Role of the Immune System and Immunotherapy in Cancer

Val R. Adams, PharmD, FCCP, BCOPAssociate Professor

Pharmacy Practice and Science DepartmentCollege of Pharmacy

University of KentuckyLexington, Kentucky

Evidence of Immune-Tumor Interactions

High frequency of cancers in immunosuppressed patients Immunosuppressive drugs

Tumors that are infiltrated by T cells have an improved prognosis. Spontaneous regression occurs. Melanoma, breast, lung cancers, etc

Circulating tumor antibodies

Why T Cells?

Abbas et al. Cellular and Molecular Immunology. Philadelphia; Saunders Elsevier; 2007. For educational purposes only.

Training the T Cell

Daud. Semin Oncol. 2015;42:s3-s11. For educational purposes only.

T-Cell Activation/Inhibition

CD28 (+)

TCR

CTLA-4 (-)

MHC-Ag

B7

B7

PD-L1 PD-1 (−)

CD40 CD40-L (+)

CD137-L CD137 (+)

Antigen-Presenting

Cell

T-cell

Ag = antigen; CD = cluster of differentiation; CTLA-4 = cytotoxic T-lymphocyte–associated antigen 4; L = ligand; MHC = major histocompatibility complex; PD-1 = programmed cell death protein 1; PD-L1 = programmed cell death protein ligand 1; TCR = T-cell receptor. Seetharamu et al. Expert Rev Anticancer Ther. 2009;9:839-849.

Signal 1

Signal 2

Getting T Cells Moving Put on the gas (activate) or Take off the brakes (checkpoint inhibitors)

Targeting Tumors Based on Somatic Mutation Frequency

Most mutated: Melanoma, lung, bladder, GI, colorectal, head and neck

Lawrence MS et al. Nature. 2013;499:214-218. For educational purposes only.

AML = acute myeloid leukemia; CLL = chronic lymphocytic leukemia; DLBCL = diffuse large B-cell lymphoma; GI = gastrointestinal.

Avoiding Immune Surveillance

IFN = interferon; IL = interleukin; TNF = tumor necrosis factor.

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

Immunotherapy Approaches Activating the immune system (gas) Vaccination

Autologous Allogeneic

Cytokines Interferon, interleukin-2, GM-CSF

Inhibiting negative signals (brakes) CTLA-4, PD-1, PD-L1 antibodies

GM-CSF = granulocyte-macrophage colony-stimulating factor.

Interleukin-2 ApprovalStudy T84-

0524T86-0097

T90-0053

92C-0094

T86-0063

T86-0170

C87-0002

L29106

N 28 84 32 3 9 64 45 5

Dose(IU/kg)

720 000 720 000 720 000 720 000 600 000 600 000 600 000 360 000–540 000

Partial response

2 (7%)

8 (10%)

3 (9%)

0 1 (11%)

6 (9%)

5 (11%)

1 (20%)

Complete response

2 (7%)

6 (7%)

2 (6%)

0 0 5 (8%)

1 (2%)

1 (20%)

G3 toxicity 24(86%)

81 (96%)

29 (91%)

2(67%)

9 (100%)

61 (95%) 45 (100%) 5(100%)

G4 toxicity 5 (18%)

20 (24%)

2 (6%)

1(33%)

4(44%)

36 (56%) 14 (31%)

2(40%)

US Food and Drug Administration. Medical Reviewers Report: BLA Supplement 97-0501. FDA.gov Web site. Published December 1997; Atkins et al. J Clin Oncol .1999;17:2105-2116.

N = 270; 43 responders (partial response = 10%, complete response = 6%); 17 alive at 5 years (~15%)Median overall survival = 11.4 months; treatment deaths, n = 8 (3%)

G = grade.

An Early Success: High-Dose Interleukin-2 in

Melanoma

Atkins et al. J Clin Oncol. 1999;17:2105-2116. For educational purposes only.

Complete responders survival10 years

Activation

Tumor vaccine is of limited impact – no approved drugs (yet). Cytokine amplification of response IL-2: low response rate, but response

durable, very toxic IFN: small degree of efficacy, significant

toxicity Antibodies play a significant role –

better fit in targeted therapy.

