Avmapki Fakzynja Co-Pack avutometinib potassium and defactinib hydrochloride Kit — NDC 71779-623-01 (Billing 71779-0623-01)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Avutometinib Avutometinib is a MEK1 inhibitor. Avutometinib induces the formation of inactive RAF/MEK complexes and prevents phosphorylation of MEK1/2 by RAF. RAF and MEK proteins are regulators of the RAS/RAF/MEK/ERK (MAPK) pathway.

Avutometinib inhibited MEK1/2 and ERK1/2 phosphorylation and proliferation of tumor cell lines harboring KRAS mutations. Treatment of cancer cells with avutometinib increased the level of phosphorylated focal adhesion kinase (FAK). Defactinib Defactinib is an inhibitor of FAK and proline-rich tyrosine kinase-2 (Pyk2), the two members of the FAK family of nonreceptor tyrosine kinases.

Defactinib inhibited FAK autophosphorylation in cancer cells in vitro and in mouse xenograft models. Avutometinib in combination with defactinib enhanced inhibition of cell proliferation in vitro and anti-tumor activity in mouse tumor models including LGSOC.

12.2Pharmacodynamics Avutometinib exposure-response relationships and the time course of pharmacodynamic response have not been fully characterized. Defactinib exposure-response relationships and the time course of pharmacodynamic response have not been fully characterized. Cardiac Electrophysiology At the recommended doses for AVMAPKI FAKZYNJA CO-PACK, a mean increase in the QTc interval >20 msec was not observed.

For the 88 patients with PR interval measured in RAMP-201, the mean PR interval increased by 16 msec from baseline to Cycle 1 Day 15 4-hours post dose.

12.3Pharmacokinetics 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

0.3L/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 t… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Avutometinib Avutometinib is a MEK1 inhibitor. Avutometinib induces the formation of inactive RAF/MEK complexes and prevents phosphorylation of MEK1/2 by RAF. RAF and MEK proteins are regulators of the RAS/RAF/MEK/ERK (MAPK) pathway.

Avutometinib inhibited MEK1/2 and ERK1/2 phosphorylation and proliferation of tumor cell lines harboring KRAS mutations. Treatment of cancer cells with avutometinib increased the level of phosphorylated focal adhesion kinase (FAK). Defactinib Defactinib is an inhibitor of FAK and proline-rich tyrosine kinase-2 (Pyk2), the two members of the FAK family of nonreceptor tyrosine kinases.

Defactinib inhibited FAK autophosphorylation in cancer cells in vitro and in mouse xenograft models. Avutometinib in combination with defactinib enhanced inhibition of cell proliferation in vitro and anti-tumor activity in mouse tumor models including LGSOC.

12.3Pharmacokinetics 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

0.3L/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 clini… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Avutometinib exposure-response relationships and the time course of pharmacodynamic response have not been fully characterized. Defactinib exposure-response relationships and the time course of pharmacodynamic response have not been fully characterized. Cardiac Electrophysiology At the recommended doses for AVMAPKI FAKZYNJA CO-PACK, a mean increase in the QTc interval >20 msec was not observed.

For the 88 patients with PR interval measured in RAMP-201, the mean PR interval increased by 16 msec from baseline to Cycle 1 Day 15 4-hours post dose.

14 CLINICAL STUDIES The efficacy of AVMAPKI FAKZYNJA CO-PACK was evaluated in RAMP-201 (NCT04625270), an open-label, multicenter study that included 57 adult patients with measurable KRAS -mutated recurrent LGSOC. Patients were required to have received at least one prior systemic therapy, including a platinum-based regimen. KRAS mutation status was determined by prospective local testing using next generation sequencing (NGS) or polymerase chain reaction of tumor tissue specimens.

Patients were excluded if they were candidates for debulking surgery, were on treatment with warfarin, had an active skin disorder requiring systemic therapy within the past year, or had an ocular disorder (including a history of retinal pathology, an active or chronic visually significant corneal disorder, or a history of glaucoma). Patients received AVMAPKI 3.2 mg orally twice weekly for the first 3 weeks out of a 4-week cycle and FAKZYNJA 200 mg orally twice daily for the first 3 weeks out of a 4-week cycle until disease progression or unacceptable toxicity.

The major efficacy outcome measure was overall response rate (ORR) assessed by blinded independent review committee (BIRC) according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. An additional efficacy outcome measure was duration of response (DoR). Tumor response assessments occurred every 8 weeks for the first 72 weeks and every 12 weeks thereafter.

