immunotherap role of pharmacist...monitoring, evaluation, and education role of pharmacist slide # 2...

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ImmunotherapyROLE OF PHARMACIST

1Pattariya Chantarasap, BCP, BCOP

Selection

Procurement

Prescribing, dosing, and transcribing

Storage

Preparing and dispensing

Administration

Monitoring, evaluation, and education

ROLE OF PHARMACIST

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2018 Nobel Prize in Medicine

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James P. Allison

Tasuku Honjo

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2019 Hematology/Oncology US FDA Approvals

CONCEPT

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HALLMARKS OF CANCER

Role of Immunotherapy

‣ Recognition of self

‣ Recognition of abnormal self

‣ Recognition of non-self

CONCEPT OF IMMUNE

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CELL INVOLVE

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Natural Killer Cell

IMMUNOTHERAPY IN CURRENT PRACTICE

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‣ Cytokines

‣ Cancer vaccines

‣ Adoptive Cell Therapy

‣ Check point inhibitors

IMMUNOTHERAPY IN CURRENT PRACTICE

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‣ Cytokines

‣ Cancer vaccines

‣ Adoptive Cell Therapy

‣ Check point inhibitors

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APPROVED AGENT

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‣ CTLA-4 inhibitor

‣ Ipilimumab

‣ PD1 inhibitor

‣ Nivolumab

‣ Pembrolizumab

‣ PD-L1 inhibitor

‣ Atezolizumab

‣ Avelumab

‣ Durvalumab

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IPILIMUMAB‣ A recombinant human immunoglobulin (Ig) G1

‣ Dose: 1 mg/kg or 3 mg/kg (depend on indication) q 3 wks for 4 dose, Molecular weight: 148000 dalton

‣ Half-life elimination: 15.4 days

‣ Clearance is increased with increasing body weight

‣ Administration via in-line filter (rate base on indicated dose)

‣ If concomitant with nivolumab: use separated filter and give nivolumab first

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NIVOLUMAB

‣ A recombinant human immunoglobulin (Ig) G4 monoclonal antibody

‣ Dose: 3 mg/kg, 240 mg q 2 wks, 480 mg q 4 wks

‣ Molecular weight: 143598 dalton

‣ Half-life elimination: 25 days

‣ Administration via in-line filter

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PEMBROLIZUMAB


‣ Dose: 200 mg fixed dose or 2 mg/kg q 3 wks




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ATEZOLIZUMAB


‣ Dose: 1200 mg or 840 mg depend on indication




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DURVALUMAB


‣ Dose: 10 mg/kg once every 2 weeks




WHAT CHANGE

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‣ New and new concept of concomitant agents

‣ Difference toxic profile

‣ Longer duration of treatment

‣ New indications, including both solid and hematologic malignancy

‣ Financial burden

SYSTEMIC THRAPY

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ChemotherapyTargeted TherapyImmunotherapy

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ImmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmmuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuunoooootttttttttttttttttttttttttttttttttttttttthhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhheeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeerrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrraaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaappppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyyTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaarrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeetttttttted Therapy Chemotherapy

IMPOWER150 TRIAL

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21 N Engl J Med 2018; 378:2288-2301

IMPOWER150 TRIAL

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IMPOWER150 TRIAL

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23 N Engl J Med 2018; 378:2288-2301

IMPOWER150 TRIAL

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24 N Engl J Med 2018; 378:2288-2301

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WHY COMBINE

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LOOK FURTHER‣ VEGF-A inhibits maturation of dendritic cell,

which is antigen presenting cell (HPC)