Approved and Investigational Immune Checkpoint Inhibitors

Val R. Adams, PharmD, FCCP, BCOPAssociate Professor

Pharmacy Practice and Science DepartmentCollege of Pharmacy

University of KentuckyLexington, Kentucky

CTLA-4 and PD-1/PD-L1 Checkpoint Blockade

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

Improved Survival with Ipilimumab in Patients with

Metastatic Melanoma

ECOG = Eastern Cooperative Oncology Group; gp100 = glycoprotein 100; q3w = every 3 weeks.Hodi 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

RANDOMIZE

Ipilimumab 3 mg/kg every 3 weeks × 4+ gp100

(n = 403)

Ipilimumab 3 mg/kg every 3 weeks × 4(n = 137)

Primary endpoint: Overall survivalSecondary endpoints: • Best overall response rate• Duration of response• Progression-free survival

gp100 alone(n = 136)

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

Median OS ipilimumab + gp100: 10 months

Median OS gp100: 6.4 monthsHR 0.68; P <.001

Median OS ipilimumab: 10.1 monthsMedian OS gp100: 6.4 months

HR 0.66; P = .003

Improved Survival with Ipilimumab

HR = hazard ratio; Ipi = ipilimumab; OS = overall survival.

PD-1 Inhibitor Activity (FDA Approved)

Melanoma Lung cancer Renal cell cancer Bladder cancer Hodgkin lymphoma Head and neck cancer

FDA = US Food and Drug Administration.

CheckMate 066: Results

CI = confidence interval.Robert et al. N Engl J Med. 2015;372:320-330. For educational purposes only.

OS rate at 1 yearNivolumab: 72.9%Dacarbazine 42.1%

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;372:2521-2532. For educational purposes only.Pembro = pembrolizumab; q2w = every 2 weeks.

Ipilimumab vs Nivolumab vs the Combination in Metastatic Melanoma

Median PFSIpi = 2.9 months

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

Nivo = nivolumab; PFS = progression-free survival.

Nivo = 6.9 monthsIpi plus Nivo = 11.5 months

HR 0.42, P <.001

Ipilimumab vs Nivolumab vs the Combination in Metastatic Melanoma

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

PD-L1+

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-1 inhibitor ± CTLA-4 inhibitor is best.

Biomarker-Directed Therapy Should we select only tumors that

express PD-L1?

The slope of the hill makes a difference indetermining gas vs brakes.Biomarker – PD-L1 might tell us about the slope.

Checkpoint Inhibitors for NSCLC

Advanced NSCLC

PD-L1 +pembrolizumab

Targeted therapy or chemotherapy

After failing chemotherapy• Nivolumab or • Pembrolizumab or• Atezolizumab

Immunotherapy is used in ~1/4 of first-line disease and after chemotherapy.

All others (Note: advanced disease)

NSCLC = non-small cell lung cancer.

*Carpinteria, California: Dako North America, Inc.

PD-L1 IHC 22C3 pharmDx for Autostainer Link 48. Agilent Technologies Web site. Available at: http://www.agilent.com/en-us/products/autostainer-link-solution-for-ihc/autostainer-link-48/autostainer-link-48. Accessed March 2017.

PD-L1 IHC 22C3 pharmDx for Autostainer Link 48*

IHC = immunohistochemistry.

PD-L1 Testing with Pembrolizumab

Pembrolizumab [package insert]. Whitehouse Station NJ: Merck & Co Inc; 2014.

*

*Whitehouse Station NJ: Merck & Co Inc; 2014.

Patients with metastatic NSCLC whose tumors have high PD-L1 expression ([Tumor Proportion Score] TPS ≥50%)

Trial Design and Treatment

Pembrolizumab 200 mg IV every 3 weeks x 35 cycles

Investigator’s choice of cytotoxic chemotherapy x 4–6

cyclesCarboplatin + pemetrexed*

Cisplatin + pemetrexed*

Carboplatin + gemcitabineCisplatin + gemcitabineCarboplatin + paclitaxel

*Pemetrexed only for nonsquamous tumors; can continue pemetrexed as maintenance after combination therapy.

International, randomized, open-label, phase III trial

IV = intravenously.

