Elsevier

European Journal of Cancer

Volume 105, December 2018, Pages 88-102
European Journal of Cancer

Original Research
Rheumatic immune-related adverse events secondary to anti–programmed death-1 antibodies and preliminary analysis on the impact of corticosteroids on anti-tumour response: A case series

https://doi.org/10.1016/j.ejca.2018.09.027Get rights and content

Highlights

  • Management of anti-PD1 related rheumatic adverse events are less well described compared with other organ specific irAEs.

  • The chronic nature of rheumatic irAE can impact the quality of life and usually requires protracted immunomodulatory agents for management.

  • Patients who sustain a rheumatic irAE secondary to anti-PD1 appear to exhibit higher objective response rates than anticipated.

Abstract

Importance

Rheumatic immune-related adverse events (irAEs) occur in approximately 10–20% of anti–programmed death 1 (anti-PD1)–treated cancer patients. There are limited data on the natural history, optimal treatment and long-term oncological outcomes of patients with rheumatic irAEs.

Objective

The objective of the study was to describe the spectrum and natural history of rheumatic irAEs and the potential impact of rheumatic irAEs and immunomodulators on anti-PD1 tumour efficacy.

Methods

Cancer patients with pre-existing rheumatic disease before anti-PD1 therapy or de novo rheumatic irAEs on anti-PD1 therapy were retrospectively reviewed across three sites. Patient demographics, treatment history, anti-PD1 irAEs, and anti-PD1 responses were evaluated. Relationships between the development or pre-existence of rheumatic irAE, use of immunomodulatory agents and outcomes were evaluated.

Results

This multicenter case series describes 36 cancer patients who had rheumatic disease before anti-PD1 therapy (n = 12) or developed de novo rheumatic irAEs (n = 24). Thirty-four of the 36 patients sustained rheumatic irAEs (median time to rheumatic irAE: 14.5 weeks), including 24 de novo (18 inflammatory arthritis, three myositis, two polymyalgia rheumatica, one fasciitis) and 10 flares in 12 patients with pre-existing rheumatic disease. Corticosteroids were used in 30 of 36 patients (median duration: 10 months), and disease-modifying antirheumatic drugs were used in 14 of 36 patients (median duration: 5.5 months). The objective response rate to anti-PD1 therapy was 69% (n = 25/36) overall and 81% (n = 21/26) in the melanoma subgroup.

Conclusions

Rheumatic irAEs are often chronic and require prolonged immunomodulatory therapy. Prospective studies are required to define optimal management of rheumatic irAEs that maintain long-term anticancer outcomes.

Introduction

Monoclonal antibodies such as nivolumab, pembrolizumab, atezolizumab and avelumab targeting the programmed death 1 (PD1)/ programmed death ligand 1 (PDL1) axis have promoted immunotherapy to the forefront of therapeutics in a wide range of cancers because of their unprecedented survival advantage over standard therapies [1], [2], [3]. However, these antibodies are associated with severe immune-related adverse events (irAEs), including severe immune toxicity in approximately 20% of patients [4]. Colitis, pneumonitis, endocrinopathy, and hepatitis are well-described irAEs, with established treatment algorithms based on clinical trial experience [5], [6], [7].

In contrast, rheumatic irAEs pose management challenges because of their persistent nature that may impact patient function and quality of life. Rheumatic irAEs often require protracted courses of immunomodulatory therapy that may negatively impact long-term cancer control. In randomised trials of anti-PD1 [8] and combination ipilimumab-nivolumab [9], rheumatic irAEs were usually mild to moderate in severity and occurred in 10–20% of patients, but were possibly underreported due to the lack of recognition by treating physicians. The predominant rheumatic irAE reported in anti-PD1 trials is arthralgia; these irAE are also inconsistently described in the literature as ‘arthritis,’ ‘joint range of motion decreased’, among other nomenclature as defined by common terminology criteria for adverse events (CTCAE) [10]. Other rheumatic manifestations such as rheumatoid arthritis (RA), psoriatic arthritis, myositis, giant cell arteritis, polymyalgia rheumatica, and Sjögren's syndrome have also been reported [11], [12], [13], [14], [15]. Unlike other organ-specific irAEs, the literature describing rheumatic irAE presentations, natural history, management and impact of immunomodulatory therapies on oncological outcomes in these patients is limited [7]. We performed a multi-institutional case series of rheumatic irAEs to help address these clinically relevant issues.

Section snippets

Objectives

This retrospective study aimed to characterise anti-PD1–related rheumatic irAEs, management patterns and the impact of rheumatic irAEs and their treatments on oncological outcomes.

Methods

This study was approved by the local ethics committee and included cancer patients who had commenced anti-PD1 therapy between 1st September 2014 and 30th March 2017, who were identified by their oncologist or rheumatologist as having a rheumatic irAE associated with anti-PD1 therapy, or had rheumatic conditions before anti-PD1 commencement. Clinical data including patient demographics, anti-PD1 treatment and related toxicity, nature and treatment of rheumatic irAEs, tumour responses and reasons

Results

Thirty-six patients (median age: 72 years [range: 53–85 years]) with metastatic disease (26 melanoma, six non–small-cell lung cancer, two head and neck squamous cell carcinoma (HNSCC), one urothelial carcinoma and one lymphoma) were included. Twelve patients had a history of rheumatic disease before commencing anti-PD1 therapy and 24 patients developed new rheumatic irAEs to anti-PD1 antibodies. Baseline characteristics and rheumatic irAEs are outlined in Table 1, Table 2. Thirty-one patients

Discussion

Anti-PD1/PDL1-induced rheumatic irAEs are common and often persist beyond cessation of these therapies, raising concerns about the impact of antirheumatic drugs on long-term cancer outcomes. Furthermore, the lack of recognition and inconsistent use of nomenclature by oncologists to describe diverse inflammatory rheumatic conditions has hampered the development of management algorithms.

Our results are broadly similar to that of prior series, where 40–60% of patients with pre-existing rheumatic

Conclusion

Rheumatic irAEs present similarly to their ordinary (non-ICI–related) counterparts and likewise require long-term immunomodulatory therapy, often beyond completion of anti-PD1 therapy. We observed a high response rate to anti-PD1 in our melanoma subgroup in association with rheumatic irAEs. However, the long-term use of corticosteroids and DMARDs might impact duration of anti-tumour response. Prospective studies are required to define the incidence, findings, natural history, and optimal

Conflict of interest

Dr Mitchell has received travel support from Pfizer. Dr Lau has received travel support from Bristol-Myers Squibb; honoraria from Bristol-Myers Squibb and Pfizer and receives a Australian Government Research Training Scholarship. Dr Khoo has received travel support from Roche. Dr Shackleton has received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Merck Serono and research funding from Bristol-Myers Squibb. Dr McArthur has been a consultant or advisor for Provectus; received

Contributions

Dr Mitchell and Dr Lau contributed equally to the manuscript.

Funding

No funding was provided for this study.

Acknowledgements

The authors wish to thank Jason Callahan for assistance with the presentation of FDG PET/CT images.

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