Change Healthcare Clinical Evidence Classification

Transcription

1 InterQual Specialty Rx Oncology Criteria Bibliography Change Healthcare Clinical Evidence Classification References cited in the clinical content are classified according to the type of evidence presented. The class ratings, I through V, are intended to provide a classification of the evidence but are not necessarily hierarchical. Classifications appear in parentheses at the end of each reference. References followed by an (NC) are not classified; examples include pre-published research or information from government, manufacturer, laboratory, or patient education websites. Classification Class I Class II Class III Class IV Class V Type of Evidence Meta-analysis, technology assessment, or systematic review Randomized controlled trial Observational or epidemiologic study Evidence-based guideline Expert opinion, panel consensus, literature review, text or reference book, descriptive study, case report, or case series Class I Class I sources synthesize the results of multiple studies. When quantitative synthesis is possible, meta-analyses can provide a more accurate estimate of the effect or association size than individual smaller studies can. A Class I study that finds insufficient evidence to support or refute an intervention (due to a lack of appropriate primary research) is inconclusive. A potential weakness of Class I studies is that they may only assess published research, potentially leaving their findings vulnerable to publication bias Change Healthcare, LLC and/or its subsidiaries. All Rights Reserved. Produced in Cork, Ireland. 1

2 Class II A randomized controlled trial (RCT) is an experimental study design in which subjects are randomly assigned to an intervention or a control group. An RCT is the gold standard for testing cause and effect relationships. Intention-to-treat analysis should be performed to account for missing data points. Class III Observational or epidemiologic studies can suggest an association between events or findings. These associations cannot be used to establish causality. Cross-sectional, cohort, and casecontrol studies are all used to identify possible risk factors. Cross-sectional studies are also used to determine the prevalence of a condition. Cohort studies are used to study incidence, the natural history of a condition, prognosis after a specific exposure, and associated harms. Nonrandomized controlled trials are sometimes used when randomization is impossible or unethical. Class IV Evidence-based guidelines are systematically developed recommendations for clinical practice. Evidence-based guidelines identify the methodology used to gather the evidence on which the recommendations are based. Usually, a grading system for both the quality of the evidence and the strength of the recommendations is provided. Guidelines that are evidencebased may also contain consensus recommendations in areas where evidence is lacking, but these recommendations are clearly identified and appropriately graded. Class V Class V references may be the best information in the absence of other evidence. Expert opinion, panel consensus, literature reviews, and descriptive studies (case reports or case series) are subject to significant bias. A case series with comparison to historical controls can be plagued with missing data, and data extraction inconsistencies are common. The use of historical controls does not address how the diagnosis of disease or its treatment has evolved over time with newer technologies or medication. Text book information may be out of date by the time the book is published. Comparative Effectiveness Research (CER) Citations are designated with the CER label as part of the evidence classification if the article cited is one of the following: 1. A clinical trial or other clinical study that directly compares two or more health care interventions for the same clinical scenario. 2. A systematic review that compares two or more health care interventions by synthesizing the research from previous clinical studies Change Healthcare, LLC and/or its subsidiaries. All Rights Reserved. Produced in Cork, Ireland. 2

