AMTAGVI
Generic: LIFILEUCEL
Basic Information
Manufacturer
Iovance Biotherapeutics Inc.
Product Type
CELLULAR THERAPY
Route of Administration
INTRAVENOUS
FDA Set ID
4121bd3f-2d6e-3bdd-e063-6294a90a3088
Indications & Usage
1 INDICATIONS AND USAGE AMTAGVI is a tumor-derived autologous T cell immunotherapy indicated for the treatment of adult patients with unresectable or metastatic melanoma previously treated with a PD-1 blocking antibody, and if BRAF V600 mutation positive, a BRAF inhibitor with or without a MEK inhibitor.
This indication is approved under accelerated approval based on objective response rate (ORR) [see Clinical Studies (14) ] .
Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
AMTAGVI is a tumor-derived autologous T cell immunotherapy indicated for the treatment of adult patients with unresectable or metastatic melanoma previously treated with a PD-1 blocking antibody, and if BRAF V600 mutation positive, a BRAF inhibitor with or without a MEK inhibitor.
This indication is approved under accelerated approval based on objective response rate (ORR).
Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s) ( 1 )
This indication is approved under accelerated approval based on objective response rate (ORR) [see Clinical Studies (14) ] .
Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
AMTAGVI is a tumor-derived autologous T cell immunotherapy indicated for the treatment of adult patients with unresectable or metastatic melanoma previously treated with a PD-1 blocking antibody, and if BRAF V600 mutation positive, a BRAF inhibitor with or without a MEK inhibitor.
This indication is approved under accelerated approval based on objective response rate (ORR).
Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s) ( 1 )
Adverse Reactions
6 ADVERSE REACTIONS The most common (incidence of greater than or equal to 20%) non-laboratory adverse reactions in order of decreasing frequency were chills, pyrexia, fatigue, tachycardia, diarrhea, febrile neutropenia, edema, rash, hypotension, alopecia, infection, hypoxia, and dyspnea.
The serious adverse reactions included: Treatment-Related Mortality [see Warnings and Precautions (5.1) ] Prolonged Severe Cytopenia [see Warnings and Precautions (5.2) ] Internal Organ Hemorrhage [see Warnings and Precautions (5.3) ] Severe Infection [see Warnings and Precautions (5.4) ] Cardiac Disorder [see Warnings and Precautions (5.5) ] Respiratory Failure [see Warnings and Precautions (5.6) ] Acute Renal Failure [see Warnings and Precautions (5.7) ] Hypersensitivity Reactions [see Warnings and Precautions (5.8) ] The most common (incidence of greater than or equal to 20%) non-laboratory adverse reactions in order of decreasing frequency were chills, pyrexia, fatigue, tachycardia, diarrhea, febrile neutropenia, edema, rash, hypotension, alopecia, infection, hypoxia, and dyspnea ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Iovance Biotherapeutics, Inc.
at 1-833-400-IOVA (4682) 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 data described in this section reflect exposure to AMTAGVI within a regimen that included cyclophosphamide, fludarabine, and IL-2 (aldesleukin) in the global, multicenter, multicohort, open-label, single-arm clinical study in which 156 adult patients with unresectable or metastatic melanoma received a single infusion of AMTAGVI [see Clinical Studies (14) ] .
The median age of the study population was 56 years (range: 20 to 79 years); 53.8% were men.
The performance status prior to tumor procurement was 68.6% with ECOG 0 and 31.4% with ECOG 1.
Table 1 summarizes the adverse reactions that occurred in at least 10% of patients treated with AMTAGVI and Table 2 describes the laboratory abnormalities of Grade 3 or 4 that occurred in at least 10% of patients.
Table 1: Adverse Reactions Observed in at Least 10% of Melanoma Patients Treated with AMTAGVI (N=156) Adverse Reaction Any Grade n (%) Grade 3 or Higher n (%) Adverse Reactions occurred from AMTAGVI infusion to 6 months (182 days) post infusion.
Blood and lymphatic system disorders Febrile neutropenia 73 (46.8) 73 (46.8) Cardiac disorders Tachycardia Tachycardia includes tachycardia and sinus tachycardia, atrial fibrillation, supraventricular tachycardia.
74 (47.4) 12 (7.7) Gastrointestinal disorders Diarrhea 73 (46.8) 3 (1.9) Vomiting 68 (43.6) 2 (1.3) Nausea 107 (68.6) 4 (2.6) General disorders and administration site conditions Chills 118 (75.6) 8 (5.1) Pyrexia 95 (60.9) 16 (10.3) Fatigue Fatigue includes fatigue, asthenia, and malaise.
