Takeda to Present Data at Upcoming Virtual Scientific Congresses, Underscoring Breadth of Oncology Portfolio and Emerging Pipeline
Takeda to Present Data at Upcoming Virtual Scientific Congresses, Underscoring Breadth of Oncology Portfolio and Emerging Pipeline
– Scientific Advancements Seek to Address Therapeutic Needs in Underserved Oncology Communities, Including Rare Leukemias and NSCLCs
– New Clinical Data Offer Practice-Changing Potential in Treatment of Chronic Myeloid Leukemia
– 11 Takeda Oncology-Sponsored Abstracts Accepted for Presentation at the 2020 American Society of Clinical Oncology (ASCO) Meeting and 22 Abstracts Accepted for Presentation at the 2020 Congress of the European Hematology Association (EHA)
Cambridge, Mass. & Osaka, Japan, May 14, 2020 – Takeda Pharmaceutical Company Limited (TSE: 4502/NYSE:TAK) (“Takeda”) today announced that the company will present data from its expanding oncology pipeline and established product portfolio at two upcoming virtual scientific congresses: the 56th Annual Meeting of the American Society of Clinical Oncology (ASCO), May 29-31 and the 25th Virtual Congress of the European Hematology Association (EHA), June 11-14.
“Takeda is committed to the research and development of new products that can help physicians address the needs of patients for whom few or no effective treatment options exist,” said Christopher Arendt, Head, Oncology Therapeutic Area Unit, Takeda. “We look forward to presenting pipeline data from two late-stage compounds – pevonedistat and mobocertinib (TAK-788) – both of which have the potential to become transformative therapies to address unmet needs and improve the lives of patients. Additionally, data from our established hematology and lung medicines expand the understanding of efficacy and safety of our products in appropriate patient populations.”
Key data to be presented include:
- Pevonedistat: Results from the Phase 2 Pevonedistat-2001 trial will be presented in an oral session at ASCO. The study investigated pevonedistat plus azacitidine versus azacitidine alone in patients with higher-risk myelodysplastic syndromes (HR-MDS), higher-risk chronic myelomonocytic leukemia (HR-CMML) or low blast acute myeloid leukemia (LB-AML). These patients typically have poor prognoses as a result of limited response to available therapies. HR-MDS, in particular, has not benefitted from treatment advancements in over a decade. The Phase 2 findings, paired with the fully enrolled Phase 3 PANTHER trial, should demonstrate the impact pevonedistat may make in improving patient care. This data was also accepted as an encore presentation at EHA and will be presented orally.
- ICLUSIG® (ponatinib): The interim analysis of the Phase 2 OPTIC trial with follow-up time of approximately 21 months will be presented in an oral session. The study is prospectively evaluating response-based dosing regimens of ponatinib with the aim of optimizing its efficacy and safety in patients with chronic-phase chronic myeloid leukemia (CP-CML) who are resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy. This data will also be presented orally at EHA. In addition to the OPTIC data, a poster featuring data from an independent review of the Phase 2 PACE trial, aimed at better understanding rates of arterial occlusive events, will be shared during the conference.
- NINLARO™ (ixazomib): At ASCO, results from the Phase 3 TOURMALINE-MM4 trial evaluating NINLARO versus placebo as maintenance therapy for newly diagnosed multiple myeloma patients not treated with autologous stem cell transplantation (ASCT) will be presented in a poster. The findings from the TOURMALINE-MM4 trial will also be presented in an oral presentation at EHA. Additionally, at EHA, updated data from the U.S. MM-6 real-world community-based trial evaluating long-term proteasome inhibition in multiple myeloma patients who have undergone an in-class transition from bortezomib to NINLARO will be presented in an oral presentation. Results from the INSIGHT MM study evaluating the impact of influenza and pneumococcal vaccine status on infection, healthcare resource utilization and death in patients with multiple myeloma will be presented in poster sessions at both ASCO and EHA.
- ALUNBRIG® (brigatinib): The company continues to expand the clinical understanding of ALUNBRIG, presenting two posters evaluating ALUNBRIG in both the TKI-naïve and TKI-resistant settings for patients with anaplastic lymphoma kinase-positive (ALK+) advanced non-small cell lung cancer (NSCLC) – a subanalysis from the ongoing Phase 3 ALTA-1L trial evaluating ALUNBRIG as a first-line treatment option and a primary analysis of the Phase 2 J-ALTA study evaluating ALUNBRIG in Japanese patients who have progressed on a second generation ALK inhibitor.
- Mobocertinib: Data on mobocertinib, a small-molecule TKI specifically designed to selectively target epidermal growth factor receptor (EGFR) and HER2 exon 20 insertion mutations, will be featured in a poster presentation evaluating comparative efficacy between mobocertinib versus real-world treatment options in refractory patients with NSCLC with EGFR exon 20 insertion mutations.
The 11 Takeda-sponsored abstracts accepted for presentation during ASCO 2020 and 22 abstracts at EHA 2020 include:
All presentations will be available on demand on the ASCO website beginning Friday, May 29 at 8:00 a.m. ET.
- Phase 2 study of Pevonedistat (P) + Azacitidine (A) vs A in Patients (pts) with Higher-Risk Myelodysplastic Syndromes (MDS)/Chronic Myelomonocytic Leukemia (CMML), or Low-Blast Acute Myelogenous Leukemia (LB AML) (NCT02610777). Abstract 7506. Oral Presentation.
- Interim Analysis (IA) of OPTIC: A Dose-Ranging Study of Three Ponatinib (PON) Starting Doses. Abstract 7502. Oral Presentation.
- An Independent Review of Arterial Occlusive Events (AOEs) in the Ponatinib (PON) Phase 2 PACE Trial (NCT01207440) in Patients (pts) with Ph+ Leukemia. Abstract 7550. Poster Presentation.
Multiple Myeloma / NINLARO (ixazomib) / TAK-079
- Ixazomib vs Placebo Maintenance for Newly Diagnosed Multiple Myeloma (NDMM) Patients Not Undergoing Autologous Stem Cell Transplant (ASCT): The Phase 3 TOURMALINE-MM4 Trial. Abstract 8527. Poster Presentation.
- Ixazomib-Dexamethasone (Ixa-Dex) Vs Physician’s Choice (PC) in Relapsed/Refractory (RR) Primary Systemic AL Amyloidosis (AL) Patients (pts) by Prior Proteasome Inhibitor (PI) Exposure in the Phase 3 TOURMALINE-AL1 Trial. Abstract 8546. Poster Presentation.
- Multiple Myeloma (MM) Vaccination (Influenza, FV and Pneumococcal, PV) Rates Worldwide and Impact on Infection, Hospitalization, and Death. Abstract 8528. Poster Presentation.
- A Phase 1b Study of TAK-079, an Investigational Anti-CD38 Monoclonal Antibody (mAb) in Patients with Relapsed/ Refractory Multiple Myeloma (RRMM): Preliminary Results. Abstract 8539. Poster Presentation.
- Correlation of Baseline Molecular and Clinical Variables with ALK Inhibitor Efficacy in ALTA-1L. Abstract 9517. Poster Discussion.
- Brigatinib in Japanese ALK Positive NSCLC Patients Previously Treated with ALK Tyrosine Kinase Inhibitors: J-ALTA. Abstract 9537. Poster Presentation.
- Indirect Comparison of TAK-788 Vs Real-World Data Outcomes in Refractory Non-Small Cell Lung Cancer (NSCLC) with EGFR Exon 20 Insertions. Abstract 9580. Poster Presentation.
- Randomized Phase 2 Study of Sapanisertib (SAP) + Paclitaxel (PAC) Vs PAC Alone in Patients (pts) with Advanced, Recurrent, or Persistent Endometrial Cancer. Abstract 6087. Poster Presentation.
- Phase 2 Study of Pevonedistat + Azacitidine Vs Azacitidine in Patients with Higher-Risk Myelodysplastic Syndromes/Chronic Myelomonocytic Leukemia or Low-Blast Acute Myelogenous Leukemia. Abstract S182. Oral Presentation.
