Avutometinib Potassium And Defactinib Hydrochloride

1 INDICATIONS AND USAGE AVMAPKI FAKZYNJA CO-PACK is indicated for the treatment of adult patients with KRAS -mutated recurrent low-grade serous ovarian cancer (LGSOC) who have received prior systemic therapy. This indication is approved under accelerated approval based on tumor response rate and duration of response [see Clinical Studies (14) ]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. AVMAPKI FAKZYNJA CO-PACK, a combination of avutometinib and defactinib, each kinase inhibitors, is indicated for the treatment of adult patients with KRAS -mutated recurrent low-grade serous ovarian cancer (LGSOC) who have received prior systemic therapy. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. ( 1 , 14 )

2 DOSAGE AND ADMINISTRATION AVMAPKI 3.2 mg administered orally twice weekly (Day 1 and Day 4) for the first 3 weeks of each 4-week cycle. ( 2.3 ) FAKZYNJA 200 mg administered orally twice daily for the first 3 weeks of each 4-week cycle. ( 2.3 ) 2.1 Patient Selection Select patients for the treatment of recurrent LGSOC with AVMAPKI FAKZYNJA CO-PACK based on the presence of a KRAS mutation in tumor specimens [see Clinical Studies (14) ] . An FDA-approved test for the detection of a KRAS mutation in LGSOC for selecting patients for treatment with AVMAPKI FAKZYNJA CO-PACK is not available. 2.2 Eye Exams and Prophylactic Skin Medications Ophthalmic Exams Conduct a comprehensive ophthalmic exam at baseline, prior to cycle 2, and every three cycles thereafter regardless of baseline exam findings, and as clinically indicated [see Warnings and Precautions (5.1) ]. Prophylactic Medications for Skin Reactions With initiation of and during at least the first 2 cycles of AVMAPKI FAKZYNJA CO-PACK administer [see Warnings and Precautions (5.2) ] : Topical corticosteroid (applied to the face, scalp, neck, upper chest and upper back) Systemic oral antibiotics 2.3 Recommended Dosage and Administration AVMAPKI Capsules The recommended dosage of AVMAPKI capsules is 3.2 mg (four 0.8 mg capsules) taken orally twice weekly (Day 1 and Day 4) for the first 3 weeks of each 4-week cycle until disease progression or unacceptable toxicity. Take AVMAPKI at the same time with each dose. AVMAPKI should be taken with food [see Clinical Pharmacology (12.3) ] . Swallow capsules whole. Do not chew, break, or open the capsules. If a dose of AVMAPKI is missed by more than 24 hours, skip the missed dose and take the next scheduled dose as prescribed. Do not take two doses at the same time to make up for a missed dose. If vomiting occurs after taking AVMAPKI, do not take an additional dose. Take the next scheduled dose as prescribed. FAKZYNJA Tablets The recommended dosage of FAKZYNJA tablets is 200 mg (one tablet) taken orally twice daily for the first 3 weeks of each 4-week cycle until disease progression or unacceptable toxicity. Take each dose of FAKZYNJA with food [see Clinical Pharmacology (12.3) ] . Swallow tablets whole. Do not chew, break or crush the tablets. If a dose of FAKZYNJA is missed by more than 6 hours, skip the missed dose and take the next scheduled dose as prescribed. Do not take two tablets at the same time to make up for a missed dose. If vomiting occurs after taking FAKZYNJA, do not take an additional dose. Take the next scheduled dose as prescribed. 