Avmapki Fakzynja Drug Information

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 . 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

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

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

Dermatitis acneiform Includes: acne, dermatitis acneiform, folliculitis, perioral dermatitis, and rash pustular

37

Pruritus 35 1.8 Dry skin 30 0 Alopecia 23 0 Photosensitivity 16

0 Musculoskeletal and connective tissue disorders Musculoskeletal pain 68

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

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

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

Venous thromboembolism 14 5.3 Metabolism and nutrition disorders Decreased appetite 18 1.8

Infections and infestations Urinary tract infection 25

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

Decreased albumin 70 0 Increased alanine aminotransferase 58 3.5 Increased blood bilirubin

48

Increased triglycerides 46 3.5 Increased alkaline phosphatase 37 1.8 Decreased potassium 23

9 Hematology Decreased hemoglobin 65 5 Decreased lymphocyte count 40

Decreased platelet count 35 0 Decreased neutrophil count 25 1.8 Urine Proteinuria

22

Clinically relevant laboratory abnormalities in < 10% of patients who received

AVMAPKI FAKZYNJA CO-PACK included increased INR and prolonged activated partial thromboplastin time.

Effect of Other Drugs on

AVMAPKI FAKZYNJA CO-PACK Strong and Moderate CYP3A4 Inhibitors Avoid concomitant use of AVMAPKI FAKZYNJA CO-PACK with strong or moderate CYP3A4 inhibitors. Defactinib is a CYP3A4 substrate. Concomitant use of defactinib with a strong CYP3A4 inhibitor increases defactinib exposure, which may increase the risk of AVMAPKI FAKZYNJA CO-PACK adverse reactions.

Strong and Moderate CYP3A4 Inducers Avoid concomitant use of AVMAPKI FAKZYNJA CO-PACK with strong or moderate CYP3A4 inducers. Defactinib is a CYP3A4 substrate. Concomitant use of defactinib with a strong CYP3A4 inducer decreases defactinib exposure, which may reduce the effectiveness of FAKZYNJA . Gastric Acid Reducing Agents Avoid concomitant use of AVMAPKI FAKZYNJA CO-PACK with proton pump inhibitors (PPIs) or H2 receptor antagonists.

If concomitant use of an acid-reducing agent cannot be avoided, administer FAKZYNJA 2 hours before or 2 hours after the administration of a locally acting antacid. Concomitant use of FAKZYNJA with gastric acid reducing agents decreases defactinib exposure, which may reduce the effectiveness of AVMAPKI FAKZYNJA CO-PACK .

Effect of

AVMAPKI FAKZYNJA CO-PACK on Other Drugs Warfarin Avoid concomitant use of AVMAPKI FAKZYNJA CO-PACK with warfarin. For patients requiring anticoagulation, an alternative to warfarin is recommended. If concomitant use is unavoidable, monitor INR frequently during treatment with AVMAPKI FAKZYNJA CO-PACK. Cases of bleeding and increased INR occurred in patients taking FAKZYNJA concomitantly with warfarin in clinical trials.

Pregnancy Risk Summary Based on the mechanisms of action, AVMAPKI FAKZYNJA CO-PACK can cause fetal harm when administered to a pregnant woman . There are no available data on the use of AVMAPKI FAKZYNJA CO-PACK in pregnant women to inform a drug-associated risk. 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. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. 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.

Pediatric Use The safety and effectiveness of AVMAPKI FAKZYNJA CO-PACK in pediatric patients has not been established.