Immunotherapies in Solid Tumors Val R. Adams, PharmD, FCCP, BCOP Associate Professor Pharmacy Practice and Science Department College of Pharmacy University of Kentucky Lexington, Kentucky
A New Paradigm in Cancer Treatment Chapter 1 Cytotoxic Chemotherapy Nonspecifically Killed Cells Normal cells were more resistant and recovered faster from toxicity than tumor cells. Derived from natural products Chapter 2 Targeted Antitumor Agents Determine molecular drivers stimulating cancer growth and block with signaling pathway Chapter 3 Immunotherapy Augment the immune system s ability to kill cancer cells
Immune System Recognition of Cancer Semin Oncol. 2015;42(suppl 3):s3-s11. For educational purposes only.
Avoiding Immune Surveillance CTLA-4 = CTLA-4 = cytotoxic T-lymphocyte-associated protein 4; DC = dendritic cell; IDO = indoleamine 2,3-dioxygenase; IFN = interferon; IL = interleukin; MDSC = myeloid-derived suppressor cell; MHC = major histocompatibility complex; NK = natural killer; NKG2D = natural killer group 2D; NKR = natural killer receptor; NKT = natural killer T; PD-1 = programmed death receptor 1; PD-L1 = programmed death ligand 1; TGF-β = transforming growth factor-β; TNF = tumor necrosis factor; TRAIL = TNF-related apoptosis-inducing ligand. Schreiber RD et al. Science. 2011;331:1565-1570. For educational purposes only.
Focus on T-cells?
Evidence of Immune Surveillance For educational purposes only.
CTL-Tumor Cell Interactions CTL = cytotoxic T lymphocyte; TCR = T-cell receptor. For educational purposes only.
Put on the Gas or Take Off the Brakes? Gas On gp100 Peptide Vaccine and Interleukin-2 Brake Off Ipilimumab (Ipi) gp100 = glycoprotein 100. Schwartzentruber et al. N Engl J Med. 2010;364:2119-2127; Hodi et al. N Engl J Med. 2010;363:711-723. For educational purposes only.
CTLA-4 and PD-1/L1 Checkpoint Blockade Ribas A. N Engl J Med. 2012;366:2517-2519. For educational purposes only.
The Goal of Checkpoint Inhibitors Immuno-oncology is focused on unleashing T-cells that recognize cancer so they can chase it down.
The Challenges: Pseudoprogression For educational purposes only.
Patterns of Response to Ipilimumab Observed in Advanced Melanoma SPD = sum of the product of perpendicular diameters. Wolchok et al. Clin Cancer Res. 2009;15:7412-7420. For educational purposes only.
Immune-Related Response Criteria (irrc) CR PR WHO Disappearance of all lesions not less than 4 weeks apart 50% decrease in SPD of all index lesions compared with baseline in 2 observations irrc Disappearance of all lesions not less than 4 weeks apart 50% decrease in SPD of all index lesions compared with baseline in 2 observations SD Not PR, CR, or PD Not PR, CR, or PD PD At least 25% increase in SPD compared with nadir and/or unequivocal progression of nonindex lesions and/or appearance of new lesions (at any single time point) At least 25% increase in tumor burden compared with nadir (at any single time point) in 2 consecutive observations at least 4 weeks apart New lesions Always represent PD Incorporated into tumor burden if possible CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease; WHO = World Health Organization. Wolchok JD, et al. Clin Cancer Res. 2009;15:7412.
Immune-Related Toxicity Skin (n=155; 33%) GI (n=66; 14%) Hepatic (n=19; 4%) Pulmonary (n=9; 2%) Endocrine (n=36; 8%) Time to Onset (median in weeks and range) Renal (n=8; 2%) 0 10 20 30 40 50 60 70 GI = gastrointestinal. Wolchok JD, et al. J Clin Oncol. 2015;33: Abstract LBA1.
PD-1/PD-L1 Inhibition: Managing for Treatment-Related Adverse Events Grade 3/4 pneumonitis Grade 3/4 nephritis Grade 3/4 infusion-related reaction Any life-threatening or grade 4 AE Any severe or grade 3 recurrent AE Hepatitis associated with AST/ALT > 5 x ULN AST/ALT 50% from baseline lasting 1 week* Total bilirubin > 3 x ULN Initiate steroid therapy Permanently discontinue PD-1 treatment *In patients with liver metastasis who begin treatment with grade 2 elevation of AST/ALT. AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal. Pembrolizumab adverse reaction management guide. Nivolumab adverse reaction management guide.