3 Bibliography Aapro et al. A phase III, double-blind, randomized trial of palonosetron compared with ondansetron in preventing chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy. Ann Oncol (9): (II CER) Aapro et al. A randomized phase III study evaluating the efficacy and safety of NEPA, a fixeddose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy. Ann Oncol (7): (II) Abraxis Bioscience, LLC. Abraxane (paclitaxel protein-bound particles for injectable suspension) prescribing information. Summit NJ: Abraxis Bioscience, LLC; Rev 7/2015. Available from: (V) Aerts et al. Use of darbepoetin alfa in European clinical practice for the management of chemotherapy-induced anaemia in four tumour types: final data from the CHOICE study. Curr Med Res Opin (7): (III) Aghajanian et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol (17): (II) Amgen Inc. Aranesp (darbepoetin alfa) prescribing information. Thousand Oaks CA: Amgen Inc.; Rev 10/2017. Available from: (V) Amgen Inc. Epogen (epoetin alfa) prescribing information. Thousand Oaks CA: Amgen Inc.; Rev 4/2017. Available from: (V) Amgen Inc. Neulasta (pegfilgrastim) prescribing information. Thousand Oaks CA: Amgen Inc.; Rev 12/2016. Available from: (V) Amgen Inc. Neupogen (filgrastim) prescribing information. Thousand Oaks CA: Amgen Inc.; Rev 7/2015. Available from: (V) Amgen Inc. Vectibix (panitumumab) prescribing information. Thousand Oaks CA: Amgen Inc; Rev 6/2017. Available from: (V) Amgen Inc.. Prolia (denosumab) prescribing information. Thousand Oaks CA: Amgen Inc; Rev 5/2017. Available from: (V) Amgen Inc.. Xgeva (denosumab) prescribing information. Thousand Oaks CA: Amgen Inc.; Rev 1/2018. Available from: (V) Ansell et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med (4): (III) Armand et al. Programmed Death-1 Blockade With Pembrolizumab in Patients With Classical Hodgkin Lymphoma After Brentuximab Vedotin Failure. J Clin Oncol (III) Attal et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med (19): (II) 2018 Change Healthcare, LLC and/or its subsidiaries. All Rights Reserved. Produced in Cork, Ireland. 3

4 Balar, AV. Pembrolizumab as first-line therapy in cisplatin-ineligible advanced urothelial cancer: Results from the total KEYNOTE-052 study population. J Clin Onc (6): abstract 284. (NC) Bang et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet (9742): (II CER) Baselga et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med (2): (II CER) Baxter Oncology GmbH. Ixempra (ixabepilone) prescribing information. Halle/Westfalen, Germany: Baxter Oncology GmbH; Rev 1/2016. Available from: Rev. (V) Bellmunt et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med (11): (II) Bennouna et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol (1): (III) Beohringer Ingelheim International GmbH. Gilotrif (afatinib) prescribing information. Ridgefield, CT. Beohringer Ingelheim International GmbH. Rev 11/2017. Available from: ation/pis/gilotrif/gilotrif.pdf (V) Bokemeyer et al. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wildtype metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer (10): (V) Bonner et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol (1):21-8. (II CER) Borghaei et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med (17): (II) Brahmer et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med (2): (II) Bristol-Myers Squibb Company. Opdivo (nivolumab) prescribing information. Princeton, NJ: Bristol-Myers Squibb Company; Rev 12/2017. Available from: (V) Bristol-Myers Squibb Company. Yervoy (ipilimumab) prescribing information. Princeton NJ: Bristol- Myers Squibb Company; Rev 12/2017. Available from: (V) Bustos et al. Evaluation of clinical use and effectiveness of darbepoetin alfa in cancer patients with chemotherapy-induced anemia. Curr Med Res Opin (1): (III) Cappuzzo et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol (6): (II) Celgene Corporation. Revlimid (lenalidomide) capsules, prescribing information. Summit, NJ; Celgene Corporation. Rev 12/2017. Available from: (V) Chan et al. Low-dose pembrolizumab for relapsed/refractory Hodgkin lymphoma: high efficacy with minimal toxicity. Ann Hematol (4): (III) 2018 Change Healthcare, LLC and/or its subsidiaries. All Rights Reserved. Produced in Cork, Ireland. 4

