cancer immunology: release the beast - avera health · cancer immunology: release the beast ......

9/26/2016

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Jacob Hobbs, PharmD, BCOP

September 30, 2016

Cancer Immunology: Release the Beast

Disclosure I have no actual or potential conflict of interest in

relation to this presentation

Objectives Describe the mechanism of action of oncologic

immunotherapy agents

Identify the current indications for immunotherapy and the associated data

Summarize the unique toxicities of immunotherapy and recommended treatment strategies

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Immunity

Accessed from Nature Reviews Cancer 4, 11-22

Tumor Immunology

Tumor

N

N

N

N

NN

TumorAntigen

DendriticCell

N

N

Resting T Cells

NN

I

I

I

I

Cytokine releaseT Cell attraction

Lymph Node

(Go Hawks!)

Activated T Cell

Priming Phase(Lymph node)

Dendritic cellT cell

MHC TCR

B7

CD28

CTLA-4

DendriticCell

T Cell

MHCTCR

B7

B7

CTLA-4

CD28

Antigen

Activation Signal

Inhibition Signal

Ribas A. N Engl J Med. 2012;366:2517-2519.

N

N

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CTLA-4 Inhibition

Dendritic cellT cell

MHC TCR

B7

CD28

CTLA-4

DendriticCell

T Cell

MHCTCR

B7

B7

CTLA-4

CD28

Antigen

Activation Signal

Inhibition Signal

Ipilimumab


N

N

Kill Phase(Peripheral Tissue)

Tumor cellT cell

MHCTCR

B7

CD28

CTLA-4

T Cell

MHCTCR

Inhibition Signal

PD-1PDL-1

Tumor Cell


Tumor

PD-1/PD-L1 Inhibition

Tumor cellT cell

MHCTCR

B7

CD28

CTLA-4

T Cell

MHC TCR

Atezolizumab

PD-1PD-L1

Tumor

PembrolizumabNivolumab


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FDA Approved Checkpoint Inhibitors

Ipilimumab(Yervoy)

• CTLA-4 inhibitor• 2011• Unresectable or

metastatic melanoma

• Adjuvant melanoma

Pembrolizumab(Keytruda)

• PD-1 inhibitor• 2014• Unresectable or

metastatic melanoma

• Metastatic NSCLC (PDL-1+)

• Metastatic Head and Neck

Nivolumab(Opdivo)

• PD-1 inhibitor• 2014• Unresectable or

metastatic melanoma

• Metastatic NSCLC

• Renal Cell• Hodgkin

Lymphoma

Atezolizumab

(Tecentriq)

• PD-L1 inhibitor• 2016• Metastatic

bladder cancer

Ipilimumab

Unresectable or metastatic melanoma 3 mg/kg IV every 3 weeks x

4 doses

Median OS of 10.1 mos vs 6.4 mos with gp100 [1]

FDA approved 2011

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

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Ipilimumab Adjuvant treatment of melanoma

10 mg/kg IV q3 weeks x 4 doses; followed by 10 mg/kg IV q12 weeks for up to 3 yrs

Approval based on median RFS 26 mos vs 17 mos with placebo[1]

Median survival not reached in either arm

52% discontinued treatment due to side effects – 5 died

In combination with nivolumab for BRAF V600 wild type, unresectable or metastatic melanoma (first line) Dosing guideline: ipilimumab 3 mg/kg IV q3w x 4 + nivolumab 1

mg/kg IV q3w x 4, then nivolumab monotherapy

PFS 11.5 months (combo), 6.9 months (nivo), 2.9 months (ipi)

ORR 57.6% (combo), 43.7% (nivo), 19% (ipi) [2]

Approval based on 61% ORR with combination vs 11% with ipilimumab monotherapy[3]

1)Eggermont AM, et al. Lancet Oncol. 2015;16:522-5302)Larkin J, et al. N Engl J Med. 2015;373:23-343)Postow MA, et al. N Engl J Med. 2015;372:2006-2017

