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1 The Evolving Role of Specialty Pharmacists in Cancer Immunotherapy: New Pathways, Agents, Opportunities, and Challenges Patrick J. Medina, PharmD, BCOP Professor Department of Medicine Stephenson Cancer Center University of Oklahoma Oklahoma City, Oklahoma Pharmacy Accreditation Pharmacy Times Office of Continuing Professional Education is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. This activity is approved for 1.0 contact hours (0.10 CEU) under the ACPE universal activity number L01-P. The activity is available for CE credit through May 4, Faculty Disclosure Patrick Medina, PharmD, BCOP, has no relevant financial relationships with commercial interest to disclose.

2 This activity is sponsored by Pharmacy Times Continuing Education and supported by an educational grant from Bristol-Myers Squibb. Learning Objectives Explain the mechanisms of action behind immune response to cancer and the role of immunotherapy in cancer treatment Distinguish new and emerging immunotherapy classes and individual agents and their efficacy, safety, and potential patient responses to therapy in cancer treatment Examine strategies to counsel and assist patients to overcome barriers to therapy, including treatment side effects to improve adherence to therapy Immunotherapy History Paul Erlich in the late 1800s described the term Magic Bullet The basic theory is related to the thought that tumor cells express an antigenic profile distinct from normal cells Immune system is capable of recognizing these antigenic differences In addition, tumor cells turn off T-cells specific for tumor antigens Pardoll D. Semin Oncol. 2015;42(4):523-38

3 How Do Tumor Cells Differ From Normal Cells? Clonal in origin Dysregulated growth and lifespan Altered tissue affinity Resistance to apoptosis Change in surface phenotypes and markers Structure and biochemical changes Altered gene expression Presence of tumor specific antigens Hanahan D, et al. Cell. 2011;144(5): Emerging Hallmarks of Cancer Reprinted from Cell, 144(5), Hanahan D, Weinberg RA., Hallmarks of cancer: the next generation , Copyright (2011), with permission from Elsevier. Immune Surveillance Reprinted from Semin Oncol, 42(4), Pardoll D, Cancer and the Immune System: Basic Concepts and Targets for Intervention, , Copyright (2015), with permission from Elsevier.

4 Immune Checkpoints Cell surface receptors Bind to ligand to modulate immune responses CTLA-4 and PD-1 are the best characterized, but many others exist CTLA-4 is thought to limit T-cell activity early in the immune response PD-1 is thought to reduce T-cell activity later, during the course of the immune response PD-1 may also be important for the suppressive function of regulatory T-cells Medina PJ, et al. Pharmacotherapy. 2016;36(3): ; Ferreri AJ, et al. Nat Rev Clin Oncol. 2010;7(8):doi: /nrclinonc c1 Targeting the Hallmarks of Cancer Reprinted from Cell, 144(5), Hanahan D, Weinberg RA., Hallmarks of cancer: the next generation , Copyright (2011), with permission from Elsevier. Types of Immunotherapy Monoclonal antibodies Bevacizumab, rituximab, and many others Direct tumor effects Complement-dependent cytotoxicity (CDCC) Antibody-dependent cellular cytotoxicity (ADCC) Cancer vaccines BCG, Sipuleucel-T, HPV Non-specific immune boosters Interleukin-2, interferon Adoptive T-cell therapy (Chimeric antigen receptor [CAR] T-cell therapy) Immune checkpoint inhibitors CTLA-4 and PD-1 monoclonal antibodies Scott AM, et al. Nat Rev Cancer. 2012;12(4):

5 Immunotherapy Vaccinations BCG live vaccine Stimulates the host to reject the tumor Injected into the bladder for bladder cancer Causes local response to tumor Non-specific HPV-16 vaccine HPV commonly linked to cervical cancer Gandhi NM, et al. BJU Int. 2013;112(3): ; Beavis AL, et al. Front Oncol. 2016;6:19. HPV Vaccine Specific immunotherapy Merck (first of 2) Approved in 2006 (Gardasil) Subtypes 16, 18, 6, 11 ~70% of high-risk types for cervical cancer ~90% of types for anogenital warts Also associated with head and neck cancers Lifetime effectiveness? 3 years Who? 9-26 year olds Others at risk Beavis AL, et al. Front Oncol. 2016;6:19. Sipuleucel T (Provenge) Adoptive cellular immunotherapy Patients undergo 3 rounds of leukapheresis Cells then sent to Dendreon: Antigen-presenting cells (APCs) are isolated and cultured with PA2024 PA2024 is a recombinant fusion protein, which serves as immunogen: Prostatic acid phosphatase and GM-CSF 3 doses of treated cells are administered to patients, each 2 weeks apart Sonpavde G, et al. Eur Urol. 2012;61(4):

