Balancing tumor response, adverse events remains 'unmet need' for checkpoint inhibitors
Coordinated care between oncology and rheumatology is one of the key principles of the EULAR recommendations for management of immune-related adverse events associated with cancer checkpoint inhibitor therapy, according to data presented at the EULAR 2020 E-Congress.
While checkpoint inhibitors have “revolutionized” the field of oncology, they “have also brought about challenges,” Karolina Benesova, MD, of the department of hematology, oncology and rheumatology at the University of Heidelberg, in Germany, said in her presentation. “They can cause a unique spectrum of toxicities, so-called immune-related adverse events, or irAEs.”
Benesova noted that while these events can affect any organ system, they have been under-reported in the literature. “In the real world, they are quite frequent,” she said.
Further, there is what Benesova called an “unmet need” to harmonize the various management strategies to relieve patients of their irAE symptoms without altering the tumor response elicited by checkpoint inhibitor therapy.
With that in mind, a task force of 23 experts convened, ultimately producing a document containing four over-arching principles and 10 recommendations.
The first principle notes that these events may occur while the second urges shared decision-making between patients, oncologists and rheumatologists. For the third principle, rheumatologists should take an active role in engaging with oncologists when managing patients with musculoskeletal signs and symptoms. The fourth suggests that mitigating musculoskeletal symptoms to an acceptable level while enabling effective anti-tumor response in immune checkpoint inhibition is essential.
The focus on collaboration between doctors and patients is necessary for one key reason, according to Benesova: “Evidence is limited,” she said.
The first recommendation urges rheumatologists to be aware of the wide spectrum of presentations of irAEs, while the second encourages oncologists to consult their rheumatology colleagues at first suspicion of a rheumatic event.
“Reports on the clinical features of rheumatic irAEs show that these can resemble the full spectrum of known rheumatic and musculoskeletal disease,” Benesova said. “However, usually, irAEs have an atypical or incomplete presentation.”
Comprehensive assessment of these patients should be performed with metastases, paraneoplastic syndromes and unrelated rheumatic diseases as part of the differential diagnosis. While management of rheumatic diseases is often aggressive, Benesova said that the task force prefers a “defensive strategy” in managing irAEs.
Regarding treatment, glucocorticoids should be considered as first-line therapy for these events. However, she noted that a low dose is optimal. “More than 10 mg prednisone daily should not be used,” Benesova said.
Steroid therapy should be followed by conventional synthetic disease-modifying anti-rheumatic drugs (DMARDs) then biologic DMARDs. Tumor necrosis factor (TNF) or interleukin (IL)-6 inhibitors are the recommended biologic approaches.
The seventh recommendation stipulates that the decision to cease or continue checkpoint inhibitor therapy should be based on the severity of the irAE, the extent of immunosuppression required to manage it, tumor response and the future oncology treatment plan.
The eighth recommendation warns of the severity of myositis, while the ninth stresses that a pre-existing rheumatic or autoimmune condition should not serve as a contraindication for checkpoint inhibitor therapy. “Half of patients with a pre-existing [rheumatic or musculoskeletal disease] will experience a flare or other irAE,” Benesova said, but she stressed that these events are usually “well manageable.”
In the final recommendation, it is noted that no single biomarker test can detect all possible autoantibodies. With that in mind, a full rheumatologic assessment is recommended prior to immune checkpoint inhibition.
Benesova stressed one key consideration for the management of irAEs. “You don’t want to lose the advantage of checkpoint inhibitor therapy,” she said.
In parting, Benesova offered a caveat for rheumatologists and oncologists referencing this document. “It is apparent, so far, that evidence-based data are limited,” she said. “Future trials should aim at closing these gaps. Updates will likely be required.”
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Benesova K, et al. Recommendations on rheumatic immune-related adverse events due to cancer immunotherapy with checkpoint inhibitors. Presented at: EULAR 2020 E-Congress; June 3-6, 2020 (virtual meeting).
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