87 (55.8) 8 (5.1) Edema Edema includes edema, face edema, generalized edema, localized edema, edema peripheral, peripheral swelling, edema genital, scrotal edema, brain edema, catheter site edema, conjunctival edema, eyelid edema, laryngeal edema, macular edema, periorbital edema, pulmonary edema, vasogenic cerebral edema, and lymphoedema.
66 (42.3) 8 (5.1) Investigations Weight increased 30 (19.2) 2 (1.3) Infections and Infestations 42 (26.9) 21 (13.5) Infection with pathogen unspecified Infection with unspecified pathogen includes cellulitis, conjunctivitis, cystitis, dermatitis infected, device related infection, diarrhea infectious, endocarditis, enterocolitis infectious, infection, meningitis, nasopharyngitis, neutropenic sepsis, pneumonia, pyuria, rash pustular, respiratory tract infection (RTI), rhinitis, sepsis, sinusitis, skin infection, urinary tract infection (UTI).
30 (19.2) 17 (10.9) Infection with pathogen specified Infection with mentioned pathogen includes bacteremia, candida infection, clostridium difficile colitis, cytomegalovirus infection or reactivation, Epstein-Barr virus infection, escherichia bacteremia, fungal skin infection, herpes simplex, herpes zoster, metapneumovirus infection, oral herpes, oral candidiasis, pneumonia klebsiella, respiratory syncytial virus infection, skin candida, tuberculosis.
19 (12.2) 6 (3.8) Metabolism and nutrition disorders Decreased appetite 48 (30.8) 2 (1.3) Nervous system disorders Headache 33 (21.2) 1 (0.6) Encephalopathy Encephalopathy includes encephalopathy, automatism, cognitive disorder, confusional state, depressed level of consciousness, disturbance in attention, hypersomnia, lethargy, leukoencephalopathy, memory impairment, mental status changes, paranoia, somnolence, and stupor.
27 (17.3) 9 (5.8) Renal and urinary disorders Acute kidney injury Acute kidney injury includes acute kidney injury, anuria, azotemia, renal failure, renal tubular dysfunction, renal tubular necrosis, oliguria, and blood creatinine increased.
31 (19.9) 11 (7.1) Hematuria 22 (14.1) 2 (1.3) Respiratory, thoracic and mediastinal disorders Hypoxia Hypoxia includes hypoxia and oxygen saturation decreased.
37 (23.7) 19 (12.2) Dyspnea Dyspnea includes dyspnea, acute respiratory failure, orthopnea, respiratory distress, respiratory failure, and dyspnea exertional 34 (21.8) 13 (8.3) Skin and subcutaneous tissue disorders Rash Rash includes rash, rash generalized, rash maculo-papular, rash papular, rash pruritic, rash erythematous, and rash macular.
58 (37.2) 15 (9.6) Alopecia 48 (30.8) 0 (0) Pruritus 21 (13.5) 0 (0) Vascular disorders Hypotension Hypotension includes hypotension, blood pressure decreased, blood pressure systolic decreased, blood pressure diastolic decreased, and orthostatic hypotension.
58 (37.2) 17 (10.9) Capillary leak syndrome 21 (13.5) 7 (4.5) Hypertension Hypertension includes hypertension, blood pressure increased, blood pressure systolic increased, and blood pressure diastolic increased.
21 (13.5) 11 (7.1) Adverse reactions that occurred in less than 10% of patients treated with AMTAGVI included the following: Eye disorders: Uveitis (4.5%).
Other eye disorders included Grade 1 or 2 retinal detachment, vision blurred, visual impairment, periorbital edema, visual acuity reduced, and retinal hemorrhage.
Immune system disorders: Infusion related reaction (6.4%), anaphylactic reaction (1.3%), and cytokine release syndrome (3.2%).
Skin and subcutaneous tissue disorders: Vitiligo (7.1%).
Table 2: Grade 3 or 4 Laboratory Abnormalities Occurring in at Least 10% of Melanoma Patients Following Treatment with AMTAGVI (N=156) Laboratory Abnormality Grades 3 or 4 (%) Frequency of Grade 3 or 4 laboratory abnormalities from AMTAGVI infusion to 6 months (182 days) post infusion.
