Why trying to ensure efficacy while minimising adverse events in rheumatological disease and cancer presents an interesting learning opportunity.
A concurrent session on malignancy and autoimmune disease at the recent Australian Rheumatology Association conference discussed the complexities of balancing disease progression and adverse events when immune checkpoint inhibitors are administered to cancer patients with concomitant rheumatological disease.
Rheumatological diseases and cancer can commonly co-occur, creating headaches for clinicians with regards to how to best manage these patients.
While speaking to delegates at the Australian Rheumatology Association’s Annual Scientific Meeting in Adelaide earlier this month, Professor Chris Karapetis, the network director for cancer services in the Southern Area Local Health Network in Adelaide, discussed some of the complexities around what to do with patients being treated with immunosuppressive therapies for autoimmune diseases who are also diagnosed with cancer.
“We usually do continue [the immunosuppressive therapies] … but we do need to consider some of the risks that are associated with the treatment, said the head of the department of medical oncology at Flinders Medical Centre.
There are four key questions that should always be considered as part of the decision-making process when treating a patient with both autoimmune disease and cancer, according to Professor Karapetis:
- What are the potential benefits of anti-cancer therapy?
- What will anti-cancer therapy do to the autoimmune disease?
- What are the potential consequences of stopping immunosuppressive therapy?
- Will immunosuppressive therapy interfere with the anti-cancer therapy?
“There is a judgement call that needs to be made. We know that chemotherapy by itself is immunosuppressive, so we always consider stopping conventional synthetic or biologic DMARDs when starting chemotherapy,” said Professor Karapetis.
“If we think that chemo alone will provide sufficient immunosuppression, we usually hold back the background immunosuppressive therapy.”
The advent of immune checkpoint inhibitors, which were originally developed in the context of advanced melanoma but have now become the standard of care across a variety of cancer types, has been a significant change in how cancer is treated. And although immune checkpoint inhibitors have proven to be highly effective, accompanying immune-related adverse events are pretty common.
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Professor Karapetis highlighted several studies assessing the incidence of immune-related adverse events following immune checkpoint inhibitor treatment in cancer patients with pre-existing rheumatological disease, including a 2024 systematic review and meta-analysis published in BMC Cancer, that arrived at a similar conclusion:
- 60-70% of these patients would experience immune-related adverse events; and
- 40-50% of patients would experience a flare in their rheumatic disease.
However, the estimated incidence of immune-related adverse events is not all bad news, according to Dr David Liew.
“A lot of [the flare burden] is incurred early on in the first six months [after starting immune checkpoint inhibitors], especially in the first three months. But notably, the severity is very manageable – 90% of these patients have grade one or grade two [reactions]. That is, they don’t need hospitalisation, and they don’t have impacts on self-care,” the rheumatologist and clinical pharmacologist from Austin Health said.
“The risk of inflammatory events is manageable, and it doesn’t need to prevent immune checkpoint inhibitor therapy. We should advocate for stable autoimmune disease patients to receive ICI therapy when they can.”
Managing inflammatory responses seems to be a key part of managing the immune-related adverse events. However, Dr Liew advised against reaching for glucocorticoids when considering potential options due to a growing body of research suggesting early, high-dose glucocorticoids impact survival in patients receiving immune checkpoint inhibitors.
So, if glucocorticoids are off the table, what alternatives are there when trying to balance immune checkpoint inhibitor efficacy and immune-related adverse events?
Tumour necrosis factor and interleukin-6 inhibitors have shown encouraging, albeit pre-clinical or very early clinical, results, according to Dr Liew.
A study comparing the safety and efficacy of TNF-alpha inhibitors, IL-6 inhibitors and methotrexate for the treatment of immune checkpoint inhibitor-associated arthritis revealed that while the three treatments yielded the similar responses with respect to cancer progression in the long-term, the TNF and IL-6 inhibitors performed better in the first two or three months immediately after treatment.
“The cost though, is that it seems that the more intensive the DMARD, the greater the impact on immune checkpoint inhibitor efficacy,” Dr Liew mused.
“Biological DMARDs do seem to do worse than methotrexate alone, and so we do have to think about what we do and where we step in with trying to get the right balance.”
Dr Liew then presented real-world data where abatacept had been used to reverse immune checkpoint inhibitor-associated myocarditis in cancer patients as an example of how clinicians could potentially strike the right balance between efficacy and adverse events.
The researchers found that patients who survived the myocarditis typically had better survival overall, and that patients who received abatacept (alone or in combination with other treatments) also had larger reductions in tumour burden compared to patients treated with other medications such as corticosteroids.
“Now, maybe this is a fluke, but the idea that we’re trying to go for here is that if we find the right balance, then we can walk this tight line where we have therapies that are decoupled in their response,” Dr Liew summarised.
“I think it comes down to this therapeutic equipoise, and that there is a sweet spot in the middle. Maybe it’s dynamic over time – perhaps initially we have to run them a little hot first with a bit of inflammation and then bring them back a little bit as we go on.
“We’ve got this distinct paradigm of checkpoint-induced autoimmune phenomena, and it’s quite a good learning opportunity.”
ARA 25 was held at the Adelaide Convention Centre from 3-6 May.
