I am proud to have led the global RAMP201 trial team which contributed to the FDA accelerated approval in KRAS-mutated recurrent low grade serous ovarian cancer.
I am so pleased that this oral drug combination has worked well in women with LGSOC who are in urgent need of new treatments. This is the first approved therapy specifically for this rare form of ovarian cancer and is a significant advance for women with low-grade serous ovarian cancer.
Professor Susana Banerjee, Global Lead Investigator of RAMP 201, Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust (pictured)
Overview:
RAMP 201 is a Phase 2 clinical trial studying the effectiveness and safety of avutometinib on its own, and in combination with defactinib in recurrent low-grade serous ovarian cancer (LGSOC). The primary analysis of the trial was recently published.
Avutometinib (3.2mg) and defactinib (200mg) was found to be the most effective strength tested with 31% of people on this combination experiencing tumour shrinkage, and 57% stable disease for a period of time.
The combination is now being studied in a Phase 3 clinical trial called RAMP 301, and has been conditionally approved by the FDA in the United States for KRAS mutated LGSOC.
The below article discusses the study findings in more detail.
Study design:
This was a multinational phase 2 clinical trial (ENGOT-ov60/GOG3052/RAMP 201) that took place in sites across the United States, Canada, UK, France, Spain, Belgium and Italy.
Who took part?
- Over 200 people in total, aged 18+ with progressive or recurrent LGSOC
- All had measurable disease (visible cancer on scans)
- All had at least one previous medical treatment, including a platinum chemotherapy (half of all participants had at least 3 previous treatments)
- Prior treatment with a MEK inhibitor such as trametinib or binimetinib was allowed
- Participants were tested for KRAS mutation status (a gene that is mutated in about one in three people with LGSOC)
Treatment arms:
The goal was to compare results and identify the most effective treatment regime.
The first part of the study investigated monotherapy vs combination therapy:
- Avutometinib (4mg) vs avutometinib (3.2mg) + defactinib (200mg)
The second part of the study compared different doses of the combination treatment:
- Avutometinib (3.2mg) + defactinib (200mg) vs acutometinib (1.6mg) + defactinib (200mg)
Treatment was administered on a four week cycle of three weeks on treatment, followed by one week off treatment. Avutometinib was taken twice weekly. Defactinib was taken twice daily.
Key Findings:
The combination of Avutometinib (3.2mg) + Defactinib (200mg) was the most effective of the treatment options tested.
Of the 109 people who received this combination (57 with KRAS mutations, 52 without KRAS mutations):
31% had an objective response (defined as at least 30% tumour shrinkage)
- 44% of those with KRAS mutations had a response
- 17% of those without KRAS mutations had a response
- Most responses were partial but 2 (2%) had a complete response (i.e. no visible cancer on scans), both had KRAS mutations
- Of those who had a response – the median* duration of response (time until the cancer grew again) was 31 months
57% had stable disease (no cancer growth – defined as less than 30% tumour shrinkage and less than 20% tumour growth)
The overall median progression free survival (PFS) i.e. time cancer remained stable or shrinking was:
- 12.9 months overall
- 22.0 months in women with KRAS mutations
- 12.8 months in those without KRAS mutations
These outcomes compare favourably to chemotherapy, which typically has response rates of 0–13% in recurrent LGSOC.
* Median means the point where half of all people have had something happen and half have not. For example: a median progression free survival of 12.9 months means that by 12.9 months half of all people on treatment had experienced cancer growth, and half had not.
Side effects:
Side effects were frequent but most were not severe.
Common side effects included:
- Nausea (67%)
- Increased creatine phosphokinase (CPK)
- Diarrhoea (58%)
- Swelling in the legs or hands (53%)
- Rash or skin reactions (50%)
- Fatigue (44%)
- Vomiting (43%)
- Blurred vision (41%)
- Dermatitis acneiform (34%)
- Increased blood bilirubin/hyperbilirubinemia (33%)
- Increased AST (31%)
- Increased ALT (25%)
- Dry skin (26%)
- Anemia (23%)
- Stomatitis (16%)
Most side effects were able to be managed by dose adjustments. Just 10% of patients stopped treatments due to side effects, which is much less than the 36% seen with the MEK inhibitor trametinib in the GOG 281/LOGS trial.
Context:
Recurrent LGSOC has low response rates to existing treatments. Avutometinib and defactinib represent a promising advance in treatment. The FDA recently granted accelerated approval of avutometinib and defactinib (brand name: Avmapki Fakzynja Co-pack) for KRAS mutant LGSOC on the strength of the results from this Phase 2 study, marking the first ever FDA approval for LGSOC.
A larger phase 3 trial (RAMP 301) is now underway. RAMP 301 is directly comparing the combination against doctor’s choice of other therapies, to confirm whether it should become the new standard of care for recurrent LGSOC.
Depending on the outcome of the phase 3 trial, it’s possible we may see broader approval for LGSOC without KRAS mutations, and approval in other countries in the future.
About the treatments:
Avutometinib is an oral MEK/RAF inhibitor that blocks cancer growth signals. It works by shutting down a pathway (MAPK) that is often overactive in LGSOC.
Defactinib is an oral drug that blocks focal adhesion kinase (FAK), a protein cancer cells use to resist MEK-targeted therapy.
Original paper:
https://ascopubs.org/doi/10.1200/JCO-25-00112 (July 11th, 2025)
Thank you to study co-author Professor Susana Banerjee for reviewing this article.
