On June 1, 2018 Celgene Corporation (NASDAQ:CELG) reported results from the OPTIMISMM study, a phase III, randomized, open-label, international clinical study of the investigational combination regimen of POMALYST (pomalidomide), bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma (RRMM) who had received at least one prior treatment including lenalidomide (Press release, Celgene, JUN 1, 2018, View Source [SID1234527036]). The results were presented at the 54th Annual American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Scientific Sessions (ASCO) (Free ASCO Whitepaper) in Chicago, Illinois on June 1-5, 2018.

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OPTIMISMM evaluated the efficacy and safety of POMALYST/IMNOVID (pomalidomide) plus bortezomib and low-dose dexamethasone (PVd) versus bortezomib and low-dose dexamethasone (Vd) in patients with early RRMM (1-3 prior lines of therapy). It is the only phase III trial to report results with a triplet combination in patients who have all received prior lenalidomide therapy. With lenalidomide becoming a standard of care, this represents a patient population for which there is a growing unmet medical need.

An analysis of the results found that the treatment with PVd resulted in significantly improved progression-free survival (PFS) and an earlier, deeper, more durable response in these patients compared to Vd treatment. The study, which included a high percentage of patients refractory to lenalidomide (71% in the PVd arm, 69% in the Vd arm), met its primary endpoint of PFS. Those receiving PVd achieved a statistically significant longer PFS than those in the Vd treatment arm (11.20 months vs. 7.10 months, respectively [P= < .0001, HR 0.61; 95% CI: (0.49-0.77)]), reducing the risk of disease progression or death by 39% in the PVd arm. The PFS benefit was observed in the following subgroups of patients: LEN-refractory, LEN-nonrefractory, prior PI exposure or high-risk cytogenetics. Overall response rate (ORR), one of the study’s secondary endpoints, was also significantly higher in the PVd treatment arm, compared to those receiving Vd (82.2% vs. 50.0%, p < 0.001). Additionally, time to treatment response was longer in the PVd arm (0.9 months PVd vs. 1.4 months Vd), complete response was higher in the PVd arm (15.7% PVd vs. 4.0% Vd) and those receiving PVd experienced a longer duration of response than those in the Vd arm (13.7 months PVd vs. 10.9 months Vd.)

In an exploratory sub-group analysis, patients who had received one prior line of therapy reported longer PFS (20.73 months in PVd arm (n=40) vs. 11.63 months in Vd arm (n=41)) and ORR (90.1% in PVd arm vs. 54.8% in Vd arm) with a 46% reduction in the risk of disease progression or death in the PVd treatment arm compared with Vd. Other secondary endpoints included overall survival and safety.

"In the early relapse setting, there remains a need for a deeper understanding of potential treatment options, and in particular for patients who have received prior lenalidomide-based therapy. These are the first phase III clinical findings to report a significant and clinically meaningful progression-free survival improvement in patients who have previously received lenalidomide, a majority of whom are lenalidomide refractory," said Paul Richardson, MD, Clinical Program Leader and Director of Clinical Research, Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute.

The most common Grade 3/4 treatment-emergent adverse events (TEAE) were neutropenia (PVd: 42% vs. Vd: 9%), infections (PVd: 31% vs. Vd: 18%) and thrombocytopenia (PVd: 27% vs. Vd: 29%.) Rates of grade 3 or 4 deep vein thrombosis in the PVd vs. Vd arms were 0.7% vs. 0.4% and rates of grade 3 or 4 pulmonary embolism in PVd vs. Vd were 4.0% vs. 0.4%. No events were fatal. SPMs occurred in 3.2% (2.7 per 100 person years) of patients treated with PVd and 1.5% (1.2 per 100 person years) of patients treated with Vd. The most common reason for treatment discontinuation was progressive disease.

"The results of the OPTIMISMM trial continue to bolster the growing body of research into combination regimens based on the foundation of our IMiD therapies," said Nadim Ahmed, President of Hematology and Oncology for Celgene. "We are excited by the findings, as they illustrate the potential for a pomalidomide-based triplet regimen to be used earlier in the treatment course. The study also included patients who received PVd immediately following progression after lenalidomide treatment, a growing and clinically relevant patient population for which no phase III data were available until now."

Pomalyst plus dexamethasone in combination with bortezomib is not approved in any country for any use.

ABOUT OPTIMISMM

OPTIMISMM is the first phase III trial to compare the efficacy and safety of PVd vs. Vd as an early line of therapy in patients with RRMM (with 1-3 prior lines of therapy) and prior lenalidomide (LEN) exposure, including LEN-refractory patients. The study was a multi-center, international, open-label, randomized phase III clinical trial to compare the efficacy and safety of a POMALYST (lenalidomide), bortezomib and low-dose dexamethasone (PVd) treatment regimen to a bortezomib and low-dose dexamethasone (Vd) treatment regimen in patients with relapsed or refractory multiple myeloma.

This global study evaluated 559 patients with relapsed or refractory multiple myeloma who had received up to three prior lines of therapy, including two or more cycles of lenalidomide treatment, who had an ECOG score of PS ≤ 2. Prior treatment with bortezomib was allowed, except for patients whose disease progressed while on a regimen containing bortezomib 1.3 mg/m2 twice weekly dosing. Patients were stratified based on age (≤ 75 years old vs > 75 years old), number of prior antimyeloma regimens (1 vs. > 1), and β2-microglobulin levels ( < 3.5 mg/L vs ≥ 3.5 to ≤ 5.5 mg/L vs > 5.5 mg/L) at screening. The median age of the patients was 67 years in the PVd group and 68 years in the Vd group.