2.4 Dosage Modifications for Adverse Reactions Dose reductions due to adverse reactions due to AVMAPKI FAKZYNJA CO-PACK are summarized in Table 1. Table 1 Recommended Dose Reductions for Adverse Reactions Dose Level AVMAPKI Capsule FAKZYNJA Tablet Starting dose 3.2 mg twice weekly for first 3 weeks of each 4-week cycle 200 mg twice daily for first 3 weeks of each 4-week cycle Dose reduction 2.4 mg twice weekly for first 3 weeks of each 4-week cycle 200 mg once daily for first 3 weeks of each 4-week cycle Permanently discontinue both AVMAPKI and FAKZYNJA in patients unable to tolerate after one dose reduction of both products. Dosage modifications for adverse reactions to AVMAPKI FAKZYNJA CO-PACK are summarized in Table 2. Table 2 AVMAPKI FAKZYNJA CO-PACK Dosage Modifications Adverse Reaction Severity Severity as defined by National Center Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0 Dose Modification N/A: Not applicable Keratitis [see Warnings and Precautions (5.1) ] Confluent superficial keratitis, a cornea epithelial defect, or 3-line or more loss in best corrected distance visual acuity Withhold AVMAPKI FAKZYNJA CO-PACK until resolved to nonconfluent superficial keratitis, then resume at same dose. Corneal ulcer or stromal opacity or best corrected distance visual acuity 20/200 or worse Corneal perforation Withhold AVMAPKI FAKZYNJA CO-PACK until resolved to nonconfluence superficial keratitis, then resume at reduced dose. Permanently discontinue AVMAPKI FAKZYNJA CO-PACK. Blurred vision [see Warnings and Precautions (5.1) ] BCVA worse than baseline but no worse than 20/200 Withhold AVMAPKI FAKZYNJA CO-PACK until resolution to baseline or 20/40, whichever is worse, then resume treatment at same dose. BCVA 20/200 or worse Withhold AVMAPKI FAKZYNJA CO-PACK until resolution to baseline or 20/40, whichever is worse, then resume at reduced dose. Conjunctivitis [see Warnings and Precautions (5.1) ] Confluent superficial punctate staining, moderate to severe vasodilation Withhold AVMAPKI FAKZYNJA CO-PACK until resolution to nonconfluent superficial keratitis, then resume at same dose. Conjunctival ulcer or neovascularization Withhold AVMAPKI FAKZYNJA CO-PACK until resolution to nonconfluent superficial keratitis, then resume at reduced dose. Retinal Pigment Epithelial (RPE) Detachment [see Warnings and Precautions (5.1) ] N/A First occurrence Repeat Optical Coherence Tomography (OCT) examination in two weeks. First follow-up OCT examination and RPE present Reduce dose of AVMAPKI FAKZYNJA CO-PACK Repeat OCT examination in two weeks. Second follow-up OCT examination and RPE present and/or loss of 1 line in BCVA : Withhold AVMAPKI FAKZYNJA CO-PACK Repeat OCT examination in two weeks. Third follow-up OCT examination RPE resolving/resolved, resume at reduced dose. No resolution, permanently discontinue AVMAPKI FAKZYNJA CO-PACK Rash [see Warnings and Precautions (5.2) ] Grade ≤ 2 Consider withholding AVMAPKI FAKZYNJA CO-PACK if rash does not respond to supportive care or recurs after resolution to Grade ≤1. Dose reduce AVMAPKI FAKZYNJA CO-PACK for intolerable Grade 2. Grade 3 Withhold AVMAPKI FAKZYNJA CO-PACK until resolved to Grade 2 then resume at reduced dose. Resume at same dose if resolved to Grade ≤1. Permanently discontinue AVMAPKI FAKZYNJA CO-PACK for recurrent Grade 3 despite dose reduction. Grade 4 Permanently discontinue AVMAPKI FAKZYNJA CO-PACK. Hepatotoxicity [see Warnings and Precautions (5.3) ] Grade 2 Withhold AVMAPKI FAKZYNJA CO-PACK for Grade 2 hyperbilirubinemia (without Gilbert's syndrome) with Grade ≤1 increase in AST and/or ALT until hyperbilirubinemia Grade ≤1, then resume at same dose. Grade 2 hyperbilirubinemia with Grade 2 increase in AST and/or ALT until hyperbilirubinemia Grade ≤1 or baseline, then resume at same dose. Permanently discontinue AVMAPKI FAKZYNJA CO-PACK for Grade 2 hyperbilirubinemia associated with Grade >2 increase in AST and/or ALT. Grade 3 Withhold AVMAPKI FAKZYNJA CO-PACK if Grade 3 hyperbilirubinemia is associated with Grade ≤1 increase in AST and/or ALT until hyperbilirubinemia Grade ≤1 or at baseline, then resume at same dose. if recurrent Grade 3 hyperbilirubinemia is associated with Grade ≤1 increase in AST and/or ALT until hyperbilirubinemia Grade ≤2 or at baseline, then resume at reduced dose. if Grade 3 increased AST and/or ALT is not associated with hyperbilirubinemia until Grade ≤2 or at baseline, then resume at reduced dose. Permanently discontinue AVMAPKI FAKZYNJA CO-PACK for Grade 3 hyperbilirubinemia