Avutometinib Plus Defactinib Makes a Phase 3 Debut in Low-Grade Serous Ovarian Cancer

Premal Thaker, MD, MS

The combination of the RAF/MEK inhibitor avutometinib (formerly VS-6766) and the FAK inhibitor defactinib (VS-6063) elicited preliminary efficacy signals in the phase 2 RAMP 201 trial (NCT04625270), leading to the further evaluation of the combination in patients with low-grade serous ovarian cancer, according to Premal Thaker, MD, MS.

In updated data from part A of RAMP 201, patients in the combination arm (n = 29) experienced a confirmed overall response rate (ORR) of 45% (95% CI, 26%-46%), including an ORR of 60% in patients with KRAS-mutant disease (n = 15) and an ORR of 29% in those with KRAS wild-type disease (n = 14). Furthermore, confirmed responses were observed in 3 of the 4 patients in the combination arm who had received a prior MEK inhibitor.¹

These findings led to the initiation of the ongoing phase 3 RAMP 301 trial (NCT06072781), which is evaluating avutometinib plus defactinib vs investigator’s choice of treatment in patients with recurrent low-grade serous ovarian cancer.² The primary end point is progression-free survival, and key secondary end points include overall survival, ORR, duration of response, disease control rate, and safety.

“[We want to] get this word out to [the] many patients [with low-grade serous ovarian cancer] who are in need of [novel treatments],” Thaker said in an interview with OncLive^®.

In the interview, Thaker discussed the differences between low-grade and high-grade serous ovarian cancer; how the RAMP-201 data paved the way for future investigations in low-grade disease; and the design and rationale of RAMP-301.

Thaker is the David G. and Lynn Mutch Distinguished Professor of Obstetrics and Gynecology, director of Gynecologic Oncology Clinical Research, and interim chief of the Division of Gynecologic Oncology at the Siteman Cancer Center in St. Louis, Missouri.

OncLive: How is low-grade serous ovarian cancer different from high-grade serous ovarian cancer?

Thaker: Low-grade ovarian cancer [usually] affects younger women. Typically, [these cancers are] found [in patients who are] in their 30s or 40s, or even as young as in their 20s. [Conversely], high-grade disease is typically found more in patients who are in their 50s and 60s, unless they have a genetic predisposition.

What unmet clinical needs do patients with serous ovarian cancer have?

Only recently [did we] realize the distinction between low-grade and high-grade [serous ovarian cancer]. In 2006, pathologists finally realized there was a difference in how [these diseases] looked under the microscope. However, in that timeframe, and even onward, we continued to treat [low-grade disease] the same way we did high-grade disease, with standard chemotherapy, taxanes, and platinum agents, and we found that [these therapies only produced] response rates of approximately 15% or less, unlike in high-grade serous ovarian cancer, where [these therapies] usually [elicit] response rates of approximately 85% to 90%, or maybe even a little higher. That made us realize the biology is different [between low-grade and high-grade disease, and that we need to better] understand the biology to get better treatments.

What work has been done to understand the biology of low-grade vs high-grade serous ovarian cancer? Is this a target-rich tumor?

The targets are different, and next-generation sequencing helps us understand a lot more of the biology. We realized that the RAS [signaling] pathway is important, along with the MAPK pathway.

Based on that, there has been a lot of targeted work investigating MEK inhibitors. Different [MEK inhibitors] have been evaluated, such as trametinib [Mekinist] and binimetinib [Mektovi]. More recently, we realized that although those [agents perform well], there are probably resistance mechanisms. I wish cancer biology were linear, but it’s not. I tell everyone, it’s all going zigzag in every such way. We also realized that adding a FAK inhibitor is important.

The newest ongoing trials are dual-therapy studies. [Findings from] the RAMP 201 trial were presented at the 2024 SGO Annual Meeting in a late-breaking abstract. [Results from this trial have] been presented before, but we keep getting more mature data.

How have earlier-generation MEK inhibitors, such as trametinib and binimetinib, performed in patients with high-grade ovarian cancer?

[These agents produced] response rates of approximately 20% to 25%. These drugs were also investigated in recurrent low-grade ovarian cancer. We’re now trying to move some of these hormonal agents or other agents into earlier lines, because recurrence is always harder to treat than when patients are [treated] up-front.

Clinical trials are ongoing to evaluate standard chemotherapy with the addition of hormonal treatment up-front vs hormonal treatment by itself to try to [answer the question]: do these patients need chemotherapy? [Low-grade serous ovarian cancers are] also estrogen receptor rich, so [agents with] targets that we typically think of [utilizing in] breast cancer, such as letrozole and anastrozole, could also be used in this disease.

How does the FAK pathway work synergistically with the RAS/MAPK pathway?

If [a disease exhibits] resistance to the RAF/MEK [pathway], the FAK pathway bypasses that and allows a resensitization to [RAF-targeted] medication. That’s why using [RAF and FAK inhibitors] in combination has been helpful in RAMP-201 to date. [In that trial], we stratified patients by KRAS [mutation status] and found that the ORR [with avutometinib plus defactinib] was 45% for the entire population. In the patients with KRAS-mutated disease, the ORR was 60%. We haven’t seen those types of responses before, so [these data are] encouraging. [RAMP-201] built on the [phase 1] FRAME study [NCT03875820], which was a smaller trial. The ongoing RAMP-301 trial is the confirmatory, larger, international phase 3 trial.

Based on data from RAMP-201, if the combination of avutometinib and defactinib moves forward in development and ultimately becomes available in the clinic for patients with low-grade serous ovarian cancer, would the combination be used in all-comers or just patients with KRAS-mutant disease?