Median:Pembrolizumab10.4 months (95% CI 6.7–not reached)Chemotherapy6 months (95% CI 4.2–6.2)

PFS

Results

OS

Estimated % patients alive at 6 months:Pembrolizumab80.2% (95% CI 72.9–85.7)Chemotherapy72.4% (95% CI 64.5–78.9)

Lung Cancer: Second-line Nivolumab

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

Lung Cancer: Second-line Atezolizumab

Rittmeyer et al. Lancet. 2017;389:255-265. For educational purposes only.

Approval for Renal Cell Cancer

Second-line Renal Cell Comparing Nivolumab to Everolimus (CheckMate 025)

Motzer et al. N Engl J Med. 2015;373:1803-1813. For educational purposes only.

NOTE: 76% of patients had tumors with less than 1% PD-L1 expression. CheckMate025 = Study of Nivolumab vs Everolimus in Pre-Treated Advanced or Metastatic Clear-cell RCC; NE = not estimable.

Approval for Bladder Cancer

Atezolizumab for Bladder Cancer –SAT after Platinum

Atezolizumab Clinical Data. Atezolizumab Web site. Available at https://www.tecentriq.com/hcp/urothelial-carcinoma/clinical-data.html. Accessed August 20, 2016. For educational purposes only.

DoR = duration of response; IC = tumor-infiltrating immune cell; IRF = independent review facility; NR = not reached; ORR = objective response rate; SAT = single-arm trial.

Recurrent or Metastatic Head and Neck Cancer

Seiwert TY, et al. Lancet Oncol. 2016;17:956-965; Ferris RL, et al. N Engl J Med. 2016;375:1856-1867. For educational purposes only.

• Keynote-12 – SAT led to accelerated approval

• Keynote-40 should be complete soon (RCT vs chemo)

PembrolizumabNivolumab

Nivolumab better than standard chemotherapy (CheckMate-141)

HPV = human papillomavirus; RCT = randomized controlled trial.

Nivolumab for Recurrent Hodgkin’s Lymphoma

Ansell SM et al. N Engl J Med. 2015;372:311-319. For educational purposes only.

ASCT = autologous stem-cell transplantation.

FDA-Approved Indications

Emerging Indications of PD-1/PD-L1 Inhibitors

CRC = colorectal cancer; Esophag = esophageal carcinoma; GBM = glioblastoma; HCC = hepatocellular carcinoma; HNSCC = head and neck squamous cell carcinoma; Mel = melanoma; Mesoth = mesothelioma; MSI = microsatellite instability; NHL = non-Hodgkin lymphoma; RCC = renal cell carcinoma; SCLC = small cell lung cancer; TNBC = triple-negative breast cancer.

Adapted from Michot JM. Eur J Cancer. 2016.

B-CellNHL

GBM

SCLC

Mesoth

HCC

TNBC

OvarianMSIHigh CRC

GBM

Hodgkin

Gastric

HNSCC

Bladder

NSCLC

RCC

PD-1/PD-L1Blockade

MelSCLCEsophag

Select Emerging Checkpoint Inhibitors

Agent Class Ongoing Phase III Studies

Tremelimumab Anti-CTLA-4 Tremelimumab-durvalumab combinationNSCLCBladder HNSCC

Durvalumab Anti-PD-L1

Avelumab Anti-PD-L1

GastricNSCLCBladderOvarianRenal cell carcinomaTriple-negative breast cancerMerkel cell carcinoma (phase II)

US National Institutes of Health. ClinicalTrials.gov Web site. Available at: https://clinicaltrials.gov/.

Immunotherapy for Cancer

Advantages Durable response Slows tumor growth Treatment can be

relatively nontoxic.

Disadvantages Low response rates Altered pattern of

response Often delayed—creation

of immune-related response criteria

Omitting expensive doses due to progression not appropriate (increased expense)

Autoimmune-related adverse effects

Patient Case SJ is a 61-year-old white female who presents with

recurrent NSCLC. HPI: 10 months ago she was diagnosed with

adenocarcinoma of the lung and started on cisplatin and pemetrexed – continuation maintenance.

