As investigators continue efforts to improve outcomes for patients with low-grade serous ovarian cancer (LGSOC), which encompasses approximately 5% of all ovarian cancers, they are expanding investigations beyond chemotherapy due to the relatively low chemosensitivity of the disease. To fill this unmet need, the investigational combination of avutometinib (formerly VS-6766) and defactinib (formerly VS-6063) is being developed with the aim of offering an additional treatment option for patients with LGSOC and has moved into phase 3 study with the initiation of the confirmatory RAMP 301 trial (NCT06072781).

“Most patients who present with a low-grade serous carcinoma are going to have surgery first, followed by—in advanced-stage disease—either chemotherapy or hormone blockade [with] an aromatase inhibitor,” Jubilee Brown, MD, professor and director of gynecologic oncology at Atrium Health Levine Cancer Institute in Charlotte, North Carolina, said in an interview with 

. “The standard of care is changing; although we still use up-front surgery, adjuvant therapy is changing. For the longest time, we’ve used paclitaxel and carboplatin as standard of care for patients with LGSOC. [However], we don’t frequently see the excellent responses [with chemotherapy] that we do in other ovarian cancers.”

There are currently no FDA-approved treatments for patients with LGSOC, and standard-of-care therapies have an overall response rate (ORR) ranging from approximately 6% to 13%. Avutometinib is an investigational RAF/MEK clamp that provides a vertical blockade of both RAF and MEK, and defactinib is a selective FAK inhibitor. FAK has been shown to mediate adaptive tumor resistance to activation of the RAS and MAPK pathways; parallel inhibition with defactinib in combination with the vertical blockade of avutometinib has displayed synergy in several tumor models, including LGSOC, melanoma, and pancreatic cancer.

“[This combination] works by capitalizing on the kinase activity of these therapies,” Ritu Salani, MD, gynecologic oncologist and director of gynecologic oncology at UCLA Health in Los Angeles, California, explained in an interview with 

. “MEK inhibitors have been used for some time to inhibit the RAS pathway, and that has been shown to be effective. Avutometinib [essentially] captures escape from that pathway and [helps to] double up the activity potential of these 2 [agents].”

Avutometinib Plus Defactinib Displays Promise in Phase 2 Study

Following positive findings from the phase 1/2 FRAME study (NCT03875820), which led to the FDA granting breakthrough therapy designation to avutometinib plus defactinib in recurrent LGSOC in May 2021, investigators initiated the phase 2 RAMP 201 study (NCT04625270).

 RAMP 201 evaluated avutometinib with or without defactinib in patients with recurrent LGSOC with measurable disease per RECIST v1.1 criteria who underwent prior chemotherapy. Prior treatment with a MEK inhibitor was permitted. The trial enrolled patients to 1 of 4 parts: selection phase (part A), expansion phase (part B), combination expansion phase (part C), and low-dose avutometinib combination phase (part D). In addition to the combination regimen, avutometinib monotherapy was also an option in parts A and B.

The recommended phase 2 dose of avutometinib and defactinib was 3.2 mg twice weekly for 21 days and 200 mg twice daily for 21 days, respectively, both given in 28-day cycles. In part D, the dose of avutometinib was halved and the dose of defactinib was the same as all other parts of the study. The primary end point was ORR in the combination arms by blinded central review.

At a data cutoff of February 23, 2024, with a minimum follow-up of 5 months, updated findings from RAMP 201 demonstrated that the pooled ORR across parts A, B, and C for all patients who received avutometinib plus defactinib (n = 109) was 27% (95% CI, 19%-36%). Additionally, patients with 

-mutated disease (n = 57) achieved an ORR of 37%; those with 

 wild-type disease (n = 52) experienced an ORR of 15%.

 mutations have come to [prominence recently], and we’re seeing those frequently in patients with LGSOC,” Salani said. “Targeting this pathway, even in those who don’t have the mutation, has still shown some effect, and this is an exciting area [of research].”

Notably, with a longer minimum follow-up of 12 months, patients who received the combination in part A (n = 29) achieved an ORR of 45% (95% CI, 26%-64%), including an ORR of 60% in patients with 

-mutated disease (n = 15) and 29% in patients with 

 wild-type disease (n = 14). Patients in this group were heavily pretreated, with a median of 4 lines of prior therapy. Most patients (86%) experienced a reduction in tumor size, and the median time to response was 5.5 months (range, 1.6-14.7).