- A Randomized, Crossover Study to Evaluate the Effects of Pevonedistat on the Qtc Interval in Patients with Advanced Malignancies. Abstract EP835. Poster Presentation.
- Interim Analysis from the OPTIC Trial, a Dose-Ranging Study of 3 Starting Doses of Ponatinib. Abstract S172. Oral Presentation.
- Retrospective Independent Review of Arterial Occlusive Events (AOEs) in the Phase 2 PACE Trial of Ponatinib in Philadelphia Chromosome Positive (Ph+) Leukemia. Abstract EP759. Poster Presentation.
Multiple Myeloma / NINLARO (ixazomib)
- Ixazomib vs Placebo as Post-Induction Maintenance Therapy in Newly Diagnosed Multiple Myeloma (NDMM) Patients (pts) Not Undergoing Autologous Stem C Transplant (ASCT): Phase 3 TOURMALINE-MM4 Trial. Abstract S200. Oral Presentation.
- Ixazomib-Dexamethasone Vs Physician’s Choice in Patients with Relapsed/Refractory Primary Systemic AL Amyloidosis (AL) by Prior Proteasome Inhibitor Exposure in the Phase 3 TOURMALINE-AL1 Trial. Abstract EP998. Poster Presentation.
- Long-Term Proteasome Inhibition in Multiple Myeloma (MM) Following an In-Class Transition From Bortezomib (Btz) to Ixazomib (Ixa): Updated Real-World (RW) Data from the US MM-6 Community-Based Study. Abstract S332. Oral Presentation.
- Global Rates of Influenza (FV) and Pneumococcal (PV) Vaccination in Multiple Myeloma (MM) Patients (Pts) in INSIGHT MM: Impact on Healthcare Resource Utilization (HRU) and Overall Survival (OS). Abstract EP967. Poster Presentation.
- Undetectable Measurable Residual Disease (MRD) as Endpoint of Maintenance Therapy: Results from the TOURMALINE-MM3 Trial of Ixazomib Vs Placebo Maintenance in Newly Diagnosed Multiple Myeloma (NDMM). Abstract EP932. Poster Presentation.
- Frontline (FL) Treatment Patterns and Use Of Maintenance Therapy (Mt) in Newly Diagnosed Multiple Myeloma (NDMM) Patients not Receiving FL Stem Cell Transplant (NSCT). Abstract EP1034. Poster Presentation.
- Ixazomib-Based Therapy in Relapsed/Refractory Multiple Myeloma (MM) Patients (Pts) Treated Via an Early Access Program (EAP) in Europe: The ‘Use Via Early Access To Ixazomib’ (UVEA-Ixa) Study. Abstract EP976. Poster Presentation.
- Multiple Myeloma Frailty Population in Spain: Preliminary Analysis of the INSIGHT MM Registry. Abstract EP1045. Poster Presentation.
- Ixazomib Real-Life-Setting Use in Combination with Lenalidomide and Dexamethasone in Relapsed or Refractory Multiple Myeloma: REMIX, A Prospective, Non-Interventional Study. Abstract EP1036. Poster Presentation.
- A Real-World Comparative Effectiveness Analysis of Proteasome Inhibitor-Based Regimens in Relapsed/Refractory Multiple Myeloma Utilizing a Nationwide Database in Japan. Abstract EP1050. Poster Presentation.
- Real-World Treatment Patterns, Healthcare Resource Utilization, and Clinical Outcomes from the HUMANS Study in Multiple Myeloma in Denmark, Sweden and Finland. Abstract EP1019. Poster Presentation.
ADCETRIS (brentuximab vedotin)
- Brentuximab Vedotin with Chemotherapy for Stage 3/4 Classical Hodgkin lymphoma (cHL): 4-Year Update of the ECHELON-1 Study. Abstract EP1135. Poster Presentation.
- Patient Characteristics, Treatment Patterns and Clinical Outcomes in the Frontline Treatment of Advanced-Stage Classical Hodgkin Lymphoma in Italy, Spain and Israel. Abstract EP1143. Poster Presentation.
- Patterns of Care and Clinical Outcomes of Peripheral T-cell Lymphoma in the Frontline Setting in France, the United Kingdom and Germany. Abstract EP1264. Poster Presentation.
- An International, Multicentre, Retrospective Study to Describe Treatment Pathways and Outcomes for Hodgkin Lymphoma in East Asia: Interim Results. Abstract EP1142. Poster Presentation.
- Treatment Pathways and Clinical Outcomes of Patients With Hodgkin Lymphoma in Latin America: Interim Results from an International, Multicentre, Retrospective Study. Abstract EP1148. Poster Presentation.
- Final Analysis of an Observational Prospective Study Describing Brentuximab Vedotin use in Routine Practice in France for Hodgkin Lymphoma and Non-Hodgkin Lymphoma. Abstract EP1153. Poster Presentation.
About ADCETRIS® (brentuximab vedotin)
ADCETRIS is an antibody-drug conjugate (ADC) comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seattle Genetics' proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-positive tumor cells.
ADCETRIS injection for intravenous infusion has received FDA approval for six indications in adult patients with: (1) previously untreated systemic anaplastic large cell lymphoma (sALCL) or other CD30-expressing peripheral T-cell lymphomas (PTCL), including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified, in combination with cyclophosphamide, doxorubicin, and prednisone, (2) previously untreated Stage III or IV classical Hodgkin lymphoma (cHL), in combination with doxorubicin, vinblastine, and dacarbazine, (3) cHL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation, (4) cHL after failure of auto-HSCT or failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates, (5) sALCL after failure of at least one prior multi-agent chemotherapy regimen, and (6) primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy.
Health Canada granted ADCETRIS approval with conditions for relapsed or refractory Hodgkin lymphoma and sALCL in 2013, and non-conditional approval for post-autologous stem cell transplantation (ASCT) consolidation treatment of Hodgkin lymphoma patients at increased risk of relapse or progression in 2017, adults with pcALCL or CD30-expressing MF who have had prior systemic therapy in 2018, for previously untreated Stage IV Hodgkin lymphoma in combination with doxorubicin, vinblastine, and dacarbazine in 2019 and for previously untreated adult patients with sALCL, peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS) or angioimmunoblastic T-cell lymphoma (AITL), whose tumors express CD30, in combination with cyclophosphamide, doxorubicin, prednisone in 2019.
ADCETRIS received conditional marketing authorization from the European Commission in October 2012. The approved indications in Europe are: (1) for the treatment of adult patients with previously untreated CD30-positive Stage IV Hodgkin lymphoma in combination with doxorubicin, vinblastine and dacarbazine (AVD), (2) for the treatment of adult patients with CD30-positive Hodgkin lymphoma at increased risk of relapse or progression following ASCT, (3) for the treatment of adult patients with relapsed or refractory CD30-positive Hodgkin lymphoma following ASCT, or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option, (4) for the treatment of adult patients with relapsed or refractory sALCL and (5) for the treatment of adult patients with CD30-positive cutaneous T-cell lymphoma (CTCL) after at least one prior systemic therapy.
In Japan, ADCETRIS received its first approval in January 2014 for relapsed or refractory Hodgkin lymphoma and ALCL, and untreated Hodgkin lymphoma in combination with doxorubicin, vinblastine, and dacarbazine in September 2018, and Peripheral T-cell lymphomas in December 2019. In December 2019, ADCETRIS obtained additional dosage & administration for the treatment of relapsed or refractory Hodgkin lymphoma and Peripheral T-cell lymphomas in pediatric. The current wording of approved indication in Japan package insert is for the treatment of patients with CD30 positive: Hodgkin lymphoma and Peripheral T-cell lymphomas.
ADCETRIS has received marketing authorization by regulatory authorities in more than 70 countries/ regions for relapsed or refractory Hodgkin lymphoma and sALCL. See important safety information below.
ADCETRIS is being evaluated broadly in more than 70 clinical trials, including a Phase 3 study in first-line Hodgkin lymphoma (ECHELON-1) and another Phase 3 study in first-line CD30-positive peripheral T-cell lymphomas (ECHELON-2), as well as trials in many additional types of CD30-positive malignancies.
