We re Reaching Ludicrous Speed: New Immunotherapy Oncology Medications Adam Peele, PharmD, BCPS, BCOP Oncology Pharmacy Manager Cone Health Disclosures Merck Pharmaceuticals Speaker s Bureau 1
Objectives Discuss history of immunotherapy Explain pharmacology of immunotherapy medications Evaluate supporting literature of the medications Describe where these agents fit into clinical practice History of Chemotherapy Cancer Res 2008; 68(21): 8643 8653 2
History of Chemotherapy Cancer Res 2008; 68(21): 8643 8653 History of Immuno Oncology 19 th century William B. Coley Tumor regression following the injection of a bacterial broth into malignant lesions 20 th century Paul Ehrlich Immune system recognizes and eliminates developing tumors 3
Ipilimumab Mechanism of Action Nature 2002; 3(7): 611 618 Blinatumomab FDA Labeled Indication Treatment of Philadelphia chromosome negative relapses or refractory B cell precursor acute lymphoblastic leukemia (ALL) Dosing Cycle 1 9 mcg/day on days 1 7 28 mcg/day days 8 28 Subsequent cycles 28 mcg/day days 1 28 Availability 35 mcg lyophilized powder in a single use vial 4
Blinatumomab Journal of Community and Supportive Oncology 2015; 13(5): 170 173. Blinatumomab Enrolled Patients Philadelphia chromosome ( ), B cell precursor ALL Who were either Primary refractory after induction Relapsed within 12 months of first remission Relapsed within 12 months of receiving allogeneic HSCT Not responded to or relapsed after first salvage or beyond Dex 10 24 mg/m2 daily (up to 5 days): BM blasts > 50% Peripheral blasts > 15,000 Elevated LDH Cycle 1 9 µg/day x 7 days then 28 µg/day x 21 days No treatment x 14 days Dexamethasone 20 mg required 1 hour prior to treatment Cycle 2 28 µg/day x 28 days No treatment x 14 days Dexamethasone 20 mg required 1 hour prior to treatment Primary Endpoint Complete remission (CR) Complete remission with partial hematologic recovery of peripheral blood counts (CRh) Lancet Oncology 2015; 16: 57 66. 5
Blinatumomab Lancet Oncology 2015; 16: 57 66. Blinatumomab Lancet Oncology 2015; 16: 57 66. 6
Blinatumomab Lancet Oncology 2015; 16: 57 66. http://s60.photobucket.com/user/millennium_falsehood/media/spaceball%20one%20references/spaceball1 21.jpg.html 7
Programmed Death Pathway The Pharmaceutical Journal 18 Nov 2014 Programmed Death Pathway Tidbits Programmed Death Receptor Abbreviation Role Location Role PD 1 Immunoinhibitory receptor T cells B cells Mononcytes NK cells Binding by ligands stimulates T cell suppression Programmed Death Ligand 1 Programmed Death Ligand 2 PD L1 Ligand T cells B cells Dendritic cells Macrophages Pancreatic islet cells Vascular endothelial cells PD L2 Ligand Macrophages Dendritic cells Binds to PD 1 receptor Binds to PD 1 receptor 8
Role of PD Pathway in Cancer Malignancies overexpress PD L1 expression Associated with poor prognosis PD L1 expression has been correlated with tumor growth Renal cell carcinoma PD L1 expression correlated with development of distant metastases Head and neck cancer FDA Approved PD 1 Agents FDA Approval Date FDA Approved Usage Dosage Form Other areas of interest Pembrolizumab September 2014 Melanoma IV Renal Cell Hepatocellular Gastric Head and neck TNBC Colon Nivolumab December 2014 Melanoma/Lung IV Gastric Pancreatic Renal Cell Solid tumors SCLC GBM CRPC 9
What s the Difference? FDA Approved Indication Dosing Frequency Infusion Time Availability Pembrolizumab Treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor 2 mg/kg Every 3 weeks 30 minutes For injection 50 mg powder for injection Injection 100 mg/ 4 ml solution Nivolumab Treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor 3 mg/kg Every 2 weeks 60 minutes Single use vials 40 mg/4 ml 100 mg/10 ml Metastatic squamous non small cell lung cancer with progression on or after platinum based chemotherapy Audience Response Question Nivolumab is administered as an IV infusion over A. 30 minutes every 3 weeks B. 60 minutes every 2 weeks C. 30 minutes every 4 weeks D. 60 minutes every 3 weeks 10
