role of the immune system and immunotherapy in cancer asembia... · 2017-04-26 · role of the...
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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?