associated with Grade ≥2 increase in AST and/or ALT. Grade 4 Withhold AVMAPKI FAKZYNJA CO-PACK for Grade 4 hyperbilirubinemia associated with Grade ≤1 increase in AST and/or ALT and if resolves within one week resume at reduced dose. Permanently discontinue AVMAPKI FAKZYNJA CO-PACK for Grade 4 increase in AST and/or ALT. Grade 4 hyperbilirubinemia associated with Grade ≤1 increase in AST and/or ALT that does not resolve within 1 week. Grade 4 hyperbilirubinemia associated with Grade ≥2 increase in AST and/or ALT. Increased Blood Creatine Phosphokinase (CPK) [see Warnings and Precautions (5.4) ] Grade 3 Withhold AVMAPKI FAKZYNJA CO-PACK, if improves to Grade ≤1 within three weeks resume at same dose. Permanently discontinue AVMAPKI FAKZYNJA CO-PACK for CPK elevation longer than three weeks. Grade 4 Withhold AVMAPKI FAKZYNJA CO-PACK, if improves to Grade ≤1 within three weeks resume at reduced dose. Permanently discontinue AVMAPKI FAKZYNJA CO-PACK for CPK elevation longer than three weeks. Any grade CPK elevation with rhabdomyolysis or other event related to CPK elevation Permanently discontinue AVMAPKI FAKZYNJA CO-PACK Other Adverse Reactions Grade 2 Consider withholding AVMAPKI FAKZYNJA CO-PACK if adverse reaction does not respond to supportive care or recurs after resolution to Grade ≤1. Grade 3 First occurrence: Withhold AVMAPKI FAKZYNJA CO-PACK until resolved to baseline or Grade ≤1 then resume at same dose. Second occurrence: Withhold AVMAPKI FAKZYNJA CO-PACK until resolved to baseline or Grade ≤1 then resume at reduced dose. Permanently discontinue AVMAPKI FAKZYNJA CO-PACK for recurrent Grade 3 despite dose reduction. Grade 4 Permanently discontinue AVMAPKI FAKZYNJA CO-PACK.

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: Ocular Toxicities [see Warnings and Precautions (5.1) ] Serious Skin Toxicities [see Warnings and Precautions (5.2) ] Hepatotoxicity [see Warnings and Precautions (5.3) ] Rhabdomyolysis [see Warnings and Precautions (5.4) ] 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Verastem at 1-833-633-8786 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The pooled safety population described in Warnings and Precautions reflect exposure to the AVMAPKI FAKZYNJA CO-PACK (combination of AVMAPKI 3.2 mg twice weekly and FAKZYNJA 200 mg twice daily) for the first 3 weeks in a 4-week cycle until disease progression or unacceptable toxicity in 136 adult patients with recurrent LGSOC treated on RAMP-201 and FRAME (NCT03875820). The median duration of treatment was 10 months (range 0 to 51 months). RAMP-201 The safety of AVMAPKI FAKZYNJA CO-PACK was evaluated in RAMP-201, a single-arm multicenter trial in 57 patients with KRAS- mutated recurrent LGSOC [see Clinical Studies (14) ] . Patients received AVMAPKI FAKZYNJA CO-PACK (AVMAPKI 3.2 mg twice weekly and FAKZYNJA 200 mg twice daily) for the first 3 weeks in a 4-week cycle until disease progression or unacceptable toxicity. The median duration of treatment was 12 months (range 0.03-40). Serious adverse reactions occurred in 32% of patients who received AVMAPKI FAKZYNJA CO-PACK. The most common (≥2%) serious adverse reactions were sepsis (9%), intestinal obstruction (3.6%), pyelonephritis (3.6%), and hydronephrosis (3.6%). Fatal adverse reactions occurred in 3.6% of patients who received AVMAPKI FAKZYNJA CO-PACK, including intestinal obstruction (1.8%) and perforation (1.8%). Permanent discontinuation of AVMAPKI FAKZYNJA CO-PACK due to an adverse reaction occurred in 14% of patients. The adverse reactions leading to permanent discontinuation included elevations in creatine phosphokinase, dyspnea, malaise, decreased glomerular filtration rate, hyperbilirubinemia, increased alanine aminotransferase, and abdominal pain (1.8% each). Dosage interruptions of AVMAPKI FAKZYNJA CO-PACK due to an adverse reaction occurred in 84% of patients. Adverse reactions which required dosage interruptions in ≥ 5% of