5 Chapman et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med (26): (II) Chawla et al. Safety and efficacy of denosumab for adults and skeletally mature adolescents with giant cell tumour of bone: interim analysis of an open-label, parallel-group, phase 2 study. Lancet Oncol (9): (III) Chen et al. Phase II Study of the Efficacy and Safety of Pembrolizumab for Relapsed/Refractory Classic Hodgkin Lymphoma. J Clin Oncol 2017:JCO (III) Chow et al. Antitumor Activity of Pembrolizumab in Biomarker-Unselected Patients With Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: Results From the Phase Ib KEYNOTE-012 Expansion Cohort. J Clin Oncol (III) Cicenas et al. Maintenance erlotinib versus erlotinib at disease progression in patients with advanced non-small-cell lung cancer who have not progressed following platinum-based chemotherapy (IUNO study). Lung Cancer :30-7. (II) Ciuleanu et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet (9699): (II) Cobleigh. Multinational study of the efficacy and safety of humanized anti-her2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. Journal of Clinical Oncology (9): (II) Coiffier et al. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-chop to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d'etudes des Lymphomes de l'adulte. Blood (12): (II) Cortes et al. Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet (9769): (II CER) Crawford et al. Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. N Engl J Med (3): (II) Cunningham et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecanrefractory metastatic colorectal cancer. N Engl J Med (4): (II CER) Dale et al. A randomized controlled phase III trial of recombinant human granulocyte colonystimulating factor (filgrastim) for treatment of severe chronic neutropenia. Blood (10): (II) Davis et al. Rituximab anti-cd20 monoclonal antibody therapy in non-hodgkin's lymphoma: safety and efficacy of re-treatment. J Clin Oncol (17): (III) de Bono et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet (9747): (II CER) del Giglio et al. XM02 is superior to placebo and equivalent to Neupogen in reducing the duration of severe neutropenia and the incidence of febrile neutropenia in cycle 1 in breast cancer patients receiving docetaxel/doxorubicin chemotherapy. BMC Cancer :332. (II) Dematteo et al. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet (9669): (II) 2018 Change Healthcare, LLC and/or its subsidiaries. All Rights Reserved. Produced in Cork, Ireland. 5

6 Dendreon Corporation. Provenge (sipuleucel-t) prescribing information. Seattle WA: Dendreon Corporation; Available from: [cited Dec ]. (V) Diaz et al. Pembrolizumab therapy for microsatellite instability high (MSI-H) colorectal cancer (CRC) and non-crc. Journal of Clinical Oncology (15_suppl):3071. (III) DiPersio et al. Phase III prospective randomized double-blind placebo-controlled trial of plerixafor plus granulocyte colony-stimulating factor compared with placebo plus granulocyte colony-stimulating factor for autologous stem-cell mobilization and transplantation for patients with non-hodgkin's lymphoma. J Clin Oncol (28): (II) DiPersio et al. Plerixafor and G-CSF versus placebo and G-CSF to mobilize hematopoietic stem cells for autologous stem cell transplantation in patients with multiple myeloma. Blood (23): (II) Doi et al. Safety and Antitumor Activity of the Anti-Programmed Death-1 Antibody Pembrolizumab in Patients With Advanced Esophageal Carcinoma. J Clin Oncol 2017:JCO (III) DSM Pharmaceuticals, Inc. Emend (fosaprepitant dimeglumine) prescribing information. Greenville NC: DSM Pharmaceuticals, Inc.; Available from: [cited May ]. (V) Eggermont et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol (5): (II) Eisai Inc. Akynzeo (netupitant and palonosetron) capsules prescribing information. Woodcliff Lake, NJ: Eisai Inc.; Available from: [cited May ]. (V) Eisai Inc. Halaven (eribulin) prescribing information. Woodcliff Lake NJ: Eisai Inc.; Rev 1/2016. Available from: (V) Eisterer et al. RETRA: evaluating the transfusion rate with darbepoetin alfa 500 microg every 3 weeks in anaemic cancer patients receiving chemotherapy. Curr Med Res Opin (2): (III) El-Khoueiry et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet (10088): (III) Ellis et al. Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer. J Clin Oncol (30): (II CER) Esquerdo et al. Effectiveness of darbepoetin alfa in a cohort of oncology patients with chemotherapy-induced anaemia. Relationship between variation in three fatigue-specific quality of life questionnaire scores and change in haemoglobin level. Clin Transl Oncol (5): (III) Farese et al. Filgrastim improves survival in lethally irradiated nonhuman primates. Radiat Res (1): (III) Ferris et al. Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med (19): (II) Fisher et al. Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol (30): (III) 2018 Change Healthcare, LLC and/or its subsidiaries. All Rights Reserved. Produced in Cork, Ireland. 6

