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Immunotherapies in Solid Tumors

Val R. Adams, PharmD, FCCP, BCOPAssociate Professor

Pharmacy Practice and Science DepartmentCollege of Pharmacy

University of KentuckyLexington, 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

Schreiber RD et al. Science. 2011;331:1565-1570. For educational purposes only.

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.

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?Brake Off

Ipilimumab (Ipi)

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.

Gas Ongp100 Peptide Vaccine and

Interleukin-2

gp100 = glycoprotein 100.

Ribas A. N Engl J Med. 2012;366:2517-2519. For educational purposes only.

CTLA-4 and PD-1/L1 Checkpoint Blockade

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

Wolchok et al. Clin Cancer Res. 2009;15:7412-7420. For educational purposes only.SPD = sum of the product of perpendicular diameters.

WHO irRC

CR Disappearance of all lesions not less than 4 weeks apart

Disappearance of all lesions not less than 4 weeks apart

PR≥ 50% decrease in SPD of all index lesions compared with baseline in 2 observations

≥ 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 non-index 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

Immune-Related Response Criteria (irRC)

Wolchok JD, et al. Clin Cancer Res. 2009;15:7412.

CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease; WHO = World Health Organization.

0 10 20 30 40 50 60 70

Skin (n=155; 33%)

GI (n=66; 14%)

Hepatic (n=19; 4%)

Pulmonary (n=9; 2%)

Endocrine (n=36; 8%)

Renal (n=8; 2%)

Time to Onset (median in weeks and range)

Immune-Related Toxicity

Wolchok JD, et al. J Clin Oncol. 2015;33: Abstract LBA1.

GI = gastrointestinal.

PD-1/PD-L1 Inhibition: Managing for Treatment-Related Adverse Events

Grade 3/4 pneumonitisGrade 3/4 nephritisGrade 3/4 infusion-related reactionAny life-threatening or grade 4 AEAny severe or grade 3 recurrent AE

Hepatitis associated withAST/ALT > 5 x ULNAST/ALT ≥ 50% ↑ from

baseline lasting ≥ 1 week* Total bilirubin > 3 x ULN

*In patients with liver metastasis who begin treatment with grade 2 elevation of AST/ALT.

Initiate steroid therapyPermanently discontinue PD-1 treatment

Pembrolizumab adverse reaction management guide. Nivolumab adverse reaction management guide. AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal.

Current Approvals

Drug (Class) Approved UseNivolumab (PD-1 inhibitor) Non-small cell lung cancer

Metastatic melanomaRenal cell carcinomaHodgkin lymphoma

Pembrolizumab (PD-1 inhibitor)

Non-small cell lung cancerMetastatic melanoma

Head and neck squamous cell cancer

Atezolizumab (PD-L1 inhibitor) Urothelial carcinoma (bladder cancer)

Ipilimumab (CTLA-4 inhibitor) 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

Lawrence MS et al. Nature. 2013;499:214-218. For educational purposes only.AML = acute monocytic leukemia; CLL = chronic lymphocytic leukemia; DLBCL = diffuse large B-cell lymphoma

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, BCOPAssociate Professor

Pharmacy Practice and Science DepartmentCollege of Pharmacy

University of KentuckyLexington, 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.

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)

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

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. PembrolizumabB. IpilimumabC. DocetaxelD. PemetrexedE. Erlotinib

Pembr

olizu

mab

Ipilim

umab

Doce

taxe

l

Pemet

rexe

d

Erlotin

ib

20% 20% 20%20%20%

PS = performance status; WT = wild type.

Case 1 (cont’d)

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

Primary endpoint – Safety/side effect profile– Antitumor activity

Secondary endpoints– OS– PFS– Biomarker PDL-1– Training group and validation group

Pembrolizumab 2 mg/kg IV q3wN = 6


Garon EB, et al. N Engl J Med. 2015;372:2018-2028.


Advanced/MetastaticNSCLCPS 0‒1N = 495

IV = intravenous; OS = overall survival; PFS = progression-free survival; q2w = every 2 weeks; q3w = every 3 weeks.