Seattle Genetics and Takeda are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and Takeda has rights to commercialize ADCETRIS in the rest of the world. Seattle Genetics and Takeda are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where Takeda is solely responsible for development costs.
ADCETRIS (brentuximab vedotin) Important Safety Information (European Union)
Please refer to Summary of Product Characteristics (SmPC) before prescribing.
ADCETRIS is contraindicated for patients with hypersensitivity to brentuximab vedotin and its excipients. In addition, combined use of ADCETRIS with bleomycin causes pulmonary toxicity.
SPECIAL WARNINGS & PRECAUTIONS
Progressive multifocal leukoencephalopathy (PML): John Cunningham virus (JCV) reactivation resulting in progressive multifocal leukoencephalopathy (PML) and death can occur in patients treated with ADCETRIS. PML has been reported in patients who received ADCETRIS after receiving multiple prior chemotherapy regimens. PML is a rare demyelinating disease of the central nervous system that results from reactivation of latent JCV and is often fatal.
Closely monitor patients for new or worsening neurological, cognitive, or behavioral signs or symptoms, which may be suggestive of PML. Suggested evaluation of PML includes neurology consultation, gadolinium-enhanced magnetic resonance imaging of the brain, and cerebrospinal fluid analysis for JCV DNA by polymerase chain reaction or a brain biopsy with evidence of JCV. A negative JCV PCR does not exclude PML. Additional follow up and evaluation may be warranted if no alternative diagnosis can be established. Hold dosing for any suspected case of PML and permanently discontinue ADCETRIS if a diagnosis of PML is confirmed.
Be alert to PML symptoms that the patient may not notice (e.g., cognitive, neurological, or psychiatric symptoms).
Pancreatitis: Acute pancreatitis has been observed in patients treated with ADCETRIS. Fatal outcomes have been reported. Closely monitor patients for new or worsening abdominal pain, which may be suggestive of acute pancreatitis. Patient evaluation may include physical examination, laboratory evaluation for serum amylase and serum lipase, and abdominal imaging, such as ultrasound and other appropriate diagnostic measures. Hold ADCETRIS for any suspected case of acute pancreatitis. ADCETRIS should be discontinued if a diagnosis of acute pancreatitis is confirmed.
Pulmonary Toxicity: Cases of pulmonary toxicity, some with fatal outcomes, including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome (ARDS), have been reported in patients receiving ADCETRIS. Although a causal association with ADCETRIS has not been established, the risk of pulmonary toxicity cannot be ruled out. Promptly evaluate and treat new or worsening pulmonary symptoms (e.g., cough, dyspnoea) appropriately. Consider holding dosing during evaluation and until symptomatic improvement.
Serious infections and opportunistic infections: Serious infections such as pneumonia, staphylococcal bacteremia, sepsis/septic shock (including fatal outcomes), and herpes zoster, cytomegalovirus (CMV) (reactivation) and opportunistic infections such as Pneumocystis jiroveci pneumonia and oral candidiasis have been reported in patients treated with ADCETRIS. Patients should be carefully monitored patients during treatment for the emergence of possible serious and opportunistic infections.
Infusion-related reactions (IRR): Immediate and delayed IRR, as well as anaphylaxis, have been reported with ADCETRIS. Carefully monitor patients during and after an infusion. If anaphylaxis occurs, immediately and permanently discontinue administration of ADCETRIS and administer appropriate medical therapy. If an IRR occurs, interrupt the infusion and institute appropriate medical management. The infusion may be restarted at a slower rate after symptom resolution. Patients who have experienced a prior IRR should be premedicated for subsequent infusions. IRRs are more frequent and more severe in patients with antibodies to ADCETRIS.
Tumor lysis syndrome (TLS): TLS has been reported with ADCETRIS. Patients with rapidly proliferating tumor and high tumor burden are at risk of TLS. Monitor these patients closely and manage according to best medical practice.
Peripheral neuropathy (PN): ADCETRIS treatment may cause PN, both sensory and motor. ADCETRIS-induced PN is typically an effect of cumulative exposure to ADCETRIS and is reversible in most cases. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness. Patients experiencing new or worsening PN may require a delay and a dose reduction or discontinuation of ADCETRIS.
Hematological toxicities: Grade 3 or Grade 4 anemia, thrombocytopenia, and prolonged (equal to or greater than one week) Grade 3 or Grade 4 neutropenia can occur with ADCETRIS. Monitor complete blood counts prior to administration of each dose.
Febrile neutropenia: Febrile neutropenia has been reported with ADCETRIS. Complete blood counts should be monitored prior to administration of each dose of treatment. Closely monitor patients for fever and manage according to best medical practice if febrile neutropenia develops.
When ADCETRIS is administered in combination with AVD, primary prophylaxis with G-CSF is recommended for all patients beginning with the first dose.
Stevens-Johnson syndrome (SJS): SJS and toxic epidermal necrolysis (TEN) have been reported with ADCETRIS. Fatal outcomes have been reported. Discontinue treatment with ADCETRIS if SJS or TEN occurs and administer appropriate medical therapy.
Gastrointestinal (GI) Complications: GI complications, some with fatal outcomes, including intestinal obstruction, ileus, enterocolitis, neutropenic colitis, erosion, ulcer, perforation and haemorrhage, have been reported with ADCETRIS. Promptly evaluate and treat patients if new or worsening GI symptoms occur.
Hepatotoxicity: Elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have been reported with ADCETRIS. Serious cases of hepatotoxicity, including fatal outcomes, have also occurred. Pre-existing liver disease, comorbidities, and concomitant medications may also increase the risk. Test liver function prior to treatment initiation and routinely monitor during treatment. Patients experiencing hepatotoxicity may require a delay, dose modification, or discontinuation of ADCETRIS.
Hyperglycemia: Hyperglycemia has been reported during trials in patients with an elevated body mass index (BMI) with or without a history of diabetes mellitus. Closely monitor serum glucose for patients who experiences an event of hyperglycemia. Administer anti-diabetic treatment as appropriate.
Renal and Hepatic Impairment: There is limited experience in patients with renal and hepatic impairment. Available data indicate that MMAE clearance might be affected by severe renal impairment, hepatic impairment, and by low serum albumin concentrations.
CD30+ CTCL: The size of the treatment effect in CD30 + CTCL subtypes other than mycosis fungoides (MF) and primary cutaneous anaplastic large cell lymphoma (pcALCL) is not clear due to lack of high level evidence. In two single arm phase II studies of ADCETRIS, disease activity has been shown in the subtypes Sézary syndrome (SS), lymphomatoid papulosis (LyP) and mixed CTCL histology. These data suggest that efficacy and safety can be extrapolated to other CTCL CD30+ subtypes. Carefully consider the benefit-risk per patient and use with caution in other CD30+ CTCL patient types.
Sodium content in excipients: This medicinal product contains 13.2 mg sodium per vial, equivalent to 0.7% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
Patients who are receiving a strong CYP3A4 and P-gp inhibitor, concomitantly with ADCETRIS may have an increased risk of neutropenia. If neutropenia develops, refer to dosing recommendations for neutropenia (see SmPC section 4.2). Co-administration of ADCETRIS with a CYP3A4 inducer did not alter the plasma exposure of ADCETRIS, but it appeared to reduce plasma concentrations of MMAE metabolites that could be assayed. ADCETRIS is not expected to alter the exposure to drugs that are metabolized by CYP3A4 enzymes.
PREGNANCY: Advise women of childbearing potential to use two methods of effective contraception during treatment with ADCETRIS and until 6 months after treatment. There are no data from the use of ADCETRIS in pregnant women, although studies in animals have shown reproductive toxicity. Do not use ADCETRIS during pregnancy unless the benefit to the mother outweighs the potential risks to the fetus.
LACTATION (breast-feeding): There are no data as to whether ADCETRIS or its metabolites are excreted in human milk, therefore a risk to the newborn/infant cannot be excluded. With the potential risk, a decision should be made whether to discontinue breast-feeding or discontinue/abstain from therapy with ADCETRIS.
FERTILITY: In nonclinical studies, ADCETRIS treatment has resulted in testicular toxicity, and may alter male fertility. Advise men being treated with ADCETRIS not to father a child during treatment and for up to 6 months following the last dose.
