Management of Toxicities of

Immunotherapy
Dr Amit Rauthan
Consultant Medical Oncologist
Manipal Hospital, Bangalore
Increasing Indications of Immunotherapy
• Melanoma
• Renal cell carcinoma
• Lung cancer
• Head and neck cancers
• Urothelial cancers
• Hodgkins Lymphoma and PMBCL
• Merkel cell cancer
• MMR deficient cancers
• Gastric cancers
• HCC
• Cervical cancer
Increased Usage
• Impressive tail of the curve

• Very less side effects

Immune Related Adverse Events
• Adverse events are due to activation of the immune system against
the body
• AEs can occur in every organ
• AEs occur more often in skin, thyroid gland, colon, liver
• Immune-mediated adverse reactions can be serious and
potentially fatal

• Immune-mediated adverse reactions may be unfamiliar to clinicians

Toxicity Spectrum

Michot European J Cancer 2016

Organ Systems Often Affected
by I-O Therapy-Related AEs
I-O therapy-related AEs target certain organ systems 1

Skin1–6 – Rash, Toxic Epidermal Necrolysis (TEN)

Endocrine system2,4,6,7–10 – Hypothyroidism, hypophisitis, diabetes

Liver2,6,11–12 – Hepatitis

Gastrointestinal tract2,6,9,13 – Diarrhoea, colitis

Nervous system6,10,14,15 – Autoimmune neuropathy

Eyes1,4,16–18 – Uveitis
Respiratory system1,5,6,10,15,19 - Pneumonitis, ILD

Hematopoietic cells6,9,12,20–22

1. Amos SM, et al. Blood. 2011;118:499–509; 2. Phan GQ, et al. PNAS. 2003;100:8372–8377; 3. Rosenberg SA. J Immunother Emphasis Tumor Immunol.
1996;19:81–84; 4. Chianese-Bullock KA, et al. J Immunother. 2005;28:412–419; 5. Harris J, et al. Med Pediatr Oncol. 1994;22:103–106; 6. Chow LQ. Am Soc Clin
Oncol Educ Book. 2013:280–285; 7. Bendle GM, et al. Nat Med. 2010;16:565–570; 8. Soni N, et al. Cancer Immunol Immunother. 1996;43:59–62; 9. Ronnblom
LE, et al. Ann Intern Med. 1991;115:178–183; 10. Fraenkel PG, et al. J Immunother. 2002;25:373–378; 11. Lamers CH, et al. J Clin Oncol. 2006;24:e20–e22; 12.
Roskrow MA, et al. Leuk Res. 1999;23:549–557; 13. Parkhurst MR, et al. Mol Ther. 2011;19:620–626; 14. Pellkofer H, et al. Brain. 2004;127:1822–1830; 15.
Smalley RV, et al. Blood. 1991;78:3133–3141; 16. Dudley ME, et al. J Clin Oncol. 2008;26:5233–5239; 17. Yeh S, et al. Ophthalmology. 2009;116:981–989; 18.
Robinson MR, et al. J Immunother. 2004;27:478–479; 19. Morgan RA, et al. Mol Ther. 2010;18:843–851; 20. Kochenderfer JN, et al. Blood. 2010;116:4099–4102;
21. Lin TS, et al. J Clin Oncol. 2010;28:4500–4506; 22. Herishanu Y, et al. Leuk Lymphoma. 2003;44:2103–2108.
Incidence
• PD1/ PDL1 inhibitors
• Grade 1-2 : 50- 60%
• Grade 3-4: 10- 15%

• Ipilimumab
• Grade 1-2: 60-86%
• Grade 3-4: 15-27%
• 2% death in initial trials
Timing
• In general, irAEs
occur quite early,
mostly within weeks
to 3 months
• Rarely can happen
even after 1 year

Weber et al J Clin Oncol 2012

Time to Onset of Grade 3/4 Treatment-related
Select AEs With the NIVO+IPI Regimen (Pooled Analysis)a

3.1 (1.0, 8.0) [0.1-55.0]

Skin
(n = 33)

7.1 (4.3, 10.6) [0.6-48.9]

Gastrointestinal
(n = 73)

8.4 (5.2, 12.1) [2.1-48.0]

Hepatic
(n = 76)

11.4 (6.7, 13.6) [2.9-19.1]

Endocrine
(n = 21)

9.4 (3.7, 19.9) [3.7-20.6]

Pulmonary
(n = 6)

16.3 (4.1, 23.7) [3.3-29.0]

Renal
(n = 7)

0 10 20 30 40 50 60

Time From Study Initiation (Weeks)

aColor boxes indicates interquartile (Q1, Q3); center vertical line indicates median; outer vertical lines indicate range [min-max]. Pooled analysis of data from CA209-004 (phase 1), CheckMate 069
(phase 2), and CheckMate 067 (phase 3)