OS Favored High Expression of PD-L1

Garon EB, et al. N Engl J Med. 2015;372:2018-2028. For educational purposes only.

394 previous tx101 no prior tx

Do we really need to test for PD-L1?

How do these pembrolizumab groups compare to chemotherapy?

JMEI Docetaxel (N = 288)1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.00 3 6 9 12 15 18 21

Survival Time (months)

Cum

ulat

ive

Pro

babi

lity TAX 317 Docetaxel (N = 55)

Survival with Docetaxel,Pemetrexed, and BSC

JMEI Pemetrexed (N = 276)

TAX 317B BSC(N = 49)

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

Primary endpoint – OS and PFS– Overall population and PD-L1+

Secondary endpoints– Biomarker PD-L1– Training group and validation

group



Docetaxel 75 mg/m2 IV q3wN = 343

Advanced/MetastaticPreviously treated

NSCLCPS 0‒1

PD-L1 expression at least 1%

Herbst et al. Lancet. 2016;387:1540-1550.

KEYNOTE-010: Prognostic or Useful to Select Therapy?

PD-L1+

Herbst et al. Lancet. 2016;387:1540-1550. For educational purposes only.

PD-L1 +

Prognostic or Useful to Select Therapy?O

vera

ll Su

rviv

al

Herbst et al. Lancet. 2016;387:1540-1550. For educational purposes only.CI = confidence interval; ECOG = Eastern Cooperative Oncology Group.

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?A. AtezolizumabB. NivolumabC. BevacizumabD. CetuximabE. Ramucirumab

Ateloli

zumab

Nivolum

abBev

acizu

mab

Cetuxim

abRam

uciru

mab

20% 20% 20%20%20%

Case 1 (cont’d)

JG5

JG5 fix spelling "Atezolizumab"Jane Griffith, 9/24/2016

Nivolumab vs Docetaxel

Primary endpoint – OS

Secondary endpoints– ORR– PFS

Previously treatedPS 0‒1

Stage IIIb/IV Squamous NSCLC

1:1

Nivolumab 3 mg/kg IV q2wn = 135

Docetaxel 75 mg/m2 IV q3wn = 137

Brahmer J et al. N Engl J Med. 2015;373:123-135.

ORR = objective response rate.

OS Favored Nivolumab

Median OS 9.2 mo vs 6.0 moP=0.00025

Brahmer J, et al. N Engl J Med. 2015;373:123-135. For educational purposes only.

Nivolumab in PD-L1‒Negative Patients

Brahmer J et al. N Engl J Med. 2015;373:appendix online. For educational purposes only.

HR = hazard ratio.

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)

Primary endpoint – OS

Secondary endpoints– Biomarker analysis– ORR– PFS

Previously treated with platinum

PS 0‒1Stage IIIb/IV

NSCLC

1:1

Atezolizumab 1200 mg IV q3wn = 144

Docetaxel 75 mg/m2 IV q3wn = 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-superior-progression-free-. Accessed June 30, 2016. For educational purposes only.

Nivolumab as First-line Treatment

Still open for accrual – Sept 2016For educational purposes only.

Further Down the Road:Clinical Trials with Immunotherapy

New Agents

New Diseases

CombinationTherapy

New Immune PathwayIdo 1 – IndoximodCD40 – APX005MTIM-3 – MBG453LAG-3 – IMP321CD27 – VarlilumabB7-H3 – EnoblituzumabGITR – AMG228

Oncolytic Virus TherapyTalimogene laherparepvec

Plus many more!!!

Overview of Melanoma Treatment with

Immunotherapies Patrick Medina, PharmD, BCOP

Professor of MedicineHematology/OncologyDirector of Pharmacy

Stephenson Cancer CenterOklahoma 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 EfficacyDabrafenib* +trametinib

BRAF inhibitor + MEK inhibitor

Increased PFS by 3.5 months vs dabrafenib monotherapy

Vemurafenib* + cobimetinib

BRAF inhibitor + MEK inhibitor

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.


Immunotherapy Interferon 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.