The combination may be used more optimistically in the KRAS-mutant population, but I think it will be used in all-comers, because even the all-comer population seems to have a better response rate [with the combination] than with single-agent MEK inhibitors. A lot of us would be more optimistic to try the combination [in all patients]. In the RAMP-201 trial, a lot of patients had received prior MEK inhibitors. They had already seen trametinib, [for example], or had been on a prior MEK inhibitor trial, and they still had responses [to avutometinib plus defactinib], which is encouraging.

[We have asked]: Why would we try [a combination] that [patients] have [previously been exposed to] part of before? [However], we’ve been able to see responses [with this approach]. That also gives us a more encouraging rationale to use it in all-comers.

RAMP-301 was presented as a trial in progress at the 2024 SGO Annual Meeting. What is the design of this trial, and what patient population is being observed?

RAMP-301 is [evaluating] the combination of defactinib and avutometinib. Avutometinib is given twice a week, and defactinib is given twice daily for 3 weeks on and 1 week off. [The control arm is receiving] physician’s choice of chemotherapy, which could be a taxane, topotecan, or pegylated liposomal doxorubicin, or either anastrozole or letrozole, which is a hormonal, non-chemotherapy treatment. Patients are stratified based on their KRAS mutation status, and they are allowed to have received a prior MEK inhibitor as well as prior bevacizumab [Avastin].

Interestingly, if patients are on the physician’s choice arm and they experience progression, they’re allowed to cross over to get the combination. For patients, it’s encouraging that even though [the trial is] randomized 1:1, and they may be disappointed to get standard chemotherapy or a hormonal agent, if they progress on standard chemotherapy, they’re allowed to cross over. That’s at least in the interest of the patients.

RAMP-301 is also an international trial. It’s being done in Asia, Europe, and the United States. It’s always nice to see ethnic differences [in clinical trial patient populations], because RAMP-201 was predominantly conducted in Europe and the United States.

Although the trial’s crossover design is beneficial for patients, it has the potential to confound results. What are your thoughts on the inclusion of the crossover design from that perspective?

The crossover design is helpful because even though we know chemotherapy does help somewhat—and that will be a secondary end point—we see that even if we don’t allow for crossovers in trials, [such as in] the PARP maintenance trials that were done in ovarian cancer, once patients progressed, they did get [the investigational] drugs secondarily. [The crossover design] makes it realistic for us to understand how to approach patients. We try to make trials perfect, but there’s always a subsequent real-world experience where we realize the reality. I hope this design allows us to investigate both potentials without minimizing the benefit [of avutometinib plus defactinib], because we are confident in the benefit we’ve seen to date [with that combination] compared [with the outcomes with] chemotherapy or hormonal agents.

[The crossover design] is still worthwhile. It’s [sometimes] hard to tell a patient to participate in [the control arm of a] phase 3 trial when you see the great, encouraging data [with the investigational agent]. The best thing that’s happened in low-grade disease is we’re getting a lot more patient support for these trials. Before, I feel like patients [with low-grade disease] felt like ovarian cancer was a big bucket that didn’t include them. Low-grade [disease comprises] a smaller percent [of all ovarian cancers], and there weren’t great novel agents. There’s a lot of buzz within the patient advocacy world. [Patients and patient advocates want treatment and clinical trial] opportunities, and this is a way to give them an opportunity.

What would you tell patients looking to enroll in this trial or oncologists looking to refer their patients about the safety profile of avutometinib plus defactinib?

[The combination] has been quite safe. [Patients] need to have eye examinations to ensure [they do not experience] visual disturbances. [However, patients] don’t need to take extra eye drops like they have with some antibody-drug conjugates. We encourage eye exams.

A more common adverse effect [AE] patients get is a rash, which is well known from a MEK inhibitor standpoint. I have many patients who say they feel like they are a kid again with acne, and they do not want that. However, there are topical agents to use for that. There are also some oral antibiotics we can suggest. Those are the main 2 AEs patients have.

[Patients can also experience] liver abnormalities on their blood tests, but those have been transient. We haven’t had to take patients off [treatment] because of that. Overall, the combination is well tolerated. Some patients will get some nausea, so we give them anti-nausea medicine. But otherwise, it’s an easy combination to give. Some patients will also get a bit of swelling, which is also associated with MEK inhibitors. They will say that at the end of the day, their legs or hands feel more swollen. However, overall, the treatment discontinuation rate because of AEs has been nominal.

What would you like oncologists who are not familiar with this research to know?

Make sure the pathology is correct. If you’re practicing in an area in the community where maybe you or your pathologist don’t see as many patients with ovarian cancer in general, ensure you know the differential between low- and high-grade disease, because sometimes you can’t just go by [patient] age or mutation pattern. Get that expert pathology. [Additionally], know that there are treatment options for these patients that are not chemotherapy based [and can elicit] durable responses, hopefully getting us to complete this trial quicker so [avutometinib plus defactinib] can go from having an FDA breakthrough designation to becoming a standard of care.

References

1. Banerjee SN, Nieuwenhuysen EV, Santin AD, et al. Avutometinib + defactinib in recurrent low-grade serous ovarian cancer (LGSOC): a subgroup analysis of ENGOT-ov60/GOG-3052/RAMP 201 part A. Presented at: 2024 SGO Annual Meeting. March 16-18, 2024; San Diego, California.
2. A study of avutometinib (VS-6766) + defactinib (VS-6063) in recurrent low-grade serous ovarian cancer (RAMP 301). ClinicalTrials.gov. Updated April 4, 2024. Accessed April 4, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT06072781