The clinical benefit rate in the overall population (n = 109) was 60%. No new safety signals were reported, and Verastem Oncology, the developer of the combination of avutometinib and defactinib, noted that plans were being made to present a mature data set at an upcoming medical meeting in the second half of 2024.

Safety findings from patients treated with avutometinib plus defactinib in parts A and B (n = 81) presented during the 2023 American Society of Clinical Oncology Annual Meeting in Chicago, Illinois, showed that only 12.3% of patients discontinued either study drug due to treatment-emergent adverse effects (AEs). Seventeen percent of patients who received the combination required a dose reduction. The most common any-grade treatment-related AEs (TRAEs) included nausea (61.7%), diarrhea (49.4%), and increased creatine phosphokinase in the blood (48.1%). Grade 3 or higher TRAEs included increased creatine phosphokinase in the blood (18.5%), fatigue (3.7%), and anemia (3.7%).

“In RAMP 201 [findings], these appear to be long-lasting responses [and the combination was] also tolerable. [It was] such a great signal that now we’re opening RAMP 301 to further investigate [this regimen],” Brown noted.

In May 2021, the FDA granted breakthrough therapy designation to avutometinib plus defactinib for the treatment of patients with recurrent LGSOC, irrespective of 

 status.4 Following the positive results from RAMP 201, the FDA granted an orphan drug designation to avutometinib with or without defactinibfor the treatment of patients with recurrent LGSOC in March 2024.

 In May, Verastem Oncology announced that it had initiated the rolling submission of a new drug application to the FDA seeking the accelerated approval of avutometinib plus defactinib for the treatment of adult patients with recurrent 

-mutated LGSOC following at least 1 prior line of systemic therapy.

RAMP 301 is an ongoing, international, open-label study that is comparing the safety and efficacy of avutometinib plus defactinib with investigator’s choice of chemotherapy in patients with recurrent LGSOC who have experienced disease progression following prior platinum-based therapy. Eligible patients must have measurable disease per RECIST v1.1 criteria, an ECOG performance status of 1 or less, as well as adequate organ function and recovery from toxicities related to previous treatments. Those who received systemic anticancer therapy within 4 weeks of the first dose of study therapy, those with high-grade disease, or patients who previously received avutometinib, defactinib, or other FAK inhibitors were excluded from the study.

After enrollment, patients are randomly assigned to receive oral avutometinib 3.2 mg twice weekly plus oral defactinib 200 mg twice daily, both for 21 days on and 7 days off in 28-day cycles, or investigator’s choice of chemotherapy. The options for chemotherapy, all given in 28-day cycles, were intravenous (IV) pegylated liposomal doxorubicin 40 mg/m

 given on days 1, 8, and 15; IV topotecan 4 mg/m

 given on days 1, 8, and 15; oral anastrozole 1 mg daily; or oral letrozole 2.5 mg daily.

“This is a 1:1 randomization, and [a feature of] this trial is that if patients [experience progression in the control arm], there is a crossover [option] where they can receive avutometinib and defactinib. The trial is designed to give patients the best outcome possible and to showcase how active this regimen is,” Salani noted.

The primary end point is progression-free survival (PFS) by blinded independent central review. Secondary end points include overall survival, investigator-assessed PFS, duration of response, disease control rate, and health-related quality of life. In May, Verastem Oncology announced that enrollment and site activations for RAMP 301 were underway in the United States, Australia, and the United Kingdom.

“RAMP 301 is exciting because it is a targeted trial; it is absolutely driven to get at the heart of the mechanism of response of what drives these tumors,” Brown said in conclusion. “RAMP 301 is a perfect example of how we can used personalized medicine in patients with LGSOC. We’re going to target the pathway that’s overexpressed and target the pathway that’s the driver for the development of these tumors.”

“Chemotherapy leaves a lot to be desired, and if we can find an active regimen with a manageable adverse effect profile, then we will be able to provide these patients with a better quality of life and better outcomes altogether,” Salani added.

Di Lorenzo P, Conteduca V, Scarpi E, et al. Advanced low grade serous ovarian cancer: a retrospective analysis of surgical and chemotherapeutic management in two high volume oncological centers. 