6 Sipuleucel-T: Patient-Specific Therapy Reprinted from Eur Urol, 61(4), Sonpavde G, Di Lorenzo G, Higano CS, Kantoff PW, Madan R, Shore ND, The role of sipuleucel-t in therapy for castration-resistant prostate cancer: a critical analysis of the literature, , Copyright (2012), with permission from Elsevier. Talimogene laherparepvec (Imlygic) Based on the herpes simplex virus, type I (HSV-1) Modified by deleting the neurovirulence genes preventing fever blister development and deleting a viral gene that blocks antigen presentation T-VEC can target and replicate in cancer cells by using surface-bound nectins to enter the cell and preferentially replicates in tumor cells by exploiting disrupted oncogenic and antiviral signaling pathways, Also generates an immune response, which is likely enhanced by the expression of GM-CSF Lawler SE, et al. J Clin Oncol. 2015;33(25): Talimogene laherparepvec FDA approved for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery Recommended starting dose is up to a maximum of 4 ml at a concentration of 10 6 plaque-forming units (PFU) per ml Subsequent doses should be administered up to 4 ml at a concentration of 10 8 PFU per ml Shipped frozen, needs to be thawed up to 48 hours Warnings for accidental exposure leading to herpetic infections in health care workers, herpetic infections, injection site complications, immune-mediated events, and plasmacytoma at injection site Herpetic infections sensitive to acyclovir and may decrease the efficacy, use caution This is a live virus; exposure precautions are necessary Imlygic (Talimogene laherparepvec) [package insert]. Thousand Oaks, CA: Amgen; 2015.

7 Antitumor Activity of Talimogene Iaherparepvec More than half experienced 25% increase in the size of lesions or appearance of new lesions before achieving a response Two-thirds of responses expected to be > 1 year Andtbacka RH, et al. J Clin Oncol. 2015;33(25): Cytokines Produced by mononuclear cells Activate the immune system to attack the cancer NK cells, lymphocytes, etc. Proteins produced with recombinant technology Short t1/2 Pharmacy principles Do not shake, refrigerate Dranoff G. Nat Rev Cancer. 2004;4(1): Interferon-alfa (Intron-A) Naturally-occurring protein Secreted by cells in response to viral infections, tumors, and other biological inducers Produce clinical benefits for disease states, such as cancer, hepatitis, and multiple sclerosis Produce general antiprolifertive effects on cancer cells and/or activate the immune system to fight the cancer Used in melanoma, myeloma, and renal cell Accessed April 1, 2016.

8 Interleukin-2 (Aldesleukin, Proleukin) Endogenous source: T lymphocytes Activity Growth factor for T-cells Stimulation of cytotoxicity in NK and T-cells Cofactor in activating macrophages and B cells Main therapeutic uses Renal cell carcinoma Malignant melanoma Accessed April 1, Interleukin-2 Adverse reactions Black box warning Vascular leak syndrome Increased risk of infection Cardiac arrhythmias End organ damage Infusion related reactions Proleukin (Interleukin-2) [package insert]. San Diego, CA: Prometheus Laboratories Inc.; Denileukin Diftitox (Ontak) Interleukin-2 fused with diphtheria toxin Activity 1. Binds to IL-2 receptor 2. Is internalized, releasing diphtheria toxin into cytosol 3. Inhibits protein synthesis, resulting in cellular death Baldo BA. Drug Saf. 2015;38(5):

9 Denileukin Diftitox Main therapeutic uses Acute graft-versus-host disease Cutaneous T-cell lymphoma Chronic lymphocytic leukemia Adverse reactions Acute hypersensitivity Same as with IL-2 alone Baldo BA. Drug Saf. 2015;38(5): Ipilimumab (Yervoy) Mechanism of action Human monoclonal antibody against CTLA-4 FDA approved for treatment of melanoma Lipson EJ. Clin Cancer Res. 2011;17(22): Ipilimumab Unresectable or metastatic melanoma 3 mg/kg administered intravenously over 90 minutes every 3 weeks for a total of 4 doses Unresectable or metastatic melanoma, in combination with nivolumab at the same dose Adjuvant melanoma 10 mg/kg administered intravenously over 90 minutes every 3 weeks for 4 doses, followed by 10 mg/kg every 12 weeks for up to 3 years or until documented disease recurrence or unacceptable toxicity Yervoy (Ipilimumab ) [package insert]. Princeton, NJ: Bristol Myers Squibb; 2015.; Opdivo (Nivolumab) [package insert]. Princeton, NJ: Bristol Myers Squibb 2015.

