The first drug for a rare and difficult-to-treat type of ovarian cancer has been granted accelerated approval by the Food and Drug Administration (FDA). The treatment, called avutometinib plus defactinib (AvmapkiTM FakzynjaTM Co-pack), was developed to treat low-grade serous ovarian cancer (LGSOC).
The phase 2 clinical trial that resulted in the approval was led in the United States by gynecologic medical oncologist Rachel Grisham, MD, of Memorial Sloan Kettering Cancer Center (MSK). Dr. Grisham is also leading the global randomized confirmatory phase 3 trial that is currently ongoing.
“This new treatment, which combines two different targeted therapies, is based on research that was done in MSK labs about a decade ago,” Dr. Grisham says. “The story of how this treatment came about illustrates the importance of continuing to do lab-based research.”
What Is Low-Grade Serous Ovarian Cancer?
LGSOC accounts for less than 10% of all cases of ovarian cancer. It is more common in younger women. The average age at the time of diagnosis is about 55, but unlike more common types of ovarian cancer, many women are diagnosed in their 20s or 30s.
As the words low grade suggest, LGSOG is considered less aggressive than other types of ovarian cancer. That’s mainly because it grows more slowly. Patients diagnosed with this cancer tend to live longer, even when the cancer has spread.
However, it is also less likely to respond to chemotherapy. In fact, chemotherapy is effective in fewer than one in 20 patients with LGSOC.
Results of the Phase 2 Trial for Avutometinib-Defactinib Combination
Many patients responded to the treatment. Overall, 44% of patients with a KRAS mutation in the phase 2 trial saw their tumors shrink, according to findings Dr. Grisham presented at the Society of Gynecologic Oncology Annual Meeting in March 2025.
All the patients in the study had previously been treated with at least one line of chemotherapy and had recurrent, measurable disease.
The highest response rates were seen in patients who tumors harbored a mutation in the gene KRAS — a mutation found in about one-third of LGSOC cases — and the new treatment was FDA approved specifically for patients whose cancers have that mutation. But there were still responses in patients without KRAS mutations, just at a lower rate. This group is being further studied in the ongoing phase 3 study.
“This treatment has shown unprecedented response rates for patients who currently have few good options,” Dr. Grisham says. “The combination works much better than the current standard treatments for this disease, which are either chemotherapy or endocrine [hormone] therapy.”
Some patients in the trial had side effects. Some of the most common ones were:
- Fatigue
- Gastrointestinal problems
- Rash
- Changes in blood counts
Avutometinib and defactinib are taken as pills. Avutometinib is taken twice a week and defactinib is taken twice a day. Patients take them for three weeks, then pause for a week before resuming that schedule.
A Targeted Therapy Approach Based on MSK Lab Research
Both drugs are targeted therapies. Avutometinib blocks two pathways responsible for cancer growth — called MEK and RAF; defactinib blocks FAK.
The lab of MSK physician-scientist David Solit, MD, was the one of the first to make the connection between MEK mutations and ovarian cancer. In 2015, the team published a paper in the Journal of Clinical Oncology that showed how defects in the MEK protein drive the growth of LGSOC. Dr. Grisham was first author, and Dr. Solit and MSK genitourinary medical oncologist and early drug development specialist Gopa Iyer, who was then a member of Dr. Solit’s lab, were senior authors.
Since then, drugs that block MEK have been used to treat LGSOC with some success, but none have been FDA approved for that purpose. Later studies from other labs found that blocking FAK as well as MEK made this approach more effective and longer-lasting.
The MEK and FAK pathways act “downstream” from KRAS — a class of proteins that are responsible for many types of cancer. Because the KRAS protein is difficult to block, Dr. Grisham, Dr. Solit, and their colleagues believe this combination approach is likely to be more effective.
“This FDA approval means that patients with LGSOC now have a really good option for treating their cancer,” Dr. Grisham says. “We expect this therapy will become the new standard of care for LGSOC patients with KRAS mutations.”
