Tumour- and Class-specific Patterns of Immune-Related Adverse Events of Immune Checkpoint Inhibitors

A Systematic Review

L. Khoja; D. Day; T. Wei-Wu Chen; L. L. Siu; A. R. Hansen

Ann Oncol. 2017;28(10):2377-2385.

Abstract and Introduction

Abstract

Background Immune checkpoint inhibitor (ICI) monoclonal antibodies (mAbs) targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1) or its ligand (PD-L1) produce unique toxicity profiles. The objective of this review was to identify patterns and incidence of immune-related adverse events (irAE) based on tumour type and ICI class.

Methods Medline, EMBASE and COCHRANE databases were searched to identify prospective monotherapy trials of ICIs from 2003 to November 2015. Paired reviewers selected studies for inclusion and extracted data. Odds ratio (OR), χ ² tests and multivariable regression models were used to analyse for effect size and associations.

Results We identified 48 trials (6938 patients), including 26 CTLA-4, 17 PD-1, 2 PD-L1 trials, and 3 studies tested both CTLA-4 and PD-1. Grade 3/4 irAE were more common with CTLA-4 mAbs compared with PD-1 (31% versus 10%). All grades colitis (OR 8.7, 95% CI 5.8–12.9), hypophysitis (OR 6.5, 95% CI 3.0–14.3) and rash (OR 2.0, 95% CI 1.8–2.3) were more frequent with CTLA-4 mAbs; whereas pneumonitis (OR 6.4, 95% CI 3.2–12.7), hypothyroidism (OR 4.3, 95% CI 2.9–6.3), arthralgia (OR 3.5, 95% CI 2.6–4.8) and vitiligo (OR 3.5, 95% CI 2.3–5.3) were more common with PD-1 mAbs. Comparison of irAE from the three most studied tumour types in PD-1 mAbs trials [melanoma (n = 2048), non-small-cell lung cancer (n = 1030) and renal cell carcinoma (n = 573)] showed melanoma patients had a higher frequency of gastrointestinal and skin irAE and lower frequency of pneumonitis.

Discussion CTLA-4 and PD-1 mAbs have distinct irAE profiles. Different immune microenvironments may drive histology-specific irAE patterns. Other tumour-dependent irAE profiles may be identified as data emerge from ICI trials.

Introduction

Immune surveillance involves detection and elimination of cancer cells by the immune system.^[1] A hallmark of cancer is a failure of surveillance that leads to tolerance, equilibrium and escape with the establishment of malignant disease. Examples of mechanisms of adaptive immune resistance include downregulation of major histocompatibility complex antigen expression, secretion of immunosuppressive cytokines and negative regulation of cytotoxic CD8+ T cells via checkpoint inhibition.^[2]

Impressive single agent activity of various immune checkpoint inhibitors (ICIs) has resulted in regulatory approval of several agents in a variety of solid tumour indications.^[3–9] To enhance antitumour immune responses, combination strategies that include ICI with chemotherapy, targeted molecules and other immune-based therapies are being explored. Successful combination strategies will depend not only on antitumour immune response and survival outcomes, but also on the toxicity profile and tolerability.

Immune-related adverse events (irAE) from ICI, differ from toxicities caused by cytotoxic or molecularly targeted agents. The time to toxicity may be delayed and not follow a cyclical pattern as seen with conventional cytotoxics. Mechanisms of toxicity remain to be defined and may well be heterogeneous between patients even with the same agent. The over-reactive immune response may be driven by the removal of tolerance by ICI unmasking low-level self-reactive T cells, macrophage-mediated toxicity or production of antibodies from activated B cells.^[2] These irAE are wide ranging in terms of organs affected and severity. Dermatologic, endocrine, neurologic, gastrointestinal, respiratory and musculoskeletal toxicities may occur alone or in constellation. The majority are self-limiting or resolve with immunosuppressants such as corticosteroids. Persistent irAE that do not resolve with corticosteroids require tumour necrosis factor α receptor antagonists such as infliximab, in the case of colitis or mycophenolate in the case of refractory hepatitis, an inhibitor of purine synthesis in T and B cells. Only a small minority of irAE do not respond to these immune modulators.^[10]