patients included elevations in creatine phosphokinase (25%), hyperbilirubinemia (25%), diarrhea (12%), edema (11%), fatigue (9%), vision blurred (9%), vitreoretinal disorders (7%), transaminitis (7%), paronychia (5%), nausea (5%), abdominal pain (5%), vomiting (5%), dyspnea (5%), sepsis (5%), and rash (5%). Dose reductions of AVMAPKI FAKZYNJA CO-PACK due to an adverse reaction occurred in 44% of patients. Adverse reactions which required dose reductions in ≥ 5% of patients were elevations in creatine phosphokinase (9%), fatigue (5%), hyperbilirubinemia (5%), and dermatitis acneiform (5%). 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. Table 3 summarizes the adverse reactions in RAMP-201. Table 3 Adverse Reactions (≥10%) in Patients with KRAS-Mutated Recurrent LGSOC who Received AVMAPKI FAKZYNJA CO-PACK in RAMP-201 Severity as defined by National Center Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Adverse Reaction AVMAPKI FAKZYNJA CO-PACK N = 57 All Grades % Grade 3 or 4 No Grade 4 treatment-emergent adverse events occurred. % Gastrointestinal disorders Nausea 74 1.8 Diarrhea 68 7 Vomiting 49 3.5 Abdominal pain Includes multiple terms 39 1.8 Dyspepsia 37 0 Stomatitis 35 3.5 Constipation 30 0 Dry mouth 18 0 Decreased Weight 11 0 General disorders and administration site condition Fatigue 72 3.5 Edema 67 1.8 Skin and subcutaneous tissue disorders Rash Includes: butterfly rash, dermatitis, drug eruption, erythema, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, and rash pruritic 72 3.5 Dermatitis acneiform Includes: acne, dermatitis acneiform, folliculitis, perioral dermatitis, and rash pustular 37 5.3 Pruritus 35 1.8 Dry skin 30 0 Alopecia 23 0 Photosensitivity 16 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain 68 1.8 Joint swelling 11 0 Eye disorders Vitreoretinal disorders Includes: chorioretinopathy, detachment of retinal pigment epithelium, macular fibrosis, macular hole, maculopathy, retinal detachment, retinal drusen, retinal vein occlusion, retinopathy, serous retinal detachment, serous retinopathy, subretinal fluid, vitreous detachment, and vitreous floaters 37 3.5 Visual impairment Includes: asthenopia, astigmatism, halo vision, metamorphopsia, photophobia, photopsia, vision blurred, visual field defect, and visual impairment 35 0 Dry eye 12 0 Respiratory disorders Dyspnea 26 5.3 Cough 25 0 Nervous system disorders Dizziness 23 1.8 Headache 16 0 Neuropathy peripheral 14 0 Dysgeusia 11 0 Vascular disorders Hemorrhage 23 0 Hypertension 16 5.3 Venous thromboembolism 14 5.3 Metabolism and nutrition disorders Decreased appetite 18 1.8 Infections and infestations Urinary tract infection 25 3.5 Paronychia 14 1.8 Upper respiratory tract infection 11 0 Clinically relevant adverse reactions in < 10% of patients who received AVMAPKI FAKZYNJA CO-PACK included urticaria and decreased ejection fraction. Table 4 summarizes the laboratory abnormalities in RAMP-201. Table 4 Select Laboratory Abnormalities (≥ 10%) in Patients with KRAS-Mutated Recurrent LGSOC who Received AVMAPKI FAKZYNJA CO-PACK in RAMP-201 Laboratory Abnormality AVMAPKI FAKZYNJA CO-PACK All Grades (%) The denominator used to calculate the rate varied from 45 to 57 based on the number of patients with a baseline value and at least one post-treatment value. Grade 3 or 4 (%) Chemistry Increased creatine phosphokinase 82 19 Increased aspartate aminotransferase 70 3.5 Decreased albumin 70 0 Increased alanine aminotransferase 58 3.5 Increased blood bilirubin 48 3.5 Increased triglycerides 46 3.5 Increased alkaline phosphatase 37 1.8 Decreased potassium 23 9 Hematology Decreased hemoglobin 65 5 Decreased lymphocyte count 40 1.8 Decreased platelet count 35 0 Decreased neutrophil count 25 1.8 Urine Proteinuria 22 4.4 Clinically relevant laboratory abnormalities in < 10% of patients who received AVMAPKI FAKZYNJA CO-PACK included increased INR and prolonged activated partial thromboplastin time.

