Advances in Hematology. volume 16, issue 1 - spring 2017

Transcription

1 Advances in Hematology volume 16, issue 1 - spring 2017

2 Into the Storm I believe we track the weather better than Doppler radar. Even before the storm made landfall, touched the ground or blew through town, we had already coordinated with our sales team and customers to be on standby for an uncoventional delivery of their supplies. As soon as we knew what customers had been affected by the storm and determined if we could feasibly get to them, we hand-delivered the orders to the Distribution Center team. We loaded up our cars with the boxes, got gas and headed out. Our shipping companies might not have been able to get through, but we drove overnight, into the storm, to make sure our patients didn t miss their treatment the next day. Because at Oncology Supply, we believe a cancer patient should only have to battle one storm at a time. S. Vaughn Supervisor, Customer Setup Oncology Supply (15 years)

3 TECENTRIQ THE FIRST AND ONLY FDA-APPROVED ANTI-PDL1 CANCER IMMUNOTHERAPY NOW APPROVED FOR 2 TUMOR TYPES FOR PREVIOUSLY TREATED LOCALLY ADVANCED OR METASTATIC UROTHELIAL CARCINOMA TECENTRIQ is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who: Have disease progression during or following platinum-containing chemotherapy Have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Important Safety Information Serious Adverse Reactions Please refer to the full Prescribing Information for important dose management information specific to adverse reactions. Immune-related pneumonitis. Immune-mediated pneumonitis or interstitial lung disease have occurred. Fatal cases have been observed in patients with urothelial carcinoma (UC) and non-small cell lung cancer (NSCLC). Permanently discontinue TECENTRIQ for Grade 3 or 4 pneumonitis Immune-related hepatitis. Immune-mediated hepatitis and liver test abnormalities, including a fatal case of hepatitis in a patient with UC, have occurred. Permanently discontinue TECENTRIQ for Grade 3 or 4 immune-mediated hepatitis Immune-related colitis. Immune-mediated colitis or diarrhea, including a fatal case of diarrhea-associated renal failure in a patient with UC, occurred. Permanently discontinue TECENTRIQ for Grade 4 diarrhea or colitis Immune-related endocrinopathies. Immune-related thyroid disorders, adrenal insufficiency, hypophysitis, and type 1 diabetes mellitus, including diabetic ketoacidosis, have occurred. Permanently discontinue TECENTRIQ for Grade 4 hypophysitis Other immune-related adverse reactions. Meningoencephalitis, myasthenic syndrome/myasthenia gravis, Guillain-Barré syndrome, ocular inflammatory toxicity, and pancreatitis, including increases in serum amylase and lipase levels, have occurred. Permanently discontinue TECENTRIQ for any grade of meningitis or encephalitis, or any grade of myasthenic syndrome/myasthenia gravis or Guillain-Barré syndrome. Permanently discontinue TECENTRIQ for Grade 4 or any grade of recurrent pancreatitis FOR PREVIOUSLY TREATED METASTATIC NON-SMALL CELL LUNG CANCER TECENTRIQ is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) who have disease progression during or following platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving TECENTRIQ. ALK=anaplastic lymphoma kinase; EGFR=epidermal growth factor receptor; PD-L1=programmed death-ligand 1. Learn more at TECENTRIQ.com/learn Infection. Severe infections, such as sepsis, herpes encephalitis, and mycobacterial infection leading to retroperitoneal hemorrhage, have occurred. Fatal cases have been observed in patients with UC and NSCLC Infusion-related reactions. Severe infusion reactions occurred. Permanently discontinue TECENTRIQ in patients with Grade 3 or 4 infusion reactions Embryo-fetal toxicity. TECENTRIQ can cause fetal harm in pregnant women. Advise patients of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TECENTRIQ and for at least 5 months after the last dose Advise female patients not to breastfeed while taking TECENTRIQ and for at least 5 months after the last dose Most Common Adverse Reactions The most common adverse reactions (rate 20%) in UC included fatigue (52%), decreased appetite (26%), nausea (25%), urinary tract infection (22%), pyrexia (21%), and constipation (21%). The most common adverse reactions in NSCLC (rate 20%) included fatigue (46%), decreased appetite (35%), dyspnea (32%), cough (30%), nausea (22%), musculoskeletal pain (22%), and constipation (20%). You may report side effects to the FDA at FDA-1088 or medwatch. You may also report side effects to Genentech at Please see Brief Summary of Prescribing Information on adjacent pages Genentech USA, Inc. All rights reserved. PDL/072716/0182

