AVMAPKI FAKZYNJA CO-PACK
Generic: AVUTOMETINIB POTASSIUM AND DEFACTINIB HYDROCHLORIDE
Basic Information
Manufacturer
Verastem Inc.
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
FDA Set ID
65889527-1406-45df-8a85-e2690dcf427d
Indications & Usage
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 )
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 )
Adverse Reactions
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.
( 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.