7 Fizazi et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet (9768): (II CER) Friedman et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol (28): (III CER) Fuchs CS. KEYNOTE-059 cohort 1: Efficacy and safety of pembrolizumab (pembro) monotherapy in patients with previously treated advanced gastric cancer. Clin Onc (15. suppl, 4003). (NC) Genentech Inc. Avastin (bevacizumab) prescribing information. South San Francisco CA: Genentech, Inc.; Rev 12/2016. Available from: (V) Genentech, Inc. Herceptin (trastuzumab) prescribing information. South San Francisco CA: Genentech, Inc.; Rev 4/2017. Available from: (V) Genentech, Inc. Kadcyla (ado-trastuzumab emtansine) prescribing information. South San Francisco CA: Genentech, Inc.; Rev 7/2016. Available from: (V) Genentech, Inc. Perjeta ; (pertuzumab) prescribing information. South San Francisco CA: Genentech, Inc.; Rev 3/2016. Available from: (V) Genentech, Inc. Rituxan (rituximab) prescribing information. San Francisco CA: Genentech, Inc.; Rev 4/2016. Available from: (V) Genentech, Inc. Zelboraf (vemurafenib) prescribing information. San Francisco, CA: Genentech, Inc.; Rev 11/2017. Available from: (V) Genzyme Inc. Plerixafor (Mozobil) prescribing information. Cambridge, MA: Genzyme, Inc.; Rev 8/2015. Available from: (V) Gianni et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol (1): (II) Gianni et al. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol (3): (II) Godfrey et al. PD-1 blockade induces remissions in relapsed classical Hodgkin lymphoma following allogeneic hematopoietic stem cell transplantation. J Immunother Cancer :11. (V) Gradishar et al. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol (31): (II CER) Gradishar et al. Significantly longer progression-free survival with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic breast cancer. J Clin Oncol (22): (III CER) Gralla et al. A phase III study evaluating the safety and efficacy of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting over repeated cycles of chemotherapy. Ann Oncol (7): (II) 2018 Change Healthcare, LLC and/or its subsidiaries. All Rights Reserved. Produced in Cork, Ireland. 7

8 Grbic et al. The incidence of osteonecrosis of the jaw in patients receiving 5 milligrams of zoledronic acid: data from the health outcomes and reduced incidence with zoledronic acid once yearly clinical trials program. J Am Dent Assoc (11): (III) Green et al. A randomized double-blind multicenter phase III study of fixed-dose singleadministration pegfilgrastim versus daily filgrastim in patients receiving myelosuppressive chemotherapy. Ann Oncol (1): (II) Grunberg et al. Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy: randomized, double-blind study protocol--ease. J Clin Oncol (11): (II) Gu et al. PD-L1 and gastric cancer prognosis: A systematic review and meta-analysis. PLoS One (8):e (I) Habermann et al. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol (19): (II CER) Hallek et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet (9747): (II CER) Hankey et al. Pegfilgrastim Improves Survival of Lethally Irradiated Nonhuman Primates. Radiat Res (6): (III) Hanna et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with nonsmall-cell lung cancer previously treated with chemotherapy. J Clin Oncol (9): (II CER) Heil et al. A randomized, double-blind, placebo-controlled, phase III study of filgrastim in remission induction and consolidation therapy for adults with de novo acute myeloid leukemia. The International Acute Myeloid Leukemia Study Group. Blood (12): (II) Heinrich et al. Phase II, open-label study evaluating the activity of imatinib in treating lifethreatening malignancies known to be associated with imatinib-sensitive tyrosine kinases. Clin Cancer Res (9): (III) Henry et al. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol (9): (II CER) Herbaux et al. Efficacy and tolerability of nivolumab after allogeneic transplantation for relapsed Hodgkin lymphoma. Blood (18): (III) Herbst et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet (10027): (II) Hesketh et al. Efficacy and safety of NEPA, an oral combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy: a randomized dose-ranging pivotal study. Ann Oncol (7): (II) Hesketh et al. The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapyinduced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin--the Aprepitant Protocol 052 Study Group. J Clin Oncol (22): (V) Hodi et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med (8): (II CER) 2018 Change Healthcare, LLC and/or its subsidiaries. All Rights Reserved. Produced in Cork, Ireland. 8