4 TECENTRIQ [atezolizumab] Initial U.S. Approval: 2016 This is a brief summary of information about TECENTRIQ. Before prescribing, please see full Prescribing Information. 1 INDICATIONS AND USAGE 1.1 Locally Advanced or Metastatic Urothelial Carcinoma TECENTRIQ (atezolizumab) is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who: Have disease progression during or following platinum-containing chemotherapy Have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials [see Clinical Studies (14.1)]. 1.2 Metastatic Non-Small Cell Lung Cancer TECENTRIQ is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) who have disease progression during or following platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving TECENTRIQ [see Clinical Studies (14.2)]. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Immune-Related Pneumonitis Immune-mediated pneumonitis or interstitial lung disease, defined as requiring use of corticosteroids and with no clear alternate etiology, occurred in patients receiving TECENTRIQ. Monitor patients for signs with radiographic imaging and for symptoms of pneumonitis. Administer steroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for Grade 2 or greater pneumonitis, followed by corticosteroid taper. Withhold TECENTRIQ until resolution for Grade 2 pneumonitis. Permanently discontinue TECENTRIQ for Grade 3 or 4 pneumonitis [see Dosage and Administration (2.2)]. Across clinical trials, 2.6% (51/1978) of patients developed pneumonitis. Fatal pneumonitis occurred in two patients. Urothelial Carcinoma In 523 patients with urothelial carcinoma who received TECENTRIQ, pneumonitis occurred in six (1.1%) patients. Of these patients, there was one patient with fatal pneumonitis, one patient with Grade 3, three patients with Grade 2, and one patient with Grade 1 pneumonitis. TECENTRIQ was held in all cases and five patients were treated with corticosteroids. Pneumonitis resolved in three patients. The median time to onset was 2.6 months (range: 15 days to 4.2 months). The median duration was 15 days (range: 6 days to 3.1+ months). NSCLC In 1027 patients with NSCLC who received TECENTRIQ, pneumonitis occurred in 38 (3.7%) patients. Of these patients, there was one patient with fatal pneumonitis, two patients with Grade 4, thirteen patients with Grade 3, eleven patients with Grade 2, and eleven patients with Grade 1 pneumonitis. TECENTRIQ was held in 24 patients and 21 patients were treated with corticosteroids. Pneumonitis resolved in 26 of the 38 patients. The median time to onset was 3.3 months (range: 3 days to 18.7 months). The median duration was 1.4 months (range: 0 days to months). 5.2 Immune-Related Hepatitis Immune-mediated hepatitis, defined as requiring use of corticosteroids and with no clear alternate etiology, occurred in patients receiving TECENTRIQ treatment. Liver test abnormalities occurred in patients who received TECENTRIQ. Monitor patients for signs and symptoms of hepatitis. Monitor AST, ALT, and bilirubin prior to and periodically during treatment with TECENTRIQ. Administer corticosteroids at a dose of 1 2 mg/kg/day prednisone equivalents for Grade 2 or greater transaminase elevations, with or without concomitant elevation in total bilirubin, followed by corticosteroid taper. Withhold TECENTRIQ for Grade 2 and permanently discontinue TECENTRIQ for Grade 3 or 4 immune-mediated hepatitis [see Dosage and Administration (2.2) and Adverse Reactions (6.1)]. Across clinical trials (n=1978), Grade 3 or 4 elevation occurred in ALT (2.5%), AST (2.3%), and total bilirubin (1.6%). Urothelial Carcinoma In patients with urothelial carcinoma (n=523), Grade 3 or 4 elevation occurred in ALT (2.5%), AST (2.5%), and total bilirubin (2.1%). Immune-mediated hepatitis occurred in 1.3% of patients. Of these cases, one patient died from hepatitis, five patients had Grade 3, and one patient had Grade 2 hepatitis. The median time to onset was 1.1 months (range: 0.4 to 7.7 months). TECENTRIQ was temporarily interrupted in four patients; none of these patients developed recurrence of hepatitis after resuming TECENTRIQ. NSCLC In patients with NSCLC, Grade 3 or 4 elevation occurred in ALT (1.4%), AST (1.3%), and total bilirubin (0.6%). Immune-mediated hepatitis occurred in 0.9% (9/1027) of patients. Of these nine patients, one patient had Grade 4, four patients had Grade 3, three patients had Grade 2, and one patient had Grade 1 immune-mediated hepatitis. The median time to onset was 28 days (range: 15 days to 4.2 months). TECENTRIQ was temporarily interrupted in seven patients; none of these patients developed recurrence of hepatitis after resuming TECENTRIQ. 5.3 Immune-Related Colitis Immune-mediated colitis or diarrhea, defined as requiring use of corticosteroids and with no clear alternate etiology, occurred in patients receiving TECENTRIQ. Monitor patients for signs and symptoms of diarrhea or colitis. Withhold treatment with TECENTRIQ for Grade 2 diarrhea or colitis. If symptoms persist for longer than 5 days or recur, administer 1 2 mg/kg prednisone or equivalent per day. Withhold treatment with TECENTRIQ for Grade 3 diarrhea or colitis. Treat with IV methylprednisolone 1 2 mg/kg per day and convert to oral steroids once the patient has improved. For both Grade 2 and Grade 3 diarrhea or colitis, when symptoms improve to Grade 0 or Grade 1, taper steroids over 1 month. Resume treatment with TECENTRIQ if the event improves to Grade 0 or 1 within 12 weeks and corticosteroids have been reduced to the equivalent of 10 mg oral prednisone per day. Permanently discontinue TECENTRIQ for Grade 4 diarrhea or colitis [see Dosage and Administration (2.2) and Adverse Reactions (6.1)]. Across clinical trials, colitis or diarrhea occurred in 19.7% (389/1978) of all patients. Urothelial Carcinoma In 523 patients with urothelial carcinoma who received TECENTRIQ, colitis or diarrhea occurred in 98 (18.7%) patients. Ten patients (1.9%) developed Grade 3 or 4 diarrhea. Four patients (0.8%) had immune-mediated colitis or diarrhea with a median time to onset of 1.7 months (range: 1.1 to 3.1 months). Immune-mediated colitis resolved with corticosteroid administration in three of these patients, while the other patient died without resolution of colitis in the setting of diarrhea-associated renal failure. NSCLC In 1027 patients with NSCLC who received TECENTRIQ, colitis or diarrhea occurred in 198 (19.3%) patients. Twelve patients (1.2%) developed Grade 3 colitis or diarrhea. Five patients (0.5%) had immune-mediated colitis or diarrhea with a median time to onset of 21 days (range: 12 days to 3.4 months). Of these patients, one had Grade 3, two had Grade 2, and two had Grade 1 immune-mediated colitis or diarrhea. Immune-mediated colitis or diarrhea resolved with corticosteroid administration in four of these patients, while the fifth patient died due to disease progression prior to resolution of colitis. 5.4 Immune-Related Endocrinopathies Immune-related thyroid disorders, adrenal insufficiency, and type 1 diabetes mellitus, including diabetic ketoacidosis, have occurred in patients receiving TECENTRIQ. Monitor patients for clinical signs and symptoms of endocrinopathies. Hypophysitis Hypophysitis occurred in 0.2% (1/523) of patients with urothelial cancer receiving TECENTRIQ. Monitor for signs and symptoms of hypophysitis. Administer corticosteroids and hormone replacement as clinically indicated. Withhold TECENTRIQ for Grade 2 or Grade 3 and permanently discontinue for Grade 4 hypophysitis [see Dosage and Administration (2.2) and Adverse Reactions (6.1)]. Thyroid Disorders Thyroid function was assessed routinely only at baseline and the end of the study. Monitor thyroid function prior to and periodically during treatment with TECENTRIQ. Asymptomatic patients with abnormal thyroid function tests can receive TECENTRIQ. For symptomatic hypothyroidism, withhold TECENTRIQ and initiate thyroid hormone replacement as needed. Manage isolated hypothyroidism with replacement therapy and without corticosteroids. For symptomatic hyperthyroidism, withhold TECENTRIQ and initiate an anti-thyroid drug as needed. Resume treatment with TECENTRIQ when symptoms of hypothyroidism or hyperthyroidism are controlled and thyroid function is improving [see Dosage and Administration (2.2) and Adverse Reactions (6.1)]. Across clinical trials, hypothyroidism and hyperthyroidism occurred in 3.9% (77/1978) and 1.0% (20/1978) of patients, respectively. Urothelial Carcinoma In 523 patients with urothelial carcinoma who received TECENTRIQ, hypothyroidism occurred in 2.5% (13/523). One patient had Grade 3 and twelve patients had Grade 1 2 hypothyroidism. The median time to first onset was 5.4 months (range: 21 days to 11.3 months). Thyroid stimulating hormone (TSH) was elevated and above the patient s baseline in 16% (21/131) of patients with a follow-up measurement. Hyperthyroidism occurred in 0.6% (3/523) of patients with urothelial carcinoma. Of the three urothelial carcinoma patients, one patient had Grade 2 and two patients had Grade 1 hyperthyroidism. The median time to onset was 3.2 months (range: 1.4 to 5.8 months). TSH was decreased and below the patient s baseline in 3.8% (5/131) of patients with a follow-up measurement. NSCLC In 1027 patients with NSCLC who received TECENTRIQ, hypothyroidism occurred in 4.2% (43/1027). Three patients had Grade 3 and forty patients had Grade 1 2 hypothyroidism. The median time to onset was 4.8 months (range 15 days to 31 months.) TSH was elevated and above the patient s baseline in 17% (54/315) of patients with follow-up measurement. Hyperthyroidism occurred in 1.1% (11/1027) of patients with NSCLC. Eight patients had Grade 2 and three patients had Grade 1 hyperthyroidism. The median time to onset was 4.9 months (range: 21 days to 31 months). TSH was decreased and below the patient s baseline in 7.6% (24/315) of patients with a follow-up measurement. Adrenal Insufficiency Adrenal insufficiency occurred in 0.4% (7/1978) of patients across clinical trials, including two patients with Grade 3, four patients with Grade 2, and one patient with Grade 1. Adrenal insufficiency resolved in two patients. For symptomatic adrenal insufficiency, withhold TECENTRIQ and administer methylprednisolone 1 2 mg/kg per day IV followed by oral prednisone 1 2 mg/kg per day or equivalent once symptoms improve. Start steroid taper when symptoms improve to Grade 1 and taper steroids over 1 month. Resume treatment with TECENTRIQ if the event improves to Grade 1 within 12 weeks and corticosteroids have been reduced to the equivalent of 10 mg oral prednisone per day and the patient is stable on replacement therapy, if required [see Dosage and Administration (2.2) and Adverse Reactions (6.1)]. Diabetes Mellitus New onset diabetes with ketoacidosis has occurred in patients receiving TECENTRIQ. Diabetes mellitus without an alternative etiology occurred in one (0.2%) patient with urothelial carcinoma and three (0.3%) patients with NSCLC. Initiate treatment with insulin for type 1 diabetes mellitus. For Grade 3 hyperglycemia (fasting glucose > mg/dl), withhold TECENTRIQ. Resume treatment with TECENTRIQ when metabolic control is achieved on insulin replacement therapy [see Dosage and Administration (2.2) and Adverse Reactions (6.1)]. 5.5 Other Immune-Related Adverse Reactions Other immune-related adverse reactions including meningoencephalitis, myasthenic syndrome/myasthenia gravis, Guillain-Barré, ocular inflammatory toxicity, and pancreatitis, including increases in serum amylase and lipase levels, have occurred in 1.0% of patients treated with TECENTRIQ. Meningitis / Encephalitis Monitor patients for clinical signs and symptoms of meningitis or encephalitis. Permanently discontinue TECENTRIQ for any grade of meningitis or encephalitis. Treat with IV steroids (1 2 mg/kg/day methylprednisolone or equivalent) and convert to oral steroids (prednisone 60 mg/day or equivalent) once the patient has improved. When symptoms improve to Grade 1, taper steroids over 1 month [see Dosage and Administration (2.2) and Adverse Reactions (6.1)]. Motor and Sensory Neuropathy Monitor patients for symptoms of motor and sensory neuropathy. Permanently discontinue TECENTRIQ for any grade of myasthenic syndrome/myasthenia gravis or Guillain-Barré syndrome. Institute medical intervention as appropriate. Consider initiation of systemic corticosteroids at a dose of 1 2 mg/kg/day prednisone [see Dosage and Administration (2.2) and Adverse Reactions (6.1)]. Pancreatitis Symptomatic pancreatitis without an alternative etiology occurred in 0.1% (2/1978) of patients across clinical trials. Monitor patients for signs and symptoms of acute pancreatitis. Withhold TECENTRIQ for Grade 3 serum amylase or lipase levels (> 2.0 ULN), or Grade 2 or 3 pancreatitis. Treat with 1 2 mg/kg IV methylprednisolone or equivalent per day. Once symptoms improve, follow with 1 2 mg/kg of oral prednisone or equivalent per day. Resume treatment with TECENTRIQ when serum amylase and lipase levels improve to Grade 1 within 12 weeks or symptoms of pancreatitis have resolved, and corticosteroids have been reduced to 10 mg oral prednisone or equivalent per day. Permanently discontinue TECENTRIQ for Grade 4 or any grade of recurrent pancreatitis [see Dosage and Administration (2.2) and Adverse Reactions (6.1)]. 5.6 Infection Severe infections, including sepsis, herpes encephalitis, and mycobacterial infection leading to retroperitoneal hemorrhage occurred in patients receiving TECENTRIQ. Monitor patients for signs and symptoms of infection and treat with antibiotics for suspected or confirmed bacterial infections. Withhold TECENTRIQ for Grade 3 infection [see Dosage and Administration (2.2) and Adverse Reactions (6.1)]. Across clinical trials, infections occurred in 38.4% (759/1978) of patients. Urothelial Carcinoma In 523 patients with urothelial carcinoma who received TECENTRIQ, infection occurred in 197 (37.7%) patients. Grade 3 or 4 infection occurred in sixty (11.5%) patients, while three patients died due to infections. Urinary tract infections were the most common cause of Grade 3 or higher infection, occurring in 37 (7.1%) patients. NSCLC In Study 3, a randomized trial in patients with NSCLC, infections were more common in patients treated with TECENTRIQ (43%) compared with those treated with docetaxel (34%). Grade 3 or 4 infections occurred in 9.2% of patients treated with TECENTRIQ compared with 2.2% in patients treated with docetaxel. Two patients (1.4%) treated with TECENTRIQ and three patients (2.2%) treated with docetaxel died due to infection. Pneumonia was the most common cause of Grade 3 or higher infection, occurring in 7.7% of patients treated with TECENTRIQ. 5.7 Infusion-Related Reactions Severe infusion reactions have occurred in patients in clinical trials of TECENTRIQ. Infusion-related reactions occurred in 1.3% (25/1978) of patients across clinical trials, 1.7% (9/523) of patients with urothelial carcinoma, and 1.6% (16/1027) of patients with NSCLC. Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions. Permanently discontinue TECENTRIQ in patients with Grade 3 or 4 infusion reactions [see Dosage and Administration (2.2) and Adverse Reactions (6.1)]. 5.8 Embryo-Fetal Toxicity Based on its mechanism of action, TECENTRIQ can cause fetal harm when administered to a pregnant woman. Animal studies have demonstrated that inhibition of the PD-L1/PD-1 pathway can lead to increased risk of immune-related rejection of the developing fetus resulting in fetal death. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TECENTRIQ and for at least 5 months after the last dose [see Use in Specific Populations (8.1, 8.3)]. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: Immune-Related Pneumonitis [see Warnings and Precautions (5.1)] Immune-Related Hepatitis [see Warnings and Precautions (5.2)] Immune-Related Colitis [see Warnings and Precautions (5.3)] Immune-Related Endocrinopathies [see Warnings and Precautions (5.4)] Other Immune-Related Adverse Reactions [see Warnings and Precautions (5.5)] Infection [see Warnings and Precautions (5.6)] Infusion-Related Reactions [see Warnings and Precautions (5.7)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Urothelial Carcinoma The data described in Table 1 reflects exposure to TECENTRIQ in Cohort 2 of Study 1. This cohort enrolled 310 patients in a single arm trial with locally advanced or metastatic urothelial carcinoma who had disease progression during or following at least one platinum-containing chemotherapy regimen or who had disease progression within 12 months of treatment with a platinum-containing neoadjuvant or adjuvant chemotherapy regimen [see Clinical Studies (14.1)]. Patients received 1200 mg of TECENTRIQ intravenously every 3 weeks until unacceptable toxicity or either radiographic or clinical progression. The median duration of exposure was 12.3 weeks (range: 0.1, 46 weeks). The most common adverse reactions ( 20%) were fatigue (52%), decreased appetite (26%), nausea (25%), urinary tract infection (22%), pyrexia (21%), and constipation (21%). The most common Grade 3 4 adverse reactions ( 2%) were urinary tract infection, anemia, fatigue, dehydration, intestinal obstruction, urinary obstruction, hematuria, dyspnea, acute kidney injury, abdominal pain, venous thromboembolism, sepsis, and pneumonia. Three patients (0.9%) who were treated with TECENTRIQ experienced either sepsis, pneumonitis, or intestinal obstruction which led to death. TECENTRIQ was discontinued for adverse reactions in 3.2% (10/310) of the 310 patients. Sepsis led to discontinuation in 0.6% (2/310) of patients. Adverse reactions leading to interruption of TECENTRIQ occurred in 27% of patients; the most common (> 1%) were liver enzyme increase, urinary tract infection, diarrhea, fatigue, confusional state, urinary obstruction, pyrexia, dyspnea, venous thromboembolism, and pneumonitis. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions (> 2%) were urinary tract infection, hematuria, acute kidney injury, intestinal obstruction, pyrexia, venous thromboembolism, urinary obstruction, pneumonia, dyspnea, abdominal pain, sepsis, and confusional state. Table 1 summarizes the adverse reactions that occurred in 10% of patients while Table 2 summarizes Grade 3 4 selected laboratory abnormalities that occurred in 1% of patients treated with TECENTRIQ in Cohort 2 of Study 1. Table 1: All Grade Adverse Reactions in 10% of Patients with Urothelial Carcinoma in Study 1 TECENTRIQ N = 310 Adverse Reaction All Grades (%) Grades 3 4 (%) All Adverse Reactions Gastrointestinal Disorders Nausea 25 2 Constipation Diarrhea 18 1 Abdominal pain 17 4 Vomiting 17 1

