Avutometinib and Defactinib (Monograph)

Brand name: Avmapki Fakzynja Co-pack
Drug class: Antineoplastic Agents

Introduction

Avutometinib potassium and defactinib hydrochloride, a combination of 2 kinase inhibitors, is an antineoplastic agent.¹ Avutometinib is a MEK1 inhibitor and defactinib is an inhibitor of focal adhesion kinase (FAK) and proline-rich tyrosine kinase-2 (Pyk2).¹

Uses for Avutometinib and Defactinib

Avutometinib and defactinib has the following uses:

Avutometinib and defactinib combination therapy is indicated for the treatment of adult patients with KRAS-mutated recurrent low-grade serous ovarian cancer (LGSOC) who have received prior systemic therapy.¹

Select patients for treatment based on the presence of a KRAS mutation in tumor specimens.¹

This indication is approved under accelerated approval based on tumor response rate and duration of response.¹ Continued approval may be contingent upon verification and description of clinical benefit in a confirmatory trial.¹

Avutometinib and Defactinib Dosage and Administration

General

Avutometinib potassium and defactinib hydrochloride is available in the following dosage form(s) and strength(s):

• AVMAPKI capsules: 0.8 mg of avutometinib¹

• FAKZYNJA tablets: 200 mg of defactinib¹

• The 2 drugs are copackaged in a carton containing a bottle of AVMAPKI capsules and a bottle of FAKZYNJA tablets¹

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

• The recommended dosage of avutometinib is 3.2 mg (four 0.8 mg capsules) administered orally twice weekly (Day 1 and Day 4) for the first 3 weeks of each 4-week cycle until disease progression or unacceptable toxicity.¹

• The recommended dosage of defactinib is 200 mg (one tablet) administered orally twice daily for the first 3 weeks of each 4-week cycle until disease progression or unacceptable toxicity.¹

• See Full Prescribing Information for dosage modification guidelines for adverse reactions.¹

Cautions for Avutometinib and Defactinib

Contraindications

None.¹

Warnings/Precautions

Ocular Toxicities

Avutometinib and defactinib can cause ocular adverse reactions, including visual impairment and vitreoretinal disorders.¹

Ocular adverse reactions occurred in 68% of patients with recurrent LGSOC treated with avutometinib and defactinib.¹ Common ocular adverse reactions (≥ 5%) were visual impairment (38%), dry eye (13%), orbital/periorbital edema (8%), and vitreous floaters (5%).¹ Thirty-five patients (26%) experienced vitreoretinal disorders, including retinal detachment (9%), and retinal vein occlusion (0.7%).¹ Eighteen patients (13%) experienced an ocular adverse reaction that resulted in dose interruption of avutometinib and defactinib and one patient experienced an ocular adverse reaction that resulted in dose reduction.¹

The median time to onset of symptomatic ocular adverse reactions was 5 days (range 1 to 943 days) and time to onset of asymptomatic ocular adverse reactions was 112 days (range 23 to 943 days).¹ The median time to onset of retinal detachment was 27 days (range 2 to 535 days).¹ Of the patients who experienced ocular adverse reactions, 29% had ongoing ocular events at last follow-up.¹

Refer patients to a qualified eye care professional for a comprehensive ophthalmic exam at baseline, prior to cycle 2, every three cycles thereafter, and as clinically indicated.¹ Promptly refer patients to an eye care professional for any new or worsening ocular signs or symptoms.¹

Monitor for ocular adverse reactions and withhold, reduce, or permanently discontinue avutometinib and defactinib combination therapy based on severity and persistence of ocular adverse reactions ¹

Serious Skin Toxicities

Avutometinib and defactinib can cause serious skin toxicities, including Severe Cutaneous Adverse Reactions (SCARs).¹ Cases of acute generalized exanthematous pustulosis, erythema multiforme and drug reaction with eosinophilia and systemic symptoms have been reported in clinical trials of avutometinib.¹

Skin toxicities occurred in 94% of patients with recurrent LGSOC treated with avutometinib and defactinib.¹ The most common skin toxicities (≥ 10%) were rash (67%), dermatitis acneiform (43%), dry skin (43%), pruritus (32%), and photosensitivity (13%).¹ Grade 3 skin reactions occurred in 12% of patients including dermatitis acneiform (7%), rash (7%), and pruritus (1.5%).¹ Thirteen patients (10%) developed bacterial skin infections.¹ Skin toxicity led to dose interruption of avutometinib and defactinib in 10%, to dose reduction in 7%, and to permanent discontinuation in 0.7% of patients.¹ The median time to onset of the first skin toxicity was 14 days (range 1 to 500 days).¹ At last follow-up, 66% of patients had ongoing skin toxicity.¹