12.3 Pharmacokinetics The pharmacokinetics of avutometinib and defactinib were studied in healthy subjects and in patients with advanced solid tumors and are presented as mean (%CV) unless otherwise specified. Avutometinib Avutometinib exhibits dose proportional increases peak plasma concentrations (C max ) and area under the concentration time curve (AUC) with a single dose ranging from 0.1 mg to 5 mg (0.03 to 1.6 times the approved recommended dose). No significant accumulation of avutometinib was observed at the recommended dosage. Defactinib Defactinib exhibits dose proportional increases in C max and AUC with twice daily dosing ranging from 12.5 mg to 450 mg (0.06 to 2.25 times the approved recommended dosage). Defactinib steady-state plasma concentrations are reached in approximately 15 days. Defactinib accumulation is approximately 1.5-fold at the approved recommended dosage. Absorption The median time to avutometinib peak plasma concentration (T max ) under fasted conditions is approximately 2 hours. The median time to defactinib T max under fed conditions is approximately 4 hours. Effect of Food No clinically significant differences in avutometinib AUC were observed following administration with a high-fat meal. Avutometinib C max was decreased by 29% following administration with a high-fat meal (approximately 900 to 1000 calories, 50% fat). Defactinib AUC increased by 2.7-fold and C max increased by 1.9-fold following administration with a high-fat meal (approximately 900 to 1000 calories, 50% fat). Distribution Avutometinib steady state apparent volume of distribution (V d ) is 25 L (19%). Avutometinib human plasma protein binding is 99% in vitro . Defactinib steady state apparent V d is 1,560 L (59%). Defactinib human plasma protein binding is 90% in vitro . Elimination Avutometinib estimated elimination half-life is 51 hours (28%) and the apparent oral clearance (CL/F) is 0.3 L/h (30%). Defactinib estimated elimination half-life is 9 hours (171%) and the CL/F is 69 L/h (173%). Metabolism Avutometinib is primarily metabolized by CYP3A4 and nonenzymatic degradation. Defactinib is metabolized primarily by CYP3A4 and CYP2C9. Two major metabolites, N-desmethyl sulfonamide (M2) and N-desmethyl amide (M4), were identified in plasma. M2 and M4 AUCs represent 92% and 28% of defactinib exposure, respectively. M2 is inactive and M4 is equipotent when compared to defactinib. Excretion After a single dose of radiolabeled avutometinib 2.4 mg (0.8 times the approved recommended dose), 39% (9.5% unchanged) of the dose was recovered in feces and 52% (3.2% unchanged) in urine. After a single dose of radiolabeled defactinib 400 mg (2 times the approved recommended dose), 87% (52% unchanged) of the dose was recovered in feces and 7.6% (0.8% unchanged) in urine. Specific Populations No clinically significant differences in the pharmacokinetics of avutometinib were observed based on age (21 to 87 years), sex, race (84% White, 3% Black and 2% Asian), body weight (40 to 169 kg), mild and moderate renal impairment (CLcr 30 to 89 mL/min, estimated by Cockcroft-Gault), or mild hepatic impairment (AST > ULN or total bilirubin >1 × ULN to 1.5 × ULN). The effect of severe renal impairment (CLcr < 