5 TECENTRIQ N = 310 Adverse Reaction All Grades (%) Grades 3 4 (%) General Disorders and Administration Fatigue 52 6 Pyrexia 21 1 Peripheral edema 18 1 Infections and Infestations Urinary tract infection 22 9 Metabolism and Nutrition Disorders Decreased appetite 26 1 Musculoskeletal and Connective Tissue Disorders Back/Neck pain 15 2 Arthralgia 14 1 Renal and urinary disorders Hematuria 14 3 Respiratory, Thoracic, and Mediastinal Disorders Dyspnea 16 4 Cough Skin and Subcutaneous Tissue Disorders Rash Pruritus Table 2: Grade 3 4 Laboratory Abnormalities in Patients with Urothelial Carcinoma in Study 1 in 1% of Patients Laboratory Test Grades 3 4 (%) Lymphopenia 10 Hyponatremia 10 Anemia 8 Hyperglycemia 5 Increased Alkaline phosphatase 4 Increased Creatinine 3 Increased ALT 2 Increased AST 2 Hypoalbuminemia 1 NSCLC The safety of TECENTRIQ was evaluated in Study 3, a multi-center, international, randomized, open-label trial in patients with metastatic NSCLC who progressed during or following a platinum-containing regimen, regardless of PD-L1 expression [see Clinical Studies (14.2)]. Patients received 1200 mg of TECENTRIQ (n=142) administered intravenously every 3 weeks until unacceptable toxicity or either radiographic or clinical progression or docetaxel (n=135) administered intravenously at 75 mg/m 2 every 3 weeks until unacceptable toxicity or disease progression. The median duration of exposure was 3.7 months (range: 0 19 months) in TECENTRIQ-treated patients and 2.1 months (range: 0 17 months) in docetaxel-treated patients. The most common adverse reactions ( 20%) in patients receiving TECENTRIQ were fatigue (46%), decreased appetite (35%), dyspnea (32%), cough (30%), nausea (22%), musculoskeletal pain (22%), and constipation (20%). The most common Grade 3-4 adverse reactions ( 2%) were dyspnea, pneumonia, hypoxia, hyponatremia, fatigue, anemia, musculoskeletal pain, AST increase, ALT increase, dysphagia, and arthralgia. Nine patients (6.3%) who were treated with TECENTRIQ experienced either pulmonary embolism (2), pneumonia (2), pneumothorax, ulcer hemorrhage, cachexia secondary to dysphagia, myocardial infarction, or large intestinal perforation which led to death. TECENTRIQ was discontinued due to adverse reactions in 4% (6/142) of patients. Adverse reactions leading to interruption of TECENTRIQ occurred in 24% of patients; the most common (>1%) were pneumonia, liver function test abnormality, upper respiratory tract infection, pneumonitis, acute kidney injury, hypoxia, hypothyroidism, dyspnea, anemia, and fatigue. Serious adverse reactions occurred in 37% of patients. The most frequent serious adverse reactions (> 2%) were pneumonia, dyspnea, pleural effusion, pyrexia, and venous thromboembolism. Table 3 summarizes adverse reactions that occurred in at least 10% of TECENTRIQ-treated patients and at a higher incidence than in the docetaxel arm. Table 4 summarizes selected laboratory abnormalities worsening from baseline that occurred in 10% of TECENTRIQ-treated patients and at a higher incidence than in the docetaxel arm. Table 3: Adverse Reactions Occurring in 10% of TECENTRIQ-Treated Patients with NSCLC and at a Higher Incidence than in the Docetaxel Arm (Between Arm Difference of 5% [All Grades] or 2% [Grades 3 4]) (Study 3) TECENTRIQ (n=142) Docetaxel (n=135) Adverse Reaction All grades Grade 3 4 All grades Grade 3 4 Percentage (%) of Patients General Disorders and Administration Site Conditions Pyrexia Infections and infestations Pneumonia Metabolism and nutrition disorders Decreased appetite Musculoskeletal and connective tissue disorders Arthralgia Back Pain Psychiatric Disorders Insomnia Respiratory, thoracic and mediastinal disorders Dyspnea Cough Table 4: Selected Laboratory Abnormalities Worsening from Baseline Occurring in 10% of TECENTRIQ- Treated Patients with NSCLC and at a Higher Incidence than in the Docetaxel Arm (Between Arm Difference of 5% [All Grades] or 2% [Grades 3 4]) (Study 3) Percentage of Patients with Worsening Laboratory Test from Baseline TECENTRIQ Docetaxel Test All grades (%) Grade 3 4 (%) All grades (%) Grade 3 4 (%) Hyponatremia Hypoalbuminemia Alkaline Phosphatase increased Aspartate aminotransferase increased Alanine aminotransferase increased Creatinine increased Hypokalemia Hypercalcemia Total Bilirubin increased Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. Among 275 patients in Study 1, 114 patients (41.5%) tested positive for treatment-emergent (treatment-induced or treatment-enhanced) antitherapeutic antibodies (ATA) at one or more post-dose time points. Among 135 patients in Study 3, 73 patients (54.1%) tested positive for treatment-emergent (treatment-induced or treatment-enhanced) anti-therapeutic antibodies (ATA) at one or more post-dose time points. In Study 1 and Study 3, the presence of ATAs did not appear to have a clinically significant impact on pharmacokinetics, safety or efficacy. Immunogenicity assay results are highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of incidence of ATAs to TECENTRIQ with the incidence of antibodies to other products may be misleading. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on its mechanism of action, TECENTRIQ can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on the use of TECENTRIQ in pregnant women. Animal studies have demonstrated that inhibition of the PD-L1/PD-1 pathway can lead to increased risk of immunerelated rejection of the developing fetus resulting in fetal death [see Data]. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Animal reproduction studies have not been conducted with TECENTRIQ to evaluate its effect on reproduction and fetal development. A literature-based assessment of the effects on reproduction demonstrated that a central function of the PD-L1/PD-1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to a fetus. Blockage of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to a fetus and to result in an increase in fetal loss; therefore, potential risks of administering TECENTRIQ during pregnancy include increased rates of abortion or stillbirth. As reported in the literature, there were no malformations related to the blockade of PD-L1/PD-1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 and PD-L1 knockout mice. Based on its mechanism of action, fetal exposure to atezolizumab may increase the risk of developing immune-mediated disorders or altering the normal immune response. 8.2 Lactation Risk Summary There is no information regarding the presence of atezolizumab in human milk, the effects on the breastfed infant, or the effects on milk production. As human IgG is excreted in human milk, the potential for absorption and harm to the infant is unknown. Because of the potential for serious adverse reactions in breastfed infants from TECENTRIQ, advise a lactating woman not to breastfeed during treatment and for at least 5 months after the last dose. 8.3 Females and Males of Reproductive Potential Contraception Females Based on its mechanism of action, TECENTRIQ can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with TECENTRIQ and for at least 5 months following the last dose. Infertility Females Based on animal studies, TECENTRIQ may impair fertility in females of reproductive potential while receiving treatment [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and effectiveness of TECENTRIQ have not been established in pediatric patients. 8.5 Geriatric Use Of the 310 patients with urothelial carcinoma treated with TECENTRIQ in Study 1, 59% were 65 years or older. Of the 142 patients with NSCLC treated with TECENTRIQ in Study 3, 39% were 65 years or older. No overall differences in safety or efficacy were observed between patients 65 years of age and younger patients. 8.6 Renal Impairment Based on a population pharmacokinetic analysis, no dose adjustment of TECENTRIQ is recommended for patients with renal impairment [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment Based on a population pharmacokinetic analysis, no dose adjustment of TECENTRIQ is recommended for patients with mild hepatic impairment. TECENTRIQ has not been studied in patients with moderate or severe hepatic impairment [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE There is no information on overdose with TECENTRIQ. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Inform patients of the risk of immune-related adverse reactions that may require corticosteroid treatment and interruption or discontinuation of TECENTRIQ, including: Pneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening cough, chest pain, or shortness of breath [see Warnings and Precautions (5.1)]. Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or bleeding [see Warnings and Precautions (5.2)]. Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain [see Warnings and Precautions (5.3)]. Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypophysitis, hyperthyroidism, hypothyroidism, adrenal insufficiency, or type 1 diabetes mellitus, including diabetic ketoacidosis [see Warnings and Precautions (5.4)] Meningoencephalitis, myasthenic syndrome/myasthenia gravis, and Guillain-Barré syndrome: Advise patients to contact their healthcare provider immediately for signs or symptoms of meningitis, myasthenic syndrome/myasthenia gravis, or Guillain-Barré syndrome [see Warnings and Precautions (5.5)]. Ocular Inflammatory Toxicity: Advise patients to contact their healthcare provider immediately for signs or symptoms of ocular inflammatory toxicity [see Warnings and Precautions (5.5)]. Pancreatitis: Advise patients to contact their healthcare provider immediately for signs and symptoms of pancreatitis [see Warnings and Precautions (5.5)]. Infection: Advise patients to contact their healthcare provider immediately for signs or symptoms of infection [see Warnings and Precautions (5.6)]. Infusion-Related Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions [see Warnings and Precautions (5.7)]. Rash: Advise patients to contact their healthcare provider immediately for signs or symptoms of rash [see Dosage and Administration (2.2)]. Embryo-Fetal Toxicity Advise female patients that TECENTRIQ can cause fetal harm. Instruct females of reproductive potential to use effective contraception during treatment and for at least 5 months after the last dose of TECENTRIQ [see Use in Specific Populations (8.1, 8.3)]. Lactation Advise female patients not to breastfeed while taking TECENTRIQ and for at least 5 months after the last dose [see Use in Specific Populations (8.2)]. TECENTRIQ (atezolizumab) Manufactured by: PDL/080916/0193 Genentech, Inc. Initial U.S. Approval: May 2016 A Member of the Roche Group Code Revision Date: October DNA Way TECENTRIQ is a registered trademark of Genentech, Inc. South San Francisco, CA Genentech, Inc. U.S. License No. 1048

6 Table of Contents Spring ASH 2016 Meeting Summary By Dr. Lucio Gordan Do Not Ignore MACRA AdvanceIQ Network Improves Access to Clinical Trials What s News at ION 6 Oncologistics

