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Takeda to Present Data at Upcoming Virtual Scientific Congresses, Underscoring Breadth of Oncology Portfolio and Emerging Pipeline

2020年05月15日 AM01:00
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CAMBRIDGE, Mass. & OSAKA, Japan

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:

Hematology Franchise:

  • 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.

Lung Franchise:

  • 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:

ASCO Annual Meeting 2020:

All presentations will be available on demand on the ASCO website beginning Friday, May 29 at 8:00 a.m. ET.

Pevonedistat

ICLUSIG (ponatinib)

Multiple Myeloma / NINLARO (ixazomib) / TAK-079

ALUNBRIG (brigatinib)

Mobocertinib (TAK-788)

TAK-228

EHA 25th Congress

Pevonedistat

ICLUSIG (ponatinib)

Multiple Myeloma / NINLARO (ixazomib)

ADCETRIS (brentuximab vedotin)

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.

CONTRAINDICATIONS

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.

INTERACTIONS

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.

UNDESIRABLE EFFECTS

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

BOXED WARNING

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML): JC virus infection resulting in PML and death can occur in ADCETRIS-treated patients.

Contraindication

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.

Drug Interactions

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)

CONTRAINDICATIONS

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.

ADVERSE REACTIONS

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.

DRUG INTERACTIONS

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 effec

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