AVUTOMETINIB/ DEFACTINIB KIT

Clinical Criteria Summary

Absolute neutrophil count (ANC) < 1500/mm3 (unless Duffy null phenotype) or platelets < 100,000/mm3

Moderate or severe hepatic impairment (Child-Pugh class B/C or NCI Organ Dysfunction Working Group Classification)
CrCL < 30 ml/min

Active or uncontrolled infection
Symptomatic or unstable brain metastases
Unmanageable drug interaction1 (Patients on warfarin were excluded from clinical trial, RAMP-201)

Ocular disorder defined as history of retinal pathology, active/chronic corneal disorder or history of glaucoma
Active skin disorder requiring systemic therapy

Pregnancy
Lactating
For females who can become pregnant and males with partners who can become pregnant: Counseling provided on potential risks vs benefits of treatment and the use of effective contraception during therapy and for 4 months after stopping treatment
For females who are pregnant or plan to become pregnant: Counseling provided on potential risks vs benefits of treatment and the use of effective contraception during therapy and for 1 month after stopping treatment
For females who are lactating / providing breastmilk to an infant or planning to do so: Counseling provided on avoiding breastfeeding during therapy and for 2 weeks after stopping treatment.

Recurrent KRAS-mutated low-grade serous ovarian cancer (LGSOC)
Progressive disease following at least one prior systemic therapy that included a platinum-based regimen

Comprehensive ophthalmic exam performed at baseline
Able to apply topical corticosteroid to face, scalp, upper chest and upper back daily at therapy initiation and during at least the first 2 cycles; limit unnecessary sun exposure and apply daily sunscreen with SPF > 30
Goals of care and role of Palliative Care consult have been discussed and documented

Treatment of adult patients with KRAS-mutated recurrent low-grade serous ovarian cancer (LGSOC)
Indication approved under accelerated approval based on tumor response rate and duration of response
Adult women with measurable, histologically confirmed ovarian or peritoneal LGSOC

Avutometinib 3.2 mg (four 0.8-mg caps) PO twice weekly (Day 1 and Day 4) for the first 3 weeks of each 4-week cycle
Defactinib 200 mg (one tab) PO twice daily for the first 3 weeks of each 4-week cycle until disease progression or unacceptable toxicity

Monitor for increased creatine phosphokinase (CPK), nausea, fatigue, increased aspartate aminotransferase, and rash (>25% incidence)
Assess for ocular toxicities, rhabdomyolysis, serious skin toxicities, embryo-fetal toxicity, and hepatotoxicity
Monitor INR frequently if warfarin concomitant use is unavoidable
Separate doses of gastric acid reducing agents by 2 hours if proton pump inhibitor or H2 receptor antagonist cannot be avoided
No clinically significant PK differences observed in mild or moderate renal impairment; effects unknown in severe impairment
No clinically significant PK differences observed in mild hepatic impairment; effects unknown in moderate to severe impairment

VA Oncology Pathway recommends for recurrent disease after prior chemotherapy if KRAS mutation positive
NCCN Guidelines list as Category 2A in recurrent setting in KRAS-mutation positive disease
FDA labeling restricts use to KRAS-mutated recurrent LGSOC

Boxed warnings: none
Contraindications: none
Advise pregnant women and females of reproductive potential of the potential risk to a fetus
Advise not to breastfeed
Avoid strong and moderate CYP3A4 inhibitors (may increase effects of defactinib and toxicity)
Avoid strong and moderate CYP3A4 inducers (may decrease effects of defactinib and efficacy)
Avoid warfarin; if concomitant use is unavoidable, monitor INR frequently