7 volume 16, issue 1 - spring 2017 oneonone with Mark Santos In December 2016, the American Society of Hematology (ASH) hosted its 58th annual meeting to highlight groundbreaking scientific research and the latest advances in patient care. In this issue of Oncologistics, Dr. Lucio Gordan, director of Quality and Medical Informatics for Florida Cancer Specialists and Research Institute, delivers the first in a two-part summary of the most significant presentations or abstracts presented at the meeting. See page eight for data in lymphomas and chronic lymphocytic leukemia. Vicki Albrecht, senior vice president and general manager of ION Solutions, and Barry Fortner, Ph.D., president of Oncology Supply, met in Washington, D.C., earlier this year with the Trump administration and bipartisan members of Congress to discuss policy priorities for One certainty from that meeting is that value-based care and reimbursement, specifically MACRA, is here to stay. If you still have questions about MACRA or need help collecting or submitting data, start on page 16. I am excited about ION Solutions and IntrinsiQ Specialty Solutions launch of a research network designed to increase access to groundbreaking treatment options for improved patient outcomes. Read more about AdvanceIQ Network on page 24. We are happy to provide this new practice solution along with creative GPO partnering and contracting, educational events, practice advocacy and practice management resources to enable community oncology practices to improve operational efficiency, financial performance and quality of care. Thank you for your continued partnership, Mark Santos President, ION GPO oncologistics Editorial & Design staff: Chris Vorce Senior Director, Marketing & Communications, ION Solutions Tricia Musslewhite Manager, Marketing & Communications, ION Solutions Sylvia Mugica Manager, Graphic Design, ION Solutions ION Solutions article and advertising submissions: Article submissions and suggestions, as well as advertising inquiries, may be sent to: Tricia Musslewhite Managing Editor, Oncologistics c/o ION Solutions 3101 Gaylord Parkway Frisco, TX Information presented in Oncologistics is not intended as a substitute for the personalized advice given by a healthcare provider. The opinions expressed on the pages of Oncologistics magazine are those of the authors and do not necessarily reflect the views of ION Solutions or AmerisourceBergen Specialty Group. Although Oncologistics strives to present only current and accurate information, readers should not consider it as professional advice or endorsement of any position. Although great care has been taken in compiling and checking the information given in this publication to ensure accuracy, the authors, ION Solutions, and its employees or agents shall not be responsible or in any way liable for the continued currency of the information or for any errors, omissions, or inaccuracies in this magazine, whether arising from negligence or otherwise or for any consequence arising therefrom. The staff of Oncologistics provides columns and other editorial support. In no way are they responsible for the specific views presented in Oncologistics. Oncologistics magazine is published by ION Solutions, an AmerisourceBergen Specialty Group company. All archived issues of Oncologistics are available online at Oncologistics 7

8 ASH Meeting Summary By Dr. Lucio Gordan This is part one of a two-part summary of the most salient presentations or abstracts presented at the American Society of Hematology in December This is written from one busy clinician to another, practicing hematology and oncology in the community setting. Part I includes data in lymphomas and chronic lymphocytic leukemia. Part II will focus on plasma cell dyscrasias, myeloproliferative neoplasms and myelodysplasia. 8 Oncologistics

9 Follicular Lymphomas Gallium Study a. The Gallium Study was an international randomized open-label phase 3 study involving treatment-naïve adult patients with CD20 positive low-grade non-hodgkin lymphoma, follicular type, grade 1-3A with at least stage II bulky or stage III/IV with a performance status of 2 or less. b. In this study, 1397 patients were enrolled to receive induction therapy with obinutuzumab (O) 1000 mg IV on days 1,8,15 of cycle 1 and day 1 of subsequent cycles plus standard cyclophosphamide, adriamycin, prednisone, vincristine (CHOP), cyclophosphamide, vincristine, prednisone (CVP) or bendamustine or to receive rituximab (R) 375 mg/m2 day 1 plus CHOP, CVP or bendamustine patients were analyzed. c. The patients who achieved complete remission (CR) or (PR) after 6-8 cycles were placed on either maintenance obinutuzumab or maintenance rituximab every 2 months for 2 years. CHOP chemotherapy was given every 3 weeks for 6 cycles; CVP was also given every 3 weeks for 8 cycles; bendamustine was given every 4 weeks for 6 cycles. d. The primary endpoint of the study was progression-free survival. After median follow-up of 34 months, overall response rate was 88.5% for obinutuzumab plus chemotherapy versus 86.9% for patients receiving rituximab plus chemotherapy. CR rate was 19.5% for O+chemotherapy versus 23.8% for R+chemotherapy. Three-year progression-free survival (PFS) is 80% for O+chemotherapy versus 73.3% for R+chemotherapy with a hazard ratio of 0.66 ( ) and with a P-value of Three-year overall survival (OS) was 94% for O+chemotherapy versus 92% for R+chemotherapy with P-value of e. Toxicities: Serious adverse events were seen in 46% in patients receiving O+chemotherapy versus 39.9% for patients receiving R+chemotherapy. Infections were noted in 20% in patients receiving O versus 15% in patient receiving R. Infusion reactions were almost twice as common in patients receiving O (6.7%) versus R. f. Conclusions: Obinutuzumab-based therapy conferred improved PFS, with more infusion reactions and other serious toxicities. OS was similar. g. Authors: Marcus R, et al. ASH Abstract 6. SAKK 35/10 Study a. The SAKK 35/10 was a randomized phase 2 study including treatment-naïve patients with grade 1-3A follicular non- Hodgkin lymphoma. 154 patients were randomized to receive rituximab (R) 375 mg/m2 IV on day 1 on weeks 1-4 and weeks 12-15, plus lenalidomide (L) 15 mg daily (77 patients). The other cohort of patients (77) received rituximab 375 mg/ m2 IV on day1 of weeks 1-4 and week The first restaging was done at 10 weeks and the second restaging was done between weeks b. The primary endpoint was complete remission at week 23. Secondary endpoints were PFS, time to next lymphoma treatment, CR duration and OS. c. Results: With a median follow-up of 3.5 years, CR rate at 30 months was 42% for patients receiving R+L versus 19% for patients receiving R alone. P-value was Time to next lymphoma treatment was not reached for patients receiving R+L as opposed to 2.1 year for patients receiving R alone with a hazard ratio of 0.56 and P-value of Median PFS was not reached for patients receiving R+L versus 2.3 years for patients receiving rituximab alone. The hazard ratio was 0.58 with P-value of d. Toxicities: 16% of the patients receiving combination therapy discontinued lenalidomide alone due to toxicity. Hypertension, maculopapular rash, thrombocytopenia, neutropenia, allergic reaction and fatigue (grade 3/4) were more common in patients receiving R+L. e. Conclusion: R plus L is an active combination with improved CR duration, time to next formal treatment, progression-free survival. There was no difference in 3-year OS. More toxicities were noted in the combination arm. f. Authors: Kimby E, et al. ASH Abstract 1099 Oncologistics 9

10 Diffuse Large B-cell Non-Hodgkin Lymphoma CALGB/Alliance Study a. This was the randomized phase 3 study involving untreated, newly diagnosed, stage II, III, IV diffuse large B-cell non- Hodgkin lymphoma, and stage I primary mediastinal B-cell lymphoma, performance status ECOG 2 or less, preserved left ventricular ejection fraction greater than 45% without CNS disease. b. In this study, 465 patients were enrolled and were randomized to receive dose-adjusted EPOCH-rituximab versus R-CHOP. Patients receiving DA-EPOCH-R were given rituximab 375 mg/m2 IV: cyclophosphamide 750 mg/m2 IV; doxorubicin 10 mg/ m2 IV on days 1-4; etoposide 50 mg/m2 on days 1-4, vincristine 0.4 mg/m2 IV on days 1-4, prednisone 60 mg/m2 b.i.d. days 1-5 and GCSF as needed subcutaneous on days Patients receiving R-CHOP were given rituximab 375 mg/m2 IV, cyclophosphamide 750 mg/m2 IV, doxorubicin 50 mg/m2 IV, vincristine 1.4 mg/m2 IV with maximum dose of 2 mg, prednisone 40 mg/m2 p.o. on days 1-5 and GCSF as needed. Of note, CNS prophylaxis was given if there was evidence of bone marrow or testicular involvement or elevated LDH plus at least 2 or more extranodal sites of involvement. Prophylaxis included methotrexate intrathecally for 4 doses on day 1 of cycles 3-6. c. 6 cycles of therapy were planned and the endpoint was event-free survival with secondary endpoints including response rate, overall survival and safety. d. Overall response rate was 89.3% for R-CHOP versus 88.8% for DA-EPOCH-R. No significant difference was noted as far as partial response, stable disease or progression of disease. e. There was no difference in terms of event-free survival or overall survival for patients receiving R-CHOP versus DA-EPOCH-R. Subgroup analysis did not show any convincing evidence of superiority of one regimen over the other. f. Grade 3-5 adverse events (hematologic and non-hematologic) were significantly higher in patients receiving DA-EPOCH-R. g. Summary: This study showed no difference in terms of event-free survival or overall survival for patients receiving R-CHOP versus DA-EPOCH-R. More toxicity was noted in patients receiving DA-EPOCH-R. h. Author: Wilson, W.H., et al. ASH Abstract 469. REMARC Study a. The REMARC study was a multicenter randomized, placebo-controlled phase 3 study in which 650 patients years of age with advanced treatment-naïve diffuse large B-cell non-hodgkin lymphoma, CD20 positive, or follicular IIIB, or novel transformed follicular lymphoma or indolent lymphoma were treated with 6-8 cycles standard R-CHOP chemotherapy. b. After initial therapy patients were randomized to receive lenalidomide 25 mg daily 3-weeks-on/1-week-off or 10 mg daily 3-weeks-on/1-week-off if creatinine clearance was less than 30 ml/min versus placebo for up to 2 years of maintenance. c. The primary endpoint of this study was progression-free survival and secondary endpoints included safety overall survival conversion from partial remission to complete remission. d. The median PFS was not reached in patients receiving maintenance lenalidomide versus 58 months for patients on the placebo arm with a hazard ratio of 0.70 and P-value of The median follow-up was 40 months. e. Patients receiving lenalidomide maintenance had improved PFS including elderly patients (70 years or older), patients who achieved complete remission to R-CHOP and patients with positive PET scan at randomization. f. There was no difference in OS in patients receiving lenalidomide versus placebo with a median follow-up of 52 months. g. There was no increased conversion of partial remission to complete remission for patients receiving maintenance lenalidomide versus placebo. h. Grade 3/4 toxicities including neutropenia, were more common in patients receiving lenalidomide maintenance. Of note, 36% of patients receiving maintenance lenalidomide had drug discontinued due to toxicity. 16% of patients receiving placebo discontinued due to toxicity as well. i. There was no difference in terms of hematologic malignancy or solid tumor development in either arm of the study. j. Conclusions: Lenalidomide increased PFS as compared to placebo in maintenance therapy but no difference in OS was observed. There were greater toxicities in grade 3/4 neutropenia and higher discontinuation rate for patients receiving lenalidomide. k. Authors: Thieblemont C et al, ASH Abstract 626

