AHFS Class:

• Antineoplastic Agents 10:00

Generic Name(s):

• Avutometinib Potassium

• Defactinib Hydrochloride

Avutometinib potassium is a dual rapidly accelerated fibrosarcoma (RAF)/mitogen-activated extracellular signal-regulated kinase (MEK)-1 inhibitor that promotes the formation of inactive rat sarcoma virus protein (RAF)-MEK complexes, thereby preventing RAF-mediated phosphorylation of MEK1/2.1 RAF and MEK are key regulators of the RAS/RAF/MEK/ERK (Mitogen-activated protein kinase [MAPK]) signaling pathway.1

Defactinib hydrochloride is an inhibitor of focal adhesion kinase (FAK) and proline-rich tyrosine kinase-2 (Pyk2), in cells with KRAS (Kirsten Rat Sarcoma viral oncogene homolog) mutations.1 FAK and Pyk2 kinase inhibitors belong to the FAK family of nonreceptor tyrosine kinases.1

Recurrent Low-grade Serous Ovarian Cancer

Avutometinib in combination with defactinib is used in the treatment of KRAS-mutated recurrent low-grade serous ovarian cancer (LGSOC) in adults who have received prior systemic therapy.1

This indication was approved under the accelerated approval process based on tumor response and duration of response; continued approval may be contingent upon verification in confirmatory clinical trials in which clinical benefit is described.1

Avutometinib in combination with defactinib has been designated an orphan drug by FDA for the treatment of LGSOC.2

Clinical Experience

Efficacy and safety of avutometinib in combination with defactinib were established in the RAMP-201 study (NCT04625270), a randomized, open-label, multicenter trial that included a cohort of 57 adult patients with measurable KRAS-mutated recurrent LGSOC.1,  3,  4 In the first part of the study, patients were randomized to receive either avutometinib therapy alone (4 mg 2 times per week) or avutometinib (3.2 mg 2 times per week) in combination with defactinib (200 mg twice daily).1,  3,  4 The combination of avutometinib and defactinib was selected for additional study based on better objective response rate (ORR) and tolerability compared to avutometinib monotherapy.3,  4

All patients were required to receive at least one prior systemic therapy, including a platinum-based regimen.1,  3,  4 Exclusion criteria included candidates for debulking surgery, warfarin use, presence of an active skin condition requiring systemic treatment in the past year, or history or presence of an eye condition (including a history of retinal pathology, an active or chronic visually significant corneal disorder, or a history of glaucoma).1 The median age of patients in the efficacy population was 60 years (range: 29‒87 years); 75% were White, 3.5% were Asian, 3.5% were Black or African American, and 3.5% were Hispanic or Latino.1 Among these patients, 14%, 25%, 18%, or 40% had received 1, 2, 3, or >3 prior lines of systemic therapy, respectively, and all patients received prior platinum-based chemotherapy.1 The majority of patients (84%) received prior hormonal therapy, 40% received prior bevacizumab therapy, and 21% received a prior MEK inhibitor.1

The primary end point was ORR as assessed by a blinded independent review committee (BIRC).1,  4 Secondary end points included duration of response.1,  4 Assessment of tumor response was performed every 8 weeks for the first 72 weeks and every 12 weeks thereafter.1 The BIRC-assessed ORR was 44% in patients with KRAS mutations; complete response was achieved in 3.5% of patients and partial response was achieved in 40% of patients.1,  4 The duration of response ranged from 3.3 to 31.1 months.1 In the 25 responders, tumor KRAS mutations observed were A146V, G12D, G12R, G12V, and Q61H.1

Clinical Perspective

Low-grade serous carcinoma (LGSOC) accounts for about 5% to <10% of cases of epithelial ovarian cancer.5,  6 LGSOC typically involves activating mutations in the MAPK pathway, with KRAS mutations occurring in 27% of cases.5 LGSOC generally is diagnosed at a younger age and is relatively resistant to platinum-based antineoplastic agents.5 While this type of tumor has an extended overall survival compared with high-grade serous carcinoma, patients are often initially diagnosed with advanced disease limiting prognosis.5 Over 70% of patients with LGSOC have recurrent disease.5 Response rate to salvage therapy in LGSOC is low.5