Effects on ability to drive and use machines: ADCETRIS may have a moderate influence on the ability to drive and use machines.
Monotherapy: The most frequent adverse reactions (≥10%) were infections, peripheral sensory neuropathy, nausea, fatigue, diarrhoea, pyrexia, upper respiratory tract infection, neutropenia, rash, cough, vomiting, arthralgia, peripheral motor neuropathy, infusion-related reactions, pruritus, constipation, dyspnoea, weight decreased, myalgia and abdominal pain. Serious adverse drug reactions occurred in 12% of patients. The frequency of unique serious adverse drug reactions was ≤1%. Adverse events led to treatment discontinuation in 24% of patients.
Combination Therapy: In the study of ADCETRIS as combination therapy with AVD in 662 patients with previously untreated advanced HL, the most common adverse reactions (≥ 10%) were: neutropenia, nausea, constipation, vomiting, fatigue, peripheral sensory neuropathy, diarrhoea, pyrexia, alopecia, peripheral motor neuropathy, decreased weight, abdominal pain, anaemia, stomatitis, febrile neutropenia, bone pain, insomnia, decreased appetite, cough, headache, arthralgia, back pain, dyspnoea, myalgia, upper respiratory tract infection, alanine aminotransferase increased. Serious adverse reactions occurred in 36% of patients. Serious adverse reactions occurring in ≥ 3% of patients included febrile neutropenia (17%), pyrexia (6%), and neutropenia (3%). Adverse events led to treatment discontinuation in 13% of patients.
ADCETRIS® (brentuximab vedotin) U.S. Important Safety Information
PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML): JC virus infection resulting in PML and death can occur in ADCETRIS-treated patients.
ADCETRIS concomitant with bleomycin due to pulmonary toxicity (e.g., interstitial infiltration and/or inflammation).
Warnings and Precautions
- Peripheral neuropathy (PN): ADCETRIS causes PN that is predominantly sensory. Cases of motor PN have also been reported. ADCETRIS-induced PN is cumulative. Monitor for symptoms such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness. Institute dose modifications accordingly.
- Anaphylaxis and infusion reactions: Infusion-related reactions (IRR), including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an IRR occurs, interrupt the infusion and institute appropriate medical management. If anaphylaxis occurs, immediately and permanently discontinue the infusion and administer appropriate medical therapy. Premedicate patients with a prior IRR before subsequent infusions. Premedication may include acetaminophen, an antihistamine, and a corticosteroid.
- Hematologic toxicities: Fatal and serious cases of febrile neutropenia have been reported with ADCETRIS. Prolonged (≥1 week) severe neutropenia and Grade 3 or 4 thrombocytopenia or anemia can occur with ADCETRIS. Administer G-CSF primary prophylaxis beginning with Cycle 1 for patients who receive ADCETRIS in combination with chemotherapy for previously untreated Stage III/IV cHL or previously untreated PTCL. Monitor complete blood counts prior to each ADCETRIS dose. Monitor more frequently for patients with Grade 3 or 4 neutropenia. Monitor patients for fever. If Grade 3 or 4 neutropenia develops, consider dose delays, reductions, discontinuation, or G-CSF prophylaxis with subsequent doses.
- Serious infections and opportunistic infections: Infections such as pneumonia, bacteremia, and sepsis or septic shock (including fatal outcomes) have been reported in ADCETRIS-treated patients. Closely monitor patients during treatment for bacterial, fungal, or viral infections.
- Tumor lysis syndrome: Closely monitor patients with rapidly proliferating tumor and high tumor burden.
- Increased toxicity in the presence of severe renal impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with severe renal impairment compared to patients with normal renal function. Avoid use in patients with severe renal impairment.
- Increased toxicity in the presence of moderate or severe hepatic impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with moderate or severe hepatic impairment compared to patients with normal hepatic function. Avoid use in patients with moderate or severe hepatic impairment.
- Hepatotoxicity: Fatal and serious cases have occurred in ADCETRIS-treated patients. Cases were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin, and occurred after the first ADCETRIS dose or rechallenge. Preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may increase the risk. Monitor liver enzymes and bilirubin. Patients with new, worsening, or recurrent hepatotoxicity may require a delay, change in dose, or discontinuation of ADCETRIS.
- PML: Fatal cases of JC virus infection resulting in PML and death have been reported in ADCETRIS-treated patients. First onset of symptoms occurred at various times from initiation of ADCETRIS therapy, with some cases occurring within 3 months of initial exposure. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider PML diagnosis in patients with new-onset signs and symptoms of central nervous system abnormalities. Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed.
- Pulmonary toxicity: Fatal and serious events of noninfectious pulmonary toxicity including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome have been reported. Monitor patients for signs and symptoms, including cough and dyspnea. In the event of new or worsening pulmonary symptoms, hold ADCETRIS dosing during evaluation and until symptomatic improvement.
- Serious dermatologic reactions: Fatal and serious cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with ADCETRIS. If SJS or TEN occurs, discontinue ADCETRIS and administer appropriate medical therapy.
- Gastrointestinal (GI) complications: Fatal and serious cases of acute pancreatitis have been reported. Other fatal and serious GI complications include perforation, hemorrhage, erosion, ulcer, intestinal obstruction, enterocolitis, neutropenic colitis, and ileus. Lymphoma with preexisting GI involvement may increase the risk of perforation. In the event of new or worsening GI symptoms, including severe abdominal pain, perform a prompt diagnostic evaluation and treat appropriately.
- Hyperglycemia: Serious cases, such as new-onset hyperglycemia, exacerbation of preexisting
diabetes mellitus, and ketoacidosis (including fatal outcomes) have been reported with ADCETRIS. Hyperglycemia occurred more frequently in patients with high body mass index or diabetes. Monitor serum glucose and if hyperglycemia develops, administer antihyperglycemic medications as clinically indicated.
- Embryo-fetal toxicity: Based on the mechanism of action and animal studies, ADCETRIS can cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus, and to avoid pregnancy during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS.
Most Common (≥20% in any study) Adverse Reactions: Peripheral neuropathy, fatigue, nausea, diarrhea, neutropenia, upper respiratory tract infection, pyrexia, constipation, vomiting, alopecia, decreased weight, abdominal pain, anemia, stomatitis, lymphopenia and mucositis.
Concomitant use of strong CYP3A4 inhibitors or inducers has the potential to affect the exposure to monomethyl auristatin E (MMAE).
Use in Specific Populations
Moderate or severe hepatic impairment or severe renal impairment: MMAE exposure and adverse reactions are increased. Avoid use.
Advise males with female sexual partners of reproductive potential to use effective contraception during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS.
Advise patients to report pregnancy immediately and avoid breastfeeding while receiving ADCETRIS.
Please see the full Prescribing Information, including BOXED WARNING, for ADCETRIS here
About ALUNBRIG® (brigatinib)
ALUNBRIG is a potent and selective next-generation tyrosine kinase inhibitor (TKI) that was designed to target anaplastic lymphoma kinase (ALK) molecular alterations.
ALUNBRIG is currently approved in more than 40 countries, including the U.S., Canada and the European Union (EU), for the treatment of people living with ALK+ metastatic NSCLC who have taken the medicine crizotinib, but their NSCLC has worsened or they cannot tolerate taking crizotinib. ALUNBRIG is also approved in the EU as a monotherapy for the treatment of adult patients with ALK+ advanced NSCLC previously not treated with an ALK inhibitor.
ALUNBRIG received Breakthrough Therapy Designation from the FDA for the treatment of patients with ALK+ NSCLC whose tumors are resistant to crizotinib and was granted Orphan Drug Designation by the FDA for the treatment of ALK+ NSCLC, ROS1+ and EGFR+ NSCLC.