We hypothesize that the patterns, range and severity of irAE may differ between different ICI classes. A better understanding of irAE would enable better patient management of irAE. It would also inform the design of future ICI trials particularly where combinations of agents are being explored and where tolerability is key to their success. We conducted a systematic review of prospective monotherapy trials of ICI. The objective was to identify and contrast patterns and incidence of irAE based on ICI class and tumour type.

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Abstract and Introduction
Materials and Methods
Results
Discussion
References

Table 1. Characteristics of the 48 immune checkpoint inhibitor clinical trials
Study characteristic	Trials (N=48)
Study characteristic	No.	%
ICI target(s)
CTLA-4	26	54
PD-1/PD-L1	17/2	35/4
CTLA-4/PD-1 ^a	3	6
Tumour site(s)
Melanoma	24	50
Lung	4	8
Kidney	3	6
Prostate	2	4
mesothelioma	2	4
Mixed tumour types	7	15
Others (bladder, colorectal, gastro-oesophageal, liver, ovarian, pancreas)	6	13
Phase of clinical trials
Phase I	14	29
Phase I/II	4	8
Phase II	21	44
Phase III	9	19
CTCAE version used for AE-reporting
CTCAE 2.0	4	8
CTCAE 3.0	19	40
CTCAE 4.0	19	40
Unknown	6	13
Randomized study
Yes	16	23
No	32	77
Sources of trial funding
Industry	38	79
Non-industry	8	17
Unknown	2	4
Year of publication
2003–2008	6	13
2009–2015	42	87
Region in which trial was conducted
Multi-national	20	40
North America	21	46
Europe	5	10
Japan	2	4
Trial patient number recruited per single agent arm
Median	70
Range	9–555

^aStudies including both anti-CTLA-4 and anti-PD-1 agents, as single agents or combinations. Only single agent treatment arms were included in this analysis.

Table 2. Comparison of the incidence of irAE between tumour types for patients receiving anti PD-1 agent
irAE	Melanoma versus NSCLC OR (95% CI)	P value	Melanoma versus RCC OR (95% CI)	P value
Colitis	4.2 (1.3–14.0)	0.01	NA (no event for RCC)
Diarrhoea	1.9 (1.5–2.5)	<0.001	1.3 (1.1–1.8)	0.04
Pruritus	2.4 (1.9–3.1)	<0.001	1.5 (1.2–2.0)	0.003
Rash	1.8 (1.4–2.3)	<0.001	1.6 (1.2–2.1)	0.002
Pneumonitis	0.4 (0.3–0.7)	<0.001	0.3 (0.2–0.6)	<0.001

Table 3. Risk factors correlated with pneumonitis and colitis incidence in multivariate model
	Colitis OR (95% CI)	Pneumonitis OR (95% CI)
Drug type	3.12 (1.06–9.24)	0.03 (0.007–0.148)
(CTLA-4 versus PD-1/PD-L1)	P = 0.04	P < 0.001
Tumour type	0.85 (0.28–2.57)	0.51 (0.11–2.41)
(Melanoma versus non-melanoma)	P = 0.78	P = 0.40
Higher than RP2D versus equivalent or lower than RP2D	1.74(0.51–5.94)	2.79 (0.52–15.04)
Higher than RP2D versus equivalent or lower than RP2D	P = 0.38	P = 0.23