. 2022;12:970918. doi:10.3389/fonc.2022.970918

A study of avutometinib (VS-6766) + defactinib (VS-6063) in recurrent low-grade serous ovarian cancer (RAMP 301). ClinicalTrials.gov. Updated May 27, 2024. Accessed May 28, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT06072781

Delivering novel therapies in RAS/MAPK pathway driven cancers. Verastem Oncology. May 2024. Accessed May 24, 2024. https://investor.verastem.com/static-files/e5188431-e626-442e-b97a-b50f464da498

Verastem Oncology receives breakthrough therapy designation for VS-6766 with defactinib in recurrent low-grade serous ovarian cancer. News release. Verastem Inc. May 24, 2021. Accessed May 24, 2024. bit.ly/3wtvUZo

Banerjee SN, Ring KL, Nieuwenhuysen EV, et al. Initial efficacy and safety results from ENGOT-ov60/GOG-3052/RAMP 201: a phase 2 study of avutometinib (VS-6766) ± defactinib in recurrent low-grade serous ovarian cancer (LGSOC). 

. 2023;41(suppl 16):5515. doi:10.1200/JCO.2023.41.16_suppl.5515

Verastem Oncology receives orphan drug designation from FDA for avutometinib alone or in combination with defactinib in recurrent low-grade serous ovarian cancer. News release. Verastem Oncology. March 5, 2024. Accessed May 23, 2024. https://investor.verastem.com/news-releases/news-release-details/verastem-oncology-receives-orphan-drug-designation-fda

Verastem Oncology announces the initiation of a rolling submission of NDA to FDA seeking accelerated approval of avutometinib and defactinib combination for the treatment of adult patients with recurrent KRAS mutant low-grade serous ovarian cancer. News release. Verastem Oncology. May 24, 2024. Accessed May 24, 2024. https://www.businesswire.com/news/home/20240524990712/en/Verastem-Oncology-Announces-the-Initiation-of-a-Rolling-Submission-of-NDA-to-FDA-Seeking-Accelerated-Approval-of-Avutometinib-and-Defactinib-Combination-for-the-Treatment-of-Adult-Patients-with-Recurrent-KRAS-Mutant-Low-Grade-Serous-Ovarian-Cancer

Verastem Oncology reports first quarter 2024 financial results and highlights recent business updates. News release. Verastem Oncology. May 9, 2024. Accessed May 23, 2024. https://www.businesswire.com/news/home/20240509453333/en/Verastem-Oncology-Reports-First-Quarter-2024-Financial-Results-and-Highlights-Recent-Business-Updates

Articles

Efforts to improve outcomes for patients with low-grade serous ovarian cancer (LGSOC) are expanding beyond chemotherapy due to its low chemosensitivity. The investigational combination of avutometinib and defactinib has shown promise, moving into phase 3 with the RAMP 301 trial. Phase 2 results demonstrated a 27% overall response rate, with higher efficacy in KRAS-mutated cases. The combination was well-tolerated, with manageable adverse effects. The ongoing RAMP 301 trial aims to further evaluate its efficacy and safety compared to standard chemotherapy.

As investigators continue efforts to improve outcomes for patients with low-grade serous ovarian cancer, they are expanding investigations beyond chemotherapy. 

RAMP 301 Aims to Solidify Avutometinib Plus Defactinib in Recurrent LGSOC

Dr Salani on Pathways for Targeted Therapy Development in Serous Ovarian Cancer

Ritu Salani, MD, MBA, gynecologic oncologist, director, Gynecologic Oncology, University of California, Los Angeles (UCLA), UCLA Health, discusses pathways in low-grade serous ovarian cancer that may be viable for targeted therapy development, as well as potential reasons why prior research with MEK inhibitors have shown suboptimal results.

One of the pathways involved low-grade serous ovarian cancer is the hormone pathway, Salani begins. Many patients with low-grade serous ovarian cancers tend to have high estrogen-receptor and progesterone-receptor expression levels, making them more susceptible to hormonal targeting, she explains. Studies are ongoing to investigate the replacement of chemotherapy with hormone strategies as well as the use of adjuvant hormonal therapies, she reports. These approaches could be compelling alternatives, Salani emphasizes

Another emerging target for drug development is the KRAS pathway, Salani continues. Mutations in this pathway are frequently found in patients with low-grade serous ovarian cancers, and targeting this pathway has proven effective in patients who do not harbor a 

mutation, she reports. MEK inhibitors can be used to inhibit KRAS signaling in 

-mutant tumors. Although MEK inhibitors have demonstrated favorable outcomes, progress is slow, and they have yet to significantly alter the standard of care or the overall treatment landscape for low-grade serous ovarian cancer, Salani says.