Immunotherapy in the Adjuvant Setting

EORTC 18071: A Randomized, Double-blind, Phase III Trial

Treatment option for1:• Resected stage IIIA with

metastases > 1 mm• Resected IIIB-C• Resected nodal

recurrenceDose2:• 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)

Toxicity2:• 54% grade 3 or 4

(gastrointestinal, hepatic, endocrine most common)

• 1% fatal reactions• Risk 3-fold higher than

standard dose

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.

CI = confidence interval; EORTC = European Organisation for Research and Treatment of Cancer; HR = hazard ratio; RFS = recurrence-free survival.

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 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;33:2812-2814. For educational purposes only.APC = antigen-presenting cell; DC = dendritic cell; GM-CSF = granulocyte-macrophage colony-stimulating factor; OV = oncolytic virus.

Antitumor Activity of T-VEC

Andtbacka RH, et al. J Clin Oncol. 2015;33:2780-2788. For educational purposes only.

• 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.

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.

A. DacarbazineB. Interleukin-2C. IpilimumabD. PembrolizumabE. Nivolumab and ipilimumab

What therapy would you recommend?

Case 1 (cont’d)

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

Hodi FS, et al. N Engl J Med. 2010;363:711-723.

• Randomized, double-blind phase III study

• Patients with unresectable stage III or IV melanoma

• Previously treated • ECOG performance

status of 0 or 1• HLA-A*0201 positive

Ipilimumab 3 mg/kg q3w x 4+ gp100

(n = 403)

Ipilimumab 3 mg/kg q3w x 4(n = 137)

Primary Endpoint: OSSecondary Endpoints: • Best overall response rate• Duration of response• Progression-free survival

gp100 alone(n = 136)

ECOG = Eastern Cooperative Oncology Group; gp100 = glycoprotein 100; OS = overall survival; q3w = every 3 weeks.

RANDOMIZE

Median OS ipilimumab + gp100: 10 monthsMedian OS gp100: 6.4 months

HR 0.68; P < .001

Median OS ipilimumab: 10.1 monthsMedian OS gp100: 6.4 months; HR 0.66; P = .003

Improved Survival with Ipilimumab

Hodi FS, et al. N Engl J Med. 2010;363:711-723. For educational purposes only.

Ipi = ipilimumab.

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 anti-angiogenic therapy

Classical Hodgkin lymphoma that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and post-transplantation brentuximab vedotin.

Nivolumab [package insert]. Princeton, NJ: Bristol Myers Squibb; 2016.

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 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)

Robert C, et al. N Engl J Med. 2015;372:320-330.

• Patients with unresectable stage III or IV melanoma

• No BRAF mutation• No prior treatment• ECOG performance

status of 0 or 1

RANDOMIZE

Nivolumab 3 mg/kg q2w(n = 210)

Dacarbazine 1000 mg/m2 q3w(n = 208)

Primary Endpoint: OSSecondary Endpoints:

PFS, ORR, PD-L1 expressionORR = objective response rate; q2w = every 2 weeks

CheckMate 066: Results

OS rate at 1 yearNivolumab: 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 OSPembro q2w = 74%Pembro q3w = 68%Ipilimumab = 58%

HR = 0.63, P = .0005HR = 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

Median PFS:Ipi = 2.9 mo

Larkin et al. N Engl J Med. 2015;373:23-34. For educational purposes only.

Nivo = nivolumab.

Nivo = 6.9 moIpi plus Nivo = 11.5 mo

HR = 0.42, P < .001

A New Standard for First-line Metastatic Melanoma

Dacarbazine approved 1975 (no placebo-controlled 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 cross-

resistance

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.

How would you manage the patient now?

A. Continue pembrolizumabB. Switch to nivolumabC. Switch to ipilimumabD. Switch to dacarbazineE. Move to best supportive care

Case 1 (cont’d)

Pseudoprogression with Pembrolizumab

Baseline Treatment

Ribas A, et al. ASCO 2013. Abstract 9009. For educational purposes only.

CD8+ IHC

IHC = immunohistochemistry.

