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A new study published in Nature Medicine shares results from the phase 1 FRAME trial - a first-in-human clinical trial testing a novel combination of two targeted therapies, defactinib and avutometinib, in patients with advanced solid tumours.
The drugs work by blocking key signalling pathways that cancer cells use to grow and survive. Defactinib targets the FAK pathway, while avutometinib inhibits the RAF–MEK pathway. Together, they are designed to overcome treatment resistance in certain cancers.
The trial showed encouraging results for patients with low-grade serous ovarian cancer (LGSOC) - a rare, often chemotherapy-resistant type of cancer.
Tumours shrank in a significant proportion of patients
Median progression-free survival of more than 2 years LGSOC where a KRAS mutation was detected.
The combination was relatively well tolerated compared to historical trials with MEK inhibitors.
These findings led to the phase 2 RAMP-201 trial, led by Professor Susana Banerjee at the Royal Marsden NHS Foundation Trust and Institute of Cancer Research (ICR). RAMP-201 focused on patients with KRAS-mutated recurrent LGSOC, further validating the efficacy of the drug combination.
The FRAME trial was an academic investigator initiated study led by the Drug Development Unit, a joint unit across the ICR and Royal Marsden supported by the CRUK Convergence Science Centre. The unit aims to bridge lab-based discoveries and early-phase clinical research, accelerating access to innovative cancer therapies.
FDA Accelerated approval
Based on the results from FRAME and RAMP-201, the US Food and Drug Administration (FDA) granted accelerated approval in May 2025 for the use of co-packaged defactinib and avutometinib (brand names Avmapki and Fakzynja) for treating KRAS‑mutated recurrent LGSOC.
This marks the first targeted therapy approved for this patient group, where treatment options have historically been limited.
A decision from European regulators is expected to follow.
This approval represents a significant milestone in ovarian cancer care, offering hope to those with difficult to treat ovarian cancer. By specifically targeting resistance mechanisms in KRAS-mutated LGSOC, this combination opens the door to more effective, better-tolerated treatment options.
A larger confirmatory phase 3 trial (RAMP-301) is currently underway to validate the results in a larger population.
"The Cancer Research UK convergence science centre provides an infrastructure to rapidly translate laboratory experiments into hypothesis testing investigator-initiated phase I trials that go on to impact patient care, often in cancers or cancer subtypes not prioritized in drug development efforts. The funding is also crucial to understand mechanisms of action of drugs and putative mechanisms of resistance that provides new biological insights and allows re-designing of drug trials. The FRAME study is an exemplar of efforts in translational research space at the Drug Development Unit enabled by the CRUK convergence science centre which has rapidly led to patient benefit." - Professor Udai Banerji, Co-Director of Drug Development Unit.