Avutometinib and Defactinib: A Guide to the LGSOC Treatment

Avutometinib and defactinib is a powerful drug combination that offers new hope specifically for patients with KRAS-mutated low-grade serous ovarian cancer (LGSOC).

Marketed as Avmapki Fakzynja Co-Pack, this oral treatment targets the specific genetic mutations and signaling pathways that drive cancer growth in patients with KRAS mutations, providing a breakthrough option for a cancer subtype that has historically been difficult to treat effectively.

This guide explores everything patients, caregivers, and healthcare providers need to know about avutometinib and defactinib: how these medications work specifically for KRAS-mutated tumors, who can benefit from this targeted therapy, what to expect during treatment, potential side effects, and practical information about accessing this therapy.

Whether you’re newly diagnosed with KRAS-mutated LGSOC, experiencing a recurrence with this mutation, or simply researching treatment options, this article provides the essential information you need to understand this important advancement in targeted ovarian cancer care.

Please note that this should not be interpreted as medical advice. At Not These Ovaries, we are committed to helping ovarian cancer patients get the best care and to sharing important resources so patients can ask their doctors and healthcare team informed questions.

Understanding LGSOC: A Rare and Previously Underserved Cancer

Low-grade serous ovarian cancer is a distinct type of ovarian cancer that differs significantly from the more common high-grade serous ovarian cancer (HGSOC) in both biology and treatment response.

LGSOC impacts approximately 6,000-8,000 women in the United States and about 80,000 worldwide. Unlike HGSOC, which typically affects older women with a median age of 63, LGSOC often strikes younger women, with a median age of 45.

What makes LGSOC particularly challenging is that it’s:

• Highly recurrent, with more than 80% of patients experiencing a return of their cancer
• Less responsive to standard chemotherapy treatments
• Often diagnosed at advanced stages when it has already spread
• Associated with a median survival of approximately ten years

It is estimated that about 30% of LGSOC cases have a KRAS mutation, which are now targetable with the avutometinib and defactinib combination therapy.

Before the FDA approval of the avutometinib and defactinib combination, there were no FDA-approved treatments specifically for LGSOC. Patients typically received treatments like surgery and off-label use of hormonal therapy, targeted therapy, and chemotherapy. 

According to research, LGSOC tends to be less responsive to standard chemotherapy compared to high-grade serous ovarian cancer, with chemotherapy showing limited effectiveness in this specific subtype. Hormone therapies have shown some efficacy but with modest response rates.

How Avutometinib and Defactinib Works

The Avmapki Fakzynja Co-Pack contains two innovative medications specifically designed to work together against KRAS-mutated cancer:

• Avutometinib (Avmapki) is a MEK inhibitor that works by blocking a key signaling pathway (RAS/RAF/MEK/ERK or MAPK pathway) that cancer cells use to grow and multiply. In KRAS-mutated cancers, this pathway is often hyperactivated, leading to uncontrolled cell growth. Avutometinib specifically targets MEK1 and prevents the phosphorylation of MEK1/2 by RAF, which helps stop cancer cell growth.
• Defactinib (Fakzynja) is a focal adhesion kinase (FAK) and Pyk2 (proline-rich tyrosine kinase 2) inhibitor. When avutometinib blocks MEK activity, cancer cells often activate FAK as a resistance mechanism. Defactinib blocks this resistance pathway by inhibiting both FAK and Pyk2, which disrupts cell survival and migration, making the combination more effective than either drug alone for KRAS-mutated tumors.

Together, these medications create a more complete blockade of the signaling that drives tumor growth and drug resistance in KRAS-mutated cancers dependent on the RAS/MAPK pathway. In simpler terms, this drug combination works like a double barrier: one drug blocks the cancer’s main growth pathway, while the second drug prevents the cancer from finding a workaround, making it much harder for the cancer cells to survive and spread.

The treatment is specifically approved for and particularly effective in LGSOC patients with KRAS mutations, and whose cancer has returned, which accounts for approximately 30% of LGSOC cases. These mutations are common drivers of this cancer, making these patients ideal candidates for this targeted therapy approach.

Who Can Benefit from Avutometinib and Defactinib?

The FDA has approved Avmapki Fakzynja Co-Pack specifically for adult patients who meet all of the following criteria:

• Have low-grade serous ovarian cancer (LGSOC)
• Have recurrent disease (cancer that has returned after prior treatment)
• Have a confirmed KRAS mutation in their tumor (this is a critical requirement)
• Have received prior systemic therapy

Interestingly, while the accelerated approval is specifically for KRAS-mutated LGSOC, ongoing Phase 3 trial is showing that patients without KRAS mutations are also responding to this combination, though at lower rates. This suggests the treatment’s benefits may extend beyond just KRAS-mutated tumors, potentially offering hope for an even broader group of LGSOC patients in the future.

The two-year follow-up data shows that 52% of KRAS-mutated patients and 30% of KRAS wild-type patients remained on therapy for more than one year.