Several challenges may have impeded the progress of research in this field, she states. One major issue is the rarity of low-grade serous ovarian cancer, which makes it difficult to recruit enough participants to clinical trials in a timely fashion, Salani says. Despite recruitment challenges, some promising signals have been observed. Another significant issue is the adverse effects (AEs) associated with MEK inhibitors, she notes. Many patients with low-grade serous ovarian cancer are young women, and the AEs can be particularly debilitating for them. For instance, MEK inhibitors can cause severe rashes, often on the face, which can be very disruptive and require treatment breaks. This AE can accordingly limit the continuous administration of therapy, complicating treatment protocols, Salani explains. Despite these obstacles, research aiming to leverage hormonal and KRAS pathways remains promising, she concludes.

Videos

Ritu Salani, MD, MBA, discusses pathways implicated in low-grade serous ovarian cancer that may be viable for targeted therapy development.

Dr Salani on Research With MEK Inhibition in KRAS-Mutant Serous Ovarian Cancer

, which provides oncology professionals with the resources and information they need to provide the best patient care. In both digital and print formats, 

 covers every angle of oncology practice, from new technology to treatment advances to important regulatory decisions.

In today’s episode, sponsored by Verastem Oncology, we had the pleasure of speaking with Jubilee Brown, MD, about the development of avutometinib (VS-6766) plus defactinib (VS-6063) in low-grade serous ovarian cancer. Dr Brown is a professor and director of Gynecologic Oncology at Atrium Health Levine Cancer Institute in Charlotte, North Carolina.

In our exclusive interview, Dr Brown discussed how the RAS/MAPK pathway contributes to low-grade serous ovarian cancer, unmet needs for patients with this disease, and the rationale for the ongoing phase 3 RAMP-301 trial (NCT06072781) that is evaluating avutometinib plus defactinib in this patient population.

That’s all we have for today! Thank you for listening to this episode of 

, sponsored by Verastem Oncology. Check back on Mondays and Thursdays for exclusive interviews with leading experts in the oncology field.

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Podcasts

Dr Brown discusses the rationale for the RAMP-301 trial of avutometinib plus defactinib in low-grade serous ovarian cancer.

Brown Highlights the Rationale for the RAMP-301 Trial in Low-Grade Serous Ovarian Cancer

Compounding RAF/MEK inhibition and FAK inhibition through the combination of avutometinib (VS-6766) and defactinib (VS-6063) is opening novel areas of exploration in the treatment of patients with low-grade serous ovarian cancer, according to Jubilee Brown, MD.

, treatment with avutometinib monotherapy (n = 31) yielded a confirmed overall response rate (ORR) of 10%, and treatment with the combination (n = 29) led to a confirmed ORR of 45% (95% CI, 26%-64%) in patients with recurrent low-grade serous ovarian cancer.

 The outcomes reported for avutometinib plus defactinib in RAMP 201 prompted the initiation of the ongoing phase 3 RAMP 301 trial (NCT06072781), which is evaluating the combination in this patient population.

 Notably, these trials are enrolling patients with both 

“RAMP 301 is the perfect example of how we can use personalized medicine in patients with low-grade serous ovarian cancers,” Brown said in an interview with 

In the interview, Brown, a professor and director of Gynecologic Oncology at Atrium Health Levine Cancer Institute in Charlotte, North Carolina, highlighted the role of the RAS/MAPK pathway in low-grade serous ovarian cancer, prior research with avutometinib plus defactinib in this population that served as the foundation for RAMP 301, and how this combination may address unmet needs for patients in this relatively rare disease subset.

: What is the current standard of care (SOC) for patients with low-grade serous ovarian cancer?

: For low-grade serous ovarian cancer, surgery is still the up-front modality we use first. Most patients who present with a low-grade serous carcinoma are going to have surgery first, followed by—in advanced-stage disease—either chemotherapy or hormone blockade [with] an aromatase inhibitor. The SOC is changing as we see it now. Although we still use up-front surgery, the adjuvant therapy [setting] is changing.

For the longest time, we’ve used paclitaxel and carboplatin chemotherapy as SOC for patients with low-grade serous ovarian cancer. However, we know [chemotherapy] doesn’t work as well [in low-grade serous disease] as in other [ovarian cancer] subtypes. [In low-grade serous ovarian cancer], we don’t frequently see the excellent responses [with chemotherapy] that we do in other types of ovarian cancer; therefore, we’ve looked for different [treatment] opportunities. Now, we are investigating the utility of aromatase inhibitors in this disease.