11 Marginal Zone Non-Hodgkin Lymphoma PCYC-1121: The use of ibrutinib in relapsed refractory marginal zone lymphoma a. This was a phase 2 trial with 63 patients with relapsed marginal zone lymphoma with at least 1 prior therapy, at least one anti-cd20 regimen with a performance status of ECOG 2 or better. b. The patients received ibrutinib 560 mg p.o. q. day until disease progression or development of intolerable side effects. c. The primary endpoint of the study was overall response rate. Secondary endpoints were duration of response, progressionfree survival, safety and overall survival. d. Results: The median follow-up was 19.4 months with median duration of therapy of approximately 11 months. Overall response rate in total population was 48%. Efficacy was noted across nodal, extranodal and splenic subgroups. e. The main reasons for discontinuation of therapy were disease progression (36% of patients) followed by adverse events (17% of patients). As expected, the most common adverse events included fatigue, anemia, nausea, diarrhea, thrombocytopenia, edema, arthralgia, dyspnea, upper respiratory infection. Three patients died (progression of disease, cerebral hemorrhage and varying stages of pneumonia). f. Dose-reduction was necessary in 10% of the patients. g. Conclusion: Ibrutinib monotherapy at 560 mg daily is an active drug and a good option for patients with relapsed marginal zone lymphoma with overall response rate of almost 50%. h. Authors: Not A, et al. ASH Abstract Mantle Cell Non-Hodgkin Lymphoma LyMa Study a. This was prospective randomized phase 3 clinical trial in which 299 patients were enrolled between the ages of 18 and 65 years, with treatment naïve mantle cell lymphoma with documented translocation 11:14. b. Patients were treated with R-DHAP for 4 cycles. If the PR was not achieved they received another 4 cycles of R-CHOP-14. c. Subsequently, 257 patients with at least VGPR following induction chemotherapy received autologous stem cell transplant consolidation with R-BEAM regimen. d. 240 patients post autologous stem cell transplant were randomized to receive rituximab maintenance every 2 months for 3 years versus observation (120 patients in each arm). e. Median follow-up from inclusion was 54 months and median follow-up for randomized was approximately 50 months. f. Results: 4-year event-free survival was 79% for rituximab maintenance versus 61% for observation with a hazard ratio of 0.45 and P-value of year progression-free survival was 82% for patients receiving rituximab versus 65% in the observation arm with a hazard ratio of 0.4 with P-value of Overall 4-year survival was 89% for patients receiving maintenance rituximab versus 81% in the observation arm with a hazard ratio of 0.50 with P-value of g. Conclusion: In patients treated with R-DHAP followed by consolidation autologous stem cell transplant followed by maintenance rituximab have improved event-free survival, progression-free survival and overall survival as compared no maintenance. Therefore it is at 375 mg/m2 every 2 months for 3 years should be strongly considered in a young patient with mantle cell non-hodgkin lymphoma. h. Authors: Le Gouill S, et al. Abstract 145. Oncologistics 11

12 CD30 Positive Mycosis Fungoides or Primary Cutaneous Anaplastic Large Cell Lymphoma ALCANZA study a. The ALCANZA study involved 131 patients with CD30 positive Mycosis fungoides (MF) or primary cutaneous anaplastic large cell lymphoma who received at least 1 prior therapy or radiation therapy for MF or greater than 1 prior treatment for primary cutaneous anaplastic large cell lymphoma. Patients could not have received methotrexate or bexarotene. b. The patients were randomized to receive brentuximab-vedotin at a standard dose of 1.8 mg/kg IV every 3 weeks versus methotrexate orally weekly or bexarotene 300 mg/m2 p.o. daily. This was an open-level randomized phase 3 trial. c. The primary endpoint was overall response rate and secondary endpoints included progression-free survival, analysis of symptom burden and rate of complete remission. d. Overall response rate was 56% for patients receiving brentuximab versus 12% of patients receiving methotrexate or bexarotene with P-value of less CR rate was 15% for patients receiving brentuximab-vedotin versus 1.6% for other arm with P-value of Median PFS was 16.7 months for brentuximab-vedotin versus 3.5 months methotrexate or bexarotene. e. Toxicities: 41% of patients experienced grade 3 or greater adverse events in the brentuximab-vedotin arm versus 47% on the methotrexate or bexarotene arm. Adverse events leading to drug discontinuation occurred in 24% of the patients receiving brentuximab-vedotin versus 8% in the methotrexate/bexarotene arm. Most common cause of drug discontinuation of brentuximab-vedotin was peripheral neuropathy followed skin hypersensitivity. f. There were 4 deaths in 30 days or less of the study drug in the brentuximab-vedotin arm versus 0 deaths in the methotrexate/bexarotene arm. However, deaths were felt to be unrelated to brentuximab (lymphoma progression, sepsis, pulmonary embolus). g. Conclusion: Brentuximab-vedotin demonstrated longer overall response rate in patients with CD30 positive Mycosis fungoides or primary cutaneous anaplastic large cell lymphoma. Continued response, progression-free survival and symptom assessment were improved in patients receiving brentuximab-vedotin. The safety profile was as expected for this drug (neuropathy) without any new signals in terms of unexpected toxicities. h. Authors: Kim, YH et al. ASH Abstract 182. Chronic Lymphocytic Leukemia Venetoclax (VEN) Monotherapy for Patients with Chronic Lymphocytic Leukemia (CLL) Who Relapsed After or Were Refractory to Ibrutinib or Idelalisib a. This was an open-level phase 3 study involving 64 patients with ECOG performance status of 2 or better with adequate bone marrow function, glomerulate rate of 50 ml/min or better and without a history of allogenic stem cell transplant, Richter transformation, or autoimmune cytopenias. b. The primary endpoint of the study was overall response rate and safety analysis. Secondary endpoints included duration of response, overall survival, progression-free survival and evaluation of minimal residual disease. c. The patients received venetoclax 20 mg on week 1, 50 mg on week 2, 100 mg on week 3, 200 mg on week 4, and 400 mg on week 5 and forward. d. Results: Overall response rate was 70% for patients who had relapsed/refractory disease on ibrutinib and 63% on idelalisib. The majority of the responses were partial. Median time on study of 13 months on patients who were refractory/relapsed ibrutinib and 9 months for relapsed/refractory idelalisib group. The estimated 12-month progression-free survival for all patients was 80%. Importantly 45% of the patients were found to have negative minimal residual disease in peripheral blood and 20% had minimal residual disease in bone marrow when assessed. 12 Oncologistics

13 e. The primary reason for stopping therapy was disease progression. Significant side effects noted included diarrhea, pneumonia, cytopenias and rare events such as hyperkalemia, renal dysfunction, hyperphosphatemia, febrile neutropenia. f. Conclusion: For the half who had chronic lymphocytic leukemia population, after ibrutinib, idelalisib or both, venetoclax single-agent therapy demonstrated a response of 70% of patients with refractory ibrutinib and 60% with refractory idelalisib. Durable responses were noted. MRD negativity was noted in 45% of the patients. Therefore venetoclax was considered to be highly active in this specific population with a median follow-up of 11.8 months at the time of study submission. g. Authors: Jones, J et al. ASH Abstract 637. Hodgkins Lymphoma Pembrolizumab in Relapsed/Refractory Classical Hodgkin Lymphoma: Primary End Point Analysis of the Phase 2 Keynote-087 Study a. The keynote-087 was a phase 3 study including patients with relapsed/refractory classical Hodgkin lymphoma with a performance status of ECOG 0 or 1. Three cohorts of patients were identified in the study. The first cohort was patients who had progression after autologous stem cell transplant and subsequent brentuximab-vedotin therapy (69 patients). The second cohort included patients who had failed salvage chemotherapy, brentuximab-vedotin and were ineligible for transplant (81 patients). The third cohort included patients with autologous stem cell transplant but who were not exposed to brentuximab-vedotin after transplant (60 patients). b. Patients were treated with pembrolizumab 200 mg every 3 weeks. Primary endpoint study was overall response rate. Secondary endpoints included duration of response, progression-free survival and overall survival. CT scans were performed every 12 weeks. PET/CT scan was performed on weeks 12 and 24 or sooner if clinically necessary. c. Results: The overall response rate for all patients was 69% assess by independent committee reviewer. 22% of the patients achieved complete remission and 46% achieved partial remission. Stable disease was seen in 14.8%. Of note 79% overall response was seen in patients considered to have primary refractory disease. Overall response was noted in 68% of patients who had relapsed disease after 3 or more lines of therapy. d. Toxicities: 12% of patients experienced hypothyroidism, 20% fever, 9% fatigue, 7% diarrhea, 7% skin rash. 11% of all patients experienced grade 3 or 4 adverse events. More serious events were infusion-related reactions, pneumonitis, hypothyroidism, colitis, and myositis. e. Conclusion: Pembrolizumab showed high activity in patients with relapsed/refractory classical Hodgkin lymphoma with the overall response approaching 70% of all patients. Interestingly 80% of overall response rate was noted to be primary refractory disease. No unexpected toxicities were reported. f. Authors: Moskowitz, C.H. et al. ASH Abstract Dr. Lucio Gordan, is the director of Quality and Medical Informatics for Florida Cancer Specialists and Research Institute. Would you like to read more research summaries in Oncologistics? In what topics are you most interested? Tell us at info@iononline.com. Oncologistics 13

14 We Support the Health of your Practice With the Same Dedication that You Support Your Patients Your number one priority is the health of your patients. With the changing healthcare landscape, our number one priority is the business health of your practice. Dedicated exclusively to the viability of community oncology, ION Solutions provides contracting, technology, education and advocacy support that ensures you have the tools to run your practice both efficiently and effectively. With the practice support of ION Solutions, you can navigate this changing environment and focus on providing quality care for your patients. To learn how ION Solutions enables community oncology practices to improve operational efficiency, financial performance and quality of care, contact your Strategic Account Manager or visit IONonline.com. To experience ION Solutions advocacy support, visit ourcommunitycounts.org. 14 Oncologistics

15 Oncologistics 15

16 Do Not Ignore MACRA It s Not Going Away Even with all the proposed healthcare changes under the new administration, MACRA is not going away. Government agencies and payers are committed to value-based care and reimbursements. CMS has branded the initiative the Quality Payment Program (QPP). Under the Quality Payment Program, there are two tracks your practice can choose from the Merit-based Incentive Program (MIPS) and Advanced Alternative Payment Models (APMs). The differences between the two include: MIPS, a more traditional Medicare program, the clinician s score is based on four performance areas: Quality Measure Performance (replacing PQRS) Advancing Care Information (replacing Meaningful Use) Clinical Practice Improvement Activities Cost (replacing Value-based Payment Modifier) The categories are weighted and will change over the course of a few years. Clinicians can receive a positive, negative or neutral adjustment and will be benchmarked against other clinicians. By waiting until Oct. 2 to begin collecting data you have no opportunity to improve performance and could see a negative adjustment to payments in Oncologistics