Current Approvals Drug (Class) Approved Use Nivolumab (PD-1 inhibitor) Non-small cell lung cancer Metastatic melanoma Renal cell carcinoma Hodgkin lymphoma Pembrolizumab (PD-1 inhibitor) Non-small cell lung cancer Metastatic melanoma Head and neck squamous cell cancer Atezolizumab (PD-L1 inhibitor) Ipilimumab (CTLA-4 inhibitor) Urothelial carcinoma (bladder cancer) Metastatic melanoma Nivolumab [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2016; Pembrolizumab [package insert]. Whitehouse Station, NJ; 2014; Atezolizumab [package insert]. South San Francisco, CA: Genentech Inc; 2016; Ipilimumab [package insert]; Princeton, NJ: Bristol-Myers Squibb Company; 2016.
Immunogenicity of Tumors AML = acute monocytic leukemia; CLL = chronic lymphocytic leukemia; DLBCL = diffuse large B-cell lymphoma Lawrence MS et al. Nature. 2013;499:214-218. For educational purposes only.
The New Chapter in Cancer Treatment Sharma et al. Cell. 2015;161:205-214. For educational purposes only.
Overview of NSCLC Treatment with Immunotherapies Val R. Adams, PharmD, FCCP, BCOP Associate Professor Pharmacy Practice and Science Department College of Pharmacy University of Kentucky Lexington, Kentucky
Case 1 JS is a 59-year-old male with NSCLC. History of present illness: 6 months ago, JS c/o SOB and cough s/p antibiotics without change in symptoms CXR: RUL mass biopsy c/w squamous histology; follow-up radiology shows liver metastasis, no brain metastasis s/p carboplatin/gemcitabine x 6 cycles c/o = complaint of; c/w = consistent with; CXR = chest x-ray; RUL = right unilateral; SOB = shortness of breath; s/p = status post.
Case 1 (cont d) Past medical history: Hypertension x 20 years (tx: benazepril 10 mg po qd) 25 pack-year smoking history Depression (tx: paroxetine 20 mg po qd) Laboratory results: CBC WNL Electrolytes WNL Liver function test AST and ALT increase 69 and 87, respectively Increased creatinine from baseline SCr 2 weeks ago: 1.1 mg/dl Current SCr: 1.3 mg/dl CBC = complete blood cell count; po = by mouth; qd = every day; SCr = serum creatinine; tx = treatment; WNL = within normal limits.
Case 1 (cont d) Presentation today: s/p 6 cycles of chemotherapy; last cycle ~ 3 months ago Patient s wife reports that JS experienced increased cough with streaks of blood starting a couple days ago. Patient and wife would like some cough syrup. The oncologist orders a chest CT as well as some cough syrup. CT = computed tomography.
Case 1 It s Back
Case 1 (cont d) PS = 1, EGFR WT, KRas WT, CBC with differential WNL, Chem 23 WNL except AST 69 and ALT 87. What treatment would you recommend? A. Pembrolizumab B. Ipilimumab C. Docetaxel D. Pemetrexed E. Erlotinib 20% 20% 20% 20% 20% Pembrolizumab Ipilimumab Docetaxel Pemetrexed Erlotinib PS = performance status; WT = wild type.
PD-L1 Testing with Pembrolizumab FDA = US Food and Drug Administration. For educational purposes only.
Carpinteria, CA: Dako North America, Inc. PD-L1 IHC 22C3 pharmdx for Autostainer Link 48. Dako Web site. Available at: http://www.dako.com/us/ar39/p250165/prod_products.htm. Accessed November 4, 2015. For educational purposes only.
Pembrolizumab KEYNOTE-001 Trial Advanced/Metastatic NSCLC PS 0 1 N = 495 Pembrolizumab 2 mg/kg IV q3w N = 6 Pembrolizumab 10 mg/kg IV q3w N = 287 Primary endpoint Safety/side effect profile Antitumor activity Secondary endpoints OS PFS Biomarker PDL-1 Training group and validation group Pembrolizumab 10 mg/kg IV q2w N = 202 IV = intravenous; OS = overall survival; PFS = progression-free survival; q2w = every 2 weeks; q3w = every 3 weeks. Garon EB, et al. N Engl J Med. 2015;372:2018-2028.
OS Favored High Expression of PD-L1 394 previous tx 101 no prior tx Garon EB, et al. N Engl J Med. 2015;372:2018-2028. For educational purposes only.
Do we really need to test for PD-L1? How do these pembrolizumab groups compare to chemotherapy?
