immune-related toxicities and management · immune-related toxicities and management dr kenneth...

Immune-related Toxicities

and Management

Dr Kenneth O’ByrnePrincess Alexandra Hospital and Queensland University of

Technology, Brisbane, Australia

& Trinity College, Dublin, Ireland

Spectrum of

Toxicities

Champiat et al, Ann Oncol 2016

Toxicity

Inflammatory Colitis Dermatitis

Immune

Checkpoint

Inhibitor

Myocarditis

Johnson DB et al, N Engl J

Med. 2016 Nov

3;375(18):1749-1755.

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

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

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

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

Treatment

Related

Adverse

Events

Reported in

at Least 5%

Patients

KEYNOTE 001

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)

Larkin et al, NEJM, 2015

Phase 1 CheckMate 012 Study Design: <br />Nivolumab Plus Ipilimumab in First-line NSCLC

Presented By Matthew Hellmann at 2016 ASCO Annual Meeting

Nivolumab Plus Ipilimumab in First-line NSCLC:<br />Efficacy Across All Tumor PD-L1 Expression Levels


Case of Pathological CR in One Patient Treated With Nivo 3 Q2W + Ipi 1 Q6W


Nivolumab Plus Ipilimumab in First-line NSCLC:<br />Treatment-related Select AEs


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%

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

Appearance of immune-related adverse

events of ipilimumab

Weber, JCO, 2012

Overview of

results

• 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).

Toxicity and Survival

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*

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

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

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

Assessments Prior to and on Therapy

Diarrhoea

Pneumonitis

Hepatic Dysfunction

Dermatological Toxicity

Endocrine Dysfunction

Thyroid Dysfunction

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

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

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

Progress

● Symptoms improved with NSAIDs

Other significant issue

● A CT scan after 2 cycles demonstrated ground glass

changes consistent with pneumonitis

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

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

Anti-PD1-induced rotator cuff injury

Figure 1: Full thickness rotator cuff tear

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

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

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