10 Ipilimumab: Safety The most common adverse reactions ( 5%) in patients who received 10 mg/kg were: Rash (50%) Diarrhea (49%) Fatigue (46%) Pruritus (45%) Headache (33%) Weight loss (32%) Nausea (25%) Pyrexia (18%) Colitis (16%) Decreased appetite (14%) Vomiting (13%) Insomnia (10%) Yervoy (Ipilimumab ) [package insert]. Princeton, NJ: Bristol Myers Squibb; 2015 The most common adverse reactions ( 5%) in patients who received 3 mg/kg were: Fatigue (41%) Diarrhea (32% Pruritus (31% Rash (29%) Colitis (8%) Immune-mediated adverse reactions (n = 131) Grade (3-5) (%) Any Immune Reaction 15 Enterocolitis 7 Hypo/hyperthyroidism 4 Dermatitis 2 Hepatotoxicity 1 Neurotoxicity 1 Nephritis 1 Kinetics of Appearance of Ipilimumab Immune-related Adverse Events Printed with permission from Weber JS. J Clin Oncol. 2012;30(21): Overall Survival and Progression-free Survival for Ipilimumab in Metastatic Melanoma Time to response 3.18 months Printed with permission from Hodi FS. N Engl J Med ;363(8):

11 Nivolumab (Opdivo) A human IgG4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2 FDA approved for: Unresectable or metastatic melanoma, as a single agent Unresectable or metastatic melanoma, in combination with ipilimumab Metastatic NSCLC and progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving nivolumab Advanced renal cell carcinoma who have received prior antiangiogenic therapy The dose is 3 mg/kg every 2 weeks with the exception of when it is used in combination with ipilimumab (dose is 1 mg/kg, followed by ipilimumab on the same day, every 3 weeks for 4 doses, then 3 mg/kg every 2 weeks) Opdivo (Nivolumab) [package insert]. Princeton, NJ: Bristol Myers Squibb Nivolumab: Safety Most common adverse reactions ( 20%) in patients with metastatic NSCLC were fatigue, musculoskeletal pain, decreased appetite, cough, and constipation. Immune adverse reactions (n = 287) Any Grade (%) Median Time to Onset (Months) Pneumonitis Enterocolitis Adrenal Insufficiency 0.3 NR Renal Toxicity Hepatotoxicity Hypothyroid Hyperthyroid Rash 6 NR Opdivo (Nivolumab) [package insert]. Princeton, NJ: Bristol Myers Squibb Nivolumab in NSCLC From N Engl J Med, Borghaei H, et al, Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer, 373: Copyright (2015) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

12 Nivolumab in NSCLC From N Engl J Med, Borghaei H, et al, Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer, 373: Copyright (2015) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. Pembrolizumab (Keytruda) A humanized IgG4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD- L2 FDA approved for: Unresectable or metastatic melanoma, as a single agent Metastatic NSCLC whose tumors express PD-L1 as determined by an FDA-approved test and who have disease progression on or after 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 pembrolizumab The dose is 2 mg/kg every 3 weeks Keytruda (pembrolizumab) [package insert]. Whitehouse Station, NJ: Merck & Co. Inc. Pembrolizumab: Safety The most common adverse reactions ( 20%): Fatigue (47%) Cough (30%) Nausea (30%) Pruritus (30%) Rash (29%) Decreased appetite (26%) Constipation (21%) Arthralgia (20%) Diarrhea (20%) Immune-mediated adverse reactions (n = 411) Median onset All grades n (%) Hepatitis 22 days 2 (0.5) Hypo/hyperthyroidism 1.5 mo. 5 (1.2) Hypophysitis 1.7 mo. 2 (0.5) Pneumonitis 5 mo. 12 (2.9) Colitis 6.5 mo. 4 (1) Nephritis 11.6 mo. 3 (0.7) Keytruda (pembrolizumab) [package insert]. Whitehouse Station, NJ: Merck & Co. Inc.

13 Pembrolizumab vs Ipilimumab in Metastatic Melanoma From N Engl J Med, Robert et al, Pembrolizumab versus Ipilimumab in Advanced Melanoma, 372: Copyright (2015) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. Pembrolizumab vs Ipilimumab in Metastatic Melanoma From N Engl J Med, Robert et al, Pembrolizumab versus Ipilimumab in Advanced Melanoma, 372: Copyright (2015) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. Adverse Events in the As-Treated Population From N Engl J Med, Robert et al, Pembrolizumab versus Ipilimumab in Advanced Melanoma, 372: Copyright (2015) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

