What Are Avutometinib and Defactinib (Avmapki Fakzynja Co-Pack)? FDA Approval and Licensing in Türkiye

• FDA Approval: Yes (first approval date: May 8, 2025)
• Brand Name: Avmapki Fakzynja Co-Pack
• Active Ingredients: Avutometinib and Defactinib
• Route of Administration: Oral capsules and tablets
• Class: MEK inhibitor, FAK inhibitor
• Category: Antineoplastic chemotherapy, targeted drug
• Manufacturer: Verastem Oncology
• Distribution in Türkiye: Not yet licensed in Türkiye.
• Approved Cancers: Adults with KRAS-mutated recurrent low-grade serous ovarian cancer who have previously received systemic treatment.

What Is Avmapki Fakzynja Co-Pack and How Does It Work?

Avmapki Fakzynja Co-Pack is an FDA-approved oral combination treatment for adult women with KRAS-mutated recurrent low-grade serous ovarian cancer who have previously received systemic therapy. It contains two drugs:

• Avutometinib (MEK inhibitor)
• Defactinib (FAK inhibitor)

These targeted agents are co-packaged and used on a coordinated schedule.

How Does It Work?

Avutometinib:

• Inhibits MEK1/2 enzymes, important components of the intracellular MAPK (RAS/RAF/MEK/ERK) signaling pathway.
• MEK inhibition interrupts signaling activated by the KRAS mutation, stopping tumor-cell proliferation.
• MEK suppression also indirectly increases FAK activity, creating a basis for synergy with combination treatment.

Defactinib:

• Inhibits two tyrosine kinase enzymes, focal adhesion kinase (FAK) and Pyk2.
• FAK plays a role in cell adhesion, movement, survival, and immune evasion.
• By blocking the FAK pathway, defactinib reduces tumor-cell interactions with their microenvironment and their metastatic potential.

Together, avutometinib and defactinib target both intrinsic growth signals and microenvironmental support systems in tumor cells. This dual suppression may reduce treatment resistance and improve efficacy.

FDA (US Food and Drug Administration) Approval History

May 8, 2025: The FDA granted accelerated approval to Avmapki Fakzynja Co-Pack (avutometinib capsules / defactinib tablets) for KRAS-mutated recurrent low-grade serous ovarian cancer.

December 30, 2024: Verastem Oncology announced that the FDA had accepted its new drug application for avutometinib plus defactinib in KRAS-mutated recurrent low-grade serous ovarian cancer and would assess it under priority review.

October 31, 2024: Verastem Oncology announced completion of its rolling new drug application to the FDA for avutometinib plus defactinib in KRAS-mutated recurrent low-grade serous ovarian cancer.

May 24, 2024: Verastem Oncology announced the start of a rolling submission seeking FDA accelerated approval for avutometinib plus defactinib. The application covered adults with KRAS-mutated recurrent low-grade serous ovarian cancer.

March 5, 2024: Verastem Oncology announced FDA Orphan Drug designation for avutometinib alone or with defactinib in KRAS-mutated recurrent low-grade serous ovarian cancer.

Licensing in Türkiye

It has not yet been officially licensed in Türkiye. It may be obtained from abroad through Ministry of Health special authorization procedures. It is not on the TİCK overseas medicines list.

Mechanisms of Resistance

• Activation of Alternative Signaling Pathways (Bypass Mechanisms): Avutometinib inhibits RAS/RAF/MEK/ERK signaling. However, cancer cells may overcome this suppression by activating alternative growth and survival pathways such as PI3K/AKT/mTOR, allowing proliferation to continue despite MEK inhibition.
• Microenvironmental Response to FAK Inhibition: FAK, the enzyme targeted by defactinib, is associated with tumor adhesion to connective tissue, movement, and immune evasion. Resistance may develop when stromal or immune cells in the tumor microenvironment activate non-FAK signals, reducing defactinib's effect. Cytokines such as TGF-β may sustain tumor invasiveness through other pathways.
• Evolution of KRAS Mutations: New KRAS submutations may emerge during treatment, for example from G12V to Q61H. These variants may differ in sensitivity to MEK inhibitors and cause treatment resistance.
• Cellular Adaptation and Phenotypic Change: Under treatment pressure, some cancer cells may enter a slowly dividing, treatment-resistant state known as “persister” cells. These retain the ability to proliferate again after treatment.
•  Modification of Drug Transport Systems: Particularly for defactinib, overexpression of drug-efflux proteins such as P-glycoprotein (P-gp) may prevent intracellular drug accumulation and reduce efficacy.

Avutometinib (MEK Inhibitor)

Absorption

• Rapidly absorbed after oral administration.
• When taken fasting, peak plasma concentration (Tmax) is reached in approximately 2 hours.
• A high-fat meal reduces the peak concentration by 29% but does not significantly alter total absorption (AUC).

Distribution

• Volume of distribution: 25 L
• High plasma protein binding (99%)

Metabolism

• Primarily metabolized by CYP3A4 and partly through nonenzymatic pathways.

Elimination

• Half-life (t½): approximately 51 hours
• After a single dose: 52% is excreted in urine (only 3.2% as unchanged drug) and 39% in feces (approximately 9.5% unchanged).

Defactinib (FAK Inhibitor)

Absorption

• Peak plasma concentration is reached approximately 4 hours after oral administration with food.
• With a high-fat meal: AUC (total absorption) increases 2.7-fold and Cmax (peak concentration) 1.9-fold.