17 Advanced APM You may earn an added incentive payment for participating in this model if you are providing high-quality and cost-effective care. To be considered eligible, the APM must meet several criteria. The current models approved by CMS for 2017 are: Oncology Care Model (OCM) Two-Sided Risk Comprehensive ESRD Care (CEC) Two-Sided Risk Comprehensive Primary Care Plus (CPC+) Next Generation ACO Model Shared Savings Program Track 2 Shared Savings Program Track 3 Comprehensive Care for Joint Replacement (CJR) Payment Model (Track 1- CEHRT) Vermont Medicare ACO Initiative (as part of the Vermont All-Payer ACO Model). Providers who are participating in other payment models are not eligible in Who are those eligible clinicians? For reporting in 2017, eligible clinicians are defined as physicians, physician assistants, nurse practitioners, clinical nurse specialists and certified registered nurse anesthetists. In the 2019 performance year, the category will expand to include physical or occupational therapists, speechlanguage pathologists, audiologists, nurse midwives, clinical social workers, clinical psychologists and dietitians/ nutritional professionals. Non-patient-facing professionals like radiologists will face a different set of measures. What is the Performance Year? Practices can begin collecting data from Jan. 1, 2017, but can start any time before Oct. 2, 2017, in order to report by March 31, The first payment adjustments begin on Jan. 1, Why start collecting data before Oct. 2, 2017? By collecting data early, you can look at your performance rates as an individual and as a practice. With that data, you can make adjustments to your processes. By waiting until Oct. 2, you have no opportunity to improve performance and could see a negative adjustment to payments in Do we have options for submitting data under MIPS? CMS has created a plan called Pick Your Pace. Positive adjustments are based on the performance data on the performance information submitted, not the amount of information or length of time submitted. Submit a Full Year You could earn a moderate positive payment adjustment (again, determined by your performance). Submit a Partial Year You can choose to only submit 90 days (note the Oct. 2 deadline). With this plan, you could earn a neutral or small positive payment adjustment. Submit Something You could submit a minimum amount of data, like one quality measure or one improvement activity. Submitting this helps you avoid a downward payment adjustment. Do Not Participate This is an automatic negative 4 percent payment adjustment. ION Solutions Quality Reporting Engagement Group recommends reporting the entire year of data. Your practice will have the opportunity to review its performance during the year and make adjustments for improvement. You also will have the possibility of receiving that moderate positive payment adjustment. About ION Solutions Value-Based Care Services As the U.S. healthcare system navigates toward valuebased reimbursement, providers face both opportunity and risk in their arrangement with payers. Value-based reimbursement is demanding that providers meet certain quality thresholds, while containing costs, to be optimally reimbursed. Let ION Solutions help you transition from fee-forservice to value-based care without any costly missteps you may encounter when trying to meet these demands on your own. Our Quality Reporting Engagement Group is prepared to assist your practice. For more information, us at insidesales@iononline.com or call x2. Oncologistics 17

18 PHYSICIAN SPOTLIGHT NINLARO (ixazomib) for multiple myeloma: an all-oral regimen for patients who ve received at least 1 prior therapy* Shachar Peles, MD This supplement is sponsored and developed by Takeda Oncology. Shachar Peles, MD is a paid consultant of Takeda Oncology. The treatment of multiple myeloma has advanced rapidly over the past decade. With a variety of treatment options now available, it s increasingly more important to consider the role of specific agents and how they fit within the treatment plan for your patients. Takeda Oncology spoke with Shachar Peles, MD, of Florida Cancer Specialists and Research Institute, to learn more about how he chooses the appropriate treatment for his patients. Q. How has the treatment of multiple myeloma evolved over the past decade? A. It s undergoing a revolution. In just the last few years, we ve had so many additional options and classes of agents. But you really need to think ahead in your treatment strategy. It has almost become more like a chess game, where you have to think a few moves ahead. You can t just sort of pick a drug. You have to stop and think about how it will affect your choices down the line. Q. What role does NINLARO play in your treatment approach? A. I think NINLARO with lenalidomide and dexamethasone is an effective regimen. It goes back to our basics of combining a proteasome inhibitor with an immunomodulatory drug and a corticosteroid and this is an entirely oral regimen that may be convenient for patients. The randomized data from the TOURMALINE-MM1 trial show improvement in PFS (median: 20.6 vs 14.7 months [95% CI, 17.0-NE and 95% CI, for the NINLARO and placebo regimens, respectively]; HR=0.74 [95% CI, ]; P=0.012) and rapid responses (median time to response was 1.1 months vs 1.9 months, respectively). *INDICATION NINLARO is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. Please see Important Safety Information here and on the following pages, and Brief Summary for NINLARO (ixazomib) adjacent to this advertisement. IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Thrombocytopenia has been reported with NINLARO. During treatment, monitor platelet counts at least monthly, and consider more frequent monitoring during the first three cycles. Manage thrombocytopenia with dose modifications and platelet transfusions as per standard medical guidelines. Adjust dosing as needed. Platelet nadirs occurred between Days of each 28-day cycle and typically recovered to baseline by the start of the next cycle. Gastrointestinal Toxicities, including diarrhea, constipation, nausea and vomiting, were reported with NINLARO and may occasionally require the use of antidiarrheal and antiemetic medications, and supportive care. Diarrhea resulted in the discontinuation of one or more of the three drugs in 1%

19 The randomized data from the TOURMALINE-MM1 trial showed improvement in PFS and rapid responses. So you know the efficacy is there. This is important, especially for relapsed and/or refractory patients. Q. Does a patient s lifestyle factor into your treatment decision? A. Patient lifestyle absolutely plays a role. If I have a patient who lives a significant distance from the office or has transportation difficulties, I d be more likely to suggest an oral regimen for them. If I have a patient who is employed full time and very active, again, an oral agent may make more sense. Q. What are your goals for the length of therapy with NINLARO? A. For multiple myeloma, we ve moved away from treating to the best response, taking a break, and then starting therapy again when relapse occurs. I think most of us believe that treating to progression or unacceptable toxicity is the way to go and that patients may see an improved outcome if they re able to stay on therapy. I try to set expectations with patients at the time of diagnosis and in the relapse setting, telling them that they re going to remain on treatment as long as it s working and they re tolerating therapy. As we saw in the TOURMALINE-MM1 trial, there were few discontinuations due to toxicities or adverse reactions (see right), 13% vs 11% for patients receiving the NINLARO vs placebo regimen, respectively. 1 The approval of the NINLARO regimen (NINLARO+lenalidomide+dexamethasone) was based on a statistically significant ~6 month improvement in median PFS vs the placebo regimen (placebo+lenalidomide+dexamethasone) (median: 20.6 vs 14.7 months [95% CI, 17.0-NE and 95% CI, , respectively]; HR=0.74 [95% CI, ]; P=0.012). The NINLARO regimen demonstrated rapid responses Median time to initial response (months) NINLARO regimen 1.1 Placebo+len+dex 1.9 Nonhematologic ARs occurring in 5% of patients with a 5% difference between the NINLARO regimen (n=360) and the placebo regimen (n=360) All grades, grade 3 (respectively): upper respiratory (19%, <1% vs 14%, <1%), peripheral neuropathies (28%, 2% vs 21%, 2%), diarrhea (42%, 6% vs 36%, 2%), constipation (34%, <1% vs 25%, <1%), nausea (26%, 2% vs 21%, 0%), vomiting (22%, 1% vs 11%, <1%), rash (19%, 3% vs 11%, 1%), back pain (21%, <1% vs 16%, 3%), peripheral edema (25%, 2% vs 18%, 1%) No grade 4 nonhematologic ARs occurred in either regimen Serious ARs Serious ARs reported in 2% of patients included thrombocytopenia (2%) and diarrhea (2%) TOURMALINE-MM1: a global, phase 3, randomized (1:1), double-blind, placebo-controlled study that evaluated the safety and efficacy of NINLARO (an oral proteasome inhibitor) vs placebo, both in combination with lenalidomide and dexamethasone, until disease progression or unacceptable toxicity in 722 patients with relapsed and/or refractory multiple myeloma who received 1-3 prior therapies. 2 Represents a pooling of preferred terms. ARs=adverse reactions; NE=not evaluable; PFS=progression-free survival. of patients in the NINLARO regimen and < 1% of patients in the placebo regimen. Adjust dosing for severe symptoms. Peripheral Neuropathy (predominantly sensory) was reported with NINLARO. 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%). Peripheral neuropathy resulted in discontinuation of one or more of the three drugs in 1% of patients in both regimens. Monitor patients for symptoms of peripheral neuropathy and adjust dosing as needed. Peripheral Edema was reported with NINLARO. Monitor for fluid retention. Investigate for underlying causes when appropriate and provide supportive care as necessary. Adjust dosing of dexamethasone per its prescribing information or NINLARO for Grade 3 or 4 symptoms. Cutaneous Reactions: Rash, most commonly maculo-papular and macular rash, was reported with NINLARO. Rash resulted in discontinuation of one or more of the three drugs in < 1% of patients in both regimens. Manage rash with supportive care or with dose modification.

20 PHARMACY DIRECTOR SPOTLIGHT A director of pharmacy s perspective on NINLARO (ixazomib) and oral oncolytics We are seeing an increased use of NINLARO in our pharmacy and we are gearing up for that. This supplement is sponsored and developed by Takeda Oncology. Ray Bailey, RPh Oral oncolytics are gaining greater traction in clinical practice. This is partly due to patient preference for oral administration. 3 Takeda Oncology spoke with Ray Bailey, RPh, who oversees the operations of Florida Cancer Specialists oncology specialty pharmacy, Rx To Go, to learn more about his experience with the proliferation of new orals, such as NINLARO. Q. What s your role as the director of pharmacy at Florida Cancer Specialists? A. I m responsible for overseeing the operations of the oncology specialty pharmacy, Rx To Go, including financial management, business development, new drug access, purchasing contracts, and overall formulary management. We re about putting our patients first, giving them the absolute best care. WARNINGS AND PRECAUTIONS (continued) Hepatotoxicity has been reported with NINLARO. Drug-induced liver injury, hepatocellular injury, hepatic steatosis, hepatitis cholestatic and hepatotoxicity have each been reported in < 1% of patients treated with NINLARO. Events of liver impairment have been reported (6% in the NINLARO regimen and 5% in the placebo regimen). Monitor hepatic enzymes regularly during treatment and adjust dosing as needed. Embryo-fetal Toxicity: NINLARO can cause fetal harm. Women should be advised of the potential risk to a fetus, to avoid becoming pregnant, and to use contraception during treatment and for an additional 90 days after the final dose of NINLARO. Women using hormonal contraceptives should also use a barrier method of contraception. ADVERSE REACTIONS The most common adverse reactions ( 20%) in the NINLARO regimen and greater than the placebo regimen, respectively, were diarrhea (42%, 36%), constipation (34%, 25%), thrombocytopenia (78%, 54%; pooled from adverse events and laboratory data), peripheral neuropathy (28%, 21%), nausea (26%, 21%), peripheral edema (25%, 18%), vomiting (22%, 11%), and back pain (21%, 16%). Serious adverse reactions reported in 2% of patients included thrombocytopenia (2%) and diarrhea (2%). Please see Important Safety Information on this page and Brief Summary for NINLARO (ixazomib) adjacent to this advertisement.