The median duration of response (mDOR) was 31.1 months for KRAS-mutated patients and 12.0 months for KRAS wild-type patients, and median progression-free survival (mPFS) was 19.6 months for KRAS-mutated and 12.7 months for KRAS wild-type patients. These results were consistent with the primary analysis conducted 13+ months earlier, reinforcing confidence in the durability of the treatment.

This also makes genetic testing absolutely essential for determining who might benefit from this treatment. Without confirming the presence of a KRAS mutation through testing, doctors cannot know if avutometinib and defactinib would be appropriate for a patient.

It’s important to understand that this treatment is not approved for all LGSOC patients: only those with confirmed KRAS mutations in their tumors.

The NCCN guidelines include several treatment options for LGSOC that are not FDA-approved, providing doctors with guidance despite the lack of official approval. However, the companies that manufacture these treatments do not promote them for LGSOC since they have not received FDA approval for that specific use.

Importance of Genetic Testing for KRAS Mutations

For LGSOC patients, genetic testing for KRAS mutations isn’t just helpful — it’s now crucial for accessing this effective targeted treatment. Testing for KRAS mutations and other RAS pathway alterations should be considered a standard part of LGSOC care.

According to the FDA approval documentation, KRAS mutation status in the clinical trials was determined through:

• Next-generation sequencing (NGS)
• Polymerase chain reaction (PCR) of tumor tissue specimens

A sub-analysis of RAMP 201 found that blood-based ctDNA testing is not a sufficiently reliable method for detecting KRAS mutations in LGSOC patients. Of patients with KRAS mutations confirmed in tumor tissue, 56% showed false negative results when tested via blood samples.

This is important: patients should not rely on a blood ctDNA test to rule out a KRAS mutation. Tumor tissue analysis remains the recommended testing method.

If you’re a patient with LGSOC, talk to your doctor about:

• Whether you’ve been tested for KRAS and other relevant ovarian cancer mutations
• How KRAS mutation testing might impact your treatment options
• When in your treatment journey KRAS testing should occur

Different mutations within the KRAS gene were observed in the clinical trials, including G12V (53%), G12D (35%), Q61H (3.5%), and several others — and the treatment showed efficacy across these various KRAS mutation types.

Clinical Evidence of Avutometinib Defactinib

The FDA approved avutometinib and defactinib based on results from the Phase 2 RAMP 201 trial, which tested the combination in 57 adult patients with KRAS-mutated recurrent LGSOC. Here’s what the trial showed:

• Nearly half of the patients responded to treatment: 44% of patients saw their tumors shrink significantly
• Complete disappearance in some cases: 3.5% of patients had their tumors completely disappear
• Partial shrinkage in many: 4 out of 10 of patients had their tumors shrink by at least 30%
• Long-lasting benefits: Among patients who responded, the median duration of response was 31.1 months in KRAS-mutated patients and 12.0 months in KRAS wild-type patients: consistent results that held up over nearly two-and-a-half years of follow-up.

To understand why these results are so promising, consider that traditional treatments typically show lower success rates for LGSOC:

• Chemotherapy typically helps fewer than 15% of LGSOC patients
• Hormone therapies help only about 9% of patients

The FDA granted this treatment “accelerated approval,” which means it was approved more quickly than usual because it addresses an urgent need for effective LGSOC treatments. 

Two-year follow-up data from RAMP 201 confirmed that these results are durable. With a median follow-up of 24.9 months for ongoing patients, the combination’s efficacy measures (including median duration of response and median progression-free survival) remained consistent with the primary analysis.

Importantly, 52% of KRAS-mutated patients and 30% of KRAS wild-type patients remained on therapy for more than one year, with no new safety signals emerging. These findings reinforce that avutometinib plus defactinib can provide long-term, clinically meaningful benefit.

For the approval to remain permanent, an ongoing larger study (RAMP 301) must confirm these benefits. Phase 3 trials compare the new treatment to the current standard of care, which is the next step after the Phase 2 trial that demonstrated the drug’s effectiveness and side effect profile.  

How to Take Avmapki Fakzynja Co-Pack

Avmapki Fakzynja Co-Pack is an oral treatment, making it more convenient than intravenous therapies:

• Avmapki (avutometinib capsules): 3.2 mg taken orally twice weekly (Days 1 and 4) for the first 3 weeks of each 4-week cycle. The capsules should be taken with food and swallowed whole.
• FAKZYNJA (defactinib tablets): 200 mg taken orally twice daily for the first 3 weeks of each 4-week cycle. The tablets should be taken with food and swallowed whole.

The treatment continues until disease progression or unacceptable toxicity occurs. Your healthcare provider will monitor you regularly and may adjust dosages if needed. Dose interruptions are an expected and manageable part of treatment, and 84% of patients in RAMP 201 used dose interruptions to stay on therapy long-term.