Nivolumab Unresectable or Metastatic Melanoma (front line +/-

ipilimumab, or beyond) 240 mg IV q 2 weeks

Metastatic NSCLC (2nd line or beyond) Squamous: median OS 9.2 vs 6.0 mos with docetaxel [1]

Nonsquamous: OS 12.2 vs 9.4 mos docetaxel. Median PFS favored docetaxel 4.2 vs 2.3 months but rate of PFS at 1 year higher with nivolumab 19% vs 8%[2]

Advanced RCC (following antiangiogenic therapy) Median OS 25.0 vs 19.6 months vs everolimus[3]

ORR 25% vs 5%, median PFS not significant Classical Hodgkin’s Lymphoma (following relapse or

progression after stem cell transplant and brentuximabvedotin 3 mg/kg IV q 2 weeks 23 patients - ORR 87%; PR 70%, CR 17%[4]

1) Rounds A, et al. Am J Health Syst Pharm. 2015;72:1851-1855. 2) Borghaei H, et al. N Engl J Med. 2015;373:1627-1639. 3)Motzer RJ, et al. N Engl J Med. 2015;373:1803-1813. 4)US Food and Drug Administration. Nivolumab (Opdivo) for Hodgkin Lymphoma. www.fda.gov

Pembrolizumab Unresectable or metastatic melanoma (first line or beyond) [1]

2 mg/kg IV q 3 week

ORR vs ipilimumab: 34% vs 12%, in previously untreated pts

Improved PFS and OS vs ipilimumab, less Grade 3-5 toxicity

Metastatic NSCLC (PD-L1+ with approved test) after first-line therapy[2]

Median OS all patients: 10.4 months vs 8.5 months on docetaxel, PFS non significant

OS for Patients with at least 50% PD-L1 expression: 14.9 months vs 8.2 months, PFS 5 months vs 4.1 months

Head and neck cancer, squamous cell, recurrent or metastatic after platinum-containing chemotherapy[3]

200 mg IV q 3 week until progression, toxicity, or up to 24 months

ORR 16%, 82% of responders had responses of 6 months or longer

1)Robert C, et al. N Engl J Med. 2015;372:2521-25322)Herbst RS, et al. Lancet. Published online Dec 12, 20153)US Food and Drug Administration. Pembrolizumab for head and neck cancer. www.fda.gov

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Atezolizumab Locally advanced or metastatic urothelial carcinoma with

progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant/adjuvant treatment with platinum-containing chemotherapy 1200 mg IV q 3 week

ORR 14.8% Patients with > 5% expression of PD-L1 in tumor-infiltrating immune cells: ORR

26.0%

Patients with ≤ 5% expression of PD-L1 in tumor-infiltrating immune cells: ORR 9.5%

At median follow up of 11.7 months, 84% of responders had ongoing response

Rosenberg JE, et al. Lancet 2016;387:1909-20

Summary

Metastatic Melanoma Metastatic Non Small Cell Lung Cancer

All > traditional chemo

Pembrolizumab > Ipilimumab

Nivolumab > Ipilimumab

Nivolumab + Ipilimumab > Ipilimumab

Pembrolizumab vs Nivolumab??

2nd line Pembrolizumab > Docetaxel(PD-L1 +)

2nd line Nivolumab > Docetaxel

Nivolumab vs Pembrolizumab??

1st line – Pembrolizumab?

Toxicities of Checkpoint Inhibitors

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General Toxicities Common Side Effects Fatigue Cough Nausea Decreased appetite Rash Itching