Sznol M et al. Presented at ESMO 2016; abstract 3434

9
Guidelines
• ESMO
• ASCO
• NCCN
• SITC
General Principles
• Thorough evaluation of patients at baseline
• Educate patients about the possible side effects
• High level of suspicion for any new symptom
General principles of management
• Grade 1:
• Symptomatic management
• Continue Immune Checkpoint Inhibitor (ICI)
• Grade 2:
• Hold ICI
• Start steroids- Prednisone 0.5- 1 mg/kg/ day
• Restart ICI once grade 1 and Prednisone at 10mg/day
• Grade 3:
• Hold ICI
• Consult sub-speciality, consider hospitalization
• Initiate high-dose corticosteroids (prednisone 1 to 2 mg/kg/d or methylprednisolone IV 1 to 2
mg/kg/d)
• Corticosteroids should be tapered over the course of at least 4 to 6 weeks
• If symptoms do not improve within 48 to 72 hours of high-dose corticosteroid, infliximab may be
offered for some toxicities
• May restart ICI with high level of caution.
General principles of management
• Grade 4:
• Discontinue ICI permanently (exception endocrinopathies that have been
controlled by hormone replacement)
• Initiate high-dose corticosteroids (prednisone 1 to 2 mg/kg/d or
methylprednisolone IV 1 to 2 mg/kg/d)
• Infliximab
• Mycofenolate Mofetil (MMF)
• Tacrolimus
• Others- plasmapharesis, ATG, IVIG

• Dose adjustments -not recommended

Skin Toxicity

Haanen et al., Ann Oncol 2017

Management of skin toxicity
• Grade 1 pruritis/ rash
• Emollients, anti-histaminics
• Grade 2 rash
• Topical steroids
• Cooling ointments
• Dermatology opinion
• Grade 3 or 4
• Involve Dermatologist
• Punch biopsy
• Start systemic steroids
• Admit patient of SJ syndrome or TEN
Fatigue
• Frequent and long lasting
• Often underestimated by physicians
• Unknown etiology

Boutros et al Nat Rev Clin Oncol 2016

Management of endocrinopathy
• Hypothyroidism
• Treat with Levothyroxine
• Hyperthyroidism
• Most frequent precedes hypothyroidism
• Consult endocrinologist
• Hypophysitis
• If symptoms of headache, diplopia- start steroids
• If low in TSH, ACTH, LH: substitute: levothyroxine, hydrocortisone,
testosterone
• Consult endocrinologist – long term substitution
Hypophysitis

Haanen et al., Ann Oncol 2017

Diarrhea/ colitis

Haanen et al., Ann Oncol 2017

Management of diarrhea/ colitis
• Incidence: PD1- 10%, CTLA4- 40%
• Grade 1 -
• Observation
• Start Loperamide and continue treatment
• Grade 2-
• Withhold ICI
• Stool culture / rule out C. diff.
• Oral Prednisolone/ Budesonide
• Plan colonoscopy
Management of diarrhea/ colitis
• Grade 3,4-
• Withhold ICI
• Admit
• Stool culture
• Colonoscopy
• Start high dose steroids
• If no improvement in 72 hours- escalate immunosuppression
• Infliximab ----later Tacrolimus
• Slow taper
Hepatitis

• Asymptomatic rising
enzymes- start steroids
• Rule out viral hepatitis
• Infliximab not used
• Steroid refractory- MMF,
tacrolimus
• Hepatology consult

Haanen et al., Ann Oncol 2017

Pneumonitis
• 5- 10% with PD1
• Less with CTLA4
• Incidence not increased
in lung cancer
• Sputum culture, BAL
• CT thorax
• Start systemic steroids
(1-2 mg/kg prednisone)
• Escalate in case of
deterioration: infliximab,
MMF, tacrolimus
Haanen et al., Ann Oncol 2017
Neurological Manifestations
• Many possibilities of neurological irAEs:
• Aseptical meningitis
• Mononeuritis
• Polynreuroradiculopathy (Guillain-Barre like) syndrome
• Myasthenia gravis
• Transverse Myelitis
• Involve neurologist
• MRI, CSF testing, EMG, antibodies
• Require hospitalisation
• Start systemic steroids
• Depending on diagnosis: plasmapheresis, IVIG, ? Rituximab
Clinical Situations
• Using ICI in patients with Auto immune disease
• Stopping ICI after toxicity- Impact on prognosis
• Co-relation between toxicity and response
Our experience
• 70 patients received treatment
• 65 Nivolumab
• 5 Pembrolizumab
• 20 lung cancers, 20 RCC, 10 melanomas, 8 head and neck cancers, 3
urinary bladder cancers, 2 MMR deficient colon cancers, 2 stomach
cancers, 2 breast cancers, 2 sarcomas and 1 ovarian cancer
• Patient age ranged from 31 to 87 years
• Number of cycles ranged from 2 to 18 cycles
Our experience
• Thyroid abnormality -most common side effect, seen in 19 patients (27%)
• 15 patients (21.4%) had hypothyroidism, 2 (2.8%) had hyperthyroidism,
and 2 (2.8%) had hyperthyroidism followed by hypothyroidism.
• Skin toxicity in the form of pruritis and rash was seen in 6 patients (8.5%)
• Diarrhoea was seen in 5 patients (7.1%)
• Mild elevation in liver enzymes was seen in 4 patients (5.7%)
• Pneumonitis was seen in 2 patients (2.8%)- grade 3, requiring treatment
with steroids and permanent discontinuation of immunotherapy.
• Arthritis was seen in 1 patient (1.4%)- requiring temporary interruption,
and treatment with oral steroids, with good resolution.
Conclusion
• Team approach to monitoring, diagnosis and management
• Good baseline evaluation
• Assessment before every dose
• Early diagnosis and treat early aggressively
• Effective management based on guidelines
• Extended followup
• Patient education and Physician education
• As a medical oncologist- Be in the lead!