Side Effects of Avutometinib and Defactinib

As with most cancer treatments, avutometinib and defactinib can cause side effects. Being aware of potential side effects can help patients recognize and report them promptly. The most common side effects (occurring in ≥25% of patients) include:

• Increased creatine phosphokinase (an enzyme found in the heart, brain, and skeletal muscles that’s released into the bloodstream when muscle tissue becomes damaged)
• Nausea
• Fatigue
• Increased liver enzymes (AST/ALT), an indicator of decreasing liver function / liver injury
• Rash
• Diarrhea
• Musculoskeletal pain
• Edema (swelling)
• Decreased hemoglobin (anemia)
• Vomiting
• Increased blood bilirubin (hyperbilirubinemia, which can indicate problems with the liver, bile ducts/gallbladder, or increased breakdown of red blood cells, and may cause jaundice, dark urine, or pale stools)
• Various blood count changes

More serious side effects that require immediate attention include:

• Ocular Toxicities: Including visual impairment and vitreoretinal disorders. Regular eye exams are required during treatment.
• Serious Skin Toxicities: Including photosensitivity and severe cutaneous adverse reactions. Patients should limit sun exposure and apply daily sunscreen with SPF ≥ 30.
• Hepatotoxicity: Liver function (AST/ALT) will be monitored regularly during treatment.
• Rhabdomyolysis: A condition involving the breakdown of muscle tissue that can lead to kidney damage.

Importantly, two-year follow-up data from RAMP 201 showed that side effects did not worsen or increase meaningfully over time. The types, frequency, and severity of adverse events observed at two years were consistent with earlier reports, with few new-onset events. Most adverse events were Grade 1 or 2 (mild to moderate). Only 12% of patients discontinued treatment due to adverse events: a low rate that speaks to the treatment’s manageability over the long term.

Due to these risks, patients taking the avutometinib and defactinib combination undergo regular monitoring, including eye exams, blood tests, and other assessments. Your healthcare team will help manage side effects through supportive care, dose adjustments, or temporarily pausing treatment if necessary.

Patients should avoid certain medications while on this treatment, including:

• Strong and moderate CYP3A4 inhibitors and inducers (this includes about half of all drugs used clinically, so it’s crucial to inform all members of your healthcare team — not just your oncologist or gynecologic oncologist — that you’re taking this treatment)
• Proton pump inhibitors (PPIs) or H2 receptor antagonists
• Warfarin (alternative blood thinners should be used)

Pregnant women shouldn’t take this medication as it can harm the developing fetus.

Avmapki Fakzynja Co-Pack Prices, Coupons, and Saving Tips

Cancer isn’t just emotionally challenging — it can be financially devastating. New specialty cancer medications like Avmapki Fakzynja Co-Pack can be expensive.

While wholesale acquisition cost is $48,500 for a 28-day supply, this will not come from the patient. Verastem has implemented a zero-dollar copay card program for commercially insured programs and established Verastem Cares, which is their patient assistance program, that may provide free medicine to eligible patients.

Verastem Cares is designed to help address patient access challenges and offers several key services:

• Insurance navigation: Help with confirming coverage and navigating prior authorization requirements.
• Financial and patient assistance programs: Coverage support options to reduce out-of-pocket costs, including Quick Start programs and Patient Assistance Programs for those with inadequate or no coverage.
• Logistics support: Coordination between healthcare providers, insurance companies, and specialty pharmacies.
• Educational resources: Access to valuable information about the treatment.

Learn more about Verastem Cares here. You may also call 866-351-8372 from 8 AM to 8 PM ET Mondays to Fridays to speak with case managers and ask them  any of your questions

Beyond manufacturer support, here are additional tools we recommend to help save on prescriptions and get financial support for cancer treatment cost:

• Prescription savings tools like GoodRx, which can sometimes offer discounts on specialty medications at over 70,000 pharmacies nationwide
• Cost Plus Drugs, which offers multiple medications at the lowest cost possible
• NeedyMeds provides information about programs that help people facing problems paying for medications and health care, and assists patients in applying to such programs
• OCRA’s financial assistance resources, which are specifically designed for ovarian cancer patients

Many patients benefit from meeting with an oncology social worker who can guide them to specific financial resources tailored to their situation. These professionals are usually available through your cancer treatment center and can help navigate the complex landscape of assistance programs.

Additionally, before starting any new medication, check with your insurance provider about coverage details and explore specialty pharmacy options that might offer better pricing or additional support services.

Taking Action: Next Steps for Patients

If you or a loved one has LGSOC, here are some important steps to consider:

• Speak with your gynecologic oncologist about genetic testing for KRAS mutations if you haven’t already been tested — and be sure to request tumor tissue testing, not blood-only testing
• If you have a confirmed KRAS mutation, discuss whether avutometinib and defactinib might be appropriate for your situation
• Learn about the risks and benefits of the treatment
• Explore insurance coverage and financial assistance options
• Connect with patient advocacy and ovarian cancer support groups

Remember, each patient’s situation is unique, and treatment decisions should be made in consultation with your healthcare team.

The approval of avutometinib and defactinib represents a significant milestone in LGSOC treatment, offering new hope for patients with KRAS mutations. By staying informed and working closely with your medical team, you can make the best decisions for your unique journey with this disease.