Supplementary Table 1. Studies included in the literature review
Author and Year of publication	No. safety-evaluable patients per trial	Phase of Study	CTCAE version used	Drugs/arms	Study
Hodi 2003	9	1	N/A	Ipilimumab	Biologic activity of cytotoxic T lymphocyte associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients.
Ribas 2005	39	1	2	Tremelimumab	Antitumor activity in melanoma and anti-self-responses in a phase I trial with the anti-cytotoxic T lymphocyte associated antigen 4 monoclonal antibody CP-675
Maker 2006	46	1	N/A	Ipilimumab	Intrapatient dose escalation of anti-CTLA-4 antibody in patients with metastatic melanoma.
Small 2007	14	pilot	2	Ipilimumab	A pilot trial of CTLA-4 blockade with human anti-CTLA-4 in patients with hormone refractory prostate cancer.
Yang 2007	61	2	N/A	Ipilimumab	Ipilimumab (anti-CTLA-4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis.
Weber 2008	88	1/2	N/A	Ipilimumab	Phase I/II study of ipilimumab for patients with metastatic melanoma.
Camacho 2009	117	1/2	3	Tremelimumab	Phase I/II trial of tremelimumab for patients with metastatic melanoma.
Brahmer 2010	39	1	N/A	Nivolumab	Phase I study of single agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics and immunologic correlates
Chung 2010	47	2	3	Tremelimumab	Phase II study of the anti-CTLA-4 monoclonal antibody, tremelimumab in patients with refractory metastatic colorectal cancer
Hodi 2010	131	3 randomized	3	Ipilimumab	Improved survival with ipilimumab in patients with metastatic melanoma
Kirkwood 2010	246	2	3	Tremelimumab	Phase II study of the anti-CTLA-4 monoclonal antibody, tremelimumab in patients with advanced refractory or relapsed melanoma.
O'Day 2010	155	2	3	Ipilimumab	Efficacy and safety of ipilimumab monotherapy in patients with pre-treated advanced melanoma: a multicenter single arm phase II study.
Ralph 2010	18	2	2	Tremelimumab	Modulation of lymphocyte regulation for cancer therapy: a phase II trial of tremelimumab in advanced gastric and esophgeal adenocarcinoma.
Royal 2010	27	2	3	Ipilimumab	Phase 2 trial of single agent ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma
Wolchok 2010	214	2 randomized	3	Ipilimumab	Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomized double blind multicentre phase 2 dose ranging study.
Hersh 2011	39	2 randomized	2	Ipilimumab	A phase II multicenter study of ipilimumab with or without dacarbazine in chemotherapy-naïve patients with advanced melanoma.
Brahmer 2012	207	1	3	BMS-936559	safety and activity of anti-PDL1 antibody in patients with advanced cancer
Margolin 2012	72	2	3	Ipilimumab	Ipilimumab in patients with melanoma and brain metastases: an open label phase 2 trial.
Ribas 2012	44	1	3	Tremelimumab	Safety profile and pharmacokinetic analyses of the anti-CTLA-4 antibody tremelimumab administered as a one hour infusion.
Topalian 2012	296	1	3	Nivolumab	Safety, activity and immune correlates of anti-PD1 antibody in cancer.
Calabro 2013	29	2	3	Tremelimumab	Tremelimumab for patients with chemotherapy resistant advanced malignant mesothelioma: an open label, single arm, phase 2 trial
Hamid 2013	135	1	4	Pembrolizumab	Safety and tumor responses with lambrulizumab in melanoma
Ribas 2013	325	3 randomized	3	Tremelimumab	Phase III randomized clinical trial comparing tremelimumab with standard of care chemotherapy in patients with advanced melanoma.
Sangro 2013	20	2	3	Tremelimumab	A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C.
Slovin 2013	30	1/2	3	Ipilimumab	Ipilimumab alone or in combination with radiotherapy in metastatic castration resistant prostate cancer: results from an open label multicenter phase I/II study.
Weber 2013	41	1	N/A	Nivolumab	Safety, Efficacy, and Biomarkers of Nivolumab With Vaccine in Ipilimumab-Refractory or -Naive Melanoma
Weber 2013	20	1 randomized	3	Ipilimumab	Randomized phase I pharmacokinetic study of ipilimumab with or without one of two different chemotherapy regimens in patients with untreated advanced melanoma.
Motzer 2014	167	2 randomized	4	Nivolumab	Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II Trial
Powles 2014	68	1	4	MPDL3280A	MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer
Robert 2014	206	3 randomized	4	Nivolumab	Nivolumab in previously untreated melanoma without BRAF mutation
Robert 2014	173	1 randomized	4	Pembrolizumab	Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomized dose-comparison cohort of a phase 1 trial.
Borghaei 2015	287	3 randomized	4	Nivolumab	Nivolumab vs docetaxel in advanced NSCLC
Brahmer 2015	131	3 randomized	4	Nivolumab	Nivolumab vs docetaxel in advanced squamous cell NSCLC
Calabro 2015	29	2	3	Tremelimumab	Efficacy and safety of an intensified schedule of tremelimumab for chemotherapy-resistant malignant mesothelioma: An open-label, single-arm, phase 2 study
Garon 2015	495	1	4	Pembrolizumab	Pembrolizumab for the Treatment of Non-Small-Cell Lung Cancer.
Hamanishi 2015	20	2	4	Nivolumab	safety and antitumour activity of anti-PD1 antibody nivolumab in patients with platinum resistant ovarian cancer
Joshua 2015	11	2	3	Tremelimumab	A phase 2 study of tremelimumab in patients with advanced uveal melanoma.
Larkin 2015	313/311	3 randomized	4	Nivolumab/ipilimumab/nivolumab and ipilimumab	Combined nivolumab and ipilimumab or monotherapy in metastatic melanoma
Le 2015	41	2	4	Pembrolizumab	PD-1 Blockade in Tumors with Mismatch-Repair Deficiency
Motzer 2015	406	3 randomized	4	Nivolumab	Nivolumab vs everolimus in advanced RCC
Patnaik 2015	30	1	4	Pembrolizumab	Phase I Study of Pembrolizumab (MK-3475; Anti-PD-1 Monoclonal Antibody) in Patients with Advanced Solid Tumors.
Postow 2015	46	2 randomized	4	Ipilimumab/nivolumab and ipilimumab	Nivolumab and Ipilimumab versus Ipilimumab in Untreated Melanoma
Ribas 2015	357	2 randomized	4	Pembrolizumab	Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomized, controlled, phase 2 trial.
Rizvi 2015	117	2	4	Nivolumab	Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial.
Robert 2015	555/256	3 randomized	4	Pembrolizumab/ipilimumab	Pembrolizumab versus Ipilimumab in Advanced Melanoma.
Weber 2015	268	3 randomized	4	Nivolumab	Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomized, controlled, open-label, phase 3 trial
Yamazaki 2015	20	2	3	Ipilimumab	phase II study of ipilimumab monotherapy in Japanese patients with advanced melanoma
Zimmer 2015	53	2	4	Ipilimumab	Phase II DeCOG-study of ipilimumab in pretreated and treatment-naive patients with metastatic uveal melanoma
N/A: not available