Surgery is the mainstay of LGSOC management.7 Adjuvant chemotherapy is often administered following surgical resection, but the response rate to standard cytotoxic chemotherapy is low, with overall response rates of 4‒20% for platinum-based therapies in LGSOC compared to a response rate of 90% in patients with high-grade serous disease.7 Since recurrence is common and LGSOC is relatively chemoresistant, combinations of secondary cytoreduction hormonal therapy and targeted therapies have been evaluated.7 A significant proportion of LGSOC tumors have KRAS (40%) or BRAF (5%) molecular alterations, providing an opportunity for drugs that target the MAPK pathway to offer benefit.7 Management options for recurrent LGSOC disease include secondary cytoreductive surgery and systemic therapies such as MEK inhibitors, hormonal agents, chemotherapy, bevacizumab, and avutometinib/defactinib.6

General

Pretreatment Screening

• Confirm the presence of KRAS mutation using an FDA-approved diagnostic test; however, no FDA-approved test specific for LGSOC is available.1
• Perform a comprehensive ophthalmic examination.1
• Perform a dermatologic evaluation.1
• Perform baseline liver function tests.1
• Monitor creatine phosphokinase (CPK).1
• Perform pregnancy testing in females of reproductive potential.1

Patient Monitoring

• Monitor for ophthalmic adverse reactions, including visual impairment and vitreoretinal disorders (retinal detachment and retinal vein occlusion), prior to cycle 2 and every 3 cycles thereafter, regardless of initial baseline findings, and as clinically indicated.1
• Monitor for serious skin toxicities, including severe cutaneous adverse reactions (SCARs).1
• Monitor liver function tests prior to the start of each cycle, on day 15 of the first 4 cycles, and as clinically indicated.1
• Monitor CPK before initiation of each cycle, on day 15 of the first 4 cycles, and as clinically indicated.1

Premedication and Prophylaxis

• Initiate prophylactic topical corticosteroids (applied to the face, scalp, neck, upper chest, and upper back) and systemic antibiotics with the initiation of and during at least the first 2 cycles of combination therapy.1
• Apply daily sunscreen.1

Administration

Avutometinib is available as capsules and defactinib is available as tablets.1 The drugs are commercially available as a co-pack.1

If a dose of avutometinib is missed by >24 hours, skip the missed dose and take the next dose at the regularly scheduled time.1 Do not take 2 doses at the same time.1 If a dose is vomited, do not take an additional dose; take the next dose at the regularly scheduled time.1

If a dose of defactinib is missed by >6 hours, skip the missed dose and take the next dose at the regularly scheduled time.1 Do not take 2 doses at the same time.1 If a dose is vomited, do not take an additional dose; take the next dose at the regularly scheduled time.1

Avutometinib Capsules

Do not chew, break, or open avutometinib capsules; swallow capsules whole.1

Avutometinib capsules should be taken at the same time with each dose; administer with food.1

Store avutometinib capsules in the refrigerator at 2‒8°C; dispense in the original child-resistant bottle.1 Do not discard the desiccant in the bottle.1

Defactinib Tablets

Do not chew, break, or crush defactinib tablets; swallow tablets whole.1 Defactinib tablets should be taken with food.1

Store defactinib tablets in the refrigerator at 2‒8°C; dispense in the original child-resistant bottle.1

Dosage

Dosage of avutometinib potassium is expressed in terms of avutometinib.1 Dosage of defactinib hydrochloride is expressed in terms of defactinib.1

Adults

KRAS-mutated Recurrent Low-Grade Serous Ovarian Cancer (LGSOC)

The recommended dosage of avutometinib in combination with defactinib is 3.2 mg (four 0.8 mg capsules) orally twice weekly on Day 1 and Day 4 for the first 3 weeks of each 4-week cycle.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1

The recommended dosage of defactinib in combination with avutometinib is 200 mg (one tablet) orally twice daily for the first 3 weeks of each 4-week cycle.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1