Patients were randomized 1:1 to receive PVd or Vd. In 21-day cycles, patients received POMALYST 4 mg/d on days 1-14 (PVd arm only); bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11 of cycles 1-8 and on days 1 and 8 of cycles 9 and beyond; and dexamethasone 20 mg/d (10 mg if aged > 75 years) on the days of and after receiving bortezomib treatment.

About POMALYST

Indication

POMALYST (pomalidomide) is a thalidomide analogue indicated, in combination with dexamethasone, for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or within 60 days of completion of the last therapy.

Important Safety Information

WARNING: EMBRYO-FETAL TOXICITY and VENOUS AND ARTERIAL THROMBOEMBOLISM

Embryo-Fetal Toxicity
POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment.
Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment.
POMALYST is only available through a restricted distribution program called POMALYST REMS.

Venous and Arterial Thromboembolism
Deep venous thrombosis (DVT), pulmonary embolism (PE), myocardial infarction, and stroke occur in patients with multiple myeloma treated with POMALYST. Prophylactic antithrombotic measures were employed in clinical trials. Thromboprophylaxis is recommended, and the choice of regimen should be based on assessment of the patient’s underlying risk factors.

CONTRAINDICATIONS

Pregnancy: POMALYST can cause fetal harm and is contraindicated in females who are pregnant. If POMALYST is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to a fetus.
WARNINGS AND PRECAUTIONS

Embryo-Fetal Toxicity & Females of Reproductive Potential: See Boxed WARNINGS
Males: Pomalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 4 weeks after discontinuing POMALYST, even if they have undergone a successful vasectomy. Males must not donate sperm.
Blood Donation: Patients must not donate blood during treatment with POMALYST and for 4 weeks following discontinuation of POMALYST therapy because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST.
POMALYST REMS Program: See Boxed WARNINGS
Prescribers and pharmacies must be certified with the POMALYST REMS program by enrolling and complying with the REMS requirements; pharmacies must only dispense to patients who are authorized to receive POMALYST. Patients must sign a Patient-Physician Agreement Form and comply with REMS requirements; female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements and males must comply with contraception requirements.
Further information about the POMALYST REMS program is available at www.CelgeneRiskManagement.com or by telephone at 1-888-423-5436.
Venous and Arterial Thromboembolism: See Boxed WARNINGS. Patients with known risk factors, including prior thrombosis, may be at greater risk, and actions should be taken to try to minimize all modifiable factors (e.g., hyperlipidemia, hypertension, smoking). Thromboprophylaxis is recommended, and the choice of regimen should be based on assessment of the patient’s underlying risk factors.
Increased Mortality with Pembrolizumab: In clinical trials in patients with multiple myeloma, the addition of pembrolizumab to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.
Hematologic Toxicity: Neutropenia (46%) was the most frequently reported Grade 3/4 adverse reaction in patients taking POMALYST in clinical trials, followed by anemia and thrombocytopenia. Monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. Patients may require dose interruption and/or modification.
Hepatotoxicity: Hepatic failure, including fatal cases, has occurred in patients treated with POMALYST. Elevated levels of alanine aminotransferase and bilirubin have also been observed in patients treated with POMALYST. Monitor liver function tests monthly. Stop POMALYST upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered.
Severe Cutaneous Reactions Including Hypersensitivity Reactions: Angioedema and severe cutaneous reactions including Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported. DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. Discontinue POMALYST for angioedema, skin exfoliation, bullae, or any other severe cutaneous reactions such as SJS, TEN or DRESS, and do not resume therapy.
Dizziness and Confusional State: In patients taking POMALYST in clinical trials, 14% experienced dizziness (1% Grade 3 or 4) and 7% a confusional state (3% Grade 3 or 4). Instruct patients to avoid situations where dizziness or confusional state may be a problem and not to take other medications that may cause dizziness or confusional state without adequate medical advice.
Neuropathy: In patients taking POMALYST in clinical trials, 18% experienced neuropathy (2% Grade 3 in one trial) and 12% peripheral neuropathy.
Second Primary Malignancies: Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma.
Tumor Lysis Syndrome (TLS): TLS may occur in patients treated with POMALYST. Patients at risk are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.
ADVERSE REACTIONS

The most common adverse reactions for POMALYST (≥30%) included fatigue and asthenia, neutropenia, anemia, constipation, nausea, diarrhea, dyspnea, upper-respiratory tract infections, back pain, and pyrexia.

In the phase III trial, nearly all patients treated with POMALYST + low-dose dex experienced at least one adverse reaction (99%). Adverse reactions (≥15% in the POMALYST + low-dose dex arm and ≥2% higher than control) included neutropenia (51.3%), fatigue and asthenia (46.7%), upper respiratory tract infection (31%), thrombocytopenia (29.7%), pyrexia (26.7%), dyspnea (25.3%), diarrhea (22%), constipation (21.7%), back pain (19.7%), cough (20%), pneumonia (19.3%), bone pain (18%), edema peripheral (17.3%), peripheral neuropathy (17.3%), muscle spasms (15.3%), and nausea (15%). Grade 3 or 4 adverse reactions (≥15% in the POMALYST + low-dose dex arm and ≥1% higher than control) included neutropenia (48.3%), thrombocytopenia (22%), and pneumonia (15.7%).

DRUG INTERACTIONS

Avoid concomitant use of POMALYST with strong inhibitors of CYP1A2. Consider alternative treatments. If a strong CYP1A2 inhibitor must be used, reduce POMALYST dose by 50%.