IMPORTANT SAFETY INFORMATION (Global)
Hypersensitivity to the active substance or to any of the excipients of ALUNBRIG is contraindicated
SPECIAL WARNINGS AND PRECAUTIONS FOR USE
Pulmonary Adverse Reactions: Severe, life-threatening, and fatal pulmonary adverse reactions, including those with features consistent with ILD/pneumonitis, has been reported with ALUNBRIG. Most pulmonary adverse reactions were observed within the first 7 days of treatment. Grade 1-2 pulmonary adverse reactions resolved with interruption of treatment or dose modification. Increased age and shorter interval (less than 7 days) between the last dose of crizotinib and the first dose of ALUNBRIG were independently associated with an increased rate of these pulmonary adverse reactions. Consider these factors when initiating treatment with ALUNBRIG. Some patients experienced pneumonitis later in treatment with ALUNBRIG. Monitor for new or worsening respiratory symptoms (e.g., dyspnea, cough, etc.) in the first week of treatment. Promptly investigate signs of pneumonitis in any patient with worsening respiratory symptoms. If pneumonitis is suspected, withhold ALUNBRIG, and evaluate patient for other symptoms (e.g., pulmonary embolism, tumor progression, and infectious pneumonia).
Hypertension has been reported with ALUNBRIG. Monitor blood pressure regularly during treatment with ALUNBRIG. Treat hypertension according to standard guidelines to control blood pressure. Monitor heart rate more frequently in patients if concomitant use of a medicinal product known to cause bradycardia cannot be avoided. For severe hypertension (≥ Grade 3), ALUNBRIG should be withheld until hypertension has recovered to Grade 1 or to baseline. The dose should be modified accordingly.
Bradycardia has been reported with ALUNBRIG. Use caution when administering ALUNBRIG in combination with other agents known to cause bradycardia. Monitor heart rate and blood pressure regularly. If symptomatic bradycardia occurs, withhold ALUNBRIG and evaluate concomitant medications known to cause bradycardia. If a concomitant medication known to cause bradycardia is identified and discontinued or dose adjusted, resume ALUNBRIG at the same dose following resolution of symptomatic bradycardia; otherwise, reduce the dose of ALUNBRIG following resolution of symptomatic bradycardia. In case of life-threatening bradycardia, if no contributing concomitant medication is identified or in case of recurrence, discontinue ALUNBRIG.
Visual Disturbance was reported with ALUNBRIG. Advise patients to report any visual symptoms. Withhold ALUNBRIG and obtain an ophthalmologic evaluation in patients with new or worsening visual symptoms.
Creatine Phosphokinase (CPK) Elevation has been reported with ALUNBRIG. Advise patients to report any unexplained muscle pain, tenderness, or weakness. Monitor CPK levels regularly during treatment. Withhold ALUNBRIG for Grade 3 or 4 CPK elevation. Based on the severity of the CPK elevation, and if associated with muscle pain or weakness, treatment with brigatinib should be withheld, and the dose modified accordingly.
Pancreatic Enzyme Elevation: Elevations of amylase and lipase have been reported with ALUNBRIG. Monitor lipase and amylase regularly. Withhold ALUNBRIG for Grade 3 or 4 pancreatic enzyme elevation. Based on the severity of the laboratory abnormalities, treatment with brigatinib should be withheld, and the dose modified accordingly.
Hyperglycemia: Elevations of serum glucose have occurred in patients treated with ALUNBRIG. Assess fasting serum glucose prior to initiation of ALUNBRIG and monitor periodically thereafter. Antihyperglycemic medications should be initiated or optimized as needed. If cannot control hyperglycemia with optimal medical management, withhold ALUNBRIG until adequate hyperglycemic control is achieved. Upon recovery, consider reducing the ALUNBRIG dose or permanently discontinue ALUNBRIG.
Embryo-Fetal Toxicity Based on its mechanism of action and findings in animals, ALUNBRIG can cause fetal harm when administered to pregnant women. There are no clinical data on the use of ALUNBRIG in pregnant women. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with ALUNBRIG and for at least 4 months following the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for at least 3 months after the last dose of ALUNBRIG.
The most common adverse reactions (≥ 25%) reported in patients treated with ALUNBRIG at the recommended dosing regimen were increased AST, increased CPK, hyperglycaemia, increased lipase, hyperinsulinaemia, anaemia, diarrhea, increased ALT, increased amylase, anemia, nausea, fatigue, hypophosphatemia, decreased lymphocyte count, cough, rash, increased alkaline phosphatas, increased APTT, myalgia, headache, hypertension, white blood count decreased, dyspnea and vomiting.
The most common serious adverse reactions (2%) reported in patients treated with ALUNBRIG at the recommended dosing regimen other than events related to neoplasm progression included pneumonitis, pneumonia, and dyspnoea.
CYP3A Inhibitors: Avoid concomitant use of ALUNBRIG with strong CYP3A inhibitors. If concomitant use of a strong CYP3A inhibitor cannot be avoided, reduce the dose of ALUNBRIG. After discontinuation of strong CYP3A inhibitor, resume ALUNBRIG dose tolerated prior to the initiation of the strong CYP3A inhibitor. No dose adjustment is required for ALUNBRIG in combination with moderate CYP3A inhibitors. Monitor patients closely when coadminister ALUNBRIG with moderate CYP3A inhibitors. Avoid grapefruit or grapefruit juice as it may also increase plasma concentrations of ALUNBRIG. Concomitant use of ALUNBRIG with moderate CYP3A inhibitors should be avoided. If concomitant use of moderate CYP3A inhibitors cannot be avoided, reduce the dose of ALUNBRIG. After discontinuation of a moderate CYP3A inhibitor, resume ALUNBRIG at the dose that was tolerated prior to the initiation of the moderate CYP3A inhibitor.
CYP2C8 Inhibitors: No dose adjustment is required for ALUNBRIG when coadministered with strong CYP2C8 inhibitors
P-gp and BCRP Inhibitors: No dose adjustment is required for ALUNBRIG coadministered with P-gp and BCRP inhibitors.
CYP3A Inducers: Avoid concomitant use of ALUNBRIG with strong and moderate CYP3A inducers. If concomitant use of moderate CYP3A inducers cannot be avoided, the dose of ALUNBRIG may be increased in 30 mg increments after 7 days of treatment with the current dose as tolerated, up to a maximum of twice the dose that was tolerated prior to the initiation of the moderate CYP3A inducer. After discontinuation of a moderate CYP3A inducer, resume the dose of ALUNBRIG to the dose that was tolerated prior to the initiation of the moderate CYP3A inducer.
CYP3A Substrates: Clinical drug-drug interaction studies with sensitive CYP3A substrates have not been conducted. ALUNBRIG may reduce plasma concentrations of coadministered and induce other enzymes and transporters (e.g., CYP2C, P-gp).
Transporter Substrates: ALUNBRIG inhibits P-gp, BCRP, OCT1, MATE1, and MATE2K in vitro. Coadministration of ALUNBRIG Transporter substrates may increase their plasma concentrations. Monitored patients closely when coadminister ALUNBRIG with substrates of these transporters with a narrow therapeutic index (e.g., digoxin, dabigatran, methotrexate).
SPECIAL PATIENT POPULATIONS
Women of childbearing potential/Contraception in males and females: Advised women of childbearing age not to become pregnant and advise men not to father a child during treatment with ALUNBRIG. Advised women of reproductive potential to use effective non hormonal contraception during treatment with ALUNBRIG and for at least 4 months following the final dose. Advised men with female partners of reproductive potential to use effective contraception during treatment and for at least 3 months after the last dose of ALUNBRIG.
Pregnancy: ALUNBRIG can cause fetal harm. There are no clinical data on the use of ALUNBRIG in pregnant women. ALUNBRIG should not be used during pregnancy unless the clinical condition of the mother requires treatment. If used during pregnancy, or if patient becomes pregnant while taking ALUNBRIG, advise patient of the potential harm to fetus.
Breast feeding: There are no data regarding the secretion of ALUNBRIG in human milk. Breastfeed should be stopped during treatment with ALUNBRIG.
Infertility: ALUNBRIG may cause reduced fertility in males.
Elderly Patients: The limited data on the safety and efficacy of ALUNBRIG in patients aged 65 years and older suggest that a dose adjustment is not required in elderly patients. There are no available data on
patients over 85 years of age.