Supplementary Table 2. Percentages of the most commonly reported irAE with ICI.
ICI Agent	Anti-PD-1 (n=4077)		Anti-PDL1 (n=275)		Anti-CTLA-4 (n=2520)
	All grade	Grade ≥3	All grade	Grade ≥3	All grade	Grade ≥3
Endocrine
Hypothyroidism	5.1%	0.1%	2.2%	0.0%	1.2%	0.0%
Hyperthyroidism	1.6%	0.1%	0.0%	0.0%	0.5%	0.0%
Thyroiditis	0.0%	0.0%	0.0%	0.0%	0.0%	0.0%
Blood TSH increase	0.5%	0.0%	0.0%	0.0%	0.1%	0.0%
Blood TSH decrease	0.2%	0.0%	0.0%	0.0%	0.1%	0.0%
Hypophysitis	0.2%	0.1%	0.0%	0.0%	1.2%	0.8%
Pituitary insufficiency	0.0%	0.0%	0.0%	0.0%	0.3%	0.2%
Pan hypopituitarism	0.0%	0.0%	0.0%	0.0%	0.2%	0.0%
Adrenal insufficiency	0.0%	0.0%	0.7%	0.4%	0.4%	0.2%
Type 1 diabetes	0.1%	0.1%	0.0%	0.0%	0.0%	0.0%
Gastrointestinal
Nausea	10.5%	0.3%	7.7%	0.0%	17.3%	1.2%
Vomiting	3.1%	0.3%	1.1%	0.4%	9.8%	1.0%
Diarrhea	12.1%	1.0%	7.3%	0.0%	30.2%	7.4%
Colitis	0.7%	0.4%	0.0%	0.0%	5.7%	4.1%
Hepatitis	0.4%	0.3%	0.0%	0.0%	0.4%	0.2%
ALT increase	2.0%	0.4%	0.4%	0.0%	2.5%	0.8%
AST increase	2.3%	0.4%	0.4%	0.4%	2.6%	0.9%
Transaminases increase	0.1%	0.0%	0.0%	0.0%	0.1%	0.1%
Increased Lipase	0.1%	0.1%	0.0%	0.0%	0.3%	0.1%
Increased Bilirubin	0.2%	0.0%	0.0%	0.0%	0.0%	0.0%
Musculoskeletal
Arthralgia	7.0%	0.2%	6.2%	0.0%	2.1%	0.2%
Arthritis	0.2%	0.0%	0.0%	0.0%	0.2%	0.0%
Myalgia	3.0%	0.2%	2.9%	0.0%	0.6%	0.0%
Myositis	0.1%	0.0%	0.0%	0.0%	0.0%	0.0%