Distribution

• Volume of distribution: 1,560 L (extensive distribution)
• Plasma protein binding: 90%

Metabolism

• Metabolized by CYP3A4 and CYP2C9.
• Two major metabolites form: M2 (inactive) and M4 (active, as potent as defactinib)

Elimination

• Half-life (t½): approximately 9 hours
• After a single dose: 87% is excreted in feces (approximately 52% unchanged) and 7.6% in urine (only 0.8% unchanged).

Dose Range

• Avutometinib (Avmapkı): 3.2 mg orally 2 times weekly (for example, Monday and Thursday), during the first 3 weeks of each 4-week cycle. This dose consists of 4 capsules of 0.8 mg and must be taken with food.
• Defactinib (Fakzynja): 200 mg orally 2 times daily during the first 3 weeks of each 4-week cycle. This is taken as 1 tablet of 200 mg in the morning and evening and must be taken with food.
• Avutometinib: If a dose is more than 24 hours late, skip it and take the next dose on schedule. Do not take an additional dose after vomiting.
• Defactinib: If a dose is more than 6 hours late, skip it. Do not take an additional dose after vomiting.
• This regimen continues until disease progression or unacceptable toxicity.

Drug Interactions

• Strong and Moderate CYP3A4 Inhibitors: Defactinib is metabolized by CYP3A4. Inhibitors of this enzyme can increase defactinib levels and toxicity risk. Examples include ketoconazole, itraconazole, clarithromycin, and grapefruit.
• CYP3A4 Inducers: CYP3A4 inducers accelerate defactinib metabolism, lowering drug levels and potentially reducing efficacy. Examples include rifampin, phenytoin, carbamazepine, and St. John's wort.
• Warfarin (Kumadin): Fakzynja may affect warfarin metabolism and increase bleeding risk. Alternative anticoagulants should be preferred. If warfarin is necessary, INR should be monitored frequently.
• Gastric Acid Suppressants: Defactinib's solubility depends on gastric acid. Proton pump inhibitors (PPIs) and H2 receptor antagonists may reduce absorption and efficacy. PPIs and H2 blockers should be avoided. If use is unavoidable, antacids should be given 2 hours before or 2 hours after defactinib.
• Other Interaction Warnings: P-glycoprotein (P-gp) transporters: both components are P-gp substrates. Strong inhibitors, such as verapamil, may theoretically affect plasma levels.
• UGT1A1 Inhibitors: Defactinib may inhibit this enzyme, which is involved in bilirubin metabolism, and increase the risk of hyperbilirubinemia.

Points Requiring Attention

• Ocular Toxicities: Visual disturbances, retinal detachment, and vitreoretinal disorders. Regular eye examinations are needed before and during treatment (at baseline, before cycle 2, then every 3 cycles). Blurred vision, light sensitivity, and floaters should be taken seriously. Treatment may need to be temporarily interrupted or the dose reduced.
• Skin Toxicities:Rash, acneiform dermatitis, photosensitivity, and severe skin reactions. Treatment should begin with prophylactic topical corticosteroids and oral antibiotics. Sun protection is recommended (SPF ≥ 30 sunscreen and protective clothing). Severe cases may require dose reduction or permanent discontinuation.
• Liver Toxicity (Hepatotoxicity): Increased AST, ALT, and bilirubin. Liver function tests should be performed before each cycle, particularly on day 15 of the first 4 cycles. Elevated values may require treatment interruption or dose adjustment.
• Rhabdomyolysis and Muscle Toxicity: Increased creatine phosphokinase (CPK), muscle pain, and rarely kidney damage. CPK should be measured before every cycle and on day 15 during the first 4 cycles. Severe muscle pain or dark urine should prompt medical consultation.
• Pregnancy and Reproductive Potential: Fetal harm and congenital anomalies. Female patients should have a pregnancy test before treatment. Breastfeeding is prohibited during treatment and for at least 2 weeks after the final dose.
• Drug Interactions: Caution is required with strong CYP3A4 inhibitors/inducers, gastric acid suppressants, and warfarin 
• Pediatric and Older Patients: No safety or efficacy data are available in children. Although specific dose adjustment is unnecessary in patients older than 65 years, close monitoring is recommended.

Adverse Reactions

Adverse reactions to Avmapki Fakzynja Co-Pack (avutometinib + defactinib) are based on clinical trial findings and include both common and serious reactions. Important reactions and their frequencies are summarized below:

• Increased creatine phosphokinase (CPK) 82%
• Nausea 74%
• Fatigue 72%
• Rash 72%
• Musculoskeletal pain 68%
• Diarrhea 68%
• Edema 67%
• Increased AST (liver enzyme) 70%
• Increased ALT 58%
• Elevated bilirubin 48%
• Increased triglycerides 46%
• Decreased hemoglobin 65%
• Decreased lymphocyte count 40%
• Visual disturbances 35–37%
• Vomiting 49%
• Constipation 30%
• Oral inflammation (stomatitis) 35%
• Itching (pruritus) 32%
• Dry skin 30%
• Acneiform dermatitis 3%
• Clinical Monitoring Recommendation
• Eye examinations: at regular intervals
• Liver function tests: before each cycle and on day 15 of month 1
• Muscle enzymes (CPK): before each cycle and on day 15 of month 1
• Skin assessment, with close monitoring particularly during the first 2 months