Thrombocytopenia 122 (78.2) Neutropenia 108 (69.2) Anemia 91 (58.3) Leukopenia 73 (46.8) Lymphopenia 66 (42.3) Hypophosphatemia 40 (25.6) Serious Adverse Reactions Serious adverse reactions leading to death included acute respiratory failure (n=1), renal failure (n=2), cardiac arrhythmia (n=1), severe infections (n=4) including sepsis and septic shock, pneumonia, and encephalitis, internal organ hemorrhage (n=2), ascites and liver injury (n=1) and bone marrow failure (n=1).
Deaths Among 160 patients with unresectable, or metastatic melanoma who initiated the AMTAGVI regimen, there were 12 deaths (7.5%), including 2 deaths during the lymphodepleting period, 6 deaths within 30 days following AMTAGVI administration, and additional 4 deaths 38 to 150 days following AMTAGVI administration.
Adverse reactions associated with these deaths included severe infections (sepsis, pneumonia and encephalitis), internal organ hemorrhage (abdominal hemorrhage and intracranial hemorrhage), acute renal failure, acute respiratory failure, cardiac arrythmia, extensive ascites and liver injury and bone marrow failure.
The serious adverse reactions included: Treatment-Related Mortality [see Warnings and Precautions (5.1) ] Prolonged Severe Cytopenia [see Warnings and Precautions (5.2) ] Internal Organ Hemorrhage [see Warnings and Precautions (5.3) ] Severe Infection [see Warnings and Precautions (5.4) ] Cardiac Disorder [see Warnings and Precautions (5.5) ] Respiratory Failure [see Warnings and Precautions (5.6) ] Acute Renal Failure [see Warnings and Precautions (5.7) ] Hypersensitivity Reactions [see Warnings and Precautions (5.8) ] The most common (incidence of greater than or equal to 20%) non-laboratory adverse reactions in order of decreasing frequency were chills, pyrexia, fatigue, tachycardia, diarrhea, febrile neutropenia, edema, rash, hypotension, alopecia, infection, hypoxia, and dyspnea ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Iovance Biotherapeutics, Inc.
at 1-833-400-IOVA (4682) 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 data described in this section reflect exposure to AMTAGVI within a regimen that included cyclophosphamide, fludarabine, and IL-2 (aldesleukin) in the global, multicenter, multicohort, open-label, single-arm clinical study in which 156 adult patients with unresectable or metastatic melanoma received a single infusion of AMTAGVI [see Clinical Studies (14) ] .
The median age of the study population was 56 years (range: 20 to 79 years); 53.8% were men.
The performance status prior to tumor procurement was 68.6% with ECOG 0 and 31.4% with ECOG 1.
Table 1 summarizes the adverse reactions that occurred in at least 10% of patients treated with AMTAGVI and Table 2 describes the laboratory abnormalities of Grade 3 or 4 that occurred in at least 10% of patients.
Table 1: Adverse Reactions Observed in at Least 10% of Melanoma Patients Treated with AMTAGVI (N=156) Adverse Reaction Any Grade n (%) Grade 3 or Higher n (%) Adverse Reactions occurred from AMTAGVI infusion to 6 months (182 days) post infusion.
Blood and lymphatic system disorders Febrile neutropenia 73 (46.8) 73 (46.8) Cardiac disorders Tachycardia Tachycardia includes tachycardia and sinus tachycardia, atrial fibrillation, supraventricular tachycardia.
74 (47.4) 12 (7.7) Gastrointestinal disorders Diarrhea 73 (46.8) 3 (1.9) Vomiting 68 (43.6) 2 (1.3) Nausea 107 (68.6) 4 (2.6) General disorders and administration site conditions Chills 118 (75.6) 8 (5.1) Pyrexia 95 (60.9) 16 (10.3) Fatigue Fatigue includes fatigue, asthenia, and malaise.
87 (55.8) 8 (5.1) Edema Edema includes edema, face edema, generalized edema, localized edema, edema peripheral, peripheral swelling, edema genital, scrotal edema, brain edema, catheter site edema, conjunctival edema, eyelid edema, laryngeal edema, macular edema, periorbital edema, pulmonary edema, vasogenic cerebral edema, and lymphoedema.
66 (42.3) 8 (5.1) Investigations Weight increased 30 (19.2) 2 (1.3) Infections and Infestations 42 (26.9) 21 (13.5) Infection with pathogen unspecified Infection with unspecified pathogen includes cellulitis, conjunctivitis, cystitis, dermatitis infected, device related infection, diarrhea infectious, endocarditis, enterocolitis infectious, infection, meningitis, nasopharyngitis, neutropenic sepsis, pneumonia, pyuria, rash pustular, respiratory tract infection (RTI), rhinitis, sepsis, sinusitis, skin infection, urinary tract infection (UTI).