What ovarian cancer pathways might be useful in the development of targeted therapy for patients with low-grade serous disease?

Two pathways are important in low-grade serous carcinomas. The first has to do with hormone receptor–driven tumors. We can use aromatase inhibitors in [ovarian cancer] now because of the abundance of estrogen and progesterone receptors on the tumors, which tend to be responsive to hormone blockade. The second pathway that is novel and targetable is the RAS/MAPK pathway. We can use RAF and MEK clamps now to target that pathway, which appears to be the driver for low-grade serous carcinomas.

What research is evaluating therapies targeting the RAS/MAPK pathway in this disease subtype?

Some exciting research is evaluating the RAS/MAPK pathway and how we can target that pathway. The phase 1 FRAME study [NCT03875820], the first study that investigated this RAF/MAPK pathway [in patients with advanced solid tumors, assessed] a combination of a RAF/MEK inhibitor and a FAK inhibitor. In the FRAME trial, we saw a 46% ORR in the low-grade serous ovarian cancer cohort.

That prompted the RAMP 201 trial, [which was] exciting because [it evaluated [the FAK inhibitor] defactinib in combination with [the RAF/MEK inhibitor] VS-6766, which has now developed a name: avutometinib. [RAMP 201 investigated avutometinib] alone and in combination with defactinib. We saw incredible activity here. In RAMP 201, there was an ORR of 45% in the combination arm, and these appear to be long-lasting responses as well. [The combination is] also tolerable. Interestingly, [this combination] had such a great signal that now we’re opening RAMP 301 to further investigate it.

 is also a driver in these low-grade serous carcinomas. There’s an abundance of 

 signals in low-grade serous carcinomas. In the RAMP 301 trial, it’s going to be interesting to see how that plays into response. How do patients with 

-mutant tumors do with this combination compared [with those with] 

How could this combination fill an unmet need for this patient population?

Patients with low-grade serous ovarian carcinomas represent less than 10% of patients with epithelial ovarian cancers, [and thus] have not had a lot of research directed their way in the past. There’s been a huge unmet need [for these patients], because even though [low-grade serous ovarian] cancers share the title of ovarian cancer, they’re different than the high-grade serous ovarian cancers we’re used to [treating]. The same research does not apply. They’re different cancers, so I’m excited to see interest, funding, and attention paid to these patients who have a rare tumor.

The RAMP 301 trial is exciting because it is a targeted trial. It is absolutely driven to get at the heart of the mechanism of response of what drives these tumors. We’re going to target the pathway that’s overexpressed and target the pathway that’s the driver for the development of these tumors.

Banerjee SN, Ring KL, Van Nieuwenhuysen E, et al. Initial efficacy and safety results from ENGOT-ov60/GOG-3052/RAMP 201: a phase 2 study of avutometinib (VS-6766) ± defactinib in recurrent low-grade serous ovarian cancer (LGSOC). 

. 2023;41(suppl 16). doi:10.1200/JCO.2023.41.16_suppl.5515

A study of avutometinib (VS-6766) + defactinib (VS-6063) in recurrent low-grade serous ovarian cancer (RAMP 301). ClinicalTrials.gov. Updated May 9, 2024. Accessed May 9, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT06072781

Jubilee Brown, MD, highlights the RAS/MAPK pathway in low-grade serous ovarian cancer and research with avutometinib/defactinib that prompted RAMP 301.

Avutometinib Plus Defactinib Signals Changing Tides in Low-Grade Serous Ovarian Cancer

Dr Brown on Ongoing Trials Targeting the RAS/MAPK Pathway in Ovarian Cancer

Jubilee Brown, MD, professor, division director, gynecologic oncology, Atrium Health Levine Cancer Institute, discusses ongoing investigations into treatment combinations that target the RAF/RAS/MAPK pathway in patients with ovarian cancer.

Exciting research is currently underway exploring the potential for ovarian cancer treatments targeting the RAS/MAPK pathway, Brown begins. The phase 1/2 FRAME trial (NCT03875820) was the first to delve into this pathway, focusing on a combination approach involving RAF/MEK inhibitors and FAK inhibitors in patients with advanced solid tumors, she explains. The findings from the FRAME study revealed a 46% overall response rate (ORR) within the low-grade serious ovarian cancer cohort, signaling significant promise in this area of study, Brown reports.