USE IN SPECIFIC POPULATIONS

Pregnancy: See Boxed WARNINGS. If pregnancy does occur during treatment, immediately discontinue the drug and refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. There is a POMALYST pregnancy exposure registry that monitors pregnancy outcomes in females exposed to POMALYST during pregnancy as well as female partners of male patients who are exposed to POMALYST. This registry is also used to understand the root cause for the pregnancy. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436.
Lactation: There is no information regarding the presence of pomalidomide in human milk, the effects of POMALYST on the breastfed child, or the effects of POMALYST on milk production. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in a breastfed child from POMALYST, advise women not to breastfeed during treatment with POMALYST.
Pediatric Use: Safety and effectiveness have not been established in pediatric patients.
Geriatric Use: No dosage adjustment is required for POMALYST based on age. Patients > 65 years of age were more likely than patients ≤65 years of age to experience pneumonia.
Renal Impairment: Reduce POMALYST dose by 25% in patients with severe renal impairment requiring dialysis. Take dose of POMALYST following hemodialysis on hemodialysis days.
Hepatic Impairment: Reduce POMALYST dose by 25% in patients with mild to moderate hepatic impairment and 50% in patients with severe hepatic impairment.
Smoking Tobacco: Advise patients that smoking may reduce the efficacy of POMALYST. Cigarette smoking reduces the AUC of pomalidomide by 32% by CYP1A2 induction.
Please see full Prescribing Information, including Boxed WARNINGS.

About Celgene’s Immunomodulatory Drugs

Immunomodulatory Drugs (IMiDs) are Celgene’s proprietary small molecule, orally available compounds for the treatment of some blood cancers. IMiD agents are hypothesized to have multiple mechanisms of action. They have been found to increase activation and proliferation of T cells, and proliferation of the IL-2 protein and activity of CD8+ effector T cells. IMiD agents have also been found to affect the stimulation and expression of natural killer (NK) cells, working within the environment of the cell to stimulate the immune system to attack the cancer cells, as well as attack the cancer cells directly. In addition to immunomodulatory properties, IMiD agents are hypothesized to have tumoricidal and antiangiogenic activity. Celgene’s portfolio of IMiD agents have become a foundation of multiple myeloma research, with a growing number of studies exploring these compounds as combination partners across a range of settings of the disease.

On June 1, 2018 Cambrex Corporation (NYSE: CBM), a leading manufacturer of small molecule innovator and generic Active Pharmaceutical Ingredients (APIs), reported that Steven Klosk, President and Chief Executive Officer, will present at the Jefferies 2018 Global Healthcare Conference on June 7, 2018 at 9:30 a.m. EDT in New York City (Press release, Cambrex, JUN 1, 2018, View Source [SID1234527035]).

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The live audio webcast and slide presentation can be accessed from the Cambrex website at www.cambrex.com in the Investors section under "Webcasts & Presentations", and a replay will be available for 90 days after the live event concludes

On June 1, 2018 Amgen (NASDAQ:AMGN) reported results from the Phase 3 A.R.R.O.W. trial of a once-weekly KYPROLIS (carfilzomib) dosing regimen in patients with relapsed and refractory multiple myeloma (Press release, Amgen, JUN 1, 2018, View Source;p=RssLanding&cat=news&id=2352822 [SID1234527033]). In the trial, KYPROLIS administered once-weekly at 70 mg/m2 with dexamethasone (once-weekly Kd) achieved superior progression-free survival (PFS) and overall response rates (ORR), with a comparable safety profile, versus twice-weekly KYPROLIS at 27 mg/m2 and dexamethasone (twice-weekly Kd). These data were presented during an oral session at the 54th Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) and simultaneously published in The Lancet Oncology.

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"Proteasome inhibitors, like KYPROLIS, are essential in treating patients with multiple myeloma and have helped improve patient outcomes," said Maria-Victoria Mateos, M.D., Ph.D., director of the myeloma unit, University Hospital of Salamanca-IBSAL in Salamanca, Spain. "The A.R.R.O.W. trial showed that when given once per week at the higher dose of 70 mg/m2 with dexamethasone, KYPROLIS achieved superior progression-free survival and overall response rates, with a comparable safety profile, versus the twice-weekly regimen."

The KYPROLIS clinical program continues to focus on providing solutions for physicians and patients in treating this frequently relapsing and difficult-to-treat cancer. A.R.R.O.W. is the first and only randomized Phase 3 head-to-head trial to compare two different dosing schedules of KYPROLIS.

"Through our patient-centric approach, we strive to improve outcomes and experience for patients with multiple myeloma," said David M. Reese, M.D., senior vice president of Translational Sciences and Oncology at Amgen. "Results from A.R.R.O.W. show patients can benefit from receiving KYPROLIS with a once-weekly dosing schedule. We have engaged with regulatory agencies and look forward to filing as soon as possible to potentially expand our label to include this option for patients with relapsed and refractory multiple myeloma."

A.R.R.O.W. included 478 patients with relapsed and refractory multiple myeloma who received two or three prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent (IMiD). Patients in the trial treated with once-weekly Kd achieved a statistically significant 3.6 month improvement in PFS compared to the twice-weekly regimen (median PFS 11.2 months for once-weekly Kd versus 7.6 months for twice-weekly Kd; HR=0.69; 95 percent CI: 0.54-0.88; one-sided p=0.0014).The ORR in patients treated with once-weekly Kd was 62.9 percent versus 40.8 percent for those treated with the twice-weekly regimen (p<0.0001). In addition, 7.1 percent had complete responses or better in the once-weekly arm versus 1.7 percent in the twice-weekly arm in this refractory patient population.

The overall safety profiles of the two arms were comparable, with no new safety risks identified in the once-weekly arm. The most frequently reported treatment-emergent adverse events (greater than or equal to 20 percent) in either treatment arm were anemia, diarrhea, fatigue, hypertension, insomnia and pyrexia.