PMH: N/A FH/SH: Married with 2 sons, 28 and 34 (none smoke) Drug history: NKDA PE: Findings consistent with lung cancer (lung findings) –

otherwise WNL (PS 0–1) Laboratory tests: Hepatic, renal, and chemistry levels

WNL Radiology: Multiple lesions in the liver – stage IV Genetics: Kras – WT, EGFR – WT, ALK – WT, PD-L1

unknown

FH = family history; HPI = history of present illness; N/A = not applicable; NKDA = no known drug abuse; PE = physical examination; PMH = past medical history; PS = Performance Status; SH = social history; WNL = within normal limits; WT = wild type.

What treatment would you recommend?A. None B. Carboplatin – paclitaxel – bevacizumabC. ErlotinibD. DocetaxelE. Nivolumab

After 4 cycles of nivolumab (240 mg IV on days 1, 15, 29, and 43), she has a CT scan. It shows that the liver lesions have grown and she has a new lesion in her lung. What is the next BEST step?

A. Stop all treatmentB. Change therapy to docetaxelC. Continue nivolumabD. Change to afatinib

CT = computed tomography.

Immune-Related Response Criteria and Adverse Events

Val R. Adams, PharmD, FCCP, BCOPAssociate Professor

Pharmacy Practice and Science Department

College of PharmacyUniversity of KentuckyLexington, Kentucky

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;15:7412CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease; WHO = World Health Organization.

Immune-Related Adverse Events by System

Pulmonary: Pneumonitis, respiratory failure

Endocrine: Thyroiditis, hypothyroidism, hyperthyroidism, hypophysitis, hypopituitarism, adrenal insufficiency

Cardiac: Pericarditis, myocarditis, vasculitis

GI: Nausea, colitis, perforation, pancreatitis

Heme: Red cell aplasia, pancytopenia, autoimmune neutropenia

Ocular: Uveitis, iritis, conjunctivitis, scleritis, blepharitis

Skin: Vitiligo, pruritus, rash, lichenoid deposits

Liver: Transaminitis, hepatitis

Kidney: Nephritis, renal insufficiency

Musculoskeletal: Arthralgias, myalgias

Neurologic: Neuropathy, meningitis, Guillain-Barré syndrome, myasthenia gravis, temporal arteritis

Onset: Average is 6–12 weeks after

initiation of therapy Within days of the first dose After several months of

treatment After discontinuation of therapy

May affect 1 or many organ systems

Severity: Asymptomatic to severe and life-threatening

Dose dependent Suggested cumulative effect Increased in combination with

other immunotherapy agents, chemotherapy, or radiation

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

Pattern of Immune-Related Adverse Events

Immunotherapy-Related AEs

Median time to onset for treatment-related select AEs ranged from 5.0 weeks for skin AEs to 15.1 weeks for renal AEs.

Circles represent median; bars signify ranges.

Time to Onset of Select Treatment-Related AEs(any grade; N = 474)

AE = adverse event.With direct permission from Dr Wolchok. Wolchok J, et al. J Clin Oncol. 2015;33:abstract LBA1.

POPLAR: All-Cause AEs(≥5% difference between arms)

AE profiles consistent with previous studies

For atezolizumab, other immune-mediated AEs (any grade) included: AST increased (4%) ALT increased (4%) Pneumonitis (2%) Colitis (1%) Hepatitis (1%)

ALT = alanine aminotransferase; AST = aspartate aminotransferase.Spira et al. J Clin Oncol. 2015;33:abstract 8010. For educational purposes only.

Dry skin, stomatitis, and nail disorder were additional AEs with ≥5% higher frequency with docetaxel.

Safety population includes patients who received any amount of either study treatment. Data cut-off January 30, 2015

Immune-Related Adverse Events

Assume new symptoms are autoimmune and drug related if all other causes have been ruled out Can affect any organ system Early recognition, evaluation, and

treatment are critical to adequate management and opportunity for re-treatment.

Grade 1Radiographic changes only

Consider delay of treatmentMonitor for symptoms every 2–3 daysConsider Pulmonary and ID consults

Reimage at least every 3 weeksIf worsening:

Treat as Grade 2 or 3–4

Grade 2Mild-to-moderate new symptoms

Delay therapy Monitor symptoms daily (oxygen saturation)

Supportive care: oxygen supportIV steroid: Methylprednisolone 0.5–1.0 mg/kg/day

until stableIf improving: Transition to oral steroid to taper

Dose: 60 mg prednisolone daily x 2 weeksIf progressing: Treat as grade 3–4

Hospitalize patientMultidisciplinary Evaluation and Management

Bronchoscopy, lung biopsy

Reimage every 1 to 3 daysIf improving: Taper steroids over 4 weeks

May consider reinitiation of treatmentIf no improvement in 2 weeks: Treat as grade 3–4

Management of Immune-Related Adverse Events Algorithm

ID = infectious disease.