Notably, based on data from the FRAME study, in 2021, the combination of the investigational agents that FRAME evaluated—the RAF/MEK inhibitor avutometinib (VS-6766) plus the FAK inhibitor defactinib (VS-6063)—

received breakthrough therapy designation from the FDA

 for patients with recurrent low-grade serous ovarian cancer who had received at least 1 prior line of therapy.

Building upon these promising results, the subsequent phase 2 ENGOT-ov60/GOG-3052/RAMP 201 trial (NCT04625270) further evaluated avutometinib given with or without defactinib in patients with recurrent low-grade serous ovarian cancer, Brown says. These trial findings solidified the potential efficacy of this combination and revealed a notable 45% (n = 8; 95% CI, 26%-64%) ORR in the combination arm (n = 29), showcasing durable responses alongside good tolerability, she elucidates, adding that these results sparked further investigative interest in this combination.

The encouraging efficacy and safety signals observed in RAMP 201 have paved the way for the launch of the phase 3 RAMP 301 trial (NCT06072781), aimed at a more in-depth exploration of these promising therapeutic avenues, she concludes.

Overall, the evolution of research focused on the RAS/MAPK pathway holds potential for improved outcomes for patients with low-grade serous ovarian cancer following the initial successes of the FRAME and RAMP 201 trials, which have propelled the field forward, sparking new investigations and trials, such as RAMP 301.

Jubilee Brown, MD, discusses ongoing investigations into treatments that target the RAS/MAPK pathway in patients with ovarian cancer.

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 

-mutant disease (n = 15) and an ORR of 29% in those with 

 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.

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.

 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 

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.

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

: 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 

 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 

 [mutation status] and found that the ORR [with avutometinib plus defactinib] was 45% for the entire population. In the patients with 

-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 

The combination may be used more optimistically in the 

-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 

 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 

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.

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

Premal Thaker, MD, MS, discusses how the RAMP-201 trial paved a way for the RAMP-301 trial of avutometinib/defactinib in low-grade serous ovarian cancer.

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

Premal Thaker, MD, MS, discusses the phase 3 RAMP-301 trial of avutometinib  plus defactinib in recurrent low-grade serous ovarian cancer.

  Dr Thaker on the RAMP-301 Trial of Avutometinib/Defactinib in Low-Grade Serous Ovarian Cancer

Premal Thaker, MD, MS, surgeon, David G. and Lynn Mutch Professor of Obstetrics, director of gynecology, clinical research chief, Gynecological Oncology, Division of Gynecologic Oncology, Siteman Cancer Center, discusses the ongoing evaluation of avutometinib (VS-6766) plus defactinib (VS-6063) in the phase 3 RAMP 301 trial (NCT06072781) in patients with recurrent low-grade serous ovarian cancer (LGSOC).

The randomized, global, confirmatory phase 3 RAMP 301 trial is assessing the efficacy and safety of the RAF/MEK clamp avutometinib combined with the FAK inhibitor defactinib vs standard of care (SOC) chemotherapy and hormone therapy in this population, Thaker begins. Building upon previously reported results from the phase 2 RAMP 201 study (NCT04625270) and the investigator-initiated FRAME trial (NCT03875820), the RAMP 301 trial was required by the FDA for the combination to potentially receive full approval in recurrent LGSOC.

Approximately 270 patients with histologically confirmed low-grade serious ovarian, fallopian, or peritoneal cancer will be enrolled onto the trial. Patients will be randomly assigned 1:1 to receive either the combination of twice-weekly avutometinib and twice-daily defactinib for 21 days on, 7 days off in a 28-day cycle or physician's choice of SOC chemotherapy or hormone therapy, Thaker reports. Physician’s choice treatments included pegylated liposomal doxorubicin, paclitaxel, topotecan, letrozole, or anastrozole.

Patients will be stratified based on their 

 mutation status, she continues, adding that patients are allowed to have previously received a MEK inhibitor as well as bevacizumab (Avastin). Notably, the study also allows patients who originally received a SOC treatment in the control arm to cross over to receive the investigational combination if they experience disease progression, Thaker emphasizes.

The study’s primary end point is progression-free survival (PFS). Key secondary end points include overall response rate, duration of response​, disease control rate, safety, tolerability, patient reported outcomes, and overall survival. The trial is being conducted in the United States, with planned enrollment in Canada, the United Kingdom, Europe, Australia, and Korea, Thaker says.

FDA granted orphan drug designation to avutometinib

 alone or in combination with defactinib in recurrent LGSOC. There are plans to submit a rolling new drug application for accelerated FDA approval of the combination in 2024.