Less Common Immune related adverse-events

American Cancer Society. www.cancer.org

Grade 3 and 4 ToxicityEvent Nivolumab Nivo + Ipi Ipilimumab

Tx-related AE 16.3% 55% 27.3%

Diarrhea 2.2% 9.3% 6.1%

Fatigue 1.3% 4.2% 1%

Pruritis 0 1.9% 0.3%

Rash 0.6% 4.8% 1.9%

Vomiting 0.3% 2.6% 0.3%

Increased LFT 1.3% 8.3% 1.6%

Colitis 0.6% 7.7% 8.7%

Tx-related AE leading to DC

7.7% 36.4% 14.8%

Larkin, J et al. N Engl J Med 2015;373:23-34

If not vigilant, may result in more serious immune-related AEs

Pulmonary Pneumonitis Interstitial lung

disease Acute interstitial

pneumonitis

Neurologic Autoimmune neuropathy Demyelinating

Polyneuropathy Guillain-Barre Myasthenia gravis–like

syndrome

Hepatic Hepatitis,

autoimmune

Gastrointestinal Colitis Enterocolitis Necrotizing colitis GI perforation

Eye Uveitis Iritis

Renal Nephritis,

autoimmune Renal failure

Skin Dermatitis exfoliative Erythema multiforme Stevens-Johnson

syndrome Toxic epidermal necrolysis Vitiligo Alopecia

Immune-Related AEs With Immunotherapy

Slide credit: clinicaloptions.com

Endocrine Hypothyroidism Hyperthyroidism Adrenal

insufficiency Hypophysitis

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Side Effect Time Frame - ipilimumabRash, pruritusLiver toxicityDiarrhea, colitisHypophysitis

Toxi

city

Gra

de

Wks

140 2 4 6 8 10 12

Weber JS, et al. J Clin Oncol. 2012;30:2691-2697. For educational purposes only

Corticosteroid treatment Optimal management based on clinical experience, no

prospective trials to evaluate best treatment strategy Prednisone 1 to 2 mg/kg daily or equivalent

When ≤ grade 1, taper over at least 4 weeks Half life

27 days for PD-1/PD-L1 15.4 days for ipilimumab

Temporary immunosupression does not seem to limit efficacy

Consider Pneumocystis carinii pneumonia prophylaxis in patients requiring ≥ 20 mg of prednisone or equivalent daily for ≥ 4 weeks

PPI or H2 blocker for gastritis Control blood sugars in diabetics

Naidoo J, et al. Annals of Oncology 2015(26)2375-2391

Dermatologic Most common immune related adverse event Usually seen after second cycle, can appear

within first 2 weeks Usually located across limbs and trunk Maculopapular, papulopustular, Sweet’s

syndrome, follicular or urticarial dermatitis, pruritis Rarely lichenoid dermatitis, bullous pemphigoid Vitiligo More common with PD-1 inhibitors in melanoma No cure, might be associated with favorable

outcomes

Naidoo J, et al. Annals of Oncology 2015(26)2375-2391Friedman, CF, et al. JAMA Oncology. Online June 30, 2016

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Maculopapular rash

Maculopapular rash

Dermatologic Management Grade 1 (covers <10% of BSA) and 2 (10-30% of BSA)

Can continue treatment, use supportive care Topical corticosteroids – medium to high potency Pruritis – antihistamines, cold compress, oatmeal baths, oral

or topical doxepin, oral aprepitant

Grade 3 or higher (>30% of BSA, blistering, peeling) Hold dose and start prednisone 1 mg/kg/day or equivalent Can restart when grade 1 or lower If no response within 48 hours consider additional

immunosuppression with infliximab, mycophenolate mofetil, or cyclophosphamide

Discontinue if symptoms don’t improve after 12 weeks of supportive care


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Dermatologic management Rare cases of Stevens-Johnson syndrome/toxic

epidermal necrolysis Hospitalize with IV fluids and electrolyte

replacement Prednisone 1-2 mg/kg/day or methylprednisolone 1-

4 mg/kg/day IV Discontinue treatment

Mucositis, gingivitis, sicca syndrome Steroid oral rinses, viscous lidocaine, good oral

hygiene


Diarrhea/Colitis Median time to onset – 6 to 8 weeks after

initiation

Important to distinguish diarrhea from colitis

Colitis-related mortality delayed reporting, noncompliance, and not withholding treatment