Dosage Modifications for Toxicity

Clinicians should reduce the dosage of avutometinib and defactinib in patients who develop adverse effects (see Table 1).1

Permanently discontinue both avutometinib and defactinib if patients are unable to tolerate the agents after one dose reduction of both products.1,  3 Table 2 summarizes dose modifications for specific adverse events.1

Special Populations

Hepatic Impairment

There are no specific dosage recommendations for patients with hepatic impairment.1

Renal Impairment

There are no specific dosage recommendations for patients with renal impairment.1

Geriatric Patients

There are no specific dosage recommendations for geriatric patients.1

Contraindications

• None.1

Warnings/Precautions

Ocular Toxicities

Ocular adverse events, including visual impairment and vitreoretinal disorders, can occur with avutometinib and defactinib.1 The majority of patients (68%) with recurrent low-grade serous ovarian cancer (LGSOC) experienced an ocular adverse event with the most common events, occurring in ≥5% of patients, being visual impairment (38%), dry eyes (13%), orbital/periorbital edema (8%), and vitreous floaters (5%).1 Overall, 18 patients experienced an ocular adverse event resulting in a dose interruption and one patient required a dose reduction.1

The median time for development of symptomatic ocular adverse events was sooner than for asymptomatic events (5 versus 112 days).1 At last follow-up, of the patients who experienced an ocular adverse event, the event was ongoing in 29%.1

Patients should be referred to a qualified eye care professional for a comprehensive ophthalmic exam at baseline, prior to cycle 2, every 3 cycles thereafter, and as clinically indicated; a prompt referral is needed if the patient experiences any new or worsening ocular signs or symptoms.1 Depending on the severity of the ocular adverse event, avutometinib and defactinib may need to be withheld, the dose reduced, or the combination permanently discontinued.1

Serious Skin Toxicities

Serious cutaneous adverse reactions (SCARs), including generalized exanthematous pustulosis, erythema multiforme, and drug reaction with eosinophilia and systemic symptoms have been reported with therapy.1

Skin reactions occurred in 94% of patients with recurrent LGSOC; the most common reactions, which occurred in ≥10% of patients, included rash (67%), dermatitis acneiform (43%), dry skin (43%), pruritus (32%), and photosensitivity (13%).1 Among the Grade 3 reactions, which occurred in 12% of those treated with avutometinib and defactinib, were dermatitis acneiform (7%), rash (7%), and pruritis (1.5%).1 Ten percent of patients developed a bacterial skin infection (n=13).1 Therapy was interrupted in 10% of patients, the dose was decreased in 7%, and 0.7% permanently halted therapy due to skin toxicity.1 The median time to onset of first skin toxicity was 14 days (range 1‒500 days).1 During the last follow-up, two-thirds of patients were observed to have ongoing skin toxicity.1

Prophylactic topical corticosteroids (applied to the face, scalp, neck, upper chest, and upper back) and systemic oral antibiotics were initiated at the start of therapy and administered during at least the first two cycles in the RAMP-201 study.1

Patients should limit unnecessary sun exposure and apply daily sunscreen with a sun protection factor (SPF) of at least 30.1 Patients should be monitored for skin toxicity and therapy should be withheld, the dose reduced, or the combination regimen permanently discontinued depending on the severity of the skin reaction.1

Hepatotoxicity

Hepatotoxicity has been reported with avutometinib and defactinib therapy.1 Patients with recurrent LSGOC receiving the combination regimen experienced increases in AST (73%), bilirubin (51%), ALT (49%), and alkaline phosphatase (46%), with 3% of ALT and AST, 2.3% of bilirubin, and 0.8% of alkaline phosphate elevations Grade 3/4.1 Therapy was interrupted in 20% of patients, the dose was reduced in 2.2%, and permanently discontinued in 0.7% due to elevations in liver-related laboratory values.1

Monitor liver-related laboratory values prior to initiation of each cycle of avutometinib/defactinib, on day 15 of the first four cycles, and as clinically indicated.1 Depending on the severity and duration of the hepatotoxic reaction, the combination regimen may need to be withheld, undergo a dose reduction, or be permanently stopped.1