‣ May also inhibits T cell by reducing

immigration of mature cell from thymus and

reducing cytotoxic activity

‣ May increases the levels of myeloid-derived

suppressor cell (MDSC)—>characterized by

their potent ability to suppress T and NK cell

along with promotion to regulation T cellCancer Microenvironment (2015) 8:15–21

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WHAT CHANGE

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TIMING OF TOXICITY

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TIMING OF TOXICITY

J Clin Oncol 2012; 30:2691-7

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IMPOWER150 TRIAL

N Engl J Med 2018; 378:2288-2301

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IMPOWER150 TRIAL

N Engl J Med 2018; 378:2288-2301

WHAT CHANGE

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CHECKMATE 067

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34 Lancet Oncol. 2018;19(11):1480-1492

CHECKMATE 067

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35 Lancet Oncol. 2018;19(11):1480-1492

CHECKMATE 067

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36 Lancet Oncol. 2018;19(11):1480-1492

CHECKMATE 067

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37 Lancet Oncol. 2018;19(11):1480-1492

‣ Duration of treatment (median)

‣ Ipilimumab plus nivolumab: nivolumab (IQR 2−32) and four

doses of ipilimumab (2−4);

‣ Nivolumab: 15 doses (IQR 6−54)

‣ Ilipimumab: 4 doses (IQR 2-4)

CHECKMATE 067

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38 Lancet Oncol. 2018;19(11):1480-1492

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ADVERSE EVENT

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‣ Fatigue is very common but normally mild

‣ Infusion-related reactions can occur (mostly are Grade 1)

ONSET & DURATION

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Example from Pool analysis: Safety Profile of Nivolumab Monotherapy

J Clin Oncol. 2017;35(7):785-792

ONSET & DURATION

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41 Eur J Cancer 2015; 51 (Suppl 3): S664–S665.

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Monotherapy VS Combination

MANAGEMENT

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42 Journal of Clinical Oncology. 2018) 1714-1768.

Ann Oncol (2017) 28 (suppl 4): iv119–iv142

GENERAL CONCEPT

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‣ Patient education

‣ Early detection and rule out other cause is the key

‣ High dose 0.5-2 mg/kg of steroid with slow taper over 4-6 wks is indicated in higher

grade adverse event

‣ Concurrent immunosuppressant maintenance therapy (10 mg prednisolone

equivalent dose) may be offered only if clinically indicated in individual cases

‣ Other agent e.g. Ifliximab, Mycophenolate may also indicated in refractory case

SKIN TOXICITIES

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‣ Incidence 30-50%

‣ Average onset 3-5 weeks

‣ Alopecia and mucositis can occur with incidence lower

than 10%

‣ Rare case for severe skin toxicities e.g. SJS, TEN was also

reported

SKIN TOXICITIES MANAGEMENT

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‣ ASCO guideline propose management paradigm according to type of rash

‣ Rash/inflammatory dermatitis

‣ Bullous dermatoses

‣ Severe cutaneous adverse reactions (SCARs), including SJS, TEN,

acute generalized exanthematous pustulosis, and DRESS/DIHS


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BODY SURFACE AREA


GI TOCIXITIES

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‣ Diarrhea

‣ Higher incidence in CTLA4 inhibitor (32-49%) when compare with PD1 and

PDL1inhibitor (1-40%)

‣ Average onset 6 weeks

‣ Colitis 8% to 16% in CTLA4 inhibitor and lower incidence (1-2%) in PD1 and

PDL1inhibitor

MANAGEMENT OF DIARRHEA

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Grading

G1: Increase of < 4 stools per day over baseline; mild increase in ostomy output

compared with baseline

Continue ICPi; alternatively, ICPi may be held temporarily and resumed if toxicity does not exceed G1

Monitor for dehydration and recommend dietary changes

Anti-motility agents e.g. loperamide can be helpful

Budesonide may be helpful in the early treatment of mild noninfectious diarrhea

Facilitate expedited phone contact with patient/caregiver

May obtain gastroenterology consult for prolonged G1 cases

Journal of Clinical Oncology. 2018) 1714-1768.