WHO irRC

CR Disappearance of all lesions not less than 4 weeks apart

Disappearance of all lesions not less than 4 weeks apart

PR≥ 50% decrease in SPD of all index lesions compared with baseline in 2 observations

≥ 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 non-index 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

Immune-Related Response Criteria (irRC)

Wolchok JD, et al. Clin Cancer Res. 2009;15:7412.PD = progressive disease; SD = stable disease; SPD = sum of the product of perpendicular diameters; WHO = World Health Organization.

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)

Grade 1* Grade 2* Grade 3–4*

Symptom control

NO STEROID

Continue

Anti-CTLA-4

Symptom control

NO STEROID

Resolved to grade

1

No resolution

Stool WBCStool calprotectin

Endoscopy

Likely colitis

Grade 2 Grade 3–4

Budesonide or moderate-dose

steroidHigh-dose

steroid

No response in 1 week

No response in 1 week

Infliximab

Management Algorithm for Diarrhea

*NCI Common Toxicity Criteria.NCI = National Cancer Institute; WBC = white blood cells.O’Day et al. Cancer. 2007;110:2614-2627.

Pharmacist Role

Patrick Medina, PharmD, BCOPProfessor of MedicineHematology/OncologyDirector of Pharmacy

Stephenson Cancer CenterOklahoma City, Oklahoma

Immune Checkpoint Inhibitor AEs

Dolan et al. Cancer Control. 2014;21:231-237. For educational purposes only.

AE = adverse event;.

Even

ts P

er

100

Pers

on-Y

ears

Observation period (no. pts; P-Y)

Nivolumab Toxicity Over Time

Overall 17% had grade 3 to 4 toxicities.

0–6 mo (n = 306; P-Y = 138)6–12 mo (n = 189; P-Y = 59)12–24 mo (n = 85; P-Y = 49)

14012010080604020

0

Topalian SL, et al. J Clin Oncol. 2014;32:1020-1030.

GI = gastrointestinal; Inf. = infusion; P-Y = person-year.

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 3 mg/kg were: Fatigue (41%) Diarrhea (32% Pruritus (31% Rash (29%) Colitis (8%)

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.

Immune-Mediated Adverse Reactions (n = 131)

Grade 3‒5(%)

Any immune reaction 15Enterocolitis 7Hypo/hyperthyroidism 4Dermatitis 2Hepatotoxicity 1Neurotoxicity 1Nephritis 1

PD-1 Blockade with Nivolumab: Toxicities

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.

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)

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


Any grade 1 AE orisolated hypothyroidism

Symptom management or replacement therapy for

hypothyroidism

Continue PD-1 treatment

and monitor

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

Resume if AE remains at grade 0/1 after steroid taper

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

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.


(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*In patients with liver metastasis who begin treatment with grade 2 elevation

of AST/ALT.

Initiate steroid therapy

Permanently discontinue PD-1 treatment

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

Fecher LA, et al. Oncologist 2013;18:733-743; Champiat S, et al. Ann Oncol. 2016;27:559-574.

*Please consult current package insert for individual products.

Dermatitis*B

asel

ine:

Em

ollie

nts ±

skin

moi

stur

izer

s

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

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 1• Moisturizers• Topical steroids• Monitor • Continue therapy

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)Printed with permission from Fecher. Oncologist. 2013;18:733-743.

*Please consult current package insert for individual products.

Immune-Mediated Adverse Reaction Symptoms Management

Colitis Diarrhea, abdominal pain, blood in stool

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 Hypo- or hyperthyroid, hypopituitarism, adrenal insufficiency, hypogonadism, Cushing’s syndrome (rare)

Systemic corticosteroids with appropriate hormone replacement (potentially long term)

Other irAEs Arthritis, nephritis, meningitis,pericarditis, uveitis, iritis, anemia, neutropenia

Organ system specific

Adverse Events Associated with Immune-Checkpoint Blockade*

Khalil DN. Nat Rev Clin Oncol. 2016. doi: 10.1038/nrclinonc.2016.25. *Please consult current package insert for individual products.

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 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.

2016-33 amcp-adams slides v3hypertension x 20 years (tx: benazepril 10 mg po qd) 25 pack-year...

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