Survival with Docetaxel, Pemetrexed, and BSC Cumulative Probability 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 TAX 317B BSC (N = 49) JMEI Docetaxel (N = 288) TAX 317 Docetaxel (N = 55) JMEI Pemetrexed (N = 276) 0 3 6 9 12 15 18 21 Survival Time (months) BSC = best supportive care. Hanna N, et al. J Clin Oncol. 2004;22:1589-1597; Shepherd FA, et al. J Clin Oncol. 2000;18:2095-2103.
Pembrolizumab KEYNOTE-010 Trial Advanced/Metastatic Previously treated NSCLC PS 0 1 PD-L1 expression at least 1% Primary endpoint OS and PFS Overall population and PD-L1+ Secondary endpoints Biomarker PD-L1 Training group and validation group Pembrolizumab 2 mg/kg IV q3w N = 345 Pembrolizumab 10 mg/kg IV q3w N = 346 Docetaxel 75 mg/m 2 IV q3w N = 343 Herbst et al. Lancet. 2016;387:1540-1550.
KEYNOTE-010: Prognostic or Useful to Select Therapy? PD-L1 + PD-L1+ Herbst et al. Lancet. 2016;387:1540-1550. For educational purposes only.
Prognostic or Useful to Select Therapy? Overall Survival CI = confidence interval; ECOG = Eastern Cooperative Oncology Group. Herbst et al. Lancet. 2016;387:1540-1550. For educational purposes only.
Case 1 (cont d) JS s tumor is sent for PD-L1 staining and it comes back negative. The insurance company won t authorize payment. What would you recommend now? 20% 20% 20% 20% 20% A. Atezolizumab B. Nivolumab C. Bevacizumab D. Cetuximab E. Ramucirumab JG5 Atelolizumab Nivolumab Bevacizumab Cetuximab Ramucirumab
Slide 35 JG5 fix spelling "Atezolizumab" Jane Griffith, 9/24/2016
Nivolumab vs Docetaxel Previously treated PS 0 1 Stage IIIb/IV Squamous NSCLC Primary endpoint OS Secondary endpoints ORR PFS 1:1 Nivolumab 3 mg/kg IV q2w n = 135 Docetaxel 75 mg/m 2 IV q3w n = 137 ORR = objective response rate. Brahmer J et al. N Engl J Med. 2015;373:123-135.
OS Favored Nivolumab Median OS 9.2 mo vs 6.0 mo P=0.00025 Brahmer J, et al. N Engl J Med. 2015;373:123-135. For educational purposes only.
Nivolumab in PD-L1 Negative Patients HR = hazard ratio. Brahmer J et al. N Engl J Med. 2015;373:appendix online. For educational purposes only.
Case 1 (cont d) JS decided to go on a trial with nivolumab combined with ipilimumab He is currently on his third cycle of treatment and his tumor is shrinking
Second-line NSCLC Comparing Atezolizumab to Docetaxel (POPLAR) Previously treated with platinum PS 0 1 Stage IIIb/IV NSCLC 1:1 Primary endpoint OS Secondary endpoints Biomarker analysis ORR PFS Atezolizumab 1200 mg IV q3w n = 144 Docetaxel 75 mg/m 2 IV q3w n = 143 Fehrenbacher L et al. Lancet. 2016;387:1837-1846.
Second-line NSCLC Comparing Atezolizumab to Docetaxel (POPLAR) (cont d) Fehrenbacher L, et al. Lancet. 2016;387:1837-1846. For educational purposes only.
Atezolizumab to Docetaxel (Biomarker) Fehrenbacher L, et al. Lancet. 2016;387:1837-1846. For educational purposes only.
What's Next? Besides new drugs What about PD-1 or PD-L1 as primary therapy?
First-line Pembrolizumab Merck Press Release data not yet available Study details phase III randomized trial, platinum doublet (maintenance if appropriate) vs pembrolizumab 200 mg IV N = 305 PD-L1 positive treatment-naïve advanced NSCLC Available at: http://www.mercknewsroom.com/news-release/oncology-newsroom/mercks-keytruda%c2%a0pembrolizumab-demonstrates-superiorprogression-free-. Accessed June 30, 2016. For educational purposes only.
Nivolumab as First-line Treatment For educational purposes only. Still open for accrual Sept 2016
Further Down the Road: Clinical Trials with Immunotherapy New Agents New Immune Pathway Ido 1 Indoximod CD40 APX005M TIM-3 MBG453 LAG-3 IMP321 CD27 Varlilumab B7-H3 Enoblituzumab GITR AMG228 Combination Therapy New Diseases Oncolytic Virus Therapy Talimogene laherparepvec Plus many more!!!