30 (19.2) 17 (10.9) Infection with pathogen specified Infection with mentioned pathogen includes bacteremia, candida infection, clostridium difficile colitis, cytomegalovirus infection or reactivation, Epstein-Barr virus infection, escherichia bacteremia, fungal skin infection, herpes simplex, herpes zoster, metapneumovirus infection, oral herpes, oral candidiasis, pneumonia klebsiella, respiratory syncytial virus infection, skin candida, tuberculosis.
19 (12.2) 6 (3.8) Metabolism and nutrition disorders Decreased appetite 48 (30.8) 2 (1.3) Nervous system disorders Headache 33 (21.2) 1 (0.6) Encephalopathy Encephalopathy includes encephalopathy, automatism, cognitive disorder, confusional state, depressed level of consciousness, disturbance in attention, hypersomnia, lethargy, leukoencephalopathy, memory impairment, mental status changes, paranoia, somnolence, and stupor.
27 (17.3) 9 (5.8) Renal and urinary disorders Acute kidney injury Acute kidney injury includes acute kidney injury, anuria, azotemia, renal failure, renal tubular dysfunction, renal tubular necrosis, oliguria, and blood creatinine increased.
31 (19.9) 11 (7.1) Hematuria 22 (14.1) 2 (1.3) Respiratory, thoracic and mediastinal disorders Hypoxia Hypoxia includes hypoxia and oxygen saturation decreased.
37 (23.7) 19 (12.2) Dyspnea Dyspnea includes dyspnea, acute respiratory failure, orthopnea, respiratory distress, respiratory failure, and dyspnea exertional 34 (21.8) 13 (8.3) Skin and subcutaneous tissue disorders Rash Rash includes rash, rash generalized, rash maculo-papular, rash papular, rash pruritic, rash erythematous, and rash macular.
58 (37.2) 15 (9.6) Alopecia 48 (30.8) 0 (0) Pruritus 21 (13.5) 0 (0) Vascular disorders Hypotension Hypotension includes hypotension, blood pressure decreased, blood pressure systolic decreased, blood pressure diastolic decreased, and orthostatic hypotension.
58 (37.2) 17 (10.9) Capillary leak syndrome 21 (13.5) 7 (4.5) Hypertension Hypertension includes hypertension, blood pressure increased, blood pressure systolic increased, and blood pressure diastolic increased.
21 (13.5) 11 (7.1) Adverse reactions that occurred in less than 10% of patients treated with AMTAGVI included the following: Eye disorders: Uveitis (4.5%).
Other eye disorders included Grade 1 or 2 retinal detachment, vision blurred, visual impairment, periorbital edema, visual acuity reduced, and retinal hemorrhage.
Immune system disorders: Infusion related reaction (6.4%), anaphylactic reaction (1.3%), and cytokine release syndrome (3.2%).
Skin and subcutaneous tissue disorders: Vitiligo (7.1%).
Table 2: Grade 3 or 4 Laboratory Abnormalities Occurring in at Least 10% of Melanoma Patients Following Treatment with AMTAGVI (N=156) Laboratory Abnormality Grades 3 or 4 (%) Frequency of Grade 3 or 4 laboratory abnormalities from AMTAGVI infusion to 6 months (182 days) post infusion.
Thrombocytopenia 122 (78.2) Neutropenia 108 (69.2) Anemia 91 (58.3) Leukopenia 73 (46.8) Lymphopenia 66 (42.3) Hypophosphatemia 40 (25.6) Serious Adverse Reactions Serious adverse reactions leading to death included acute respiratory failure (n=1), renal failure (n=2), cardiac arrhythmia (n=1), severe infections (n=4) including sepsis and septic shock, pneumonia, and encephalitis, internal organ hemorrhage (n=2), ascites and liver injury (n=1) and bone marrow failure (n=1).
Deaths Among 160 patients with unresectable, or metastatic melanoma who initiated the AMTAGVI regimen, there were 12 deaths (7.5%), including 2 deaths during the lymphodepleting period, 6 deaths within 30 days following AMTAGVI administration, and additional 4 deaths 38 to 150 days following AMTAGVI administration.
Adverse reactions associated with these deaths included severe infections (sepsis, pneumonia and encephalitis), internal organ hemorrhage (abdominal hemorrhage and intracranial hemorrhage), acute renal failure, acute respiratory failure, cardiac arrythmia, extensive ascites and liver injury and bone marrow failure.