9 Holmes et al. Blinded, randomized, multicenter study to evaluate single administration pegfilgrastim once per cycle versus daily filgrastim as an adjunct to chemotherapy in patients with high-risk stage II or stage III/IV breast cancer. J Clin Oncol (3): (II CER) Hortobagyi. Analysis of overall survival from a phase III study of ixabepilone plus capecitabine versus capecitabine in patients with MBC resistant to anthracyclines and taxanes. Breast Cancer Res Treat (2): (III) Howitt et al. Association of polymerase e-mutated and microsatellite-instable endometrial cancers with neoantigen load, number of tumor-infiltrating lymphocytes, and expression of PD-1 and PD-L1. JAMA Oncol (9): (III) Howitt et al. Clear cell ovarian cancers with microsatellite instability: A unique subset of ovarian cancers with increased tumor-infiltrating lymphocytes and PD-1/PD-L1 expression. Oncoimmunology (2):e (III) Hurwitz et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med (23): (II) ImClone LLC. Erbitux (cetuximab) prescribing information. Branchburg NJ: ImClone LLC; Rev 10/2016. Available from: (V) Italian Society of Osteoporosis et al. Safety profile of drugs used in the treatment of osteoporosis: a systematical review of the literature. Reumatismo (4): (IV) Jonker et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med (20): (II CER) Kabbinavar et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol (1):60-5. (III CER) Kang et al. Aprepitant for the prevention of chemotherapy-induced nausea and vomiting in children: a randomised, double-blind, phase 3 trial. Lancet Oncol (4): (II) Kantoff et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med (5): (II) Karthaus et al. Efficacy and safety of oral palonosetron compared with IV palonosetron administered with dexamethasone for the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients with solid tumors receiving cisplatin-based highly emetogenic chemotherapy (HEC). Support Care Cancer (10): (II) Kieler et al. Case report: impressive response to pembrolizumab in a patient with mismatchrepair deficient metastasized colorectal cancer and bulky disease. ESMO Open (6):e (III) Kwong et al. Low-dose pembrolizumab induced remission in patients with refractory classical Hodgkin lymphoma. Br J Haematol (1): (V) Langer et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, nonsquamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol (11): (II) Larkin et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med (1): (II) Larkins et al. FDA Approval Summary: Pembrolizumab for the Treatment of Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma with Disease Progression on or After Platinum-Containing Chemotherapy. Oncologist (7): (IV) 2018 Change Healthcare, LLC and/or its subsidiaries. All Rights Reserved. Produced in Cork, Ireland. 9