Patients in the principal clinical study used topical corticosteroids (applied to the face, scalp, neck, upper chest and upper back) and systemic oral antibiotics for prophylaxis of skin adverse reactions.¹ These medications were initiated at the start of avutometinib and defactinib therapy and administered during at least the first two cycles of treatment.¹

Limit unnecessary exposure to sunlight and apply daily sunscreen (sun protection factor [SPF] ≥ 30).¹ Monitor for skin toxicity and withhold, reduce dose, or permanently discontinue avutometinib and defactinib based on severity and persistence. ¹

Hepatotoxicity

Avutometinib and defactinib can cause hepatotoxicity.¹

In patients with recurrent LGSOC who received avutometinib and defactinib, increased AST (73%), bilirubin (51%), ALT (49%), and alkaline phosphatase (46%) occurred.¹ Grade 3-4 elevations in ALT was 3%, AST was 3%, bilirubin was 2.3% and alkaline phosphatase was 0.8%.¹ Elevations in one or more liver related laboratory values led to dose interruption for 20%, dose reduction for 2.2%, and permanent discontinuation for 0.7% of patients.¹

Increased blood bilirubin may be attributed to defactinib due to the inhibition of enzymes responsible for metabolizing (uridine diphosphate-glucuronosyltransferase (UGT)1A1) and transporting (Organic Anion Transporting Polypeptides (OATP)1B1/1B3) bilirubin. ¹

Monitor liver related laboratory values prior to the start of each cycle, on day 15 of the first four cycles, and as clinically indicated.¹ Withhold, reduce dose, or permanently discontinue avutometinib and defactinib therapy based on severity and duration of these adverse reactions. ¹

Rhabdomyolysis

Avutometinib and defactinib can cause increased creatine phosphokinase (CPK).¹ Increased CPK occurred in 75% of patients with recurrent LGSOC treated with avutometinib and defactinib, including Grade 3-4 elevations in 18% of patients.¹ Among the patients who experienced an elevation in CPK, concurrent increase in creatinine occurred in 19% (n=19/102) and myalgia occurred in 10% (n=10/102).¹ Elevation of CPK >10 times the baseline value with a concurrent increase in serum creatinine of ≥1.5 times the baseline value occurred in 0.7% of patients.¹ Increased CPK resulted in dose interruption for 22%, in dose reduction for 7%, and in discontinuation for 2.9% of patients.¹ Rhabdomyolysis has occurred in a patient with LGSOC treated with avutometinib and defactinib at the recommended dosage in a clinical trial.¹

Monitor CPK prior to the start of each cycle, on day 15 of the first four cycles, and as clinically indicated.¹ If increased CPK occurs, evaluate patients for rhabdomyolysis or other causes.¹ Withhold, reduce or permanently discontinue avutometinib and defactinib therapy based on severity and duration of the adverse reactions.¹

Embryo-fetal Toxicity

Based on the mechanisms of action, avutometinib and defactinib can cause fetal harm when administered to a pregnant woman.¹ Inhibition of either molecular pathway has been associated with embryo-fetal anomalies and lethality in animals.¹

Advise pregnant women and females of reproductive potential of the potential risk to a fetus.¹ Advise females of reproductive potential to use effective contraception during treatment with avutometinib and defactinib and for 1 month after the last dose.¹ Advise male patients with female partners of reproductive potential to use effective contraception during treatment with avutometinib and defactinib and for 4 months after the last dose.¹

Specific Populations

Pregnancy

Based on the mechanisms of action, avutometinib and defactinib can cause fetal harm when administered to a pregnant woman.¹ There are no available data on the use of avutometinib and defactinib in pregnant women to inform a drug-associated risk.¹ Animal reproductive and developmental toxicity studies have not been conducted with avutometinib or defactinib; however, inhibition of either molecular pathway has been associated with embryo-fetal anomalies and lethality in animals.¹ Advise pregnant women and females of reproductive potential of the potential risk to a fetus.¹

The background risk of major birth defects and miscarriage for the indicated population is unknown.¹ In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.¹

Lactation

There are no data on the presence of avutometinib, defactinib, or their metabolites in human milk, the effects on the breastfed child, or the effects on milk production.¹ Because of the potential for serious adverse reactions in a breastfed child, advise lactating women not to breastfeed during treatment with avutometinib and defactinib and for 2 weeks after the last dose.¹

Females and Males of Reproductive Potential

Avutometinib and defactinib can cause fetal harm when administered to a pregnant woman.¹

Verify the pregnancy status of females of reproductive potential prior to initiating treatment with avutometinib and defactinib.¹

Advise females of reproductive potential to use effective contraception during treatment with avutometinib and defactinib and for 1 month after the last dose.¹

Advise male patients with female partners of reproductive potential to use effective contraception during treatment with avutometinib and defactinib and for 4 months after the last dose.¹