About A.R.R.O.W.
The A.R.R.O.W. (RAndomized, Open-label, Phase 3 Study in Subjects with Relapsed and Refractory Multiple Myeloma Receiving Carfilzomib in Combination with Dexamethasone, Comparing Once-Weekly versus Twice-weekly Carfilzomib Dosing) trial evaluated 478 patients with relapsed and refractory multiple myeloma who have received at least two but no more than three prior therapies, including bortezomib and an immunomodulatory drug. Those included in the study were randomized to receive a 30-minute infusion of once-weekly KYPROLIS (20 mg/m2 on day 1 of cycle 1; 70 mg/m2 on days 8 and 15 of cycle 1; and 70 mg/m2 on days 1, 8 and 15 of subsequent cycles) with dexamethasone (40 mg) versus a 10-minute infusion of twice-weekly KYPROLIS (20 mg/m2 on days 1 and 2 of cycle 1; 27 mg/m2 on days 8, 9, 15 and 16 of cycle 1; and 27 mg/m2 on days 1, 2, 8, 9, 15 and 16 of subsequent cycles) with dexamethasone (40 mg). The primary endpoint of the trial was PFS, defined as the time from randomization to disease progression or death. Secondary endpoints included ORR, overall survival, and safety and tolerability. The trial was conducted in approximately 100 sites worldwide. For more information about this trial, please visit www.clinicaltrials.gov under trial identification number NCT02412878.

About Multiple Myeloma
Multiple myeloma is an incurable blood cancer, characterized by a recurring pattern of remission and relapse.1 It is a rare and life-threatening disease that accounts for approximately one percent of all cancers.2,3 Worldwide, approximately 114,000 people are diagnosed with multiple myeloma each year and 80,000 patient deaths are reported on an annual basis.2

About KYPROLIS (carfilzomib)
Proteasomes play an important role in cell function and growth by breaking down proteins that are damaged or no longer needed.4 KYPROLIS has been shown to block proteasomes, leading to an excessive build-up of proteins within cells.5 In some cells, KYPROLIS can cause cell death, especially in myeloma cells because they are more likely to contain a higher amount of abnormal proteins.4,5

Since its first approval in 2012, approximately 80,000 patients worldwide have received KYPROLIS. KYPROLIS is approved in the U.S. for the following:

In combination with dexamethasone or with lenalidomide plus dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy.
As a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.
KYPROLIS is also approved in Argentina, Australia, Bahrain, Canada, Hong Kong, Israel, Japan, Kuwait, Lebanon, Macao, Mexico, Thailand, Colombia, S. Korea, Canada, Qatar, Switzerland, United Arab Emirates, Turkey, Russia, Brazil, India, Oman and the United States. Additional regulatory applications for KYPROLIS are underway and have been submitted to health authorities worldwide.

Important U.S. KYPROLIS (carfilzomib) Safety Information

Cardiac Toxicities

New onset or worsening of pre‐existing cardiac failure (e.g., congestive heart failure, pulmonary edema, decreased ejection fraction), restrictive cardiomyopathy, myocardial ischemia, and myocardial infarction including fatalities have occurred following administration of KYPROLIS. Some events occurred in patients with normal baseline ventricular function. Death due to cardiac arrest has occurred within one day of KYPROLIS administration.
Monitor patients for clinical signs or symptoms of cardiac failure or cardiac ischemia. Evaluate promptly if cardiac toxicity is suspected. Withhold KYPROLIS for Grade 3 or 4 cardiac adverse events until recovery, and consider whether to restart KYPROLIS at 1 dose level reduction based on a benefit/risk assessment.
While adequate hydration is required prior to each dose in Cycle 1, monitor all patients for evidence of volume overload, especially patients at risk for cardiac failure. Adjust total fluid intake as clinically appropriate in patients with baseline cardiac failure or who are at risk for cardiac failure.
Patients ≥ 75 years, the risk of cardiac failure is increased. Patients with New York Heart Association Class III and IV heart failure, recent myocardial infarction, conduction abnormalities, angina, or arrhythmias may be at greater risk for cardiac complications and should have a comprehensive medical assessment (including blood pressure control and fluid management) prior to starting treatment with KYPROLIS and remain under close follow‐up.
Acute Renal Failure

Cases of acute renal failure, including some fatal renal failure events, and renal insufficiency adverse events (including renal failure) have occurred in patients receiving KYPROLIS. Acute renal failure was reported more frequently in patients with advanced relapsed and refractory multiple myeloma who received KYPROLIS monotherapy. Monitor renal function with regular measurement of the serum creatinine and/or estimated creatinine clearance. Reduce or withhold dose as appropriate.
Tumor Lysis Syndrome

Cases of Tumor Lysis Syndrome (TLS), including fatal outcomes, have occurred in patients receiving KYPROLIS. Patients with multiple myeloma and a high tumor burden should be considered at greater risk for TLS. Adequate hydration is required prior to each dose in Cycle 1, and in subsequent cycles as needed. Consider uric acid lowering drugs in patients at risk for TLS. Monitor for evidence of TLS during treatment and manage promptly. Withhold KYPROLIS until TLS is resolved.
Pulmonary Toxicity

Acute Respiratory Distress Syndrome (ARDS), acute respiratory failure, and acute diffuse infiltrative pulmonary disease such as pneumonitis and interstitial lung disease have occurred in patients receiving KYPROLIS. Some events have been fatal. In the event of drug‐induced pulmonary toxicity, discontinue KYPROLIS.
Pulmonary Hypertension

Pulmonary arterial hypertension (PAH) was reported in patients treated with KYPROLIS. Evaluate with cardiac imaging and/or other tests as indicated. Withhold KYPROLIS for PAH until resolved or returned to baseline and consider whether to restart KYPROLIS based on a benefit/risk assessment.
Dyspnea