Hepatic Impairment: No dose adjustment of ALUNBRIG is required for patients with mild hepatic impairment (Child Pugh class A) or moderate hepatic impairment (Child Pugh class B). Reduce the dose of ALUNBRIG by approximately 50% (i.e., from 180 mg to 90 mg, or from 90 mg to 60 mg) for patients with severe renal impairment
Renal Impairment: No dose adjustment of ALUNBRIG is required for patients with mild or moderate renal impairment (estimated glomerular filtration rate (eGFR) ≥ 30 mL/min). The dose of brigatinib should be reduced by approximately 40% (i.e., from 180 mg to 120 mg, 120 mg to 90 mg, or from 90 mg to 60 mg) for patients with severe hepatic impairment (Child-Pugh class C
Pediatric Patients: The safety and efficacy of ALUNBRIG in patients less than 18 years of age have not been established.
For US Prescribing Information: https://www.alunbrig.com/assets/pi.pdf
For European Union Summary of Product Characteristics: https://www.ema.europa.eu/en/medicines/human/EPAR/alunbrig
For Canada Product Monograph: https://www.takeda.com/siteassets/en-ca/home/what-we-do/our-medicines/product-monographs/alunbrig/alunbrig-pm-en.pdf
About ICLUSIG® (ponatinib) tablets
ICLUSIG is a kinase inhibitor primarily targeting BCR-ABL1, an abnormal tyrosine kinase that is expressed in chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). ICLUSIG is a targeted cancer medicine developed using a computational and structure-based drug-design platform, specifically designed to inhibit the activity of BCR-ABL1 and its mutations. ICLUSIG targets native BCR-ABL1, as well as BCR-ABL1 treatment-resistant mutations, including the most resistant T315I mutation. ICLUSIG is the only approved TKI that demonstrates activity against the T315I gatekeeper mutation of BCR-ABL1. This mutation has been associated with resistance to all other approved TKIs. ICLUSIG received full approval from the FDA in November 2016. ICLUSIG is indicated for the treatment of adult patients with CP, accelerated
phase, or blast phase CML or Ph+ ALL for whom no other TKI therapy is indicated, and treatment of adult patients with T315I-positive CML (chronic phase, accelerated phase, or blast phase) or T315I-positive Ph+ ALL. ICLUSIG is not indicated and is not recommended for the treatment of
patients with newly diagnosed chronic phase CML.
IMPORTANT SAFETY INFORMATION (U.S.)
WARNING: ARTERIAL OCCLUSION, VENOUS THROMBOEMBOLISM, HEART FAILURE, and HEPATOTOXICITY
WARNINGS AND PRECAUTIONS
See full prescribing information for complete boxed warning.
- Arterial occlusion has occurred in at least 35% of ICLUSIG® (ponatinib)-treated patients including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients less than 50 years old, experienced these events. Interrupt or stop ICLUSIG immediately for arterial occlusion. A benefit-risk consideration should guide a decision to restart ICLUSIG.
- Venous Thromboembolism has occurred in 6% of ICLUSIG-treated patients. Monitor for evidence of thromboembolism. Consider dose modification or discontinuation of ICLUSIG in patients who develop serious venous thromboembolism.
- Heart Failure, including fatalities occurred in 9% of ICLUSIG-treated patients. Monitor cardiac function. Interrupt or stop ICLUSIG for new or worsening heart failure.
- Hepatotoxicity, liver failure and death have occurred in ICLUSIG-treated patients. Monitor hepatic function. Interrupt ICLUSIG if hepatotoxicity is suspected.
Arterial Occlusions: The 35% of patients reported to have arterial occlusive events (AOEs) in the boxed warning included patients from both phase 1 and phase 2 trials. In the phase 2 trial, 33% of ICLUSIG-treated patients experienced a cardiac vascular (21%), peripheral vascular (12%), or cerebrovascular (9%) arterial occlusive event. Some patients experienced more than 1 type of event. Fatal and life-threatening events have occurred within 2 weeks of starting treatment, with doses as low as 15 mg per day. ICLUSIG can also cause recurrent or multisite vascular occlusion. Patients have required revascularization procedures. The median time to onset of the first AOE ranged from 193-526 days. The most common risk factors observed with these events were hypertension, hyperlipidemia, and history of cardiac disease. AOEs were more frequent with increasing age and in patients with a history of ischemia, hypertension, diabetes, or hyperlipidemia. In patients suspected of developing AOEs, interrupt or stop ICLUSIG.
Venous Thromboembolism: Venous thromboembolic events, including deep venous thrombosis, pulmonary embolism, superficial thrombophlebitis, and retinal vein thrombosis with vision loss, occurred in 6% of patients with an incidence rate of 5% (CP-CML), 4% (AP-CML), 10% (BP-CML), and 9% (Ph+ ALL). Consider dose modification or discontinuation of ICLUSIG in patients who develop serious venous thromboembolism.
Heart Failure: Fatal or serious heart failure or left ventricular dysfunction occurred in 6% of patients in the phase 2 trial. The most common heart failure events (each 3%) were congestive cardiac failure and decreased ejection fraction. Monitor patients for signs or symptoms consistent with heart failure and treat as clinically indicated, including interruption of ICLUSIG. Consider discontinuation if serious heart failure develops.
Hepatotoxicity: Hepatotoxic events were observed in 29% of patients (11% were grade 3 or 4). Severe hepatotoxicity occurred in all disease cohorts. Three patients with BP-CML or Ph+ ALL died: one with fulminant hepatic failure within one week of starting ICLUSIG and two with acute liver failure. The most common forms were elevations of AST or ALT (54% all grades, 8% grade 3 or 4, 5% not reversed at last follow-up), bilirubin, and alkaline phosphatase. The median time to onset of event was 3 months. Monitor liver function tests at baseline, then at least monthly or as clinically indicated. Interrupt, reduce or discontinue ICLUSIG as clinically indicated.
Hypertension: Treatment-emergent elevation of systolic or diastolic blood pressure (BP) occurred in 68% of patients, of which 12% were serious and included hypertensive crisis. Patients may require urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath. In patients with baseline BP <140/90 mm Hg, 80% developed treatment-emergent hypertension (44% Stage 1 and 37% Stage 2). In 132 patients with Stage 1 hypertension at baseline, 67% developed Stage 2. Monitor and manage BP elevations during ICLUSIG use and treat hypertension to normalize BP. Interrupt, dose reduce, or stop ICLUSIG if hypertension is not medically controlled. In the event of significant worsening, labile or treatment-resistant hypertension, interrupt treatment and consider evaluating for renal artery stenosis.
Pancreatitis: Pancreatitis was reported in 7% of patients (6% were serious or grade 3/4). Many of these cases resolved within 2 weeks with dose interruption or reduction of ICLUSIG. The incidence of treatment-emergent lipase elevation was 42% (16% grade 3 or greater). Check serum lipase every 2 weeks for the first 2 months and monthly thereafter or as clinically indicated. Consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse. Dose interruption or reduction may be required. In cases where lipase elevations are accompanied by abdominal symptoms, interrupt treatment with ICLUSIG and evaluate patients for pancreatitis. Do not consider restarting ICLUSIG until patients have complete resolution of symptoms and lipase levels are <1.5 x ULN.
Increased Toxicity in Newly Diagnosed CP-CML: In a prospective, randomized clinical trial in the first-line treatment of newly diagnosed patients with CP-CML, ICLUSIG 45 mg once daily increased the risk of serious adverse reactions 2-fold compared to imatinib 400 mg once daily. The median exposure to treatment was less than 6 months. The trial was halted for safety in October 2013. Arterial and venous thrombosis and occlusions occurred at least twice as frequently in the ICLUSIG arm compared to the imatinib arm. Compared to imatinib, ICLUSIG exhibited a greater incidence of myelosuppression, pancreatitis, hepatotoxicity, cardiac failure, hypertension, and skin and subcutaneous tissue disorders. ICLUSIG is not indicated and is not recommended for the treatment of patients with newly diagnosed CP-CML.
Neuropathy: Overall, 20% of patients experienced a peripheral neuropathy event of any grade (2% were grade 3/4). The most common were paresthesia (5%), neuropathy peripheral (4%), hypoesthesia (3%), dysgeusia (2%), muscular weakness (2%), and hyperesthesia (1%). Cranial neuropathy developed in 2% of patients (<1% grade 3/4). Of the patients who developed neuropathy, 26% developed neuropathy during the first month of treatment. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Consider interrupting ICLUSIG and evaluate if neuropathy is suspected.
