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Research Efforts Under Evaluation in Low-Grade Serous Ovarian Cancer
Volume 1
Issue 1

RAMP 301 Aims to Solidify Avutometinib Plus Defactinib in Recurrent LGSOC

Author(s):

Key Takeaways

  • Avutometinib and defactinib combination targets RAF/MEK and FAK pathways, showing synergy in LGSOC.
  • Phase 2 RAMP 201 study showed a 27% overall response rate, with 37% in KRAS-mutated cases.
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Jubilee Brown, MD

Jubilee Brown, MD



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).1,2

“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 OncologyLive. “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.3

“[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 OncologyLive. “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).4 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.3

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.3

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 KRAS-mutated disease (n = 57) achieved an ORR of 37%; those with KRAS wild-type disease (n = 52) experienced an ORR of 15%.

KRAS 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 KRAS-mutated disease (n = 15) and 29% in patients with KRAS 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%).5

“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 KRAS 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 2024.6 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 KRAS-mutated LGSOC following at least 1 prior line of systemic therapy.7

Details of the RAMP 301 Trial

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.2,3

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/m2 given on day 1; IV paclitaxel 80 mg/m2 given on days 1, 8, and 15; IV topotecan 4 mg/m2 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.8

“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.

References

  1. 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. Front Oncol. 2022;12:970918. doi:10.3389/fonc.2022.970918
  2. 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
  3. 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
  4. 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
  5. 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). J Clin Oncol. 2023;41(suppl 16):5515. doi:10.1200/JCO.2023.41.16_suppl.5515
  6. 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
  7. 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
  8. 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
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