Overview of Melanoma Treatment with Immunotherapies Patrick Medina, PharmD, BCOP Professor of Medicine Hematology/Oncology Director of Pharmacy Stephenson Cancer Center Oklahoma City, Oklahoma
Treatment Surgery Margin depends on size of tumor Sentinel node dissection All lesions >1 mm thick Radiation Palliation of metastatic disease Chemotherapy/Targeted Adjuvant Metastatic Immunotherapy Adjuvant Metastatic NCCN Clinical Practice Guidelines in Oncology: Melanoma. Version 3.2016. NCCN.org Web site. Available at: https://www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf. Accessed September 2016.
Targeted Therapy Drug Mechanism Efficacy Dabrafenib* + trametinib Vemurafenib* + cobimetinib BRAF inhibitor + MEK inhibitor BRAF inhibitor + MEK inhibitor Increased PFS by 3.5 months vs dabrafenib monotherapy PFS improved in patients on combination vs vemurafenib alone (9.9 mo vs 6.2 mo) * Can be used as a single agent NCCN category 1 for BRAF mutated and listed as preferred if rapid clinical response needed NCCN = National Comprehensive Cancer Network; PFS = progression-free survival. NCCN Clinical Practice Guidelines in Oncology: Melanoma. Version 3.2016. NCCN.org Web site. Available at: https://www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf. Accessed September 2016.
Interferon Immunotherapy NCCN recommended for adjuvant therapy in stages IB to III (category 2A) Interleukin-2 Glycoprotein produced by activated lymphocytes Activates T-cells, lymphocytes, and NK cells RR 15% 20% CR ~5% Durable (70 months) CR = complete response; NK = natural killer; RR = response rate. NCCN Clinical Practice Guidelines in Oncology: Melanoma. Version 3.2016. NCCN.org Web site. Available at: https://www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf. Accessed September 2016.
Immunotherapy in the Adjuvant Setting
EORTC 18071: A Randomized, Double-blind, Phase III Trial CI = confidence interval; EORTC = European Organisation for Research and Treatment of Cancer; HR = hazard ratio; RFS = recurrence-free survival. 1. NCCN Clinical Practice Guidelines in Oncology: Melanoma. Version 3.2016. NCCN.org Web site. Available at: https://www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf. Accessed September 2016; 2. Eggermont AMM, et al. Lancet Oncol. 2015;16:522-530. For educational purposes only. Treatment option for 1 : Resected stage IIIA with metastases > 1 mm Resected IIIB-C Resected nodal recurrence Dose 2 : 10 mg/kg every 3 weeks for 4 doses, followed by 10 mg/kg every 12 weeks for up to 3 years (or recurrence/toxicity) Toxicity 2 : 54% grade 3 or 4 (gastrointestinal, hepatic, endocrine most common) 1% fatal reactions Risk 3-fold higher than standard dose
Talimogene Laherparepvec (T-VEC) Mechanism: produces an antitumor immune response Indication: indicated for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery Talimogene laherparepvec [package insert]. Thousand Oaks, CA: Amgen; 2015.
Talimogene Laherparepvec 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 surfacebound 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 APC = antigen-presenting cell; DC = dendritic cell; GM-CSF = granulocyte-macrophage colony-stimulating factor; OV = oncolytic virus. Lawler SE et al. J Clin Oncol. 2015;33:2812-2814. For educational purposes only.
Antitumor Activity of T-VEC 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 PR = partial response. Andtbacka RH, et al. J Clin Oncol. 2015;33:2780-2788. For educational purposes only.
Immunotherapy in the Metastatic Setting
Case 1 A 69-year-old woman with no prior significant PMH developed a primary skin melanoma in the left thigh area that was 1.4 mm thick at the time of diagnosis. At the time of excision, the left inguinal sentinel lymph node biopsy was positive. A follow-up PET scan showed an abdominal nodule approximately 3 cm. No other abnormalities were noted. PET = positron emission tomography; PMH = past medical history.
Case 1 (cont d) PMH: not contributory otherwise healthy Drug history: NKDA no current drugs Physical exam and labs within normal limits, except for noted skin lesion (nearly healed) BRAF is wild type. NKDA = no known drug allergies.
Case 1 (cont d) What therapy would you recommend? A. Dacarbazine B. Interleukin-2 C. Ipilimumab D. Pembrolizumab E. Nivolumab and ipilimumab
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 Ipilimumab [package insert]. Princeton, NJ: Bristol Myers Squibb; 2015; Nivolumab [package insert]. Princeton, NJ: Bristol Myers Squibb; 2015.