Skin
Pruritus	14.0%	0.1%	5.1%	0.0%	21.8%	0.4%
Rash	12.2%	0.3%	5.5%	0.0%	21.4%	1.1%
Vitiligo	4.0%	0.0%	0.0%	0.0%	1.1%	0.0%
Alopecia	0.5%	0.0%	0.0%	0.0%	0.3%	0.0%

Lung
Cough	2.8%	0.0%	0.0%	0.0%	3.3%	0.1%
Dyspnoea	2.8%	0.6%	0.0%	0.0%	3.3%	0.6%
Pneumonitis	2.4%	0.7%	0.0%	0.0%	0.4%	0.1%

Constitutional symptoms
Asthenia	4.5%	0.2%	1.8%	0.4%	1.7%	0.2%
Fatigue	25.2%	1.0%	14.9%	1.1%	21.9%	2.2%
Pyrexia	3.2%	0.1%	4.4%	0.0%	6.0%	0.2%
Infusion-related reaction	0.8%	0.1%	7.6%	0.4%	0.4%	0.0%
Decreased appetite (anorexia)	8.5%	0.3%	5.1%	0.0%	9.8%	0.9%
Chills	0.9%	0.0%	1.5%	0.0%	0.6%	0.0%
Blood and lymphatic disorders
Anaemia	4.8%	0.7%	0.7%	0.0%	1.6%	0.3%
Lymphopenia	1.0%	0.4%	2.6%	0.4%	0.9%	0.1%