Dyspnea was reported in patients treated with KYPROLIS. Evaluate dyspnea to exclude cardiopulmonary conditions including cardiac failure and pulmonary syndromes. Stop KYPROLIS for Grade 3 or 4 dyspnea until resolved or returned to baseline. Consider whether to restart KYPROLIS based on a benefit/risk assessment.
Hypertension

Hypertension, including hypertensive crisis and hypertensive emergency, has been observed with KYPROLIS. Some of these events have been fatal. It is recommended to control hypertension prior to starting KYPROLIS. Monitor blood pressure regularly in all patients. If hypertension cannot be adequately controlled, withhold KYPROLIS and evaluate. Consider whether to restart KYPROLIS based on a benefit/risk assessment.
Venous Thrombosis

Venous thromboembolic events (including deep venous thrombosis and pulmonary embolism) have been observed with KYPROLIS. Thromboprophylaxis is recommended for patients being treated with the combination of KYPROLIS with dexamethasone or with lenalidomide plus dexamethasone. The thromboprophylaxis regimen should be based on an assessment of the patient’s underlying risks.
Patients using oral contraceptives or a hormonal method of contraception associated with a risk of thrombosis should consider an alternative method of effective contraception during treatment with KYPROLIS in combination with dexamethasone or lenalidomide plus dexamethasone.
Infusion Reactions

Infusion reactions, including life‐threatening reactions, have occurred in patients receiving KYPROLIS. Symptoms include fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration of KYPROLIS. Premedicate with dexamethasone to reduce the incidence and severity of infusion reactions. Inform patients of the risk and of symptoms of an infusion reaction and to contact a physician immediately if they occur.
Hemorrhage

Fatal or serious cases of hemorrhage have been reported in patients receiving KYPROLIS. Hemorrhagic events have included gastrointestinal, pulmonary, and intracranial hemorrhage and epistaxis. Promptly evaluate signs and symptoms of blood loss. Reduce or withhold dose as appropriate.
Thrombocytopenia

KYPROLIS causes thrombocytopenia with recovery to baseline platelet count usually by the start of the next cycle. Thrombocytopenia was reported in patients receiving KYPROLIS. Monitor platelet counts frequently during treatment with KYPROLIS. Reduce or withhold dose as appropriate.
Hepatic Toxicity and Hepatic Failure

Cases of hepatic failure, including fatal cases, have been reported during treatment with KYPROLIS. KYPROLIS can cause increased serum transaminases. Monitor liver enzymes regularly regardless of baseline values. Reduce or withhold dose as appropriate.
Thrombotic Microangiopathy

Cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), including fatal outcome have occurred in patients receiving KYPROLIS. Monitor for signs and symptoms of TTP/HUS. Discontinue KYPROLIS if diagnosis is suspected. If the diagnosis of TTP/HUS is excluded, KYPROLIS may be restarted. The safety of reinitiating KYPROLIS therapy in patients previously experiencing TTP/HUS is not known.
Posterior Reversible Encephalopathy Syndrome (PRES)

Cases of PRES have occurred in patients receiving KYPROLIS. PRES was formerly known as Reversible Posterior Leukoencephalopathy Syndrome. Consider a neuro‐radiological imaging (MRI) for onset of visual or neurological symptoms. Discontinue KYPROLIS if PRES is suspected and evaluate. The safety of reinitiating KYPROLIS therapy in patients previously experiencing PRES is not known.
Increased Fatal and Serious Toxicities in Combination with Melphalan and Prednisone in Newly Diagnosed Transplant‐ineligible Patients

In a clinical trial of transplant‐ineligible patients with newly diagnosed multiple myeloma comparing KYPROLIS, melphalan, and prednisone (KMP) vs bortezomib, melphalan, and prednisone (VMP), a higher incidence of serious and fatal adverse events was observed in patients in the KMP arm. KYPROLIS in combination with melphalan and prednisone is not indicated for transplant‐ineligible patients with newly diagnosed multiple myeloma.
Embryo‐fetal Toxicity

KYPROLIS can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals.
Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS. Males of reproductive potential should be advised to avoid fathering a child while being treated with KYPROLIS. If this drug is used during pregnancy, or if pregnancy occurs while taking this drug, the patient should be apprised of the potential hazard to the fetus.
ADVERSE REACTIONS

The most common adverse reactions occurring in at least 20% of patients treated with KYPROLIS in the combination therapy trials: anemia, neutropenia, diarrhea, dyspnea, fatigue, thrombocytopenia, pyrexia, insomnia, muscle spasm, cough, upper respiratory tract infection, hypokalemia

On June 1, 2018 Agios Pharmaceuticals, Inc. (NASDAQ:AGIO), a leader in the field of cellular metabolism to treat cancer and rare genetic diseases, reported the first data from the ongoing Phase 1 study evaluating single agent AG-881 in advanced glioma and other solid tumors (Press release, Agios Pharmaceuticals, JUN 1, 2018, View Source [SID1234527032]). The data were featured in an oral presentation at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting. AG-881 is an investigational, oral, selective, potent inhibitor of mutant isocitrate dehydrogenase-1 (IDH1) and IDH2 enzymes, which was designed for enhanced brain penetrance for development in IDH-mutant glioma.

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"IDH mutant glioma is a distinct disease where patients are typically diagnosed in their thirties and forties and endure a deteriorating quality of life from the side effects associated with multiple rounds of surgery, radiation and chemotherapy and ultimately die of their disease," said Ingo Mellinghoff, M.D., Memorial Sloan Kettering Cancer Center, an investigator for the study. "The AG-881 Phase 1 dose-escalation data are encouraging, as they demonstrate a favorable safety profile at lower dose levels and show signals of clinical activity that support further evaluation of the role of inhibiting mutant IDH in low-grade glioma."