Improved Survival with Ipilimumab in Patients with Metastatic Melanoma Randomized, doubleblind phase III study Patients with unresectable stage III or IV melanoma Previously treated ECOG performance status of 0 or 1 HLA-A*0201 positive R A N D O M I Z E Ipilimumab 3 mg/kg q3w x 4 + gp100 (n = 403) Ipilimumab 3 mg/kg q3w x 4 (n = 137) gp100 alone (n = 136) Primary Endpoint: OS Secondary Endpoints: Best overall response rate Duration of response Progression-free survival ECOG = Eastern Cooperative Oncology Group; gp100 = glycoprotein 100; OS = overall survival; q3w = every 3 weeks. Hodi FS, et al. N Engl J Med. 2010;363:711-723.
Improved Survival with Ipilimumab Median OS ipilimumab + gp100: 10 months Median OS gp100: 6.4 months HR 0.68; P <.001 Ipi = ipilimumab. Median OS ipilimumab: 10.1 months Median OS gp100: 6.4 months; HR 0.66; P =.003 Hodi FS, et al. N Engl J Med. 2010;363:711-723. For educational purposes only.
Nivolumab 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 had disease progression on FDA-approved therapy for these aberrations prior to receiving nivolumab. Advanced renal cell carcinoma patients who have received prior antiangiogenic therapy Classical Hodgkin lymphoma that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and posttransplantation brentuximab vedotin. FDA = US Food and Drug Administration; IgG4 = immunoglobulin G4; NSCLC = non-small cell lung cancer; PD-1 = programmed death receptor 1; PD-L1 = programmed death ligand 1; PD-L2 = programmed death ligand 2. Nivolumab [package insert]. Princeton, NJ: Bristol Myers Squibb; 2016.
Nivolumab Unresectable or metastatic melanoma 240 mg every 2 weeks In combination with ipilimumab: dose is 1 mg/kg, followed by ipilimumab on the same day, every 3 weeks for 4 doses, then 240 mg every 2 weeks Metastatic NSCLC 240 mg every 2 weeks Advanced renal cell carcinoma 240 mg every 2 weeks Classical Hodgkin lymphoma 3 mg/kg every 2 weeks Nivolumab [package insert]. Princeton, NJ: Bristol Myers Squibb; 2016.
Nivolumab for First-line Treatment of Metastatic Melanoma (CheckMate 066) Patients with unresectable stage III or IV melanoma No BRAF mutation No prior treatment ECOG performance status of 0 or 1 R A N D O M I Z E Nivolumab 3 mg/kg q2w (n = 210) Dacarbazine 1000 mg/m 2 q3w (n = 208) ORR = objective response rate; q2w = every 2 weeks Robert C, et al. N Engl J Med. 2015;372:320-330. Primary Endpoint: OS Secondary Endpoints: PFS, ORR, PD-L1 expression
CheckMate 066: Results OS rate at 1 year Nivolumab: 72.9% Dacarbazine: 42.1% Robert C, et al. N Engl J Med. 2015;372:320-330. For educational purposes only.
Pembrolizumab 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 patients 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 had disease progression on FDA-approved therapy for these aberrations prior to receiving pembrolizumab. Recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. The dose is 2 mg/kg every 3 weeks for NSCLC and melanoma. The dose is 200 mg every 3 weeks for HNSCC. Pembrolizumab [package insert]. Whitehouse Station, NJ: Merck & Co Inc.
Ipilimumab vs Pembrolizumab in Metastatic Melanoma (KEYNOTE-006) One-year OS Pembro q2w = 74% Pembro q3w = 68% Ipilimumab = 58% HR = 0.63, P =.0005 HR = 0.69, P =.0036 Robert et al. N Engl J Med. 2015;367:1694-1703. For educational purposes only.
Ipilimumab vs Nivolumab vs the Combination in Metastatic Melanoma Nivo = nivolumab. Median PFS: Ipi = 2.9 mo Larkin et al. N Engl J Med. 2015;373:23-34. For educational purposes only. Nivo = 6.9 mo Ipi plus Nivo = 11.5 mo HR = 0.42, P <.001
A New Standard for First-line Metastatic Melanoma Dacarbazine approved 1975 (no placebocontrolled trials) Ipilimumab >dacarbazine Nivolumab >dacarbazine Pembrolizumab >ipilimumab Nivolumab >ipilimumab Nivolumab and ipilimumab >ipilimumab PD-1i +/- CTLA-4 inhibitor is best CTLA-4 = cytotoxic T-lymphocyte-associated protein 4; PD-1i = programmed death 1 inhibitor.
