Immune-related Toxicities and Management · Immune-related Toxicities and Management Dr Kenneth...
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Immune-related Toxicities
and Management
Dr Kenneth O’ByrnePrincess Alexandra Hospital and Queensland University of
Technology, Brisbane, Australia
& Trinity College, Dublin, Ireland
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Spectrum of
Toxicities
Champiat et al, Ann Oncol 2016
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Toxicity
Inflammatory Colitis Dermatitis
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Immune
Checkpoint
Inhibitor
Myocarditis
Johnson DB et al, N Engl J
Med. 2016 Nov
3;375(18):1749-1755.
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Improved Survival with Ipilimumab in Patients
with Metastatic Melanoma
F. Stephen Hodi, M.D., Steven J. O'Day, M.D., David F. McDermott, M.D., Robert W. Weber, M.D., Jeffrey A. Sosman, M.D., John B. Haanen, M.D., Rene Gonzalez, M.D.,
Caroline Robert, M.D., Ph.D., Dirk Schadendorf, M.D., Jessica C. Hassel, M.D.,
Wallace Akerley, M.D., Alfons J.M. van den Eertwegh, M.D., Ph.D., Jose Lutzky, M.D., Paul Lorigan, M.D., Julia M. Vaubel, M.D., Gerald P. Linette, M.D., Ph.D., David
Hogg, M.D., Christian H. Ottensmeier, M.D., Ph.D., Celeste Lebbé, M.D., Christian Peschel, M.D., Ian Quirt, M.D., Joseph I. Clark, M.D., Jedd D. Wolchok, M.D., Ph.D., Jeffrey S. Weber, M.D., Ph.D., Jason Tian, Ph.D., Michael J. Yellin, M.D., Geoffrey M.
Nichol, M.B., Ch.B., Axel Hoos, M.D., Ph.D., and Walter J. Urba, M.D., Ph.D.
N Engl J Med 2010; 363(8):711-723
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Kaplan–Meier Curves for Overall
Survival and Progression-free
Survival in the Intention-to-Treat
Population
Hodi FS et al. N Engl J Med 2010;363:711-723
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Phase 3 CA209-066: Study Design
Eligible patients
with
unresectable or
metastatic
melanoma
• BRAF wild-type
• Previously
untreated
Stratified by:
• PD-L1 status
• M-stage
R
1:1
Nivolumab3 mg/kg IV Q2W
+
PlaceboIV Q3W
N=210
(206 treated)
PlaceboIV Q2W
+
Dacarbazine1000 mg/m2 IV Q3W
N=208
(205 treated)
Treat until
progressiona
or
unacceptable
toxicity
Primary
endpoint:
• OS
Secondary
endpoints:
• PFS
• ORR
• PD-L1 as
biomarker
aPatients may be treated beyond initial RECIST v1.1-defined progression if considered by the investigator to
be experiencing clinical benefit and tolerating study drug
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Primary Endpoint: OS
HR 0.42 (99.79% CI, 0.25–0.73; P < 0.0001)(Boundary for statistical significance 0.0021)
NR=not reached. Based on 5August 2014 database lock
Patients who diedn/N
Median OS mo (95% CI)
Nivolumab 50/210 NR
Dacarbazine 96/208 10.8 (9.3, 12.1)
Patients at RiskNivolumab
Dacarbazine
210
208
185
177
150
123
105
82
45
22
8
3
0
0
Nivolumab (N=210)
Dacarbazine (N=208)
Months
100
90
80
70
60
0
50
40
30
20
10
0 3 6 9 12 15 18
Pa
tie
nts
Su
rviv
ing
(%
)
1-yr OS 73%
1-yr OS 42%
Censored
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%
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Treatment
Related
Adverse
Events
Reported in
at Least 5%
Patients
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KEYNOTE 001
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CheckMate 067: Phase III Trial of Nivo + Ipi vs
Nivo vs Ipi for 1st line Treatment of Melanoma
● Coprimary endpoints: PFS, OS (OS data still blinded)
● Secondary endpoints: ORR, tumor PD-L1 expression and efficacy, safety
Previously untreated pts with unresectable stage
III/IV melanoma and ECOG PS 0-1
(N = 945)
Nivo 1 mg/kg + Ipi 3 mg/kg q3w for 4 doses, then Nivo 3 mg/kg q2w
(n = 314)
Nivo 3 mg/kg q2w + Placebo(n = 316)
Wolchok JD, et al. ASCO 2015. Abstract LBA1.