"With no curative or approved targeted therapies for low-grade glioma and a poor long-term prognosis, we are committed to exploring the novel mechanism of action of our IDH inhibitors in this indication," said Chris Bowden, M.D., chief medical officer at Agios. "Data from our ivosidenib and AG-881 Phase 1 trials and the ongoing perioperative study, combined with feedback from regulators and the neurology community, will inform our pivotal development plan."

The ongoing Phase 1 dose-escalation trial is assessing the safety and tolerability of AG-881 in IDH1/2 mutant advanced solid tumors, including glioma. As of the March 29, 2018 data cut-off, 93 patients (52 with glioma and 41 with other solid tumors) have been treated with single agent AG-881. Enrollment is complete and 17 glioma patients and 1 non-glioma solid tumor patient remain on treatment. Study design, status and baseline characteristics for the 52 glioma patients are reported below.

Forty-eight percent of patients (n=25) had World Health Organization (WHO) classified Grade 2 tumors, 42% (n=22) had Grade 3 tumors, 8% (n=4) had Grade 4 tumors and 2% (n=1) was unknown.
Ninety-two percent of patients (n=48) had an IDH1 mutation and 6% (n=3) had an IDH2 mutation. One patient did not have a biopsy but was confirmed as IDH mutant positive due to 2-HG elevation by magnetic resonance spectroscopy (MRS).
The median age of these patients is 42.5 years (ranging from 16-73 years).
Patients received a median of two prior systemic therapies (ranging from one to six).
— Seventy-three percent of patients (n=38) had previously received temozolomide and 58% percent (n=30) had previously received radiotherapy.
Patients received daily doses of AG-881 ranging from 10 mg to 300 mg.
The median treatment duration was seven months (ranging from 0-27 months) for all glioma patients, 12 months (ranging from 1-27 months) for non-enhancing glioma and 3 months (ranging from 0- 27 months) for patients with enhancing disease.
Safety Data

The safety analysis conducted for all 93 treated patients as of the data cut-off demonstrated that AG-881 has a favorable safety profile at dose levels below 100 mg.

The majority of adverse events (AEs) reported by investigators were mild to moderate, with the most common (>33%) being fatigue, nausea, increases in alanine aminotransferase (ALT) and increases in aspartate aminotransferase (AST).
Grade 3 or higher AEs were observed in 33% of all patients (n=31).
Dose limiting toxicities (DLTs) of Grade 2 or higher elevated transaminases occurred in five glioma patients at the higher dose levels (≥100 mg) and resolved to Grade ≤1 with dose modification or discontinuation. There were no treatment-related on-treatment deaths.
A maximum tolerated dose (MTD) was not reached by Bayesian model; the doses chosen for further clinical development were based on safety, pharmacokinetics and pharmacodynamics data.

Efficacy Data

Efficacy data from the 52 glioma patients (23 with non-enhancing and 29 with enhancing disease) as of the data cut-off showed:

One patient with non-enhancing disease and a 1p19q co-deletion had a sustained minor response according to the investigator by Response Assessment in Neuro-Oncology for low grade glioma (RANO-LGG) and remains on treatment.
Seventy-five percent of patients (n=39) had a best response of stable disease, including 20 patients with non-enhancing disease.
Thirty-five percent of patients (n=18, including 13 patients with non-enhancing disease) remained on treatment for ≥1 year.
Efficacy data from the 41 patients with non-glioma solid tumors as of the data cut-off showed:

One patient with cholangiocarcinoma had a partial response, 37% of patients (n=15) had stable disease and 44% (n=18) had progressive disease.
The median treatment duration was 2 months (ranging from 0-18 months).
Ongoing Perioperative Study in Glioma
A perioperative ‘window’ trial with ivosidenib and AG-881 (10 mg and 50 mg) in up to 45 IDH1m non-enhancing low-grade glioma patients is ongoing. The goal of the trial is to confirm CNS penetrance and tumor 2-HG suppression of ivosidenib and AG-881 as part of the strategy to finalize pivotal development plans by year-end 2018.

About Glioma
Glioma presents in varying degrees of tumor aggressiveness, ranging from slower growing (low grade glioma) to rapidly progressing (high grade glioma-Glioblastoma Multiforme). Common symptoms include seizures, memory disturbance, sensory impairment and neurologic deficits. The long-term prognosis is poor with a five-year survival rate of 33 percent. Approximately 11,000 low-grade glioma patients are diagnosed annually in the U.S. and EU and approximately 80 percent have an IDH1 mutation.

On June 1, 2018 AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, reported findings from an interim analysis of the Phase 3 iNNOVATE (PCYC-1127) study evaluating IMBRUVICA (ibrutinib) plus RITUXAN (rituximab) in previously untreated and relapsed/refractory patients with Waldenström’s macroglobulinemia (WM), a rare type of non-Hodgkin’s lymphoma (NHL) (Press release, AbbVie, JUN 1, 2018, View Source [SID1234527031]). At a median follow up of 26.5 months, the study successfully met its primary endpoint, demonstrating a significant improvement in progression-free survival (PFS) with ibrutinib plus rituximab compared to rituximab alone (30 month PFS rates were 82 percent versus 28 percent, respectively). Patients taking ibrutinib plus rituximab also experienced an 80 percent reduction in relative risk of disease progression or death than those only treated with rituximab (hazard ratio, 0.20; confidence interval: 0.11-0.38, P <0.0001). Additionally, the data found that the combination with ibrutinib provided reductions in infusion reactions associated with rituximab and immunoglobin M (IgM) flare.1

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Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

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These data were presented today in an oral presentation at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago (abstract #8003) and were simultaneously published in The New England Journal of Medicine. The data were also selected for the 2018 Best of ASCO (Free ASCO Whitepaper) Meetings. With the support of these positive findings, a supplemental New Drug Application (sNDA) to expand the use of IMBRUVICA as a combination therapy in WM was submitted to the U.S. Food and Drug Administration (FDA) for review. The Independent Data Monitoring Committee (IDMC) in late 2017 recommended unblinding iNNOVATE based on these positive findings.