10 Le et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science (6349): (III) Le et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med (26): (III) Lilly USA, LLC. Alimta (pemetrexed for injection) prescribing information. Indianapolis IN: Lilly USA, LLC; Rev 10/2017. Available from: (V) McCarthy et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med (19): (II) McLaughlin et al. Rituximab chimeric anti-cd20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol (8): (III) Mehra. Efficacy and safety of pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC): Pooled analyses after long-term follow-up in KEYNOTE-012. J Clin Oncol suppl; abstr (NC) Merchant et al. Phase I Clinical Trial of Ipilimumab in Pediatric Patients with Advanced Solid Tumors. Clin Cancer Res (6): (III) Merck & Co., Inc.. Keytruda (pembrolizumab) prescribing information. Whitehouse Station, NJ: Merck & Co., Inc. Rev 11/2017. Available from: (V) Merck Sharp & Dohme Corp. Emend (aprepitant) capsules for oral use and Emend (aprepitant) for oral suspension prescribing information Whitehouse Station, NJ: Merck Sharp & Dohme Corp.; Available from: [May ] (V) Millennium Pharmaceuticals, Inc. Velcade (bortezomib) prescribing information. Cambridge MA: Millennium Pharmaceuticals, Inc.; Rev 6/2017. Available from: (V) Mills et al. The relationship between mismatch repair deficiency and PD-L1 expression in breast carcinoma. Am J Surg Pathol 2017:epub. (III) Moore et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol (15): (II) Muro et al. Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE- 012): a multicentre, open-label, phase 1b trial. Lancet Oncol (6): (III) National Comprehensive Cancer Network. The NCCN clinical practice guidelines in oncology, B- cell lymphomas (Version ). Fort Washington, PA: National Comprehensive Cancer Center; National Comprehensive Cancer Network. The NCCN clinical practice guidelines in oncology, chronic lymphocytic leukemia/small lymphocytic leukemia. (Version ). Fort Washington, PA: National Comprehensive Cancer Network; (IV) National Comprehensive Cancer Network. The NCCN clinical practice guideline in oncology, myelodysplastic syndromes (V1.2018). Fort Washington, PA: National Comprehensive Cancer Network; (IV) National Comprehensive Cancer Network. The NCCN clinical practice guidelines in oncology, antiemesis (V ). Fort Washington, PA: National Comprehensive Cancer Network; (IV) 2018 Change Healthcare, LLC and/or its subsidiaries. All Rights Reserved. Produced in Cork, Ireland. 10

11 National Comprehensive Cancer Network. The NCCN clinical practice guidelines in oncology, pancreatic cancer (V ). Fort Washington, PA: National Comprehensive Cancer Network; (IV) National Comprehensive Cancer Network, The NCCN clinical practice guidelines in oncology, cancer- and chemotherapy-induced Anemia. (V2.2017). Fort Washington, PA: National Comprehensive Cancer Network; (IV) National Institute for Health and Clinical Care Excellence. Erythropoiesis-stimulating agents (epoetin and darbepoetin) for treating anemia in people with cancer having chemotherapy (including review of TA 142) Available from: [cited Nov ] (IV) National Osteoporosis Foundation. Clinician's guide to prevention and treatment of osteoporosis: National Osteoporosis Foundation; 2014 (IV) Nemunaitis et al. Long-term follow-up of patients who received recombinant human granulocyte-macrophage colony stimulating factor after autologous bone marrow transplantation for lymphoid malignancy. Bone Marrow Transplant (1): (III) Nemunaitis et al. Phase III randomized, double-blind placebo-controlled trial of rhgm-csf following allogeneic bone marrow transplantation. Bone Marrow Transplant (6): (II) Nemunaitis et al. Recombinant granulocyte-macrophage colony-stimulating factor after autologous bone marrow transplantation for lymphoid cancer. N Engl J Med (25): (II) Nemunaitis et al. Use of recombinant human granulocyte-macrophage colony-stimulating factor in autologous marrow transplantation for lymphoid malignancies. Blood (2): (III) Novartis Pharma Stein AG. Zometa (zoledronic acid) prescribing information. Stein, Switzerland: Novartis Pharma Stein AG; Rev 12/2016. Available from: (V) Novartis Pharmaceuticals Corp. Gleevec (imatinib) prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corp; Rev 9/2017. Available from: (V) Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5(6): (V) O'Neal L. Sargramostim (Leukine/GM-CSF) for Autologous (Au) or Allogeneic (Allo) Bone Marrow Transplant (BMT) Engraftment Delay or Failure (ED/F) After Total Body Irradiation Conditioning (TBI) (Abstract). International Journal of Radiation Oncology (3):S92-S3. (III) Ortho Biotech Products, LP. Procrit (epoetin alfa) prescribing information. Raritan NJ: Ortho Biotech Products LP; Available from: [cited Dec ]. (V) Ortho Biotech Products, LP. Procrit (epoetin alfa) prescribing information. Raritan NJ: Ortho Biotech Products LP; Rev 4/2017. Available from: (V) OSI Pharmaceuticals, Inc. Tarceva (erlotinib) tablets, oral. Northbrook, IL: OSI Pharmaceuticals, Inc. Rev 10/2016. Available from: (V) 2018 Change Healthcare, LLC and/or its subsidiaries. All Rights Reserved. Produced in Cork, Ireland. 11