Until disease progression or unacceptable
toxicity
Stratified by PD-L1 expression (< 5% vs ≥ 5%), BRAF status, and AJCC M stage
Ipi 3 mg/kg q3w for 4 doses + Placebo(n = 315)
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Larkin et al, NEJM, 2015
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Phase 1 CheckMate 012 Study Design: <br />Nivolumab Plus Ipilimumab in First-line NSCLC
Presented By Matthew Hellmann at 2016 ASCO Annual Meeting
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Nivolumab Plus Ipilimumab in First-line NSCLC:<br />Efficacy Across All Tumor PD-L1 Expression Levels
Presented By Matthew Hellmann at 2016 ASCO Annual Meeting
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Case of Pathological CR in One Patient Treated With Nivo 3 Q2W + Ipi 1 Q6W
Presented By Matthew Hellmann at 2016 ASCO Annual Meeting
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Nivolumab Plus Ipilimumab in First-line NSCLC:<br />Treatment-related Select AEs
Presented By Matthew Hellmann at 2016 ASCO Annual Meeting
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Toxicities
● Grade 3-5 adverse effects:
– 7-19% of anti-PD1/PDL1 antibodies
● Discontinuation rate of immune checkpoint
inhibitors due to toxicities:
– 3-8% for anti-PD1/PDL1 antibodies
– Up to 15% for ipilimumab
– Combination treatment (nivo/ipi): 36%
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Frequency of Toxicities
Very Common (>10%) Rash
Pruritus
Fatigue
Colitis *
Diarrhoea
Common (>1%) Pneumonitis
Hypophysitis
Hyperthyroidism
Hypothyroidism
Vitiligo
Transaminitis
Anaemia
Arthralgia
Myalgia
Rare to Uncommon (<1%) Hepatitis
Nephritis
Hypophysitis
Neutropenia
T1DM
Pancreatitis
Uveitis
Haematological
Neurologic. Eg:
Encephalitis
Guillain-Barre
Aseptic meningitis
Transverse myelitis
Myasthenia Gravis
Myocarditis
*only very common in anti-CTLA-4 antibodies. Common in PD-1/PD-L1 antibodies
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Appearance of immune-related adverse
events of ipilimumab
Weber, JCO, 2012
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Overview of
results
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• Phase III IMpower150 study has met its co-primary
endpoint of progression-free survival (PFS)
• The combination of TECENTRIQ® (atezolizumab)
and Avastin® (bevacizumab) plus chemotherapy
(paclitaxel and carboplatin) provided a statistically
significant and clinically meaningful reduction in
the risk of disease worsening or death (PFS)
compared to Avastin plus chemotherapy in the first-
line treatment of people with advanced non-
squamous non-small cell lung cancer (NSCLC).