Sequential Ipilimumab and PD1 Antagonists Although they are both classified as immune checkpoint inhibitors, they work differently. Clear evidence that there is no crossresistance Weber et al. Lancet Oncol. 2015;16:375-384; Roberts et al. Lancet. 2014;384:1109-1117.
Can We Afford the Combination? Ipilimumab 3 mg/kg x 4 doses $33,985 per dose (5 x 50-mg vials) Nivolumab 3 mg/kg q2w until progression $7,201 per dose (3 x 100-mg vials) Pembrolizumab 2 mg/kg q3w until progression (4 x 50-mg vials ) ~ $9,128 Combination of ipilimumab 3 mg/kg q3w x 4 and nivolumab 1 mg/kg q3w x 4 $36,385 per cycle, then nivolumab 3 mg/kg q2w Assumes 85-kg patient. Good RX.com Web site. Available at: http://www.good Rx.com. Accessed November 5, 2015.
Ipilimumab Does Not Add Value to High PD-L1 Expressing Tumors PD-L1 expression may predict which patients should be treated with nivolumab monotherapy Larkin et al. N Engl J Med. 2015;373:23-34. For educational purposes only.
Case 1 (cont d) PD-L1 was tested and the TPS was 10% positive (not performed with the 22C3 pharmdx * assay). Treatment with pembrolizumab 2 mg/kg IV every 3 weeks was started. Just before the third dose (6 weeks from the first dose), a scan was performed and the abdominal mass had increased by 50%. *Carpinteria, CA: Dako North America, Inc. IV = intravenous; TPS = tumor proportion score.
Case 1 (cont d) How would you manage the patient now? A. Continue pembrolizumab B. Switch to nivolumab C. Switch to ipilimumab D. Switch to dacarbazine E. Move to best supportive care
Pseudoprogression with Pembrolizumab Baseline Treatment CD8+ IHC IHC = immunohistochemistry. Ribas A, et al. ASCO 2013. Abstract 9009. For educational purposes only.
Immune-Related Response Criteria (irrc) CR PR WHO Disappearance of all lesions not less than 4 weeks apart 50% decrease in SPD of all index lesions compared with baseline in 2 observations irrc Disappearance of all lesions not less than 4 weeks apart 50% decrease in SPD of all index lesions compared with baseline in 2 observations SD Not PR, CR, or PD Not PR, CR, or PD PD At least 25% increase in SPD compared with nadir and/or unequivocal progression of nonindex lesions and/or appearance of new lesions (at any single time point) At least 25% increase in tumor burden compared with nadir in 2 consecutive observations at least 4 weeks apart New lesions Always represent PD Incorporated into tumor burden if possible PD = progressive disease; SD = stable disease; SPD = sum of the product of perpendicular diameters; WHO = World Health Organization. Wolchok JD, et al. Clin Cancer Res. 2009;15:7412.
Follow-up Pembrolizumab was continued and the scan 4 weeks later revealed tumor shrinkage by 50%. When asked about toxicity, the patient says that she has been having diarrhea for the last week, which is occasionally bloody. The loperamide she has been taking doesn t work too well and she requests a prescription for something stronger.
How do you manage this patient now? A. Refer the patient to an emergency department with directions to begin treatment immediately with IV hydration and dexamethasone at 4 mg every 6 hours. B. Comfort the patient by stating that occasional episodes of loose stools are actually frequent in the population and could be related to diet, and recommend no further evaluation before her next infusion of pembrolizumab. C. Obtain a full history including the frequency and severity of the gastrointestinal symptoms; recommend a stringent diet, oral hydration, and loperamide; and follow up with the patient in the next day to assess the status of the loose stools. D. Continue the pembrolizumab infusions, but prescribe oral prednisone 60 mg/day for 5 days, followed by a 1-month taper. E. Not sure Case 1 (cont d)
Management Algorithm for Diarrhea Grade 1 * Grade 2 * Grade 3 4 * Symptom control NO STEROID Continue Anti-CTLA-4 Resolved to grade 1 Symptom control NO STEROID No resolution Stool WBC Stool calprotectin Endoscopy Grade 2 Budesonide or moderate-dose steroid Likely colitis Grade 3 4 High-dose steroid No response in 1 week No response in 1 week * NCI Common Toxicity Criteria. NCI = National Cancer Institute; WBC = white blood cells. O Day et al. Cancer. 2007;110:2614-2627. Infliximab
Pharmacist Role Patrick Medina, PharmD, BCOP Professor of Medicine Hematology/Oncology Director of Pharmacy Stephenson Cancer Center Oklahoma City, Oklahoma
Immune Checkpoint Inhibitor AEs AE = adverse event;. Dolan et al. Cancer Control. 2014;21:231-237. For educational purposes only.