Nothing known to prevent immune-related diarrhea

Developing colitis with ipilimumab does not prohibit use of PD-1 inhibitors


Diarrhea/Colitis Management Minimal increase in bowel movements over

baseline Loperamide, atropine, diphenoxylate and atropine Oral budesonide 9 mg daily

Symptoms persist more than 3 days or worsen Rule out infectious cause Hold therapy Oral prednisone 1 to 2 mg/kg/day or IV methylprednisolone

2mg/kg twice daily Get endoscopic or radiologic evaluation to confirm diagnosis

Symptoms don’t improve on corticosteroids Add infliximab 5 mg/kg once every 2 weeks until controlled Colonoscopy not needed unless diagnosis is unclear


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Hepatitis Commonly 8 to 12 weeks after starting treatment

Most cases are asymptomatic

AST/ALT elevations more common than total bilirubin

No characteristic radiographic finding noted, hepatomegaly or periportal edema in severe cases

Monitor liver function before every dose

Rule out viral or other drug induced hepatitis

Consider radiologic evaluation to exclude malignancy

Median time to resolution 8 weeks


Hepatitis Management

Grade Treatment Follow-up

1AsymptomaticAST/ALT ≤ 2.5 x ULNT Bilirubin ≤ 1.5 x ULN

•Continue therapy if asymptomatic•Monitor LFT routinely until resolved

•If LFTs worsen or patient develops symptoms, treat as higher grade

2AST/ALT 2.6-5 x ULNT Bilirubin 1.6-3 x ULN

•Hold therapy•Oral prednisone 0.5 - 1 mg/kg/day or equivalent•Monitor LFT daily

•After symptoms improve, taper steroids ≥1 month with weekly LFT•Resume once ≤ grade 1

3 - 4AST/ALT > 5 x ULNT Bilirubin > 3 x ULN

•Discontinue immunotherapy•IV prednisolone 2-4 mg/kg/day or equivalent•Monitor LFT daily•If no improvement in 3 days, add mycophenolate mofetil 500-1000mg every 12 hours or tacrolimus•*Do not add infliximab*

•After symptoms and LFT improve, taper steroids ≥ 1 month with weekly LFT•Could add antithymocyte globulin 1.5 mg/kg for 2 consecutive days if no response•Patients may have a rebound in LFT elevations


Pneumonitis More common in lung and renal cell carcinoma

Occurs later, 7.4 – 24.3 months after starting

Can be fatal if not treated appropriately

Check CT scan for shortness of breath, cough, fever, chest pain, or hypoxia

Naidoo J, et al. Annals of Oncology 2015(26)2375-2391Friedman, CF, et al. JAMA Oncology. Online June 30, 2016Nishino M, et al. JAMA Oncology. Online August 18, 2016

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Pneumonitis Management

Grade Treatment Follow-up

1AsymptomaticRadiologic changes only

•Continue therapy•Monitor for symptoms every 3 days

•Repeat CT chest scan every cycle•If symptoms develop, treat as higher grade

2Mild to moderate new symptoms

•Hold therapy•Oral prednisone 1 mg/kg/day or equivalent•Monitor for symptoms daily

•If improve to ≤ grade 1 within 3 days of supportive care, resume therapy at next dose•If persistent after 3 days, discontinue therapy•After symptoms improve, taper steroids ≥1 month

3 - 4Severe or life-threatening new symptomsWorsening hypoxia

•Discontinue immunotherapy•Hospitalization•Consider pulmonary/infectious disease consults and bronchoscopy•IV prednisolone 2-4 mg/kg/day or equivalent•Prophylactic antibiotics

•After symptoms improve to ≤ grade 1 or baseline, taper steroids ≥ 6 weeks•If worsens in 48 hours consider adding infliximab, cyclophosphamide, or mycophenolate mofetil


Endocrine Toxicities Incidence difficult to assess due to variable

methods of assessment in clinical trials

Hypophysitis and hypothyroidism most common

Rare hyperthyroidism, thyroiditis, adrenal insufficiency, and insulin-dependent diabetes