Grade 3–4Severe new symptoms

New or worsening hypoxiaLife-threatening

Discontinue therapyHospitalize

Pulmonary and ID consultsMethylprednisolone 2.0–4.0 mg/kg/day

Prophylactic antibioticsBronchoscopy, lung biopsy

If improving: Taper steroids over 6 weeks

If no improvement in 48 hours or worsening: Add additional

immunosuppression

Management of Immune-Related Adverse Events Algorithm (cont.)

ID = infectious disease.

Val R. Adams, PharmD, FCCP, BCOP

Associate ProfessorPharmacy Practice and Science

DepartmentCollege of Pharmacy

University of KentuckyLexington, Kentucky

Matthew Farber, MASenior Director

Oncology Disease StateWalgreens Specialty

PharmacyDeerfield, Illinois

Evolving Role for Pharmacists

• Focus on chronic conditions• Non-oncology medications

Traditional Retail

• Focus on orally administered medications

Specialty Pharmacy

• Traditional IV medications• Oral therapies when available

In-Office Dispensing

• All of the above• Management of immunotherapies during treatment

Hospital Inpatient or Outpatient

Administration of Immunotherapy

I-O therapy administered

via IV

Still a role for pharmacist

Multiple therapies/

drug interactions

Side effect management

Patient receives I-O

therapyAEs can

determine continuation of therapy.

I-O = immuno-oncology.

Time of Pharmacist Intervention

Initiation of treatment• Drug/drug interactions• Patient/caregiver

education on AEs• Different schedule of

AEs

Continuation of treatment• Better adherence if side

effects actively managed• Understanding of

comorbidities

Patient and Family Education Time to response differs

from standard therapy. Response in baseline

lesions Stable disease with slow

decline in tumor volume Response following initial

increase in tumor volume or new lesion

Patients may develop signs of disease progression after treatment. Sudden and painful increase in

tumor size, rash, low-grade fever, bone pain

Treatment can continue through this disease “pseudo-progression.”

Different AE profile than chemotherapy

Early recognition of irAEs is essential to effective treatment.

Patients must notify their care provider if symptoms develop or they are admitted to a local facility.

irAEs are related to the mechanism of action of immunotherapies.

irAEs are treatable and respond well to steroids.

.

irAE = immune-related adverse events.

Importance of NavigationGiven the cost implications, additional conversations are needed to determine best treatment decision (financial toxicity).

Cancer Center staff is instrumental in key conversations with patients and caregivers.

Pharmacists can play a role as an extension of the care team.

Financial ToxicityFinancial concerns are often associated with oral therapies given cost sharing.• Oral therapies on patient pharmacy benefit as

opposed to medical benefit• 10%–20% co-pay vs fixed dollar amount

Immunotherapies can carry their own cost implications for patients. • Even though drugs are administered on the medical

benefit, there are still concerns.• Cost of managing side effects, which can occur right

away, 5 weeks after treatment, or even up to 15 weeks out

Active Surveillance

Side Effect Management

Opportunities for retail pharmacy/SP involvement

Financial Monitoring

Costs of supportive care medications/

comorbidities

SP = specialty pharmacy.

Financial Assistance for More than Just Drug Co-pay

• Insurance may not cover costs of genetic tests required for certain I-O treatments

Prior to Treatment

• Ongoing throughout and posttreatment

Cost of Supportive Care Medications/Side Effects

• Patient may need to be on disability/still pay bills, etc

Ongoing Costs

Still Learning the Long-term Needs of I-O Patients

Given that these treatments were approved on fast track designation, there is much we do not know about the long-term impacts on these patients.

Long-term surveillance will fall to many members of the care

delivery team

Pharmacists Need to Be Flexible

Understanding the long-term needs of I-O

patients

Learning about the new

side effects

Work with providers/ caregivers/

insurers

Questions?