30 mL/min) or moderate to severe hepatic impairment (AST or ALT ≥ 2.5 × ULN or total bilirubin ≥ 1.5 × ULN) on avutometinib pharmacokinetics is unknown. No clinically meaningful differences in the pharmacokinetics of defactinib were observed based on age (21 to 87 years), sex, race (82% White, 3% Black and 2% Asian), body weight (40 to 169 kg), mild and moderate renal impairment (CLcr 30 to 89 mL/min), or mild hepatic impairment (AST > ULN or total bilirubin >1 × ULN to 1.5 × ULN). The effect of severe renal impairment (CLcr < 30 mL/min) or moderate to severe hepatic impairment (AST or ALT ≥ 2.5 × ULN or total bilirubin ≥ 1.5 × ULN) on defactinib pharmacokinetics is unknown. Drug Interaction Studies Clinical Studies Strong CYP3A4 Inhibitors: No clinically significant differences in avutometinib pharmacokinetics were observed when used concomitantly with itraconazole (strong CYP3A4 inhibitor). Defactinib C max increased by 2.2-fold and AUC by 3.9-fold following concomitant use with itraconazole (strong CYP3A4 inhibitor) 200 mg daily for 10 days. M4 AUC increased by 2.2-fold and C max decreased by 6.8%. Strong CYP3A4 Inducers: Avutometinib AUC decreased by 34% with no clinically significant change in C max following coadministration with phenytoin (strong CYP3A4 inducer) three times daily for 23 days and a single dose of avutometinib 2.4 mg (0.8 times the approved recommended dose) on Day 17. Defactinib C max decreased by 83% and AUC by 87% following coadministration with phenytoin (strong CYP3A4 inducer) three times daily for 23 days and a single dose of defactinib 200 mg (1.0 times the approved recommended dose) on Day 14. M4 AUC decreased by 79% and C max decreased by 70%. Proton Pump Inhibitors (PPIs): Defactinib displayed pH-dependent aqueous solubility [see Description (11) ] . Defactinib AUC decreased by 79% and C max decreased by 85% following concomitant use of multiple doses of omeprazole (PPI) 40 mg daily. M4 AUC decreased by 83% and C max decreased by 88%. In Vitro Studies CYP450 Enzymes: Avutometinib is a CYP3A4 substrate, but not a substrate of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Avutometinib is not an inhibitor of CYP3A4, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Avutometinib is not an inducer of CYP3A4, CYP2B6, and CYP1A2. Defactinib is a CYP3A4 and CYP2C9 substrate, but not a substrate of CYP1A2, CYP2B6, CYP2C8, CYP2C19, and CYP2D6. Defactinib is a reversible inhibitor of CYP3A4 and CYP2C9, but not CYP1A2, CYP2B6, CYP2C8, CYP2C19, and CYP2D6. Defactinib is a time-dependent inhibitor of CYP3A4. Defactinib is an inducer of CYP2B6, and CYP1A2, but not CYP3A4. UGT Enzymes: Defactinib may inhibit UGT1A1 at clinically relevant concentrations. Transporter Systems: Avutometinib is a substrate of P-gp and BCRP, but not a substrate of MATE1, MATE2-K, OAT1, OAT3, OATP1B1, OATP1B3, OCT1 and OCT2. Avutometinib is not an inhibitor of P-gp, BCRP, MATE1, MATE2-K, OAT1, OAT3, OATP1B1, OATP1B3, OCT1 and OCT2. Defactinib is a BCRP and P-gp substrate, but not a substrate of MATE1, MATE2-K, OAT1, OAT3, OATP1B1, OATP1B3, OCT1, and OCT2. Defactinib is an inhibitor of P-gp, BCRP, OATP1B1, OATP1B3, and MATE2-K, but not an inhibitor of MATE1, OAT1, OAT3, OCT1, and OCT2.