Rhabdomyolysis

Rhabdomyolysis has been reported with avutometinib and defactinib therapy at recommended doses.1 An increase in CPK has been reported in three-quarters of patients with recurrent LGSOC treated with avutometinib/defactinib, including Grade 3/4 elevations in 18% of patients.1 Concurrent increases in creatinine occurred in 19% and muscle pain occurred in 10% of patients who experienced an increase in CPK levels.1 In 0.7% of patients, increases in CPK of greater than 10 times the baseline value with accompanying elevations in serum creatinine ≥1.5 times the baseline value were reported.1 The dose of avutometinib/defactinib was interrupted in 22%, reduced in 7%, and halted in 2.9% of patients with elevated CPK.1

Monitor CPK levels prior to the initiation of each cycle, on day 15 of the first four cycles, and as clinically indicated.1 Patients should be assessed for the presence of rhabdomyolysis or other cause in the presence of a CPK elevation.1 Depending on the severity and duration of the event, therapy would need to be withheld, reduced, or permanently discontinued.1

Fetal/Neonatal Morbidity and Mortality

Avutometinib/defactinib may cause fetal harm in humans based on its mechanism of action; the mechanism of action has been associated with embryo-fetal anomalies and death in animals.1

Verify pregnancy status in females of reproductive potential prior to initiating therapy.1 Women with reproductive potential should use effective contraceptive methods while receiving therapy and for 1 month following the last dose.1 Male partners of women with reproductive potential should use effective contraceptive methods during treatment and for 4 months following the last dose.1

Specific Populations

Pregnancy

Based on its mechanism of action, the combination regimen (avutometinib/defactinib) may cause fetal harm if administered to pregnant women.1 Reproductive and developmental toxicity studies have not been conducted in animals.1 Confirm pregnancy status prior to initiation of therapy in females of reproductive potential.1 Apprise pregnant women and females of reproductive potential of the drug-associated risk to the fetus.1

Lactation

It is not known whether avutometinib, defactinib, or their metabolites are distributed into human milk; the effects of the drug on breastfed infants or on milk production are also unknown.1 Lactating women should not breastfeed during treatment and for 2 weeks following the last dose because of the potential risk of serious harm to the breastfed child.1

Females and Males of Reproductive Potential

Confirm pregnancy status prior to initiation of therapy in females of reproductive potential.1 Females of reproductive potential should use effective methods of contraception during therapy and for 1 month after the last dose.1 Male partners of females with reproductive potential should use effective methods of contraception during therapy and for 4 months after the last dose.1 Avutometinib and defactinib may irreversibly impair fertility in males and females of reproductive potential based on animal studies.1

Pediatric Use

The safety and efficacy of avutometinib/defactinib have not been established in pediatric patients.1

Geriatric Use

Of the 136 patients in clinical trials of avutometinib/defactinib, 29% were ≥65 years of age.1 No overall differences in the safety of avutometinib/defactinib were observed between geriatric and younger patients; however there was an insufficient number of patients ≥65 years of age to determine if these patients respond differently to therapy from younger patients.1

Hepatic Impairment

No clinically significant differences in the pharmacokinetics of avutometinib or defactinib were observed in patients with mild hepatic impairment (AST > upper limit of normal [UNL] or total bilirubin >1 times the ULN to 1.5 times the ULN).1 The effect of moderate or severe hepatic impairment (AST or ALT ≥2.5 times the ULN or total bilirubin 1.5 times the ULN) on the pharmacokinetics of avutometinib or defactinib are unknown.1

Renal Impairment

No clinically significant differences in the pharmacokinetics of avutometinib or defactinib were observed in patients with mild and moderate renal impairment (creatinine clearance 30 to 89 mL/min).1 The effect of severe renal impairment (creatinine clearance <30 mL/min) on the pharmacokinetics of avutometinib or defactinib is unknown.1