Supplementary Table 3. Patient numbers for different doses and schedules of ICI agents ^a
Pembrolizumab
Dose	Patient number	Percentage
1mg/kg q2w	4	0.2%
2mg/kg q3w	295	16.5%
2mg/kg q2w	3	0.2%
3mg/kg q2w	3	0.2%
10mg/kg q3w	883	49.4%
10mg/kg q2w	588	32.9%
Various^b	13	0.7%
Total	1789
Nivolumab
Dose	Patient number	Percentage
0.1mg/kg q2w	18	1%
0.3mg/kg q3w	59	3%
0.3mg/kg q2w	19	1%
1mg/kg q2w	89	4%
2mg/kg q3w	54	2%
3 mg/kg q2w	1829	80%
10mg/kg q3w	54	2%
10mg/kg q2w	130	6%
Various^b	39	2%
Total	2291
Ipilimumab
Dose	Patient number	Percentage
0.3mg/kg q3w	73	5%
3mg/kg q4w	66	4%
3mg/kg q3w	937	59%
5mg/kg q3w	6	0%
10mg/kg q3w	359	23%
Various^b	154	10%
Total	1595
Tremelimumab
Dose	Patient number	Percentage
3mg/kg q4w	3	0.3%
6mg/kg q4w	3	0.3%
10mg/kg q4w	95	10.3%
15mg/kg q90d	785	85.2%
Various^b	44	4.8%
Total	930

^aSome patients were treated at multiple dose levels in dose-escalation studies. ^b'Various' includes trials using single doses, varying doses along the treatment course and intrapatient dose escalation. q2w, every 2 weeks; q90d, every 90 days.

Supplementary Table 4. Correlation of toxicity (all grades) and dose of drug for each ICI agent (where analysis was possible)
	High dose (10mg/kg q2wk)	Low dose (3mg/kg q2wk)	OR	P value
Nivolumab
Hypothyroidism	2.4%	3.7%	0.65	0.34
Diarrhoea	9.76%	11.3%	0.85	0.52
Fatigue	25.9%	25.0%	1.04	0.80
Arthralgia	4.9%	4.2%	1.16	0.67
Rash	9.3%	10.6%	0.86	0.56
Vitiligo	0.0%	2.6%	NA	NA
Pneumonitis	3.9%	1.4%	2.76	0.01
Pembrolizumab
	High dose (10mg/kg q2wk or q3wk)	Low dose 1 or 2mg/kg q2wk or q3wk	OR	P value
Hypothyroidism	7.8%	5.6%	1.27	0.17
Diarrhoea	12.7%	10.1%	1.30	0.20
Fatigue	23.3%	24.2%	0.95	0.75
Arthralgia	10.0%	8.2%	1.25	0.33
Rash	12.8%	13.0%	0.98	0.90
Vitiligo	5.7%	6.2%	0.92	0.73
Pneumonitis	2.5	1.6%	1.54	0.36
Ipilimumab
	High dose (10mg/kg q3wk)	Low dose (3mg/kg q3wk or q4wk)	OR	P value
Hypothyroidism	0%	1.7%	NA	NA
Diarrhoea	26.6%	27.6%	0.95	0.73
Fatigue	21.6%	23.7%	0.88	0.43
Arthralgia	0.0%	4.4%	NA	NA
Rash	20.7%	21.9%	0.74	0.63
Vitiligo	0.0%	2.5%	NA	NA
Pneumonitis	0.3%	0.8%	0.37	0.33

Supplementary Table 5. Incidence of possible drug-related grade 5 events per ICI agent and reported causes
	No. of deaths	Total no. of patients	%	Reported causes
Ipilimumab	19	1592	1.2%	Colitis/diarrhoea x3, bowel perforation x3, hepatic failure x2, vascular leak syndrome x2, multiorgan failure, glomerulonephritis, hypovolemic shock, respiratory infection, aspergillus infection after prolonged immunosuppression for colitis, pulmonary embolus and sepsis, pancytopenia, acute myeloid leukemia, cardiac arrest
Tremelimumab	10	925	1.1%	bowel perforation x3, sudden death x2, pneumonia, septic shock, electrolyte imbalance, pulmonary embolus, hemorrhage
Nivolumab	7	2291	0.3%	Pneumonitis x3, encephalitis, neutropenia, pneumonia, ischaemic stroke
Pembrolizumab	2	1786	0.1%	Interstitial lung disease, cryptococcal pneumonia following prolonged steroid therapy for gastritis
BMS-936559	0	207	0.0%
MPDL3280A/Atezolizumab	0	68	0.0%