21 The NINLARO regimen represented a sustainable treatment for patients Discontinuation rates of the full regimen due to ARs 1 13% NINLARO regimen (n=360) 11% Placebo+len+dex (n=360) Discontinuation rates were low and comparable with the NINLARO and placebo regimens. 80% of patients continued at the starting dose of NINLARO without dose reduction. 1 Q. How has your pharmacy evolved with the proliferation of oral oncolytics? A. In the beginning, I don t think any of us really knew how big oral oncolytics were going to be. At first we were just filling medications, talking to patients about interactions, side effects, and administration, and kind of checking in every now and again. But that just doesn t work for orals. As an oncology pharmacy, you have to get a lot more involved to manage patients. I found that the way orals were dispensed and how patients were taken care of varied widely in practices around the United States. But what motivates me is helping patients, so we decided early on that patients were going to receive our full attention and care. SPECIAL POPULATIONS Hepatic Impairment: Reduce the NINLARO starting dose to 3 mg in patients with moderate or severe hepatic impairment. Q. What has been your experience with NINLARO? A. The NINLARO regimen offers patients the convenience of an all-oral treatment plan, so they can take their medication at home. At Florida Cancer Specialists, we have had success dispensing NINLARO with Rx To Go. We are seeing an increased use of NINLARO in our pharmacy and we are gearing up for that. What motivates me is helping patients because there may be a great need for orals. Renal Impairment: Reduce the NINLARO starting dose to 3 mg in patients with severe renal impairment or end-stage renal disease requiring dialysis. NINLARO is not dialyzable. Q. How does the pharmacist interact and engage with patients? A. When it comes to oral oncolytics, we ve developed an adherence platform where we can manage our patients. It s interesting because even though a patient refills their prescription on time, it doesn t mean they re taking it properly. As a pharmacist, we want to make sure we can help measure how well a patient is responding to therapy and to me, the best measure of a good outcome is persistency. So we re trying to connect with our patients and help get them over that hump during the first couple of months and see how long they can remain on therapy, as long as they are tolerating it and responding to it. Lactation: Advise nursing women not to breastfeed during treatment with NINLARO and for 90 days after the last dose. DRUG INTERACTIONS: Avoid concomitant administration of NINLARO with strong CYP3A inducers. REFERENCES: 1. Data on File 117, Takeda Pharmaceuticals International Co. 2. Moreau P, Masszi T, Grzasko N, et al; for the TOURMALINE-MM1 Study Group. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;374(17): Weingart SN, Brown E, Bach PB, et al. NCCN Task Force report: oral chemotherapy. J Natl Compr Canc Netw. 2008;6(suppl 3):S1-S14. Takeda Oncology and are registered trademarks of Takeda Pharmaceutical Company Limited. NINLARO is a registered trademark of Millennium Pharmaceuticals, Inc. Copyright 2017, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in USA 1/17 USO/IXA/16/0327

22 BRIEF SUMMARY OF PRESCRIBING INFORMATION NINLARO (ixazomib) capsules, for oral use 1 INDICATION NINLARO (ixazomib) is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. 5 WARNINGS AND PRECAUTIONS 5.1 Thrombocytopenia: Thrombocytopenia has been reported with NINLARO with platelet nadirs typically occurring between Days of each 28-day cycle and recovery to baseline by the start of the next cycle. Three percent of patients in the NINLARO regimen and 1% of patients in the placebo regimen had a platelet count 10,000/mm 3 during treatment. Less than 1% of patients in both regimens had a platelet count 5000/mm 3 during treatment. Discontinuations due to thrombocytopenia were similar in both regimens (< 1% of patients in the NINLARO regimen and 2% of patients in the placebo regimen discontinued one or more of the three drugs).the rate of platelet transfusions was 6% in the NINLARO regimen and 5% in the placebo regimen. Monitor platelet counts at least monthly during treatment with NINLARO. Consider more frequent monitoring during the first three cycles. Manage thrombocytopenia with dose modifications and platelet transfusions as per standard medical guidelines. 5.2 Gastrointestinal Toxicities: Diarrhea, constipation, nausea, and vomiting, have been reported with NINLARO, occasionally requiring use of antidiarrheal and antiemetic medications, and supportive care. Diarrhea was reported in 42% of patients in the NINLARO regimen and 36% in the placebo regimen, constipation in 34% and 25%, respectively, nausea in 26% and 21%, respectively, and vomiting in 22% and 11%, respectively. Diarrhea resulted in discontinuation of one or more of the three drugs in 1% of patients in the NINLARO regimen and < 1% of patients in the placebo regimen. Adjust dosing for Grade 3 or 4 symptoms. 5.3 Peripheral Neuropathy: The majority of peripheral neuropathy adverse reactions were Grade 1 (18% in the NINLARO regimen and 14% in the placebo regimen) and Grade 2 (8% in the NINLARO regimen and 5% in the placebo regimen). Grade 3 adverse reactions of peripheral neuropathy were reported at 2% in both regimens; there were no Grade 4 or serious adverse reactions. The most commonly reported reaction was peripheral sensory neuropathy (19% and 14% in the NINLARO and placebo regimen, respectively). Peripheral motor neuropathy was not commonly reported in either regimen (< 1%). Peripheral neuropathy resulted in discontinuation of one or more of the three drugs in 1% of patients in both regimens. Patients should be monitored for symptoms of neuropathy. Patients experiencing new or worsening peripheral neuropathy may require dose modification. 5.4 Peripheral Edema: Peripheral edema was reported in 25% and 18% of patients in the NINLARO and placebo regimens, respectively. The majority of peripheral edema adverse reactions were Grade 1 (16% in the NINLARO regimen and 13% in the placebo regimen) and Grade 2 (7% in the NINLARO regimen and 4% in the placebo regimen). Grade 3 peripheral edema was reported in 2% and 1% of patients in the NINLARO and placebo regimens, respectively. There was no Grade 4 peripheral edema reported. There were no discontinuations reported due to peripheral edema. Evaluate for underlying causes and provide supportive care, as necessary. Adjust dosing of dexamethasone per its prescribing information or NINLARO for Grade 3 or 4 symptoms. 5.5 Cutaneous Reactions: Rash was reported in 19% of patients in the NINLARO regimen and 11% of patients in the placebo regimen. The majority of the rash adverse reactions were Grade 1 (10% in the NINLARO regimen and 7% in the placebo regimen) or Grade 2 (6% in the NINLARO regimen and 3% in the placebo regimen). Grade 3 rash was reported in 3% of patients in the NINLARO regimen and 1% of patients in the placebo regimen. There were no Grade 4 or serious adverse reactions of rash reported. The most common type of rash reported in both regimens included maculo-papular and macular rash. Rash resulted in discontinuation of one or more of the three drugs in < 1% of patients in both regimens. Manage rash with supportive care or with dose modification if Grade 2 or higher. 5.6 Hepatotoxicity: Drug-induced liver injury, hepatocellular injury, hepatic steatosis, hepatitis cholestatic and hepatotoxicity have each been reported in < 1% of patients treated with NINLARO. Events of liver impairment have been reported (6% in the NINLARO regimen and 5% in the placebo regimen). Monitor hepatic enzymes regularly and adjust dosing for Grade 3 or 4 symptoms. 5.7 Embryo-Fetal Toxicity: NINLARO can cause fetal harm when administered to a pregnant woman based on the mechanism of action and findings in animals. There are no adequate and well-controlled studies in pregnant women using NINLARO. Ixazomib caused embryo-fetal toxicity in pregnant rats and rabbits at doses resulting in exposures that were slightly higher than those observed in patients receiving the recommended dose. Females of reproductive potential should be advised to avoid becoming pregnant while being treated with NINLARO. If NINLARO is used during pregnancy or if the patient becomes pregnant while taking NINLARO, the patient should be apprised of the potential hazard to the fetus. Advise females of reproductive potential that they must use effective contraception during treatment with NINLARO and for 90 days following the final dose. Women using hormonal contraceptives should also use a barrier method of contraception. 6 ADVERSE REACTIONS The following adverse reactions are described in detail in other sections of the prescribing information: Thrombocytopenia [see Warnings and Precautions (5.1)] Gastrointestinal Toxicities [see Warnings and Precautions (5.2)] Peripheral Neuropathy [see Warnings and Precautions (5.3)] Peripheral Edema [see Warnings and Precautions (5.4)] Cutaneous Reactions [see Warnings and Precautions (5.5)] Hepatotoxicity [see Warnings and Precautions (5.6)] 6.1 CLINICAL TRIALS EXPERIENCE Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety population from the randomized, double-blind, placebo-controlled clinical study included 720 patients with relapsed and/or refractory multiple myeloma, who received NINLARO in combination with lenalidomide and dexamethasone (NINLARO regimen; N=360) or placebo in combination with lenalidomide and dexamethasone (placebo regimen; N=360). The most frequently reported adverse reactions ( 20%) in the NINLARO regimen and greater than the placebo regimen were diarrhea, constipation, thrombocytopenia, peripheral neuropathy, nausea, peripheral edema, vomiting, and back pain. 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. Table 4: Non-Hematologic Adverse Reactions Occurring in 5% of Patients with a 5% Difference Between the NINLARO Regimen and the Placebo Regimen (All Grades, Grade 3 and Grade 4) System Organ Class / Preferred Term NINLARO + Lenalidomide and Dexamethasone N=360 All Placebo + Lenalidomide and Dexamethasone N=360 N (%) N (%) Grade 3 Grade 4 All Grade 3 Grade 4 Infections and infestations Upper respiratory tract infection 69 (19) 1 (< 1) 0 52 (14) 2 (< 1) 0 Nervous system disorders Peripheral neuropathies* 100 (28) 7 (2) 0 77 (21) 7 (2) 0 Gastrointestinal disorders Diarrhea Constipation Nausea Vomiting 151 (42) 122 (34) 92 (26) 79 (22) 22 (6) 1 (< 1) 6 (2) 4 (1) (36) 90 (25) 74 (21) 38 (11) 8 (2) 1 (< 1) 0 2 (< 1) Skin and subcutaneous tissue disorders Rash* 68 (19) 9 (3) 0 38 (11) 5 (1) 0 Musculoskeletal and connective tissue disorders Back pain 74 (21) 2 (< 1) 0 57 (16) 9 (3) 0 General disorders and administration site conditions Edema peripheral 91 (25) 8 (2) 0 66 (18) 4 (1) 0 Note: Adverse reactions included as preferred terms are based on MedDRA version *Represents a pooling of preferred terms (Continued on next page)

