Rheumatologists need to learn how to manage the significant inflammatory side effects experienced by many patients whose cancer is being treated with checkpoint inhibitors, according to presenters at EULAR 2018 in Amsterdam.
Immune-related adverse events (irAEs) are becoming a major issue with checkpoint inhibitors, such as anti-CTA4 (ipilimumab), anti-PD-1 (nivolumab, pembrolizumab) and anti PD-L1 (atezoluzumab, durvalumab) as they are being used in a widening number of cancer indications, the meeting heard.
Their unique mechanism of action of ‘releasing the brakes’ on the immune system has resulted in a new spectrum of side effects for which expertise in autoimmune conditions is needed, explained Dr Ellen Kapiteijn, of the Department of Clinical Oncology, Leiden University Medical Centre in the Netherlands.
“The checkpoint inhibitors can give inflammation of any organ and you should be aware of this if you start to give these treatments,” she said.
No organ system has been spared immune-related adverse events (irAEs) and they are common, with up to 75% of patients experiencing them with anti-CTA4 therapy and up to 30% of those taking drugs targeting PD-1/PD-L1, said Professor Leonard Calabrese, a rheumatologist at the Cleveland Clinic Lerner College of Medicine, Ohio.
While most adverse events are Grade 1 (mild) or Grade 2 (moderate) and non-limiting to cancer therapy, clinical trials have shown that Grade 3 (severe) effects are experienced by up to 40% of patients taking high-dose therapy targeting CTA4 experience and by 10- 20% of patients taking drugs targeting PD-1 and PD-L1.
“This should resonate really well to a rheumatology audience because what we are talking about here is multiple end organ automimmune or autoinflammatory complications, which is a space that rheumatologists live in more than any other specialist,” said Professor Calabrese.
Cancer clinical trials have reported only limited data on rheumatic irAEs, he noted. Musculoskeletal symptoms were inconsistently captured in early clinical trials of checkpoint inhibitors because arthritis is not a life-threatening complication and the focus is usually on recording Grade 3 or Grade 4 (life threatening) complications.
Professor Calabrese cited an example of inflammatory arthritic adverse events being reported only in 5 of 33 trials, with a cumulative incidence of 1-7%, and xerophythalmia and zeroxtomia in four trials with incidence ranging from 3-24%, and there are some reports of vasculitis, sarcoid and myositis.
Professor Calabrese said it is only now becoming apparent that up to 50% of patients taking PD-1 associated therapies experience some form of inflammatory arthritis.
“This disease appears to be chronic and in the entire landscape of irAEs there are no other complications that are parallel to this,” he told the EULAR conference.
The challenge for rheumatologists is to work with oncologists to optimise the treatment of cancer and allow patients to be maintained on an effective therapy, he suggested.
While most oncologists are comfortable with the initial management of irAEs, by Grade 3 they should be involving the appropriate subspecialists, Professor Calabrese said.
He highlighted one barrier to managing inflammatory adverse effects of checkpoint inhibitors, which is that many patients are participating in oncology clinical trials that have specific rules in terms of therapies that patients are allowed. For example, in most patients are allowed no more than 20mg of prednisolone.
DMARDs or targeted therapy should be considered if adverse events are severe and standard high-dose glucocorticoids has failed, said Professor Calabrese. But TNF inhibitors may not be appropriate because of associated undesirable effects with long term treatment.
Two recent updates of oncology treatment guidelines from the American Society of Clinical Oncology and the Society for Immunotherapy of Cancer have included recommendations for managing rheumatic diseases for the first time, Calabrese said. “So you can go to these two guidelines and at least get a starting point of management.”
EULAR has also set up a treatment guideline committee for irAEs, which will hold its first meeting in July with the aim of publishing guidelines early next year.