Ocular Toxicity: Serious ocular toxicities leading to blindness or blurred vision have occurred in patients. Retinal toxicities including macular edema, retinal vein occlusion, and retinal hemorrhage occurred in 2%. Conjunctival irritation, corneal erosion or abrasion, dry eye, conjunctivitis, conjunctival hemorrhage, hyperaemia and edema or eye pain occurred in 14%. Visual blurring occurred in 6%. Other ocular toxicities include cataracts, periorbital edema, blepharitis, glaucoma, eyelid edema, ocular hyperaemia, iritis, iridocyclitis, and ulcerative keratitis. Conduct comprehensive eye exams at baseline and periodically during treatment.
Hemorrhage: Hemorrhage occurred in 28% of patients (6% serious, including fatalities). The incidence of serious bleeding events was higher in patients with AP- or BP-CML, and Ph+ ALL. Gastrointestinal hemorrhage and subdural hematoma were the most commonly reported serious bleeding events occurring in 1% each. Most hemorrhagic events occurred in patients with grade 4 thrombocytopenia. Interrupt ICLUSIG for serious or severe hemorrhage and evaluate.
Fluid Retention: Fluid retention occurred in 31% of patients. The most common events were peripheral edema (17%), pleural effusion (8%), pericardial effusion (4%) and peripheral swelling (3%). Serious events occurred in 4%. One instance of brain edema was fatal. Serious treatment-emergent events included: pleural effusion (2%), pericardial effusion (1%), and edema peripheral (<1%). Monitor patients for fluid retention and manage as clinically indicated. Interrupt, reduce, or discontinue ICLUSIG as clinically indicated.
Cardiac Arrhythmias: Arrhythmias occurred in 19% of patients (7% were grade ≥3). Arrhythmia of ventricular origin was reported in 3% of all arrhythmias, with one case being grade ≥3. Symptomatic bradyarrhythmias that led to pacemaker implantation occurred in 1% of patients. Atrial fibrillation was the most common arrhythmia (7%), approximately half of which were grade 3 or 4. Other grade 3 or 4 arrhythmia events included syncope (2%), tachycardia and bradycardia (each 0.4%), and electrocardiogram QT prolonged, atrial flutter, supraventricular tachycardia, ventricular tachycardia, atrial tachycardia, atrioventricular block complete, cardio-respiratory arrest, loss of consciousness, and sinus node dysfunction (each 0.2%). For 27 patients, the event led to hospitalization. In patients with signs and symptoms suggestive of slow heart rate (fainting, dizziness) or rapid heart rate (chest pain, palpitations or dizziness), interrupt ICLUSIG and evaluate.
Myelosuppression: Myelosuppression was reported in 59% of patients (50% were grade 3/4). The incidence of these events was greater in patients with AP- or BP-CML, and Ph+ ALL than in patients with CP-CML. Severe myelosuppression (grade 3 or 4) was observed early in treatment, with a median onset time of 1 month (range <1-40 months). Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated and adjust the dose as recommended
Tumor Lysis Syndrome: Two patients (<1%, one with AP-CML and one with BP-CML) treated with ICLUSIG developed serious tumor lysis syndrome. Hyperuricemia occurred in 7% of patients. Due to the potential for tumor lysis syndrome in patients with advanced disease, ensure adequate hydration and treat high uric acid levels prior to initiating therapy with ICLUSIG.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Post-marketing cases of RPLS have been reported in ICLUSIG-treated patients. RPLS is a neurological disorder that can present with signs and symptoms such as seizure, headache, decreased alertness, altered mental functioning, vision loss, and other visual and neurological disturbances. Hypertension is often present, and diagnosis is made with supportive findings on magnetic resonance imaging of the brain. If RPLS is diagnosed, interrupt ICLUSIG treatment and resume treatment only once the event is resolved and if the benefit of continued treatment outweighs the risk of RPLS.
Impaired Wound Healing and Gastrointestinal Perforation: Impaired wound healing occurred in patients receiving ICLUSIG. Withhold ICLUSIG for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of ICLUSIG after resolution of wound healing complications has not been established. Gastrointestinal perforation or fistula occurred in patients receiving ICLUSIG. Permanently discontinue in patients with gastrointestinal perforation.
Embryo-Fetal Toxicity: Based on its mechanism of action and findings from animal studies, ICLUSIG can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of ponatinib to pregnant rats during organogenesis caused adverse developmental effects at exposures lower than human exposures at the recommended human dose. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with ICLUSIG and for 3 weeks after the last dose.
Most Common Adverse Reactions: The most common non-hematologic adverse reactions (≥20%) were abdominal pain, rash, constipation, headache, dry skin, arterial occlusion, fatigue, hypertension, pyrexia, arthralgia, nausea, diarrhea, lipase increased, vomiting, myalgia and pain in extremity. Hematologic adverse reactions included thrombocytopenia, anemia, neutropenia, lymphopenia, and leukopenia.
To report SUSPECTED ADVERSE REACTIONS, contact Takeda at 1-844-817-6468 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Strong CYP3A Inhibitors: Avoid concurrent use or reduce ICLUSIG dose if co-administration cannot be avoided.
Strong CYP3A Inducers: Avoid concurrent use.
USE IN SPECIFIC POPULATIONS
Females and Males of Reproductive Potential: Ponatinib may impair fertility in females and it is not known if these effects are reversible. Verify pregnancy status of females of reproductive potential prior to initiating ICLUSIG.
Lactation: Advise women not to breastfeed during treatment with ICLUSIG and for 6 days after last dose.
For more information about ICLUSIG, including the Important Safety Information with Boxed Warning, please see below or visit www.ICLUSIG.com. For the Prescribing Information, please visit https://www.iclusig.com/pdf/ICLUSIG-Prescribing-Information.pdf. For more information about ongoing research, please visit www.clinicaltrials.gov.
About NINLAROTM (ixazomib) capsules
NINLARO™ (ixazomib) is an oral proteasome inhibitor which is being studied across the continuum of multiple myeloma treatment settings. NINLARO was first approved by the U.S. Food and Drug Administration (FDA) in November 2015 and is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. NINLARO is currently approved in more than 60 countries, including the United States, Japan and in the European Union, with more than 10 regulatory filings currently under review. It was the first oral proteasome inhibitor to enter Phase 3 clinical trials and to receive approval.
NINLAROTM (ixazomib): GLOBAL IMPORTANT SAFETY INFORMATION
SPECIAL WARNINGS AND PRECAUTIONS
Thrombocytopenia has been reported with NINLARO (28% vs. 14% in the NINLARO and placebo regimens, respectively) with platelet nadirs typically occurring between Days 14-21 of each 28-day cycle and recovery to baseline by the start of the next cycle. It did not result in an increase in hemorrhagic events or platelet transfusions. Monitor platelet counts at least monthly during treatment with NINLARO and consider more frequent monitoring during the first three cycles. Manage with dose modifications and platelet transfusions as per standard medical guidelines.
Gastrointestinal toxicities have been reported in the NINLARO and placebo regimens respectively, such as diarrhea (42% vs. 36%), constipation (34% vs. 25%), nausea (26% vs. 21%), and vomiting (22% vs. 11%), occasionally requiring use of antiemetic and anti-diarrheal medications, and supportive care.
Peripheral neuropathy was reported with NINLARO (28% vs. 21% in the NINLARO and placebo regimens, respectively). The most commonly reported reaction was peripheral sensory neuropathy (19% and 14% in the NINLARO and placebo regimens, respectively). Peripheral motor neuropathy was not commonly reported in either regimen (< 1%). Monitor patients for symptoms of peripheral neuropathy and adjust dosing as needed.
Peripheral edema was reported with NINLARO (25% vs. 18% in the NINLARO and placebo regimens, respectively). Evaluate patients for underlying causes and provide supportive care, as necessary. Adjust the dose of dexamethasone per its prescribing information or the dose of NINLARO for severe symptoms
Cutaneous reactions occurred in 19% of patients in the NINLARO regimen compared to 11% of patients in the placebo regimen. The most common type of rash reported in both regimens was maculo-papular and macular rash. Manage rash with supportive care, dose modification or discontinuation.