23 Brief Summary (cont d) Table 5: Thrombocytopenia and Neutropenia (pooled adverse event and laboratory data) NINLARO + Lenalidomide and Dexamethasone N=360 Placebo + Lenalidomide and Dexamethasone N=360 N (%) N (%) Any Grade Grade 3-4 Any Grade Grade 3-4 Thrombocytopenia 281 (78) 93 (26) 196 (54) 39 (11) Neutropenia 240 (67) 93 (26) 239 (66) 107 (30) Herpes Zoster Herpes zoster was reported in 4% of patients in the NINLARO regimen and 2% of patients in the placebo regimen. Antiviral prophylaxis was allowed at the physician s discretion. Patients treated in the NINLARO regimen who received antiviral prophylaxis had a lower incidence (< 1%) of herpes zoster infection compared to patients who did not receive prophylaxis (6%). Eye Disorders Eye disorders were reported with many different preferred terms but in aggregate, the frequency was 26% in patients in the NINLARO regimen and 16% of patients in the placebo regimen. The most common adverse reactions were blurred vision (6% in the NINLARO regimen and 3% in the placebo regimen), dry eye (5% in the NINLARO regimen and 1% in the placebo regimen), and conjunctivitis (6% in the NINLARO regimen and 1% in the placebo regimen). Grade 3 adverse reactions were reported in 2% of patients in the NINLARO regimen and 1% in the placebo regimen. The following serious adverse reactions have each been reported at a frequency of < 1%: acute febrile neutrophilic dermatosis (Sweet s syndrome), Stevens- Johnson syndrome, transverse myelitis, posterior reversible encephalopathy syndrome, tumor lysis syndrome, and thrombotic thrombocytopenic purpura. 7 DRUG INTERACTIONS 7.1 Strong CYP3A Inducers: Avoid concomitant administration of NINLARO with strong CYP3A inducers (such as rifampin, phenytoin, carbamazepine, and St. John s Wort). 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Risk Summary: Based on its mechanism of action and data from animal reproduction studies, NINLARO can cause fetal harm when administered to a pregnant woman. There are no human data available regarding the potential effect of NINLARO on pregnancy or development of the embryo or fetus. Ixazomib caused embryo-fetal toxicity in pregnant rats and rabbits at doses resulting in exposures that were slightly higher then those observed in patients receiving the recommended dose. Advise women of the potential risk to a fetus and to avoid becoming pregnant while being treated with NINLARO. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Animal Data: In an embryo-fetal development study in pregnant rabbits there were increases in fetal skeletal variations/abnormalities (caudal vertebrae, number of lumbar vertebrae, and full supernumerary ribs) at doses that were also maternally toxic ( 0.3 mg/kg). Exposures in the rabbit at 0.3 mg/kg were 1.9 times the clinical time averaged exposures at the recommended dose of 4 mg. In a rat dose range-finding embryo-fetal development study, at doses that were maternally toxic, there were decreases in fetal weights, a trend towards decreased fetal viability, and increased post-implantation losses at 0.6 mg/kg. Exposures in rats at the dose of 0.6 mg/kg was 2.5 times the clinical time averaged exposures at the recommended dose of 4 mg. 8.2 Lactation: No data are available regarding the presence of NINLARO or its metabolites in human milk, the effects of the drug on the breast fed infant, or the effects of the drug on milk production. Because the potential for serious adverse reactions from NINLARO in breastfed infants is unknown, advise nursing women not to breastfeed during treatment with NINLARO and for 90 days after the last dose. 8.3 Females and Males of Reproductive Potential: Contraception - Male and female patients of childbearing potential must use effective contraceptive measures during and for 90 days following treatment. Dexamethasone is known to be a weak to moderate inducer of CYP3A4 as well as other enzymes and transporters. Because NINLARO is administered with dexamethasone, the risk for reduced efficacy of contraceptives needs to be considered. Advise women using hormonal contraceptives to also use a barrier method of contraception. 8.4 Pediatric Use: Safety and effectiveness have not been established in pediatric patients. 8.5 Geriatric Use: Of the total number of subjects in clinical studies of NINLARO, 55% were 65 and over, while 17% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment: In patients with moderate or severe hepatic impairment, the mean AUC increased by 20% when compared to patients with normal hepatic function. Reduce the starting dose of NINLARO in patients with moderate or severe hepatic impairment. 8.7 Renal Impairment: In patients with severe renal impairment or ESRD requiring dialysis, the mean AUC increased by 39% when compared to patients with normal renal function. Reduce the starting dose of NINLARO in patients with severe renal impairment or ESRD requiring dialysis. NINLARO is not dialyzable and therefore can be administered without regard to the timing of dialysis 10 OVERDOSAGE: There is no known specific antidote for NINLARO overdose. In the event of an overdose, monitor the patient for adverse reactions and provide appropriate supportive care. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Dosing Instructions Instruct patients to take NINLARO exactly as prescribed. Advise patients to take NINLARO once a week on the same day and at approximately the same time for the first three weeks of a four week cycle. Advise patients to take NINLARO at least one hour before or at least two hours after food. Advise patients that NINLARO and dexamethasone should not be taken at the same time, because dexamethasone should be taken with food and NINLARO should not be taken with food. Advise patients to swallow the capsule whole with water. The capsule should not be crushed, chewed or opened. Advise patients that direct contact with the capsule contents should be avoided. In case of capsule breakage, avoid direct contact of capsule contents with the skin or eyes. If contact occurs with the skin, wash thoroughly with soap and water. If contact occurs with the eyes, flush thoroughly with water. If a patient misses a dose, advise them to take the missed dose as long as the next scheduled dose is 72 hours away. Advise patients not to take a missed dose if it is within 72 hours of their next scheduled dose. If a patient vomits after taking a dose, advise them not to repeat the dose but resume dosing at the time of the next scheduled dose. Advise patients to store capsules in original packaging, and not to remove the capsule from the packaging until just prior to taking NINLARO. Thrombocytopenia: Advise patients that they may experience low platelet counts (thrombocytopenia). Signs of thrombocytopenia may include bleeding and easy bruising. Gastrointestinal Toxicities: Advise patients they may experience diarrhea, constipation, nausea and vomiting and to contact their physician if these adverse reactions persist. Peripheral Neuropathy: Advise patients to contact their physicians if they experience new or worsening symptoms of peripheral neuropathy such as tingling, numbness, pain, a burning feeling in the feet or hands, or weakness in the arms or legs. Peripheral Edema: Advise patients to contact their physicians if they experience unusual swelling of their extremities or weight gain due to swelling. Cutaneous Reactions: Advise patients to contact their physicians if they experience new or worsening rash Hepatotoxicity: Advise patients to contact their physicians if they experience jaundice or right upper quadrant abdominal pain Other Adverse Reactions: Advise patients to contact their physicians if they experience signs and symptoms of acute febrile neutrophilic dermatosis (Sweet s syndrome), Stevens-Johnson syndrome, transverse myelitis, posterior reversible encephalopathy syndrome, tumor lysis syndrome, and thrombotic thrombocytopenic purpura Pregnancy: Advise women of the potential risk to a fetus and to avoid becoming pregnant while being treated with NINLARO and for 90 days following the final dose. Advise women using hormonal contraceptives to also use a barrier method of contraception. Advise patients to contact their physicians immediately if they or their female partner become pregnant during treatment or within 90 days of the final dose. Concomitant Medications: Advise patients to speak with their physicians about any other medication they are currently taking and before starting any new medications. Please see full Prescribing Information for NINLARO at NINLARO-hcp.com. NINLARO is a registered trademark of Millennium Pharmaceuticals, Inc. Millennium Pharmaceuticals, Inc. is a wholly owned subsidiary of Takeda Pharmaceutical Company Limited Millennium Pharmaceuticals, Inc. NOV 2016 USO/IXA/15/0123(3)

24 AdvanceIQ Network Improves Access to Clinical Trials Network enables community oncologists to access innovative treatment opportunities IntrinsiQ Specialty Solutions and ION Solutions, both a part of AmerisourceBergen, have launched AdvanceIQ Network, a resource designed to better match independent community oncology practices with clinical trials and research opportunities. Through AdvanceIQ Network, these practices in the U.S. will have a more streamlined approach to identifying, qualifying for and enrolling in targeted clinical trials that offer groundbreaking treatment options for improved patient outcomes. AdvanceIQ will be made available to the more than 5,300 community specialty providers who are a part of ION Solutions and will help eliminate barriers that can prevent participation in clinical trials, including limited resources or time. Practices select the types of research in which they would like to participate, as well as provide access to de-identified patient information. Clinical trial developers can then leverage the AdvanceIQ Network to find practices treating patients who meet specific trial criteria. This offering not only enhances clinical trial matching and leverages new innovative trial recruitment solutions, but also increases patient access to the most advanced therapies and treatment strategies. AdvanceIQ Network will help to facilitate clinical trials, investigator research, prospective patient registries, retrospective outcomes research studies and panel studies. Participating practices and their physicians also will receive contract management resources, ongoing research education and training and grant submission support. We are constantly striving to provide exceptional support for patients, as well as providers, in order to drive better outcomes and ultimately enhance care, said Vicki Albrecht, Ph.D., senior vice president and general manager at ION Solutions. By leveraging our expertise and network to connect our oncology providers to new trials, AdvanceIQ can truly make an impact in supporting broader access to innovative research in a community setting. For more information about AdvanceIQ Network, please visit The launch of AdvanceIQ Network addresses one of healthcare s biggest challenges access. As specialty care continues to grow, it s critically important we create new pathways, through both innovation and partnerships, to connect patients to cutting-edge therapies found in clinical trials, said Susan Weidner, senior vice president at IntrinsiQ Specialty Solutions. 24 Oncologistics

25 LEADING THE WAY to a more comfortable treatment experience At Midatech Pharma US Inc, we are taking oncology supportive care in a new direction. Our unique portfolio of innovative products is designed to help make your patients treatment journey as smooth as possible. Bioadherent Oral Gel Oncologistics 25

26 What s News at ION Better Manage Drug Spend and Optimize Reimbursements with Protocol Analyzer Over the past five years, the cost of oncology medicines has risen 72 percent, and while there were an increased number of generics because of the loss of patent exclusivity, the cost increases of branded drugs offset any savings that could be realized. As the number one expense for practices, you need to keep a sharper focus on inventory management in order to at least maintain the same level of revenue. ION Solutions Protocol Analyzer can help calculate your potential gain or loss by dose, MBU or drug protocol. Medicare fee schedules are loaded automatically each quarter and practices can have their commercial payer fee schedules uploaded as well. You also can look to see how drug reimbursement will compare to Medicare. With a protocol cost analysis, dashboards will show by color coding the levels of profitability, including the patient s co-pay. In addition, Protocol Analyzer can create reports with your drugs and your costs which you can schedule to have ed to you monthly. Access Protocol Analyzer on the Nucleus Connect platform directly through the homepage of the ION Solutions website, ION Solutions, HealthGrid Collaborate to Provide Patient Engagement Technology ION Solutions and Orlando-based patient engagement company HealthGrid have announced a partnership to deliver a best-in-class patient engagement platform for community oncologists. The platform, powered by HealthGrid technology, will enable ION members who dispense and administer oral chemotherapy to connect with patients anytime, anywhere and through any mobile device. The tool will provide practices with actionable reminders, surveys, education and notifications to increase patient connectivity and improve medication adherence. ION Solutions is committed to providing community oncologists with critical resources that will better allow them to deliver exceptional patient care, said Mark Santos, R.Ph., president of ION GPO. We are excited to partner with HealthGrid to offer our members an advanced solution that will enhance patient engagement by improving access to critical health information and care management. As more patients begin to use self-administered oral medications, it has become increasingly important to enhance the connectivity and communication between the provider and patient. By offering this newest engagement platform to the largest network of dispensing practices, ION Solutions and HealthGrid have established a solution to ensure community oncologists stay connected with their patients even outside the four walls of the medical practice or pharmacy. Creating a patient engagement ecosystem is a critical part of cancer care, and HealthGrid is proud to bring intelligent patient engagement capabilities to ION s network of providers, said Raj Toleti, co-founder and CEO of HealthGrid. When a patient-centered care delivery model for oncology care management is in place, the entire care process is more effective, and ultimately drives a better patient experience and improved outcomes. 26 Oncologistics

27 ION Solutions Educational Programs 2017 Meeting Schedule Meeting Date Meeting Name Location Venue September 7-8 Smart ID Charlotte, NC Westin Charlotte September 8-10 National Healthcare Practitioners Charlotte, NC Westin Charlotte October 6-8 Immuno-Oncology Orlando, FL Hyatt Regency Grand Cypress November 3-5 ION National Baltimore, MD Hilton All ION Solutions meeting materials are archived on iononline.com. Visit the website to view slides and videos from past meetings. Registration will be available approximately 60 days prior to each event. To register, visit *Meeting dates subject to change.* Oncologistics 27

28 Shrinking margins have pushed independent specialty practices to place even greater focus on operational efficiency. In response, successful practices have turned to their GPO and distribution partner for customized inventory management, as well as integrated technologies and business consulting, to increase time with patients. Improving cash flow takes a streamlined workflow. It takes AmerisourceBergen. ItTakesAmerisourceBergen.com SPECIALTY DISTRIBUTION \ GPO SERVICES \ TECHNOLOGY AND BUSINESS CONSULTING \ SPECIALTY PHARMACY