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Slide 9
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Slide 10
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Slide 11
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Slide 12
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Slide 13
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Toxicity and Survival
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PFS 1.4 mths vs 8.0 mths (p<0.001)
Survival by Toxicity Subgroup
Med OS: 5.9 mths vs NR (p=0.001)
15 months follow-up*
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Slide 14
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Key to Optimal Patient Management
● All members of the healthcare team should be educated about
potential AEs
● Rapid and timely diagnostic and therapeutic intervention is
imperative for optimal control of irAEs
– Persistent grade 2 irAEs and grade 3/4 irAEs are treated with
steroids
– Early discontinuation of steroids may predispose to relapse
● Reinitiation of treatment may be possible with optimal
management
● Approximately 5% to 10% of patients experience evidence of
enlarging tumor lesions prior to a response
Optimal management is attainable through continued communication
between all members of the healthcare team and individual patients
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Patient and Family Education
● Assess for both pt and caregiver
– Knowledge of therapy and the disease process
– Educational level and preferred learning methods
● Provide information on:
– Administration schedule of therapy
– Time to response
• Time required to mount antitumor response
– Tumor assessment
• May demonstrate early progression or new lesions,
prior to demonstrating response
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Patient Education on Novel Therapies
● Pt education should include information on:
– Adverse reaction profiles that differs from standard
chemotherapy
– Early recognition of irAEs essential for effective
treatment
– irAEs are infrequent, treatable and respond well to
steroids
– Who and when to call for adverse reactions
● Reinforce teaching points at every point of contact,
office and treatment visits, and phone contact
– Notify your healthcare team if you are admitted to
another hospital
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Assessments Prior to and on Therapy
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Diarrhoea
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Pneumonitis
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Hepatic Dysfunction
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Dermatological Toxicity
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Endocrine Dysfunction
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Thyroid Dysfunction
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Checkpoint Inhibitors: Managing for Treatment-
Related Adverse Events
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
wk*
● Total bilirubin > 3 x ULN
Initiate steroid therapy
Inflixamab for colitis
Mycophenolate for hepatitis
Consider permanent discontinuation of therapy
Check Guidelines for Nivolumab, Pembrolizumab
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Case 4
● A 56 year old woman with a previous history of
localised breast (2006) and colon cancer (2008) in the
past was diagnosed in 2nd June 2014 with ?NSCLC,
?mesothelioma
– She had a history of workplace exposure to asbestos
● Received carboplatin and gemcitabine July – Sept:
progressive disease after 2 cycles of therapy
● Drainage effusion with VATS biopsy and pleurodesis
– Histology confirmed epithelioid mesothelioma
● Carboplatin and pemetrexed commenced 21st Oct 2014
– After 1 cycle patient persued alternative therapy
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Progress
● Subsequently commenced single agent pemetrexed 28th
April 2015
● After 3 cycles developed haemoptysis
– ulcerated tumur seen on bronchoscopy; CT stable
– Received radiotherapy to her mediastinum
– Continued on pemetrexed
● In September 2015 found to have progressive disease
and was commenced on an anti-PD1 therapy October
2016
● After 3 cycles of treatment developed arthralgia
● After 5 cycles evidence of left rotator cuff inflammation
● MRI was performed to outrule metastatic disease
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Progress
● Symptoms improved with NSAIDs
Other significant issue
● A CT scan after 2 cycles demonstrated ground glass
changes consistent with pneumonitis
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Progress
● As patient asymptomatic from pneumonitis
continued therapy
● The mesothelioma was stable, with evidence of
a minor response after 6 cycles
● Because of persistent arthralgia and expenses
incurred with therapy treatment then stopped
(January 2016)
– Arthragia and rotator cuff symptoms resolved
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Follow-up
● Following discontinuation of therapy, patient
remained well until June 2016
● Although CT stable, she developed dysphagia
● Endoscopy confirmed mesothelioma invasion
of the oesophagus
– Did not respond to re-challenge with
Pembrolizumab
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Anti-PD1-induced rotator cuff injury
Figure 1: Full thickness rotator cuff tear
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Key Points
● Education of patients/families
● Be vigilant for toxicities
– Exclude other causes
– Immune Checkpoint Inhibitors can affect any
organ
● Initiate early treatment
● Be aware of late toxicities
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Implications
● What is the optimal duration of therapy?
● Important question
– re costs, utilisation of hospital resources
– Late and chronic toxicities that don’t resolve
without stopping therapy