Pembrolizumab for Melanoma Unresectable or metastatic melanoma Previously treated with ipilimumab therapy Pembrolizumab 2 mg/kg IV over 30 minutes every 3 weeks Pembrolizumab 10 mg/kg IV over 30 minutes every 3 weeks O V E R A L L R E S P O N S E Lancet 2014; 384: 1109 1117 Pembrolizumab for Melanoma Lancet 2014; 384: 1109 1117 11
Pembrolizumab for Melanoma Lancet 2014; 384: 1109 1117 Pembrolizumab for Melanoma Lancet 2014; 384: 1109 1117 12
Nivolumab for Melanoma Stage IIIc or IV metastatic melanoma Disease progression on previous therapy based upon BRAF mutational status ECOG 0 1 Lancet Oncology 2015; 16: 375 384 Nivolumab 3 mg/kg every 2 weeks Investigator s Choice DTIC 1000 mg/m2 q 3 weeks Carboplatin/Paclita xel O B J E C T I V E R E S P O N S E O V E R A L L S U R V I V A L Nivolumab for Melanoma Lancet Oncology 2015; 16: 375 384 13
Nivolumab for Melanoma Lancet Oncology 2015; 16: 375 384 Nivolumab for Melanoma Lancet Oncology 2015; 16: 375 384 14
What do the Guidelines Recommend? Anti PD1 Agents Consensus among NCCN Panel that both drugs have higher response rates and less toxicity than ipilimumab Both drugs should be included as options for first line treatment NCCN Melanoma Guidelines Version 3.2015 http://forums.evga.com/overtake date showing m1793394 p4.aspx 15
Nivolumab for Lung Stage IIIB or IV squamouscell NSCLC Disease recurrence after one prior platinum containing regimen ECOG 0 1 Nivolumab 3 mg/kg IV over 60 minutes every 2 weeks Docetaxel 75 mg/m 2 IV over 60 minutes every 3 weeks O V E R A L L S U R V I V A L NEJM 2015; 373 (2): 123 135 Nivolumab for Lung NEJM 2015; 373 (2): 123 135 16
Nivolumab for Lung NEJM 2015; 373 (2): 123 135 Nivolumab for Lung NEJM 2015; 373 (2): 123 135 17
Nivolumab for Lung NEJM 2015; 373 (2): 123 135 Nivolumab for Lung NEJM 2015; 373 (2): 123 135 18
Pembrolizumab for Lung Locally advanced or metastatic non small cell lung cancer ECOG less than 1 Adequate organ function Pembrolizumab 2 mg/kg IV over 30 minutes every 3 weeks Pembrolizumab 10 mg/kg IV over 30 minutes every 3 weeks Pembrolizumab 10 mg/kg IV over 30 minutes every 2 weeks S A F E T Y R E S P O N S E NEJM 2015; 372 (21): 2018 2028 Pembrolizumab for Lung Biomarker selection Used anti PD L1 antibody clone 22C3 and a prototype immunohistochemical assay PD L1 positivity defined as staining in at least 1% of cells Trial expanded to include previously treated NSCLC that expressed a high level of PD L1 NEJM 2015; 372 (21): 2018 2028 19
Pembrolizumab for Lung Lancet 2014; 384: 1109 1117 Pembrolizumab for Lung Response Rates Overall Response Rate 19.4% Current or Former Smokers 22.5% Never Smokers 10.3% No disease progression 84.4% Median DOR Previously treated Previously untreated Median PFS Previously treated Previously untreated 12.5 months 10.4 months (range 1, 10.4) 23.3 months (range 1, 23.3) 3.7 months 3 months 6 months Median Overall Survival Previously treated Previously untreated 12 months 9.3 months 16.2 months NEJM 2015; 372 (21): 2018 2028 20
Pembrolizumab for Lung NEJM 2015; 372 (21): 2018 2028 Pembrolizumab for Lung NEJM 2015; 372 (21): 2018 2028 21
Pembrolizumab for Lung NEJM 2015; 372 (21): 2018 2028 What do the Guidelines Recommend? Nivolumab Subsequent therapy for patients with metastatic squamous cell carcinoma who have progressed on or after platinum based chemotherapy Category 1 recommendation NCCN Non Small Cell Lung Cancer Guidelines Version 6.2015 22
Audience Response Question Nivolumab and Pembrolizumab are both FDA approved for: A. NSCLC B. Melanoma C. Kidney D. SCLC https://bhermannview.wordpress.com/2015/06/08/what s the matter colonel bernie sanders chicken/ 23
We re Reaching Ludicrous Speed: New Immunotherapy Oncology Medications Adam Peele, PharmD, BCPS, BCOP Oncology Pharmacy Manager Cone Health 24