12 OSO Biopharmaceuticals, LLC. Aloxi (palonosetron) injectable prescribing information. Albuquerque NM: OSO Biopharmaceuticals, LLC; Available from: [cited May ]. (V) Overman et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol (III) Pappo. Phase II study of ipilimumab (IPI) in children and adolescents with unresectable stage III or IV malignant melanoma. J Clin Oncol (15s): abstract e21006 (NC) Perez et al. Efficacy and safety of ixabepilone (BMS ) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. J Clin Oncol (23): (III CER) Pfeffer et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med (21): (II) Pfreundschuh et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-b-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol (5): (II CER) Piccart-Gebhart et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med (16): (II) Piro et al. Extended Rituximab (anti-cd20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-hodgkin's lymphoma. Ann Oncol (6): (III) Poli-Bigelli et al. Addition of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy improves control of chemotherapy-induced nausea and vomiting. Results from a randomized, double-blind, placebo-controlled trial in Latin America. Cancer (12): (V) Price et al. Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study. Lancet Oncol (6): (II) Pujade-Lauraine et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. J Clin Oncol (13): (II) Rakel et al. Role of zoledronic acid in the prevention and treatment of osteoporosis. Clin Interv Aging : (V) Rapoport et al. Aprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with a broad range of moderately emetogenic chemotherapies and tumor types: a randomized, double-blind study. Support Care Cancer (4): (II) Rapoport et al. Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of cisplatin-based highly emetogenic chemotherapy in patients with cancer: two randomised, active-controlled, double-blind, phase 3 trials. Lancet Oncol (9): (II) Reck et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med (19): (II) Ribas et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol (8): (II) 2018 Change Healthcare, LLC and/or its subsidiaries. All Rights Reserved. Produced in Cork, Ireland. 12

13 Rizzo et al. Use of epoetin and darbepoetin in patients with cancer: 2007 American Society of Hematology/American Society of Clinical Oncology clinical practice guideline update. Blood (1): (IV) Robak et al. Rituximab plus fludarabine and cyclophosphamide prolongs progression-free survival compared with fludarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia. J Clin Oncol (10): (II CER) Robert et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med (4): (II) Rosen et al. Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer (8): (II CER) Rosen et al. Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: a phase III, double-blind, randomized trial--the Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group. J Clin Oncol (16): (II) Rowe et al. A randomized placebo-controlled phase III study of granulocyte-macrophage colony-stimulating factor in adult patients (> 55 to 70 years of age) with acute myelogenous leukemia: a study of the Eastern Cooperative Oncology Group (E1490). Blood (2): (II) Saad et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormonerefractory metastatic prostate carcinoma. J Natl Cancer Inst (19): (II) Saltz et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol (12): (II CER) Sandler et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med (24): (II CER) Sandoz. Filgrastim-sndz (Zarxio) prescribing information. Princeton, NJ: Sandoz, Inc.; Rev 3/2015. Available from: (V) Sanofi-Aventis. Sargramostim (Leukine). Bridgewater, NJ: Sanofi-Aventis U.S. LLC; Rev 2/2017. Available from: (V) Sanofi-Aventis U.S. LLC. Jevtana (cabazitaxel) prescribing information. Bridgewater NJ: Sanofi- Aventis U.S. LLC; Available from: [Dec ]. (V) Sanofi-Aventis U.S. LLC. Zaltrap (ziv-aflibercept) prescribing information Bridgewater NJ: Sanofi-Aventis U.S. LLC; Available from: [cited Jan ]. (V) Scagliotti et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol (21): (II CER) Schultz et al. Improved early event-free survival with imatinib in Philadelphia chromosomepositive acute lymphoblastic leukemia: a children's oncology group study. J Clin Oncol (31): (III) Schwartzberg et al. Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of moderately emetogenic chemotherapy or 2018 Change Healthcare, LLC and/or its subsidiaries. All Rights Reserved. Produced in Cork, Ireland. 13

