Avutometinib Potassium and Defactinib Hydrochloride

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 )

AVMAPKI FAKZYNJA CO-PACK is AVMAPKI (avutometinib) capsules co-packaged with FAKZYNJA (defactinib) tablets. AVMAPKI capsules contain 0.8 mg avutometinib and are white capsules with "6766" printed on the cap and the strength "0.8 mg" printed on the body in black ink. FAKZYNJA tablets contain 200 mg defactinib and are white to off-white tablets, oval and debossed with "VS2" on one side. AVMAPKI Capsules: 0.8 mg of avutometinib ( 3 ) FAKZYNJA Tablets: 200 mg of defactinib ( 3 )

None. None. ( 4 )

Ocular Toxicities: Ocular toxicities, including visual impairment and vitreoretinal disorders, occurred. Perform comprehensive ophthalmic evaluation at baseline, prior to cycle 2, every three cycles thereafter, and as clinically indicated. Withhold AVMAPKI FAKZYNJA CO-PACK for ocular toxicities until improvement at the same or reduced dose. Permanently discontinue AVMAPKI FAKZYNJA CO-PACK for any grade 4 toxicity. ( 2.4 , 5.1 ) Serious Skin Toxicities : Skin toxicities, including photosensitivity and severe cutaneous adverse reactions (SCARs), occurred. Adhere to concomitant medications. Monitor for skin toxicities and interrupt, reduce or permanently discontinue AVMAPKI FAKZYNJA CO-PACK based on severity, tolerability and duration. ( 2.4 , 5.2 ) Hepatotoxicity : Monitor liver function tests prior to each cycle, on day 15 of the first 4 cycles, and as clinically indicated. Withhold, reduce or discontinue AVMAPKI FAKZYNJA CO-PACK based on severity and persistence of abnormality. ( 2.4 , 5.3 ) Rhabdomyolysis: Monitor creatine phosphokinase prior to the start of each cycle, on day 15 of the first four cycles, and as clinically indicated. If increased CPK occurs, evaluate patients for rhabdomyolysis or other causes. Withhold, reduce or permanently discontinue AVMAPKI FAKZYNJA CO-PACK based on severity and duration of the adverse reaction. ( 2.4 , 5.4 ) Embryo-Fetal Toxicity : AVMAPKI FAKZYNJA CO-PACK can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. ( 5.5 , 8.1 , 8.3 )

5.1 Ocular Toxicities AVMAPKI FAKZYNJA CO-PACK can cause ocular adverse reactions, including visual impairment and vitreoretinal disorders. Ocular adverse reactions occurred in 68% of patients with recurrent LGSOC treated with AVMAPKI FAKZYNJA CO-PACK. Common ocular adverse reactions (≥ 5%) were visual impairment (38%), dry eye (13%), orbital/periorbital edema (8%), and vitreous floaters (5%). Thirty-five patients (26%) experienced vitreoretinal disorders, including retinal detachment (9%), and retinal vein occlusion (0.7%). Eighteen patients (13%) experienced an ocular adverse reaction that resulted in dose interruption of AVMAPKI FAKZYNJA CO-PACK and one patient experienced an ocular adverse reaction that resulted in dose reduction. The median time to onset of symptomatic ocular adverse reactions was 5 days (range 1 to 943 days) and to onset of asymptomatic ocular adverse reactions was 112 days (range 23 to 943 days). The median time to onset of retinal detachment was 27 days (range 2 to 535 days). Of the patients who experienced ocular adverse reactions, 29% had ongoing ocular events at last follow-up. Refer patients to a qualified eye care professional for a comprehensive ophthalmic exam at baseline, prior to cycle 2, every three cycles thereafter, and as clinically indicated. Promptly refer patients to an eye care professional for any new or worsening ocular signs or symptoms. Monitor for ocular adverse reactions and withhold, reduce, or permanently discontinue AVMAPKI FAKZYNJA CO-PACK based on severity and persistence of ocular adverse reactions [see Dosage and Administration (2.4) ].

5.2 Serious Skin Toxicities AVMAPKI FAKZYNJA CO-PACK can cause serious skin toxicities, including Severe Cutaneous Adverse Reactions (SCARs). Cases of acute generalized exanthematous pustulosis, erythema multiforme and drug reaction with eosinophilia and systemic symptoms have been reported in clinical trials of avutometinib (a drug in AVMAPKI FAKZYNJA CO-PACK). Skin toxicities occurred in 94% of patients with recurrent LGSOC treated with AVMAPKI FAKZYNJA CO-PACK. The most common skin toxicities (≥ 10%) were rash (67%), dermatitis acneiform (43%), dry skin (43%), pruritus (32%), and photosensitivity (13%). Grade 3 skin reactions occurred in 12% of patients including dermatitis acneiform (7%), rash (7%), and pruritus (1.5%). Thirteen patients (10%) developed bacterial skin infections. Skin toxicity led to dose interruption of AVMAPKI FAKZYNJA CO-PACK in 10%, to dose reduction in 7%, and to permanent discontinuation in 0.7% of patients. The median time to onset of the first skin toxicity was 14 days (range 1 to 500 days). At last follow-up, 66% of patients had ongoing skin toxicity. Patients in RAMP-201 used topical corticosteroids (applied to the face, scalp, neck, upper chest and upper back) and systemic oral antibiotics for prophylaxis of skin adverse reactions. These medications were initiated at the start of AVMAPKI FAKZYNJA CO-PACK and administered during at least the first two cycles of treatment. Limit unnecessary exposure to sunlight and apply daily sunscreen (sun protection factor [SPF] ≥ 30). Monitor for skin toxicity and withhold, reduce dose, or permanently discontinue AVMAPKI FAKZYNJA CO-PACK based on severity and persistence [see Dosage and Administration (2.4) ].