Thrombotic microangiopathy, sometimes fatal, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), have been reported in patients who received NINLARO. Monitor for signs and symptoms of TPP/HUS and stop NINLARO if diagnosis is suspected. If the diagnosis of TPP/HUS is excluded, consider restarting NINLARO. The safety of reinitiating NINLARO therapy in patients previously experiencing TPP/HUS is not known.
Hepatotoxicity, drug-induced liver injury, hepatocellular injury, hepatic steatosis, and hepatitis cholestatic have been uncommonly reported with NINLARO. Monitor hepatic enzymes regularly and adjust dose for Grade 3 or 4 symptoms.
Pregnancy- NINLARO can cause fetal harm. Advise male and females patients of reproductive potential to use contraceptive measures during treatment and for an additional 90 days after the final dose of NINLARO. Women of childbearing potential should avoid becoming pregnant while taking NINLARO due to potential hazard to the fetus. Women using hormonal contraceptives should use an additional barrier method of contraception.
Lactation- It is not known whether NINLARO or its metabolites are excreted in human milk. There could be potential adverse events in nursing infants and therefore breastfeeding should be discontinued.
SPECIAL PATIENT POPULATIONS
Hepatic Impairment: Reduce the NINLARO starting dose to 3 mg in patients with moderate or severe hepatic impairment.
Renal Impairment: Reduce the NINLARO starting dose to 3 mg in patients with severe renal impairment or end-stage renal disease (ESRD) requiring dialysis. NINLARO is not dialyzable and, therefore, can be administered without regard to the timing of dialysis.
Co-administration of strong CYP3A inducers with NINLARO is not recommended.
The most frequently reported adverse reactions (≥ 20%) in the NINLARO regimen, and greater than in the placebo regimen, were diarrhea (42% vs. 36%), constipation (34% vs. 25%), thrombocytopenia (28% vs. 14%), peripheral neuropathy (28% vs. 21%), nausea (26% vs. 21%), peripheral edema (25% vs. 18%), vomiting (22% vs. 11%), and back pain (21% vs. 16%). Serious adverse reactions reported in ≥ 2% of patients included thrombocytopenia (2%) and diarrhea (2%). For each adverse reaction, one or more of the three drugs was discontinued in ≤ 1% of patients in the NINLARO regimen.
For European Union Summary of Product Characteristics: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003844/WC500217620.pdf
For US Prescribing Information: https://www.ninlarohcp.com/pdf/prescribing-information.pdf
For Canada Product Monograph: http://www.takedacanada.com/ninlaropm
About Mobocertinib (TAK-788)
Mobocertinib is a potent, small-molecule TKI specifically designed to selectively target EGFR and HER2 exon 20 insertion mutations. The U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation to mobocertinib in 2020 for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy. Mobocertinib also received Orphan Drug Designation from the U.S. FDA in 2019 for the treatment of lung cancer with HER2 mutations or EGFR mutations including exon 20 insertion mutations.
Results from the ongoing Phase 1/2 trial of mobocertinib, which is evaluating the efficacy and safety of mobocertinib at 160 mg once daily in previously treated patients with EGFR exon 20 insertions, showed mobocertinib yielded a median progression free survival (PFS) of 7.3 months and a confirmed overall response rate (ORR) of 43% (n=12/28) in patients with locally advanced or metastatic EGFR exon 20 insertion mutant NSCLC. The safety profile of mobocertinib was manageable (N= 72). The most common treatment-related adverse events (AEs) were diarrhea (85%), nausea (43%) rash (36%), vomiting (29%) and decreased appetite (25%). These results were presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting.
The mobocertinib development program began in the NSCLC population and is expected to expand to additional underserved populations in other tumor types. Mobocertinib is an investigational drug for which efficacy and safety have not been established.
Pevonedistat is the first and only small-molecule inhibitor of NEDD8-activating enzyme (NAE) and is being studied as a first-line treatment for patients with HR-MDS, HR-CMML and low-blast acute myeloid AML. By selectively targeting NAE, pevonedistat has been shown to disrupt the proteasome-ubiquitin system that targets proteins for degradation, leading to cancer cell death.
Pevonedistat is being evaluated in multiple clinical trials, including:
- PANTHER (NCT03268954)
- This global, randomized, controlled, open-label, multi-center, Phase 3 clinical trial is designed to evaluate the safety and efficacy of pevonedistat in combination with azacitidine versus single-agent azacitidine in participants with higher-risk MDS or CMML, or low-blast AML, who have not received prior therapies. Approximately 450 participants have been enrolled at 130 sites in 20 countries. The primary endpoint of the trial is event free survival (EFS), which is defined as death or transformation to AML in participants with MDS or CMML, whichever occurs first, and is defined as death in participants with low-blast AML. The key secondary endpoint is OS.
- PEVOLAM (NCT04090736)
- The PEVOLAM study is a randomized, controlled, open-label, multi-center, Phase 3 clinical trial conducted in collaboration with PETHEMA Foundation, designed to evaluate the safety and efficacy of pevonedistat plus azacitidine versus azacitidine monotherapy in participants with AML, who are ineligible for transplant / induction chemotherapy and have not received prior therapies. Approximately 466 participants will be enrolled in Spain and Portugal. The primary endpoint of the trial is OS.
- Pevonedistat-1016 (NCT03814005)
- The Pevonedistat-2002 study is a non-randomized, open label, multi-center Phase 1/1b clinical trial of pevonedistat in combination with azacitidine designed to characterize the pharmacokinetic of pevonedistat, assess the safety, and determine the dose of pevonedistat, in combination with azacitidine, in participants with MDS, CMML and AML who also have severe renal impairment or mild hepatic impairment. 60 participants will be enrolled in the United States and Spain. The primary endpoint of the trial is area under the plasma concentration-time curve evaluated after a single dose at pre-determined time frames.
Takeda’s Commitment to Oncology
Our core R&D mission is to deliver novel medicines to patients with cancer worldwide through our commitment to science, breakthrough innovation and passion for improving the lives of patients. Whether it’s with our hematology therapies, our robust pipeline, or solid tumor medicines, we aim to stay both innovative and competitive to bring patients the treatments they need. For more information, visit www.takedaoncology.com.
About Takeda Pharmaceutical Company Limited
Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) is a global, values-based, R&D-driven biopharmaceutical leader headquartered in Japan, committed to bringing Better Health and a Brighter Future to patients by translating science into highly-innovative medicines. Takeda focuses its R&D efforts on four therapeutic areas: Oncology, Rare Diseases, Neuroscience, and Gastroenterology (GI). We also make targeted R&D investments in Plasma-Derived Therapies and Vaccines. We are focusing on developing highly innovative medicines that contribute to making a difference in people's lives by advancing the frontier of new treatment options and leveraging our enhanced collaborative R&D engine and capabilities to create a robust, modality-diverse pipeline. Our employees are committed to improving quality of life for patients and to working with our partners in health care in approximately 80 countries.
For more information, visit https://www.takeda.com.
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For the purposes of this notice, “press release” means this document, any oral presentation, any question and answer session and any written or oral material discussed or distributed by Takeda Pharmaceutical Company Limited (“Takeda”) regarding this release. This press release (including any oral briefing and any question-and-answer in connection with it) is not intended to, and does not constitute, represent or form part of any offer, invitation or solicitation of any offer to purchase, otherwise acquire, subscribe for, exchange, sell or otherwise dispose of, any securities or the solicitation of any vote or approval in any jurisdiction. No shares or other securities are being offered to the public by means of this press release. No offering of securities shall be made in the United States except pursuant to registration under the U.S. Securities Act of 1933, as amended, or an exemption therefrom. This press release is being given (together with any further information which may be provided to the recipient) on the condition that it is for use by the recipient for information purposes only (and not for the evaluation of any investment, acquisition, disposal or any other transaction). Any failure to comply with these restrictions may constitute a violation of applicable securities laws.
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