"The iNNOVATE study provides further evidence of the potential clinical benefit of IMBRUVICA-based combination therapy in patients with Waldenström’s macroglobulinemia," said Thorsten Graef, M.D., Ph.D., Head of Clinical Development at Pharmacyclics LLC, an AbbVie company. "The data from this chemotherapy-free combination regimen suggests that patients with Waldenström’s macroglobulinemia, including those who are newly diagnosed, could have another beneficial therapeutic option in the future."

WM is a rare and incurable form of NHL with limited treatment options. There are about 2,800 new cases of WM in the U.S. each year.2 In January 2015, IMBRUVICA received FDA approval for all lines of treatment in WM and is the first and only FDA-approved therapy specifically indicated for this disease. IMBRUVICA has been available in the U.S. since 2013 and is FDA-approved for use in five B-cell blood cancers, as well as previously-treated chronic graft-versus-host disease. IMBRUVICA is a first-in-class Bruton’s tyrosine kinase (BTK) inhibitor jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

"The iNNOVATE trial broadens our understanding about how to treat patients with WM, including those with certain subtypes or genomic abnormalities," said Dr. Meletios A. Dimopoulos, Professor and Chairman of the Department of Clinical Therapeutics, National and Kapodistrian University of Athens School of Medicine, Athens, Greece and lead investigator of the iNNOVATE study.* "As a clinician, I’m hopeful that the data from iNNOVATE could potentially lead to a new option for treating this rare and incurable disease."

To view all IMBRUVICA company-sponsored or investigator-initiated studies being presented at ASCO (Free ASCO Whitepaper) 2018, please visit: View Source

Abstract #8001: Randomized phase 3 trial of ibrutinib/rituximab vs placebo/rituximab in Waldenström’s Macroglobulinemia
Oral presentation: Friday, June 1, 3:45pm CDT

In the iNNOVATE study, PFS occurred at a higher rate in patients treated with ibrutinib plus rituximab compared to rituximab alone, with PFS rates of 82% versus 28% at 30 months, respectively. Notably, ibrutinib plus rituximab exhibited longer duration of PFS in all relevant patient subgroups, including treatment-naïve, relapsed, and in patients with MYD88L265P and CXCR4WHIM mutations, versus rituximab. Patients taking ibrutinib plus rituximab also experienced an 80 percent reduction in relative risk of disease progression or death than those only treated with rituximab (median PFS, not reached [NR] vs 20.3 months; HR, 0.20; CI: 0.11-0.38, P <0.0001).

iNNOVATE is a Pharmacyclics-sponsored, placebo-controlled, double-blind, Phase 3 study, which evaluated relapsed/refractory and treatment-naïve WM patients (n=150) who were randomized to receive intravenous rituximab 375 mg/m2 once weekly for four consecutive weeks, followed by a second once-weekly for four consecutive weeks rituximab course after a three-month interval. All patients received either ibrutinib 420 mg or placebo once daily continuously until criteria for permanent discontinuation were met. The IRC-determined primary endpoint was PFS, with secondary objectives including overall response rate, hematological improvement measured by hemoglobin, time-to-next treatment (TTnT), overall survival (OS), and number of participants with adverse events (AEs) as a measure of safety and tolerability within each treatment arm.

Overall response rates and major response rates were significantly higher for ibrutinib plus rituximab versus rituximab (92% vs 47%; 72% vs 32% [both P <0.0001]). In addition, there was also an improvement in hemoglobin seen in patients treated with the combination versus rituximab (73% vs 41%, P <0.0001).

Of the patients on ibrutinib plus rituximab, 75% continued on treatment. Median TTnT was NR for ibrutinib plus rituximab and 18 months for rituximab (HR, 0.096; P <0.0001). The 30-month OS rates were 94% versus 92% in the two arms.

At the median time on treatment (ibrutinib plus rituximab, 25.8 months; rituximab plus placebo, 15.5 months,), grade 3 or higher treatment-emergent AEs occurred in 60% of patients treated with ibrutinib plus rituximab, versus 61% of patients treated with rituximab. Serious AEs occurred in 43% versus 33% of patients on ibrutinib plus rituximab vs rituximab. No fatal AEs occurred with ibrutinib plus rituximab and 3 with rituximab. Meaningful reductions in any grade IgM flare (8% vs 47%) and grade 3 or higher infusion reactions were observed (1% vs 16%) with ibrutinib plus rituximab.

About IMBRUVICA
IMBRUVICA (ibrutinib) is a first-in-class, oral, once-daily therapy that mainly works by blocking a protein called Bruton’s tyrosine kinase (BTK). BTK is a key signaling molecule in the B-cell receptor signaling complex that plays an important role in the survival and spread of malignant B cells as well as other serious, debilitating conditions.3 IMBRUVICA blocks signals that tell malignant B cells to multiply and spread uncontrollably.

