banerji said, adding that it is particularly unusual for patients to respond to a single agent.

In the Lancet Oncology study, however, one patient who responded to VS-6766 monotherapy has now been in the study for more than four years. "That duration and the reproducibility … is what's exciting," he said.

Although encouraging, the data are still from a small number of evaluable patients. Out of 58 patients enrolled in the study, 29 were included in the biomarker-selected, basket trial portion, including 10 patients with NSCLC, five patients with gynecologic malignancies, four patients each with colorectal cancer or melanoma, and six patients with multiple myeloma. Twenty-six of these patients were evaluable for overall response.

Banerji and colleagues reported a 30 percent objective response rate among NSCLC patients, a 60 percent response rate among patients with gynecologic malignancies, and a 16.7 percent response rate among multiple myeloma patients. Of the six patients with solid cancers who saw their tumors shrink after VS-6766 treatment, five experienced responses lasting at least six months. Responses were not observed among colorectal cancer or melanoma patients.

Two of the NSCLC patients who responded to the drug had tumors harboring KRAS G12V mutations and one had a KRAS G12R mutation. Patients with gynecologic malignancies who responded to the drug included those with low-grade, serous ovarian cancer harboring KRAS G12D mutations or BRAF V600E mutations, as well as KRAS G12V-mutated endometrial cancer patients. The multiple myeloma patient who responded to VS-6766 — and who remains on treatment after 72 weeks of disease stability — harbors a KRAS G12V mutation. The NSCLC patient who Banerji highlighted as having remained on treatment for more than four years has a KRAS G12V mutation.

In a recent analysis of six tumor types known to commonly harbor KRAS mutations, KRAS G12V was among the more frequently observed mutations, although the prevalence of the G12V mutation varied by tumor type. "What's really exciting is the KRAS G12V [responses]," Verastem CSO Jonathan Pachter said in an interview. "We could select patients around that [biomarker], and we think that is the path going forward."

Registrational studies

Based on the strength of the Phase I trial, Verastem will further evaluate VS-6766 with its collaborators, including Banerji's team. The company plans to launch two Phase II clinical trials by year end evaluating the agent in KRAS-mutated NSCLC and low-grade serous ovarian cancer. The randomized trials will evaluate VS-6766 alone or in combination with Verastem's FAK inhibitor defactinib.

Earlier this year, the company presented preliminary results from the FRAME trial, which suggested that combining VS-6766 and defactinib could be effective against KRAS-mutated advanced solid tumors. However, the randomized design of the forthcoming trials will truly isolate the effect of adding defactinib to the regimen.

"One question that we really need to nail is the contribution of the FAK inhibitor," Pachter said. "Because, as this paper shows, the RAF-MEK inhibitor VS-6766 alone is active in these diseases. But the question is, is the FAK inhibitor making it better?"

Within the upcoming randomized NSCLC clinical trial evaluating VS-6766 alone versus VS-6766 plus defactinib, Pachter said that the investigators will focus foremost on patients with the KRAS G12V mutations, but will enroll patients with other KRAS mutations, too. Both the NSCLC study, as well as the Phase II ovarian cancer study, will be registration-enabling, offering Verastem the opportunity to seek accelerated approval from the US Food and Drug Administration for either VS-6766 monotherapy or the VS-6766-defactinib combination.

In the ovarian cancer setting, specifically, depending on how the trial plays out, Verastem could seek approval either in the biomarker-defined, KRAS-mutated subpopulation or in all patients regardless of biomarker status. "Low-grade serous ovarian cancer is not the most common ovarian cancer, but it affects younger women in particular, and they often have a RAS mutation," Banerji explained. "It's actually a huge area of unmet need. Chemotherapy has very little to offer to these patients. They're often very chemo-resistant."

Beyond ovarian cancer and NSCLC, VS-6766 may be active against other malignancies, too. In the study published in Lancet Oncology, for instance, VS-6766 also showed activity in one patient with a rare, HRAS-mutated scalp cancer, which also presents an area for future study. In the multiple myeloma cohort in the same study, investigators are still enrolling patients with RAS or RAF mutations. And in patients with solid tumors, this trial is now evaluating the combination of VS-6766 and everolimus (Novartis' Afinitor), which Banerji hopes to read out early results from early next year.

A pancreatic cancer cohort has also been added to the ongoing, non-randomized FRAME trial assessing VS-6766 and defactinib. "We know that as many as 98 percent of pancreatic cancer patients have KRAS mutations," Pachter said. "We'll get a look at whether the FAK inhibitor plus the RAF-MEK inhibitor is active there. We think this could really be the tip of the iceberg as far as indications where RAS is important."

Unique mechanism, improved dosing

Although the FDA has approved several MEK inhibitors for patients with BRAF-mutated melanoma and NSCLC, VS-6766 is unique in its ability to not only inhibit MEK, but also "functionally inhibit RAF," Banerji explained. The drug blocks the interaction of other kinases that are functionally connected to RAF, and in so doing, effectively cuts off the signals that RAS-mutated tumors are dependent on for growth.

"The RAF-MEK dual inhibitor [is unique] relative to all the MEK inhibitors out there," Pachter said. "People talk about the need to hit more than one target in the RAS pathway to get a durable response, and to our knowledge, this is the only agent in the world that hits a vertical blockade, meaning two different hits in the pathway with one drug."

Banerji highlighted another aspect that he sees as unique to VS-6766: its long half-life. While past MEK inhibitors have required once- or twice-daily administration due to their short half-lives, Verastem's agent has a half-life of over two days, allowing patients to receive the drug in an intermittent dosing schedule without sacrificing the agent's activity.

This is significant because prior to the Lancet Oncology study, the drug's development had been stalled by its associated toxicities. A first-in-human trial for VS-6766 (then called RO5126766) conducted between 2008 and 2011 had tested a dosing schedule of 2.7 mg four continuous days per week, and while the drug had shown encouraging activity, patients experienced significant toxicities, such as rash, raised creatinine phosphokinase, and diarrhea.

In the current trial, researchers tested out twice- and thrice-weekly dosing schedules that, according to Banerji, "took a lot of academic courage" to attempt, since there are very few cancer drugs that are effective when dosed twice weekly. "We were swimming against the popular opinion that [you have to] give a drug all the time for it to work," he said.

The twice-per-week dosing schedule of 4mg of VS-6766 ultimately limited toxicities in patients while still maintaining the drug's efficacy. This is the dosing schedule that Verastem will use in the registration-enabling trials that will determine whether VS-6766 becomes a treatment option for patients with KRAS-mutated cancers.

Still, having established the intermittent dosing schedule that now allows for future assessment of VS-6766 without dose-limiting toxicities, Banerji is eager to see the results of these upcoming trials. "You can't predict the end of the experiment before doing it," he said, "But we certainly are excited by what we've seen so far."