14 anthracycline and cyclophosphamide regimens in patients with cancer: a randomised, activecontrolled, double-blind, phase 3 trial. Lancet Oncol (9): (II) Scottish Intercollegiate Guidelines Network (SIGN). Management of osteoporosis and the prevention of fragility fractures. A national clinical guideline. Edinburgh: SIGN; (IV) Seiwert et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol (7): (III) Sharma et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol (3): (III) Shepherd et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med (2): (II) Sicor Biotech UAB. Tbo-filgrastim (Granix) prescribing information. Vilnius, Lithuania: Sicor Biotech UAB; Rev 2/2017. Available from: (V) Slamon et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med (11): (II CER) Sloan et al. PD-L1 expression in mismatch repair-deficient endometrial carcinomas, including Lynch syndrome-associated and MLH1 promoter hypermethylated tumors. Am J Surg Pathol (3): (III) Socinski et al. Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial. J Clin Oncol (17): (II) Soria et al. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. Lancet Oncol (8): (II) Sosman et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med (8): (II) Sparano et al. Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol (20): (I) Stahel et al. Randomized study of recombinant human granulocyte colony-stimulating factor after high-dose chemotherapy and autologous bone marrow transplantation for high-risk lymphoid malignancies. J Clin Oncol (9): (II) Stopeck et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol (35): (II CER) Tella and Gallagher. Prevention and treatment of postmenopausal osteoporosis. J Steroid Biochem Mol Biol : (V) TESARO Inc. Varubi (rolapitant) tablets, for oral use prescribing information. Waltham, MA: TESARO, Inc.; Available from: [cited May ]. (V) Tessier-Cloutier et al. Programmed cell death ligand 1 cut-point is associated with reduced disease specific survival in resected pancreatic ductal adenocarcinoma. BMC Cancer (1):618. (III) 2018 Change Healthcare, LLC and/or its subsidiaries. All Rights Reserved. Produced in Cork, Ireland. 14

15 Tewari et al. Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med (8): (II) Thomas et al. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol (33): (II CER) Toh et al. The potential value of immunotherapy in colorectal cancers: review of the evidence for programmed death-1 inhibitor therapy. Clin Colorectal Cancer (4): (I) Van Cutsem et al. Aflibercept Plus FOLFIRI vs. Placebo Plus FOLFIRI in Second-Line Metastatic Colorectal Cancer: a Post Hoc Analysis of Survival from the Phase III VELOUR Study Subsequent to Exclusion of Patients who had Recurrence During or Within 6 Months of Completing Adjuvant Oxaliplatin-Based Therapy. Target Oncol (3): (II) Van Cutsem et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med (14): (II CER) Van Cutsem et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol (13): (II CER) Verma et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med (19): (II) Vermorken et al. Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. J Clin Oncol (16): (III CER) Vermorken et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med (11): (II CER) Vogel et al. First and subsequent cycle use of pegfilgrastim prevents febrile neutropenia in patients with breast cancer: a multicenter, double-blind, placebo-controlled phase III study. J Clin Oncol (6): (II) Von Hoff et al. Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol (34): (II) Warr et al. Efficacy and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and vomiting in patients with breast cancer after moderately emetogenic chemotherapy. J Clin Oncol (12): (II) Weber et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-ctla-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol (4): (II) Xu et al. A case report and literature review of primary resistant Hodgkin lymphoma: a response to anti-pd-1 after failure of autologous stem cell transplantation and brentuximab vedotin. Onco Targets Ther : (V) Younes et al. Nivolumab for classical Hodgkin's lymphoma after failure of both autologous stemcell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol (9): (III) 2018 Change Healthcare, LLC and/or its subsidiaries. All Rights Reserved. Produced in Cork, Ireland. 15