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Grading

G2: Increase of 4-6 stools per day over baseline; moderate increase in ostomy

output compared with baseline

Should hold ICPi temporarily until patient’s symptoms recover to G1; can consider permanently discontinuing CTLA-4 agents and may restart PD-1

May also include supportive care with medications such as Imodium

Administer corticosteroids, unless diarrhea is transient, starting with initial dose of 1 mg/kg/day prednisone or equivalent When symptoms improve to G1 or less, taper corticosteroids over at least 4-6 weeks

EGD/colonoscopy, endoscopy evaluation should be highly recommended to stratify patients for early treatment with infliximab

Stool inflammatory markers can be considered (lactoferrin and calprotectin)

Repeat colonoscopy is optionalfor disease activity monitoring to achieve complete remission, especially if there is a plan to resume ICPi



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Grading

G3: Increase of 7 or more stools per day over baseline, incontinence, hospitalization

indicated, severe increase in ostomy output compared with baseline, limiting

self-care ADL

Should consider permanently discontinuing CTLA-4 agents and may restart PD-1, PD-L1 agents if patient can recover to G1 or less.

Administer corticosteroids (initial dose of 1-2 mg/kg/d prednisone or equivalent)

Consider hospitalization or outpatient facility for patients with dehydration or electrolyte imbalance

If symptoms persist 3-5 days or recur after improvement, consider administering IV corticosteroid or noncorticosteroid (eg, infliximab)

EGD/colonoscopy, endoscopy evaluation, and stool inflammatory marker

Consider colonoscopy in cases where patients have been on immunosuppression and may be at risk for opportunistic infections as an independent cause for diarrhea (ie, CMV colitis) and for those who are anti-TNF or corticosteroid refractory



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Grading

G4: Life-threatening consequences; urgent intervention indicated

Permanently discontinue treatment

Should admit patient when clinically indicated; patients managed as outpatients should be very closely monitored

EGD/colonoscopy, endoscopy evaluation, and stool inflammatory marker

Administer 1-2 mg/kg/d methylprednisolone or equivalent until symptoms improve to G1, and then start taper over 4-6 weeks

Consider early infliximab 5-10 mg/kg if symptoms refractory to corticosteroid within 2-3 days

Consider lower GI endoscopy if symptoms are refractory despite treatment or there is concern of new infections



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‣ Ifliximab dose: 5mg/kg every 2 weeks

‣ Mycophenolate (500-1000 mg bid) or vedolizumab may be indicated in ifliximab

refractory case

‣ No role of prophylactic with budesonide

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ESMO Guideline

ENDOCRINOPATHIES

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‣ Thyroid gland disorder is the most common

(higher incidence with hypothyroidism)

‣ Hyperthyroid is often transient and may precede

hypothyroidism

‣ Incidence of thyroid dysfunction requiring thyroid

hormone replacement was 21%

‣ More common with PD1/PDL1 when compare

with CTLA4 blocker

ENDOCRINOPATHIES

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‣ Thyroid gland disorder is the most common

(higher incidence with hypothyroidism)

‣ Hyperthyroid is often transient and may precede

hypothyroidism

‣ Incidence of thyroid dysfunction requiring thyroid

hormone replacement was 21%

‣ More common with PD1/PDL1 when compare

with CTLA4 blocker

MANAGEMENT OF THYROID DISORDER

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MANAGEMENT OF THYROID DISORDER

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SPECIAL POPULATION

‣ IgG is known to cross the placenta and harm the fetus based on mechanism of action, reliable contraceptive is strongly recommended

‣ Ipilimumab: 3 months

‣ Nivolumab: 5 months

‣ Pembrolizumab: 4 months

‣ Durvalumab: 3 months

‣ Atezolizumab: 5 months

‣ Avelumab: 1 month

WHAT NEXT

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‣ More potential of check point target: BTLA,

VISTA, TIM3, LAG3, CD47, IDO

‣ Targeting on costimulatory receptors:4-1BB

(CD137): urelumab, OX40 (CD134)

Thank you

immunotherap role of pharmacist...monitoring, evaluation, and education role of pharmacist slide # 2...

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