5.3 Hepatotoxicity AVMAPKI FAKZYNJA CO-PACK can cause hepatotoxicity. In patients with recurrent LGSOC who received AVMAPKI FAKZYNJA CO-PACK, increased AST (73%), bilirubin (51%), ALT (49%), and alkaline phosphatase (46%) occurred. Grade 3-4 elevations in ALT was 3%, AST was 3%, bilirubin was 2.3% and alkaline phosphatase was 0.8%. Elevations in one or more liver related laboratory values led to dose interruption for 20%, dose reduction for 2.2%, and permanent discontinuation for 0.7% of patients. Increased blood bilirubin may be attributed to defactinib (a component of AVMAPKI FAKZYNJA CO-PACK) due to the inhibition of enzymes responsible for metabolizing (uridine diphosphate-glucuronosyltransferase (UGT)1A1) and transporting (Organic Anion Transporting Polypeptides (OATP)1B1/1B3) bilirubin [see Clinical Pharmacology (12.3) ]. Monitor liver related laboratory values prior to the start of each cycle, on day 15 of the first four cycles, and as clinically indicated. Withhold, reduce dose, or permanently discontinue AVMAPKI FAKZYNJA CO-PACK based on severity and duration of these adverse reactions [see Dosage and Administration (2.4) ].

5.4 Rhabdomyolysis AVMAPKI FAKZYNJA CO-PACK can cause increased creatine phosphokinase (CPK). Increased CPK occurred in 75% of patients with recurrent LGSOC treated with AVMAPKI FAKZYNJA CO-PACK, including Grade 3-4 elevations in 18% of patients. Among the patients who experienced an elevation in CPK, concurrent increase in creatinine occurred in 19% (n=19/102) and myalgia occurred in 10% (n=10/102). Elevation of CPK >10 times the baseline value with a concurrent increase in serum creatinine of ≥1.5 times the baseline value occurred in 0.7% of patients. Increased CPK resulted in dose interruption for 22%, in dose reduction for 7%, and in discontinuation for 2.9% of patients. Rhabdomyolysis has occurred in a patient with LGSOC treated with AVMAPKI FAKZYNJA CO-PACK at the recommended dosage in a clinical trial. Monitor CPK prior to the start of each cycle, on day 15 of the first four cycles, and as clinically indicated. If increased CPK occurs, evaluate patients for rhabdomyolysis or other causes. Withhold, reduce or permanently discontinue AVMAPKI FAKZYNJA CO-PACK based on severity and duration of the adverse reactions [see Dose Modifications (2.4) ] .

5.5 Embryo-Fetal Toxicity Based on the mechanisms of action, AVMAPKI FAKZYNJA CO-PACK can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . 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. Advise females of reproductive potential to use effective contraception during treatment with AVMAPKI FAKZYNJA CO-PACK and for 1 month after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with AVMAPKI FAKZYNJA CO-PACK and for 4 months after the last dose [see Use in Specific Populations (8.3) ] .

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.

Strong and moderate CYP3A4 inhibitors : Avoid concomitant use with AVMAPKI FAKZYNJA CO-PACK. ( 7.1 ) Strong and moderate CYP3A4 inducers : Avoid concomitant use with AVMAPKI FAKZYNJA CO-PACK. ( 7.1 ) Warfarin : Avoid concomitant use of AVMAPKI FAKZYNJA CO-PACK with warfarin and use an alternative to warfarin. ( 7.2 ) Gastric acid reducing agents : Avoid concomitant use of AVMAPKI FAKZYNJA CO-PACK with proton pump inhibitors (PPIs) or H2 receptor antagonists. If 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. ( 7.1 )

7.1 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 [see Clinical Pharmacology (12.3) ], 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 [see Clinical Pharmacology (12.3) ] . 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 [see Clinical Pharmacology (12.3) ] .

7.2 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.

Lactation : Advise not to breastfeed. ( 8.2 ) Infertility : May impair fertility in males and females. ( 8.3 )

8.1 Pregnancy Risk Summary Based on the mechanisms of action, AVMAPKI FAKZYNJA CO-PACK can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . 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.

8.2 Lactation Risk Summary There are no data on the presence of avutometinib, defactinib, or their metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise lactating women not to breastfeed during treatment with AVMAPKI FAKZYNJA CO-PACK and for 2 weeks after the last dose.

8.3 Females and Males of Reproductive Potential AVMAPKI FAKZYNJA CO-PACK can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating treatment with AVMAPKI FAKZYNJA CO-PACK. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with AVMAPKI FAKZYNJA CO-PACK and for 1 month after the last dose. Males Advise male patients with female partners of reproductive potential to use effective contraception during treatment with AVMAPKI FAKZYNJA CO-PACK and for 4 months after the last dose. Infertility Based on animal studies, AVMAPKI FAKZYNJA CO-PACK may impair fertility in females and males of reproductive potential. The effects on fertility were not reversible in animals [see Nonclinical Toxicology (13.1) ] .

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

8.5 Geriatric Use Of the 136 patients in clinical studies of AVMAPKI FAKZYNJA CO-PACK, 29% were age 65 years or older. No overall differences in safety were observed between patients age 65 years or older and younger patients. Clinical studies of AVMAPKI FAKZYNJA CO-PACK did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

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.