Common Adverse Effects

The most common adverse reactions reported in ≥25% of patients receiving avutometinib in combination with defactinib, including laboratory abnormalities, were increased creatine phosphokinase, nausea, fatigue, increased AST, rash, diarrhea, musculoskeletal pain, edema, decreased hemoglobin, increased ALT, 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

Avutometinib is primarily metabolized by cytochrome (CYP) 3A4 and nonezymatic degradation.1 Defactinib is metabolized primarily by CYP3A4 and CYP2C9.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Concomitant administration of avutometinib with itraconazole, a strong CYP34 inhibitor, did not produce clinically significant changes in avutometinib pharmacokinetics.1 However, administration of defactinib with itraconazole 200 mg daily for 10 days resulted in a 2.2-fold increase in peak plasma concentration and a 3.9-fold increase in AUC of defactinib.1

Concomitant administration of phenytoin 3 times daily for 23 days and a single-dose of avutometinib 2.4 mg on day 17 decreased the AUC of avutometinib by 34%, but did not affect peak plasma concentrations.1 Concomitant administration of phenytoin 3 times daily for 23 days and a single dose of defactinib 200 mg on day 14 reduced peak plasma concentrations of defactinib by 83% and AUC by 87%; AUC and peak plasma concentrations of M4, the equipotent metabolite of defactinib, decreased by 79% and 70%, respectively, following phenytoin exposure.1

Concomitant use of strong or moderate CYP3A4 inhibitors should be avoided as use may increase the risk of adverse reactions.1

Concomitant use of strong or moderate CYP3A4 inducers should be avoided as use may decrease effectiveness.1

Gastric Acid Reducing Agents

Concomitant administration of defactinib with multiple doses of omeprazole 40 mg daily decreased the AUC and maximum concentration of defactinib by 83% and 88%, respectively.1

Concomitant administration of proton pump inhibitors or H₂-receptor antagonists should be avoided.1 If concomitant use cannot be avoided, administer defactinib 2 hours before or 2 hours after the acid reducing agents.1

Warfarin

Concomitant use of warfarin with avutometinib/defactinib should be avoided.1 An alternative anticoagulant is recommended.1 If concomitant use is necessary, monitor INR frequently.1

Bleeding and increased INR have been reported with the concomitant administration of warfarin and defactinib.1

Description

Avutometinib is a MEK1 inhibitor.1 The drug promotes the formation of inactive RAF/MEK complexes, thereby preventing RAF-mediated phosphorylation of MEK1/2.1 RAF and MEK are key regulators of the RAS/RAF/MEK/ERK (MAPK) signaling pathway.1 Avutometinib inhibits phosphorylation of MEK1/2 and ERK1/2 and reduces proliferation in tumor cell lines harboring KRAS mutations.1 Additionally, treatment with avutometinib increases levels of phosphorylated FAK in cancer cells.1

Defactinib is an inhibitor of FAK and Pyk2, both members of the FAK family of nonreceptor tyrosine kinases.1 Defactinib inhibits FAK autophosphorylation in cancer cells in vitro as well as in mouse xenograft models.1 When used in combination with avutometinib, defactinib demonstrates enhanced inhibition of cell proliferation in vitro and increases antitumor activity in mouse tumor models, including in low-grade serous ovarian cancer.1

Avutometinib demonstrates dose proportional increases in maximum serum concentration and AUC following single doses ranging from 0.1 mg to 5 mg (0.03 to 1.6 times the recommended dose) with no clinically significant accumulation observed at the recommended dosing regimen.1 Defactinib demonstrates dose proportional increases in maximum serum concentration and AUC with twice daily dosing over a range of 12.5 mg to 450 mg (0.06 to 2.25 times the recommended dose).1 Steady-state plasma concentrations are achieved in about 15 days, with approximately 1.5-fold accumulation observed at the recommended dosing regimen.1