14 Immunotherapy Introduces a New Era of Toxicity Management Immune-related adverse events (iraes) The 5 Pillars of Immunotherapy Toxicity Management Printed with permission from Champiat S. Ann Oncol. 2016;27(4): Enterocolitis/ Pneumonitis/ Neuropathies* Grade 1 (< 4 stools/day over baseline) Monitor and continue therapy Grade 2 (4-6 stools/day over baseline) Monitor and continue therapy when grade 1 Symptoms persist, start prednisone 1mg/kg/day with a 4 week taper and continue therapy when grade 1 If symptoms persist or relapse on taper start IV steroids Grade 3/4 IV methylprednisolone 2 mg/kg and discontinue therapy (GI consult and hospitalization recommended) Consider infliximab 5 mg/kg IV ever 2 weeks if symptoms persist *Please consult current package insert for individual products Fecher LA, et al. Oncologist 2013;18(6): ; Champiate S, et al. Ann Oncol. 2016;27(4):

15 Baseline: Emollients ± skin moisturizers Hepatitis* Grade 1 - AST or ALT <1-2.5 X the upper limit of normal (ULN), or total bilirubin X the ULN Monitor and continue therapy Grade 2 - AST or ALT >2.5-5 X the ULN, or total bilirubin >1.5-3 X the ULN Monitor and continue therapy when grade 1 Symptoms persist, start prednisone 1mg/kg/day with a 4 week taper and continue therapy when grade 1 If symptoms persist or relapse on taper start IV steroids Grade 3/4 - AST or ALT >5 X the ULN, or total bilirubin >3 times the ULN IV methylprednisolone 2 mg/kg and discontinue (consider hepatology consult and hospitalization recommended) Consider if symptoms persist mycophenolate 500 mg PO every 12 hours *Please consult current package insert for individual products Fecher LA, et al. Oncologist 2013;18(6): ; Champiat S, et al. Ann Oncol. 2016;27(4): Dermatitis* Signs/symptoms: Rash < 30% of the body surface Dry skin Pruritus (localized) Vitiligo *Please consult current package insert for individual products Signs/symptoms: Rash > 30% of the body surface Pruritus (diffuse and constant) Blisters, ulcerations, bullae, necrotic or hemorrhagic lesions Toxic epidermal necrolysis Printed with permission from Fecher. The Oncologist. 2013;18: Grade 1 Moisturizers Topical steroids Monitor Continue therapy Grade 2 Topical steroids Antihistamines Persistent symptoms > 1-2 weeks start oral prednisone 1 mg/kg/day Dermatology consult Restart when grade 1 or less Grade 3 or 4 Systemic steroids (taper over 4 weeks after symptoms resolve) May need hospitalization Dermatology consult Discontinue therapy (may consider restarting if grade 3 and resolution of symptoms) Tumor Immunotherapy: Tips Counseling Diarrhea Shortness of breath, chest pain, cough Weight gain/loss, muscle aches, abdominal pain Headaches, weakness, vision changes Decreased urine output Monitoring Liver function tests, serum creatinine, thyroid function Signs/symptoms of immune-mediated adverse reaction (pneumonitis, colitis, etc.) Treatment Corticosteroid until improvement to grade 1 or less and then taper over 1 month

16 Patient ID Card Name, Family name: Immunotherapy drug(s): I am currently receiving an immunotherapy, which may increase the risk of occurrence of autoimmune diseases and in particular: pneumonitis (inflammation of the lungs) colitis (inflammation of the gut) hepatitis (inflammation of the liver) nephritis (inflammation of the kidneys) endocrinopathy: hypophysitis, thyroid dysfunction, diabetes, adrenal insufficiency (inflammation of the hormone producing organs) cutaneous rash (inflammation of the skin) as well as other immune-related adverse events: neurological, hematological, ophthalmological, The management of these dysimmune adverse events is specific and sometimes urgent. It absolutely requires coordination with the health care team which has prescribed the treatment: Prescriber ID and contact information (reported at the back of this card) Champiat S, et al. Ann Oncol. 2016;27(4): Barriers to Care Cost Melanoma Ipilimumab $158,282 Nivolumab $103,220 Pembrolizumab $14,500/month at lower dose (up to 1 million per year if higher doses used) Talimogene $65,000/dose Combination of ipilimumab + nivolumab $295,566 Patient with a 20% co-pay = $60,000 out of their own pocket All companies have patient support programs that should be routinely used Adverse effect management can be tricky, and patients may have to come off and on drugs Responses often take time, pseudoprogression is possible Andrews A. Am Health Drug Benefits. 2015; 8(Spec Issue): 9. Additional Resources American Cancer Society eeffects/treatmenttypes/immunotherapy/index Research Cancer Immunotherapy National Cancer Institute mmunotherapy-using-immune-system