Difficult to diagnose – headache, fatigue, nausea, depression


Hypophysitis Management Fatigue, headache, hypogonadism, hypotension,

hypoglycemia

Enlargement of pituitary gland

All or some of the pituitary hormones can be reduced (ACTH, THS, FSH, LH, growth hormone, prolactin)

Symptomatic - prednisone 1 mg/kg/day or equivalent

Hydrocortisone 20 mg every morning and 10 mg every evening for hypoaldrenalism


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Thyroid Management Usually seen after 2 to 4 infusions of ipilimumab, variable

with PD-1/PD-L1 inhibitors Check thyroid function at baseline Recommended before every dose of ipilimumab,

periodically with PD-1/PD-L1 inhibitors Primary hypothyroidism (low free T4 and high TSH) –

thyroid hormone replacement and can continue immunotherapy

Secondary hypothyroidism from hypophysitis (low free T4 and low TSH) – thyroid hormone replacement and hydrocortisone

Hyperthyroidism – standard antithyroid pharmacotherapy Thyroiditis – beta blockers in symptomatic cases


Andrenal Insufficiency Management Can rarely cause adrenal crisis – dehydration,

hypotension, hyperkalemia, hyponatremia Hospitalize and hydrate aggressively Consult endocrinology Stress dose IV corticosteroids Long term hydrocortisone supplementation likely Consider increased doses during medically stressful

situations Surgery Infection

Evaluate clinical situation before restarting immunotherapy


Less Common Toxicity Pancreatitis

Treat with corticosteroids if all other causes excluded If elevated amylase and/or lipase but no symptoms or

inflammation shown on scans – do not need to start steroids Uveitis, episcleritis, conjunctivitis

Consult ophthalmologist Topical intraocular corticosteroids – prednisolone 1 %

suspension Oral corticosteroids with grade 3 or 4, or refractory cases

Nephritis Several reports with ipilimumab monotherapy and in

combination with nivolumab Oral or IV corticosteroids Discontinue therapy if grade 3 or 4


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Less Common Toxicity

• Neuropathy, aseptic meningitis, temporal arteritis, myasthenia gravis-like syndrome, posterior reversible encephalopathy syndrome, Guillain-Barre syndrome

• IV methylprednisolone 2 mg/kg/day• Plasmapheresis and IV immunoglobulin• Grade 3 or 4 permanently discontinue

Neurologic

• Red cell aplasia, neutropenia, acquire hemophilia A

• Corticosteroids• Bone marrow biopsy if diagnosis remains

unclearHematologic


Side effect management summary Any grade 1 or isolated hypothyroidism – symptom

management and continue treatment

Grade 2 pneumonitis, nephritis, hepatitis, symptomatic hypophysitis, and all other grade 3 AE Hold treatment, start steroids

Grade 3 or 4 pneumonitis, nephritis, hepatitis, infusion-related reaction, any other grade 4 reaction, any recurrent grade 3 AE, no improvement to ≤ grade 1 or cannot taper steroids to ≤ 10 mg/day of prednisone or equivalent within 12 weeks Permanently discontinue

Common Checkpoint Inhibitor Questions

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Why did nivolumab’s dose change? Attempt to reduce dosing errors and wait time 80 kg was the approximate median body weight in clinical trials – 80 kg

x 3 mg/kg = 240 mg Model-based simulation to evaluate predicted exposure

Data derived from an integrated population pharmacokinetic analysis dataset with data from patients in 9 nivolumab trials

Range of predicted exposure with 240 mg overlapped with 3 mg/kg dosing for a wide range of body weights Median % difference in geometric means in systemic exposure

~5% melanoma and NSCLC ~3% renal cell carcinoma

Weight range 35 – 168 kg Dose/exposure response appears to be flat

Difference in dose not likely to affect efficacy and safety Hodgkin Lymphoma – 3 mg/kg IV q 2 weeks Melanoma in combination with ipilimumab – 1 mg/kg IV q 3 weeks x 4

doses, then 240mg

Data to File. NIVO 166. Bristol-Myers Squibb Company, Princeton, NJData to File. NIVO 170. Bristol-Myers Squibb Company, Princeton, NJ

What is pseudoprogression?