Nivolumab Toxicity Over Time Events Per 100 Person-Years 140 120 100 80 60 40 20 0 Observation period (no. pts; P-Y) 0 6 mo (n = 306; P-Y = 138) 6 12 mo (n = 189; P-Y = 59) 12 24 mo (n = 85; P-Y = 49) Overall 17% had grade 3 to 4 toxicities. GI = gastrointestinal; Inf. = infusion; P-Y = person-year. Topalian SL, et al. J Clin Oncol. 2014;32:1020-1030.
Kinetics of Appearance of Ipilimumab Immune-Related Adverse Events Weber JS. J Clin Oncol. 2012;30:2691-2697. For educational purposes only.
Case 2 JM is a 67-year old male diagnosed with NSCLC. Squamous subtype, EGFR and ALK mutation negative, PD-L1 positive He was originally started on paclitaxel/carboplatin but progressed after 4 cycles. The decision was made to start nivolumab 3 mg/kg every 2 weeks. He tolerated therapy well for the first 5 doses, but prior to his sixth dose, his test results reveal grade 4 hepatotoxicity (bilirubin 3.8 mg/dl).
Case 2 (cont d) Which of the following is correct regarding the management of this adverse effect? A. Continue therapy and start oral prednisone 1 mg/kg daily B. Continue therapy and start mycophenolate 500 mg PO every 12 hours C. Hold therapy and start infliximab 5 mg/kg IV every 2 weeks D. Hold therapy and start IV methylprednisolone 2 mg/kg daily PO = by mouth.
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%) 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
PD-1 Blockade with Nivolumab: Toxicities Anti-PD-1 Related Adverse Event, n (%) All Grades Grade 3/4 Any select event 54 (58) 5 (5) Skin 36 (38) 2 (2) Gastrointestinal 18 (19) 2 (2) Endocrinopathies 13 (14) 2 (2) Hepatic 7 (7) 1 (1) Infusion reaction 6 (6) Pulmonary 4 (4) Renal 2 (2) 1 (1) Early respiratory symptoms can be fatal pneumonitis Renal insufficiency can also occur rarely Endocrinopathies and enterocolitis are more characteristic of ipilimumab but may occur in patients receiving a PD-1 blocking drug Sznol M, et al. ASCO 2013. CRA9006; Topalian SL, et al. N Engl J Med. 2012;366:2443-2454.
Adverse Events in the As-Treated Population From Robert et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372:2521-2532. (2015) Massachusetts Medical Society. For educational purposes only.
Differences in Toxicity and Schedule Supplement to: Robert C, et al. N Engl J Med. 2015;372:2521-2532. For educational purposes only.
Less Common Immune-Related Adverse Events Hematologic (hemolytic anemia, thrombocytopenia) Cardiovascular (myocarditis, pericarditis, vasculitis) Ocular (blepharitis, conjunctivitis, iritis, scleritis, uveitis) Renal (nephritis) Several case reports of rare autoimmune-based toxicities in patients treated with ipilimumab Lupus nephritis Inflammatory enteric neuropathy Tolosa-Hunt syndrome Myocardial fibrosis Acquired hemophilia A Autoimmune polymyositis
PD-1/PD-L1 Inhibition: Managing for Treatment-Related Adverse Events Any grade 1 AE or isolated hypothyroidism Symptom management or replacement therapy for hypothyroidism Grade 2 pneumonitis, nephritis, colitis, hepatitis Symptomatic hypophysitis Any grade 3 AE Hold PD-1 treatment and administer steroids After improvement to grade 1, taper steroids over at least 1 month Continue PD-1 treatment and monitor Resume if AE remains at grade 0/1 after steroid taper Nivolumab Immune-Mediated Adverse Reactions Management Guide. BMS.com Web site. Available at: https://bmsdm.secure.force.com/opdivohcp/servlet/servlet.filedownload?file=00pi000000gl6roeal. Updated March 2015. Accessed November 2015. A Guide to Monitoring Patients During Treatment with Pembrolizumab: A resource for adverse reaction management. Keytruda Web site. Available at: https://www.keytruda.com/static/pdf/adverse-reaction-management-tool.pdf. Updated 2015. Accessed November 2015. Permanently discontinue if: No improvement to grade 1 within 12 weeks Cannot taper steroids to 10 mg/day of prednisone or equivalent within 12 weeks
