Immune checkpoint inhibitors (ICI) represent an important new treatment modality for cancer patients. Despite the important clinical benefits of ICI therapy, these treatments can also cause a variety of immune-related adverse events (irAEs). The mechanisms leading to irAEs are unclear, although irAEs caused by ICI resemble autoimmune disease. That’s the reason why all the clinical trials leading to the approval of ICI therapy actively excluded patients with preexisting active autoimmune disease because of apprehension that these individuals might be at risk for treatment induced irAEs.
The objective of this observational study of patients with cancer and preexisting autoimmune disease (AD) is to evaluate the efficacy and safety of ICI.
Many patients who are diagnosed with cancer have a preexisting autoimmune disease, for example, approximately 14–25% of patients with lung cancer also have an AID. However, in our series only 7.4% of patients with cancer treated with ICI had a preexisting AID. This low prevalence in our sample may be due to several factors. Firstly, the use of immunotherapy in patients with preexisting autoimmune disease is not very widespread due to the lack of experience. The increased risk of irAEs, which can be unpredictable and potentially very serious, and the risk of AID symptom exacerbation (flare-ups) in patients with preexisting AID has led these patients to be frequently excluded from immunotherapy clinical trials. For this reason, there is very little evidence and very little clinical experience in the use of immunotherapy in these patients. Secondly, our sample includes patients receiving immunotherapy within a clinical trial, whose exclusion criteria include suffering or having some autoimmune-based pathology.
In our study, we found that 4 of the 15 patients (26.67%) with preexisting AID had autoimmune exacerbations. This percentage was lower to that observed in other series. Johnson et al retrospectively evaluated 30 patients with preexisting autoinmune disease and metastatic melanoma. Of the 30 patients who received ipilimumab, 15 (50%) experienced irAEs or flares of their underlying autoimmune disease. Leonardi et al13 retrospectively analyzed the safety of anti-PD-1 and PD-L1 antibodies (nivolumab, pembrolizumab, or atezolizumab) in 56 patients with non-small-cell lung cancer (NSCLC) and preexisting autoimmune disease. 55% of patients developed a flare and/or irAEs. Danlos et al compared 45 patients with underlying AD to 352 patients without AD who were treated with anti-PD-1 agents in the Registry of Severe Adverse Reactions to Immunomodulatory Antibodies Used in Oncology (REISAMIC) between 2014 and 2016. 47.1% of the patients with AD experienced an AD flare, 65.9% experienced an irAEs, and 9.4% developed a grade 3/4 irAEs. In a recent review of 41 case reports published to date, in 65.6% of patient immunotherapy resulted in a flare-up of the baseline disease; being severe and very severe in 22.7% of patients.
Of the 4 patients in our study with preexisting AID that had flares, one was treated with atezolizumab, two with nivolumab, and one with pembrolizumab, so we cannot think that a certain drug could interfere with previous AID more than another.
The most frequent cause of discontinuation of immunotherapy was not immune-related adverse events, as we might expect from patients with preexisting AID, it was progression of tumor disease (40%). Only 3 of the 15 patients (20%) had to discontinue immunotherapy for toxicity. Despite the fact that five patients died during our follow-up period, no deaths occurred as a consequence of treatment.
On the other hand, although it is true that irAEs occurred (not related to preexisting AID) in 10 of the 15 patients (66.7%), most were mild and easy to control. Of the 5 patients (33.3%) who did not have any irAEs, two experienced worsening of their disease. Three patients (20%) did not present any immune-related adverse event or not to their pre-existing AID. The incidence of irAEs observed in Johnson et al. did not exceed the incidence of irAEs found by other studies in a population without AID. In our study, 66.7% of patients with AID present irAEs.
Despite the limited information in this regard, some studies have concluded that ICI can be used in patients with previous AID, since the potential risks do not seem to outweigh the benefit of these treatments.
Khan SA and collaborators observed that AID were relevant in NSCLC, 14% of patients with NSCLC had a concurrent AID and they could be treated with ICI, since they observed that patients with AID present a mortality from cancer and from any cause similar to those patients who do not have AID. In patients with melanoma and AID, Johnson DB et al.14 concluded that ipilimumab treatment can be considered, always leading to close surveillance and monitoring of the patient, and the Menzies et al. study obtained a similar conclusion regarding anti-PD1 therapy.