IMBRUVICA is FDA-approved in six distinct patient populations: chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenström’s macroglobulinemia (WM), along with previously-treated mantle cell lymphoma (MCL), previously-treated marginal zone lymphoma (MZL) and previously-treated chronic graft-versus-host disease (cGVHD).4

IMBRUVICA was first approved for adult patients with MCL who have received at least one prior therapy in November 2013.
Soon after, IMBRUVICA was initially approved in adult CLL patients who have received at least one prior therapy in February 2014. By July 2014, the therapy received approval for adult CLL patients with 17p deletion, and by March 2016, the therapy was approved as a frontline CLL treatment.
IMBRUVICA was approved for adult patients with WM in January 2015.
In May 2016, IMBRUVICA was approved in combination with bendamustine and rituximab (BR) for adult patients with previously treated CLL/SLL.
In January 2017, IMBRUVICA was approved for adult patients with MZL who require systemic therapy and have received at least one prior anti-CD20-based therapy.
In August 2017, IMBRUVICA was approved for adult patients with cGVHD that failed to respond to one or more lines of systemic therapy.
Accelerated approval was granted for the MCL and MZL indications based on overall response rate. Continued approval for MCL and MZL may be contingent upon verification and description of clinical benefit in confirmatory trials.

IMBRUVICA has been granted four Breakthrough Therapy Designations from the U.S. FDA. This designation is intended to expedite the development and review of a potential new drug for serious or life-threatening diseases.5 IMBRUVICA was one of the first medicines to receive FDA approval via the new Breakthrough Therapy Designation pathway.

IMBRUVICA is being studied alone and in combination with other treatments in several blood and solid tumor cancers and other serious illnesses. IMBRUVICA has one of the most robust clinical oncology development programs for a single molecule in the industry, with more than 130 ongoing clinical trials. There are approximately 30 ongoing company-sponsored trials, 14 of which are in Phase 3, and more than 100 investigator-sponsored trials and external collaborations that are active around the world. To date, 100,000 patients around the world have been treated with IMBRUVICA in clinical practice and clinical trials.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Fatal bleeding events have occurred in patients treated with IMBRUVICA. Grade 3 or higher bleeding events (intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA.
The mechanism for the bleeding events is not well understood.

IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies and patients should be monitored for signs of bleeding.

Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections: Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 14% to 29% of patients. Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have occurred in patients treated with IMBRUVICA. Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections.

Monitor and evaluate patients for fever and infections and treat appropriately.

Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 13 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 13%) based on laboratory measurements occurred in patients with B-cell malignancies treated with single agent IMBRUVICA.

Monitor complete blood counts monthly.

Cardiac Arrhythmias: Fatal and serious cardiac arrhythmias have occurred with IMBRUVICA therapy. Grade 3 or greater ventricular tachyarrhythmias occurred in 0 to 1% of patients, and Grade 3 or greater atrial fibrillation and atrial flutter occurred in 0 to 6% of patients. These events have occurred particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of cardiac arrhythmias.

Periodically monitor patients clinically for cardiac arrhythmias. Obtain an ECG for patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness, syncope, chest pain) or new onset dyspnea. Manage cardiac arrhythmias appropriately, and if it persists, consider the risks and benefits of IMBRUVICA treatment and follow dose modification guidelines.

Hypertension: Hypertension (range, 6 to 17%) has occurred in patients treated with IMBRUVICA with a median time to onset of 4.6 months (range, 0.03 to 22 months). Monitor patients for new onset hypertension or hypertension that is not adequately controlled after starting IMBRUVICA.

Adjust existing anti-hypertensive medications and/or initiate anti-hypertensive treatment as appropriate.

Second Primary Malignancies: Other malignancies (range, 3 to 16%) including non-skin carcinomas (range, 1 to 4%) have occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy was non-melanoma skin cancer (range, 2 to 13%).

Tumor Lysis Syndrome: Tumor lysis syndrome has been infrequently reported with IMBRUVICA therapy. Assess the baseline risk (e.g., high tumor burden) and take appropriate precautions.

Monitor patients closely and treat as appropriate.

Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA and for 1 month after cessation of therapy. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Advise men to avoid fathering a child during the same time period.

ADVERSE REACTIONS

B-cell malignancies: The most common adverse reactions (≥20%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were thrombocytopenia (62%)*, neutropenia (61%)*, diarrhea (43%), anemia (41%)*, musculoskeletal pain (30%), bruising (30%), rash (30%), fatigue (29%), nausea (29%), hemorrhage (22%), and pyrexia (21%).

The most common Grade 3 or 4 adverse reactions (≥5%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia (39%)*, thrombocytopenia (16%)*, and pneumonia (10%).

Approximately 6% (CLL/SLL), 14% (MCL), 11% (WM) and 10% (MZL) of patients had a dose reduction due to adverse reactions. Approximately 4%-10% (CLL/SLL), 9% (MCL), and 9 % (WM [6%] and MZL [13%]) of patients discontinued due to adverse reactions.

cGVHD: The most common adverse reactions (≥20%) in patients with cGVHD were fatigue (57%), bruising (40%), diarrhea (36%), thrombocytopenia (33%)*, stomatitis (29%), muscle spasms (29%), nausea (26%), hemorrhage (26%), anemia (24%)*, and pneumonia (21%).

The most common Grade 3 or 4 adverse reactions (≥5%) reported in patients with cGVHD were fatigue (12%), diarrhea (10%), neutropenia (10%)*, pneumonia (10%), sepsis (10%), hypokalemia (7%), headache (5%), musculoskeletal pain (5%), and pyrexia (5%).

Twenty-four percent of patients receiving IMBRUVICA in the cGVHD trial discontinued treatment due to adverse reactions. Adverse reactions leading to dose reduction occurred in 26% of patients.

*Treatment-emergent decreases (all grades) were based on laboratory measurements and adverse reactions.

DRUG INTERACTIONS

CYP3A Inhibitors: Dose adjustment may be recommended.

CYP3A Inducers: Avoid coadministration with strong CYP3A inducers.

SPECIFIC POPULATIONS
Hepatic Impairment (based on Child-Pugh criteria): Avoid use of IMBRUVICA in patients with severe baseline hepatic impairment. In patients with mild or moderate impairment, reduce IMBRUVICA dose.