The median age was 60 years (range: 29 to 87); 75% were White, 3.5% were Asian, 3.5% were Black or African American, and 18% did not have race reported; 3.5% of patients were Hispanic or Latino; 72% had an ECOG PS of 0 and 28% had ECOG PS of 1. The KRAS mutations identified by local testing were G12V (53%), G12D (35%), Q61H (3.5%), G12C (1.8%), G12R (1.8%), A146V (1.8%), and mutations not otherwise specified at G12x (1.8%) and on codon 12/13 (1.8%). Fourteen percent of patients had received 1 prior line of systemic therapy, 25% of patients had received 2 prior lines, 18% had received 3 prior lines and 40% had received more than 3 prior lines of systemic therapy.

All patients had received prior platinum-based chemotherapy, 84% received prior hormonal therapy (as maintenance or treatment), 40% received prior bevacizumab and 21% received a prior MEK inhibitor. Efficacy results are presented in Table 5. Table 5 Efficacy Results in RAMP-201 AVMAPKI FAKZYNJA CO-PACK N = 57 Confirmed Overall Response Rate (95% CI) ORR 95% CI calculated using Clopper-Pearson method 44% (31,58) Complete response 3.5% Partial response 40% Duration of Response (DoR) Range (months) 3.3,

31.1The tumor KRAS mutations observed in the 25 responders were A146V, G12D, G12R, G12V, and Q61H.

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Avutometinib Carcinogenesis Carcinogenicity studies have not been conducted with avutometinib. Mutagenesis Avutometinib was not mutagenic in the bacterial reverse mutagenesis (Ames) assay and was not clastogenic in an in vitro Chinese hamster lung chromosome aberration assay or an in vivo rat bone marrow micronucleus assay. Impairment of Fertility Dedicated fertility studies have not been conducted with avutometinib.

In repeat dose toxicity studies, avutometinib was administered orally once daily for up to 13-weeks duration in rats and monkeys. In female rats, atrophy of the ovary was observed at doses ≥ 0.04 mg/kg/day (approximately ≥ 0.25 times the human exposure at the recommended dose based on AUC). Atrophy of the uterus and thinning of the mucosa and increased single cell necrosis of the mucosal epithelium in the vagina were observed at 0.16 mg/kg/day (0.5 times the human exposure at the recommended dose based on AUC).

In female monkeys, thinning of the vaginal mucosa was observed at doses ≥ 0.02 mg/kg/day (≥ 0.7 times the human exposure at the recommended dose based on AUC). All findings were reversible. Defactinib Carcinogenesis Carcinogenicity studies have not been conducted with defactinib.

Mutagenesis Defactinib was not mutagenic in the bacterial reverse mutagenesis (Ames) assay and was not clastogenic in an in vitro Chinese hamster lung cell chromosome aberration assay. Defactinib was positive in the in vitro micronucleus assay through an aneugenic mechanism and in the in vivo rat bone marrow micronucleus assay. Impairment of Fertility Dedicated fertility studies have not been conducted with defactinib.

In male rats administered defactinib for up to 13 weeks, small prostate, seminal vesicle, and testes, decreased prostate weight, diffuse tubule degeneration/atrophy of the testes and sperm granuloma of the epididymis were observed at doses ≥ 125 mg/kg/day (below the human exposure at the recommended dose based on AUC). At the end of the recovery period, findings in the testes were observed. In male dogs administered defactinib for up to 13 weeks, increased prostate and testes weights and testicular degeneration and cellular debris in the epididymis were observed at doses ≥ 1 mg/kg/day (below the human exposure at the recommended dose based on AUC).

At the end of the recovery period, findings in the testes and epididymis that included cellular debris, duct dilation, and hypospermia were observed.

13.2Animal Toxicology and/or Pharmacology Avutometinib In repeat-dose toxicity studies up to 13-weeks duration in rats and monkeys, tissue mineralization in multiple organs was observed at doses ≥ 0.01 mg/kg/day and 0.03 mg/kg/day, respectively (≥ 0.06 and 1.4 times the human exposure at the recommended dose based on AUC, respectively) as well as increased inorganic phosphorus in rats. In a cardiovascular telemetry study in monkeys, a single oral dose of avutometinib increased systolic, diastolic, and mean blood pressure at 1 mg/kg (approximately 15 times the human C max at the recommended dose).

In the repeat-dose toxicology studies up to 13-weeks duration in rats, myocardial degeneration and necrosis were observed at doses ≥ 0.01 mg/kg/day (below the human exposure at the recommended dose based on AUC). Defactinib In a cardiovascular telemetry study in dogs, a single oral dose of defactinib decreased myocardial contractility at doses ≥ 5 mg/kg (approximately the human exposure at the recommended dose based on AUC) and increased ventricular systolic, diastolic and mean blood pressure at doses ≥ 25 mg/kg/day (≥ 2.7 times the human exposure at the recommended dose based on AUC).

In the 13-week repeat-dose toxicology study in dogs, myocardium hypertrophy was observed at doses ≥ 1 mg/kg/day (below the human exposure at the recommended dose based on AUC) at the end of the dosing and recovery periods.