Screening Wk 8: “Progression” Wk 12: Improvement

Wk 16: Continued Improvement

Wk 72: CR Wk 108: Continued CR

Ribas A, et al. Clin Cancer Res. 2009;15:7116-7118.

Response to ipilimumab

Slide credit: clinicaloptions.com

Should we test for PD-L1 expression? Mixed results with response to checkpoint

inhibitors

Only FDA indication that requires testing is pembrolizumab use in non small cell lung cancer

Different cut off levels used for positivity

Different tests used for each drug

Expression can vary among primary and metastatic sites

PD-1 expression can change through time and treatment

Shien K, et al. Lung Cancer. 2016;99:79-87

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Shien K, et al. Lung Cancer. 2016;99:79-87

Can I use it in my patient with an autoimmune condition? Excluded from clinical trials Johnson DB, et al JAMA Oncol 2016;2(2):234-240

Retrospective review of 30 patients who had preexisting autoimmune disorders who received ipilimumab for melanoma

Rheumatoid arthritis, psoriasis, inflammatory bowel disease, lupus, multiple sclerosis, thyroiditis

43% were on immunosuppression during treatment 27% exacerbated autoimmune condition requiring treatment 10 patients developed Grade 3 – 5 autoimmune AE – 2 cases were

reversible 50% had no flare in underlying autoimmune disease or AE 20% objective response, 1 durable complete response 1 death from immune related colitis – psoriasis patient

Use clinical judgment, discuss risks with patient

My patient is responding to therapy but had a serious adverse event. Should I rechallenge?

Same adverse event or new severe effects may arise Monitor very closely 53 yo male with metastatic melanoma

Grade 3 colitis after 3 cycles of ipilimumab Resolved with high dose corticosteroids

Also developed hypophysitis Required thyroid and steroid replacement

Later developed grade 3 arthralgia on nivolumab High dose corticosteroids, followed by sulfasalazine and

hydroxychloroquine

6 months later tried pembrolizumab Admitted for liver failure 11 days after first dose, died within 3

days

Ludlow SP, et al. Melanoma Research 2016,26:316-318

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Use with low dose corticosteroids? No known drug – drug interactions

Patients receiving immunosuppressants excluded from trials

Corticosteroids suppress T cells

Would likely blunt drug efficacy but to what extent?

Use in pregnancy/breastfeeding? No during therapy and for at least 3 months after stopping

ipilimumab, 4 months for pembrolizumab, 5 months for nivolumab and atezolizumab

Keytruda (package insert). Merck. Accessed online September 8, 2016Opdivo (package insert). Bristol-Myers Squibb. Accessed online September 8, 2016Yervoy (package insert). Bristol-Myers Squibb. Accessed online September 8, 2016Tecentriq (package insert). Genentech. Accessed online September 8, 2016

Are checkpoint inhibitors expensive?

Tartari F, et a. Cancer Treat Rev. 2016;48:20-4Image from alivecampus.com

What is next? Figuring out who would benefit most

Combination with other immunotherapy, chemotherapy, targeted agents

Find tangible biomarkers to help predict response

Understand the optimal dosing and duration of treatment

Improve the management of toxicities

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Questions 1) Patient KG is starting nivolumab for metastatic melanoma.

Which of the following items should be monitored regularly during treatment?A. Blood pressureB. EKGC. Liver function testsD. Blood glucose

2) KG later develops grade 3 diarrhea after several months of therapy. What is the most appropriate treatment recommendation?A. Resume therapy and start loperamide 2 mg every 2 hours as neededB. Hold therapy and start loperamide 2 mg every 2 hours as neededC. Hold therapy and start a 6 day methylprednisolone taper dose packD. Hold therapy and start prednisone 1 to 2 mg/kg daily tapered over

several weeks

Questions?

cancer immunology: release the beast - avera health · cancer immunology: release the beast ......

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