While a high-fat meal (i.e., approximately 900‒1000 calories with 50% from fat) did not have a clinically significant effect on the AUC of avutometinib, it reduced maximum serum concentration by 29%.1 Under fasted conditions, the median time to maximum serum concentration for avutometinib is approximately 2 hours.1 A high-fat meal increased the AUC and maximum serum concentration of defactinib by 2.7- and 1.9-fold, respectively.1 Under fed conditions, the median time to maximum serum concentration of defactinib is approximately 4 hours.1 Avutometinib is 99% and defactinib is 90% bound to human plasma proteins.1

Avutometinib is primarily metabolized by cytochrome (CYP) 3A4 and nonezymatic degradation.1 Defactinib is metabolized primarily by CYP3A4 and CYP2C9.1 Defactinib has 2 major metabolites: N-desmethyl sulfonamide (M2), an inactive metabolite that represents 92% of exposure, and N-desmethyl amide (M4), which accounts for 28% of exposure and is as potent as defactinib.1

Following oral administration of a single dose of avutometinib 2.4 mg (0.8 times the approved recommended dose), 39% is recovered in the feces (9.5% as unchanged drug) and 52% is recovered in the urine (3.2% as unchanged drug).1 Following oral administration of a single dose of defactinib 400 mg (2 times the approved recommended dose), 87% is recovered in the feces (52% as unchanged drug) and 7.6% is recovered in urine (0.8% as unchanged drug).1 The estimated elimination half-life of avutometinib is 51 hours whereas the estimated elimination half-life of defactinib is 9 hours.1

Advice to Patients

• Advise patients of the risk of ocular toxicity, the need to have an eye exam before and during treatment, and to report any visual changes, pain, or inflammation around the eyes to their healthcare provider.1
• Advise patients of the risk of serious skin reactions with therapy, the need to use prophylactic topical steroids and oral antibiotics, limit sun exposure, apply sunscreen with a sunscreen protection factor (SPF) >30, and to notify their healthcare provider if they develop a rash, progressively worsening skin reactions, or blistering of the skin or mouth.1
• Advise patients of the risk of hepatotoxicity and to notify their healthcare provider if they observe any signs or symptoms of liver dysfunction.1
• Advise patients of the risk of rhabdomyolysis and to notify their healthcare provider if they have signs and symptoms of muscle breakdown.1
• Advise patients to inform their clinician immediately if they are or plan to become pregnant or plan to breastfeed.1 Advise female patients of reproductive potential to complete a pregnancy test prior to initiation of therapy, and to use effective methods of contraception during therapy and for 1 month after the last dose.1 Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the last dose.1 Advise patients to not breastfeed during treatment and for 2 weeks after the last dose.1
• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary and herbal supplements, as well as any concomitant illnesses.1
• Advise patients of other important precautionary information.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Verastem Inc. AVMAPKI FAKZYNJA CO-PACK^® (avutometinib potassium and defactinib hydrochloride) prescribing information. 2025 May. [Web]

2. U.S. Food and Drug Administration. Search orphan drug designations and approvals. Avutometinib and defactinib. From the FDA website. [Web]

3. US Food and Drug Administration. CENTER FOR DRUG EVALUATION AND RESEARCH. APPLICATION NUMBER: 219616Orig1s000. MULTI-DISCIPLINE REVIEW. [Web]

4. Banerjee SN, Van Nieuwenhuysen E, Aghajanian C, et al. Efficacy and safety of avutometinib ± defactinib in recurrent low-grade serous ovarian cancer: Primary Analysis of ENGOT-OV60/GOG-3052/RAMP 201. J Clin Oncol. 2025 Sep;43(25):2782-2792.

5. Gershenson DM, Miller A, Brady WE, et al. Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS): an international, randomised, open-label, multicentre, phase 2/3 trial. Lancet. 2022 Feb 5;399(10324):541-553.

6. Grisham RN, Slomovitz BM, Andrews N, et al. Low-grade serous ovarian cancer: expert consensus report on the state of the science. Int J Gynecol Cancer. 2023 Sep 4;33(9):1331-1344.

7. Gonzalez A, Nagel CI, Haight PJ. Targeted therapies in low-grade serous ovarian cancers. Curr Treat Options Oncol. 2024 Jul;25(7):854-868.