PD-1/PD-L1 Inhibition: Managing for Treatment-Related Adverse Events (cont d) Grade 3/4 pneumonitis Grade 3/4 nephritis Grade 3/4 infusion-related reaction Any life-threatening or grade 4 AE Any severe or grade 3 recurrent AE Hepatitis associated with: AST/ALT > 5 x ULN AST/ALT 50% from baseline lasting 1 week * Total bilirubin > 3 x ULN Initiate steroid therapy Permanently discontinue PD-1 treatment * In patients with liver metastasis who begin treatment with grade 2 elevation of AST/ALT. ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal. Nivolumab Immune-Mediated Adverse Reactions Management Guide. BMS.com Web site. Available at: https://bmsdm.secure.force.com/opdivohcp/servlet/servlet.filedownload?file=00pi000000gl6roeal. Updated March 2015. Accessed November 2015. A Guide to Monitoring Patients During Treatment with Pembrolizumab: A resource for adverse reaction management. Keytruda Web site. Available at: https://www.keytruda.com/static/pdf/adverse-reaction-management-tool.pdf. Updated 2015. Accessed November 2015.
Hepatitis * Grade 1 AST or ALT < 1 2.5 x ULN, or total bilirubin 1 1.5 x ULN Monitor and continue therapy Grade 2 AST or ALT > 2.5 5 x ULN, or total bilirubin > 1.5 3 x ULN Monitor and continue therapy when grade 1 If symptoms persist, start prednisone 1 mg/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 ULN, or total bilirubin > 3 x ULN IV methylprednisolone 2 mg/kg and discontinue (consider hepatology consult and hospitalization recommended) If symptoms persist, consider mycophenolate 500 mg PO every 12 hours *Please consult current package insert for individual products. Fecher LA, et al. Oncologist 2013;18:733-743; Champiat S, et al. Ann Oncol. 2016;27:559-574.
Dermatitis * Baseline: Emollients ± skin moisturizers Signs/symptoms: Rash < 30% of the body surface Dry skin Pruritus (localized) Vitiligo Signs/symptoms: Rash > 30% of the body surface Pruritus (diffuse and constant) Blisters, ulcerations, bullae, necrotic or hemorrhagic lesions Toxic epidermal necrolysis *Please consult current package insert for individual products. Printed with permission from Fecher. Oncologist. 2013;18:733-743. Grade 1 Moisturizers Topical steroids Monitor Continue therapy Grade 2 Topical steroids Antihistamines Persistent symptoms > 1 2 weeks after start of 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)
Immune-Mediated Adverse Reaction Colitis Adverse Events Associated with Immune-Checkpoint Blockade * Symptoms Diarrhea, abdominal pain, blood in stool Management Antidiarrheals followed by systemic corticosteroids if persistent; infliximab if refractory Pneumonitis Dyspnea, cough Systemic corticosteroids Hepatitis ALT/AST, bilirubin elevation Systemic corticosteroids; mycophenolate mofetil if refractory Dermatitis Pruritic/macular/papular rash, Stevens-Johnson syndrome (rare), toxic epidermal necrolysis (rare) Topical betamethasone or oral antihistamines; systemic corticosteroids if refractory Neuropathy Sensory/motor neuropathy, Guillain- Barre syndrome (rare), myasthenia gravis (rare) Systemic corticosteroids Endocrinopathy Other iraes Hypo- or hyperthyroid, hypopituitarism, adrenal insufficiency, hypogonadism, Cushing s syndrome (rare) Arthritis, nephritis, meningitis, pericarditis, uveitis, iritis, anemia, neutropenia Systemic corticosteroids with appropriate hormone replacement (potentially long term) Organ system specific Khalil DN. Nat Rev Clin Oncol. 2016. doi: 10.1038/nrclinonc.2016.25. *Please consult current package insert for individual products.
Cost Melanoma Barriers to Care 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 and pseudoprogression is possible. Andrews A. Am Health Drug Benefits. 2015;8(Spec Issue):9.
Pharmacy Management of Immunotherapy Toxicity Champiat S. Ann Oncol. 2016;27:559-574. For educational purposes only.
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 that has prescribed the treatment: Prescriber ID and contact information (reported on the back of this card) Champiat S, et al. Ann Oncol. 2016;27:559-574.