Based on animal studies, avutometinib and defactinib may impair fertility in females and males of reproductive potential.¹ The effects on fertility were not reversible in animals.¹

Pediatric Use

The safety and effectiveness of avutometinib and defactinib in pediatric patients has not been established.¹

Geriatric Use

Of the 136 patients in clinical studies of avutometinib and defactinib, 29% were 65 years of age or older.¹ No overall differences in safety were observed between patients 65 years of age or older and younger patients.¹ Clinical studies of avutometinib and defactinib did not include sufficient numbers of patients 65 years of age and over to determine whether they respond differently from younger patients.¹

Common Adverse Effects

The most common (≥ 25%) adverse reactions, including laboratory abnormalities, were increased creatine phosphokinase, nausea, fatigue, increased aspartate aminotransferase, rash, diarrhea, musculoskeletal pain, edema, decreased hemoglobin, increased alanine aminotransferase, vomiting, increased blood bilirubin, increased triglycerides, decreased lymphocyte count, abdominal pain, dyspepsia, dermatitis acneiform, vitreoretinal disorders, increased alkaline phosphatase, stomatitis, pruritus, visual impairment, decreased platelet count, constipation, dry skin, dyspnea, cough, urinary tract infection, and decreased neutrophil count.¹

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

• Strong and moderate CYP3A4 inhibitors: Avoid concomitant use with avutometinib and defactinib.¹

• Strong and moderate CYP3A4 inducers: Avoid concomitant use with avutometinib and defactinib.¹

• Warfarin: Avoid concomitant use of avutometinib and defactinib with warfarin and use an alternative to warfarin.¹

• Gastric acid reducing agents: Avoid concomitant use of avutometinib and defactinib with proton pump inhibitors (PPIs) or H2 receptor antagonists.¹ If use of an acid-reducing agent cannot be avoided, administer defactinib 2 hours before or 2 hours after the administration of a locally acting antacid.¹

Actions

Mechanism of Action

Avutometinib is a MEK1 inhibitor.¹ Avutometinib induces the formation of inactive RAF/MEK complexes and prevents phosphorylation of MEK1/2 by RAF.¹ RAF and MEK proteins are regulators of the RAS/RAF/MEK/ERK (MAPK) pathway.¹ Avutometinib inhibited MEK1/2 and ERK1/2 phosphorylation and proliferation of tumor cell lines harboring KRAS mutations.¹ Treatment of cancer cells with avutometinib increased the level of phosphorylated focal adhesion kinase (FAK).¹

Defactinib is an inhibitor of FAK and proline-rich tyrosine kinase-2 (Pyk2), the two members of the FAK family of nonreceptor tyrosine kinases.¹ Defactinib inhibited FAK autophosphorylation in cancer cells in vitro and in mouse xenograft models.¹

Avutometinib in combination with defactinib enhanced inhibition of cell proliferation in vitro and anti-tumor activity in mouse tumor models including LGSOC.¹

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling (Patient Information).¹

• Inform patients of the need for eye exams before and during treatment with avutometinib and defactinib.¹ Advise patients to contact their healthcare provider if they experience any visual changes, pain, or inflammation around their eye(s).¹

• Inform patients that skin reactions have occurred during treatment with avutometinib and defactinib.¹ Advise patients to use prophylactic topical steroids and oral antibiotics.¹ Advise patients to contact their healthcare provider if they develop a rash, progressively worsening skin reactions, or blistering of the skin or mouth.¹

• Advise patients that they will need to undergo laboratory testing to monitor their liver function.¹ Advise patients to contact their healthcare provider for signs or symptoms of liver dysfunction ¹

• Inform patients that they will need to undergo laboratory testing to monitor CPK levels.¹ Advise patients to contact their healthcare provider for signs or symptoms of rhabdomyolysis.¹

• Inform patients to avoid concomitant use of avutometinib and defactinib with PPIs or H2 receptor antagonists.¹

• Advise patients that if use of an acid reducing agent cannot be avoided, to take defactinib 2 hours prior to, or 2 hours after, the administration of a locally acting antacid.¹

• Advise pregnant women and females of reproductive potential of the potential risk to a fetus.¹

• Advise females to inform their healthcare providers of a known or suspected pregnancy.¹ Advise females of reproductive potential to use effective contraception during treatment with avutometinib and defactinib and for 1 month after the last dose.¹ Advise male patients with female partners of reproductive potential to use effective contraception during treatment with avutometinib and defactinib and for 4 months after the last dose.¹

• Advise women not to breastfeed during treatment with avutometinib and defactinib and for 2 weeks after the last dose.¹

• Advise males and females of reproductive potential that avutometinib and defactinib may impair fertility.¹

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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