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Immune-related adverse effects of checkpoint inhibitors frequent but manageable
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Although flares and immune-related adverse effects due to checkpoint inhibitor therapy can be frequent and potentially severe, they are “mostly manageable” without the need for discontinuation among patients with preexisting autoimmune diseases, according to data published in Arthritis & Rheumatology.
“Immune checkpoints inhibitors (ICI) are becoming a standard of care in various cancers,” Divi Cornec, MD, PhD, of the Hospital La Cavale Blanche, in Brest, France, and colleagues wrote. “Although blocking these immune checkpoints enhances the anti-tumor immune response, it may also break the self-tolerance leading to immune-related adverse effects (IRAEs).”
“These inflammatory and/or autoimmune manifestations are frequent, up to 70% to 90% for anti PD-1 and anti CTLA-4 respectively, and sometimes severe ( 10% to 20%),” they added. “Virtually all the organs can be affected, and the occurrence of authentic autoimmune diseases have been reported. Therefore, most patients with preexisting inflammatory or autoimmune disease (PAD) have been excluded from clinical trials.”
To analyze the safety and efficacy of immune checkpoint inhibitor therapy among patients with cancer and preexisting autoimmune diseases, Cornec and colleagues conducted a retrospective cohort study using three national networks in France — the Groupe Français de Pneumo-Cancérologie, the Groupe de Cancérologie Cutanée and the Club Rhumatismes et Inflammations. A standardized retrospective data extraction form was distributed through the networks’ mailing list between January 2017 and January 2018.
The researchers included 112 patients, all identified by oncologists, rheumatologists and internists from academic or nonacademic hospitals. The median follow-up period was 8 months. Exclusion criteria included a diagnosis of the autoimmune disease after the start of checkpoint inhibitor therapy, and the absence of a follow-up. Specific questionnaires collected data on baseline characteristics and cancer and autoimmune disease history, and medical records were used to confirm type of checkpoint therapy, checkpoint-related adverse effects and tumor response. Autoimmune disease flares and other immune-related adverse effects were reported separately.
Among the 112 included patients, 31 had preexisting psoriasis, 20 had rheumatoid arthritis and 14 had inflammatory bowel disease. In addition, 24 were being treated with immunosuppressive therapy while starting checkpoint inhibitors.
According to the researchers, disease flare or other immune-related adverse effects occurred in 71% of studied patients, with 47% experiencing a flare and 42% reporting other immune-related events. Immunosuppressive therapy was required for 43% of patients, with permanent checkpoint discontinuation reported in 21%.
Median progression free survival was shorter among patients receiving immunosuppressive therapy at that start of checkpoint therapy, at 3.8 months compared with 12 months for those without (P = .006). In addition, median progression free survival was also shorter in those who experienced a disease flare or other immune-related adverse effect, with a trend toward better survival among patients without any immunosuppressive therapy or checkpoint discontinuation.
“Although IRAEs are frequent and potentially severe, patients with PAD are good candidates for ICI treatment,” Cornec and colleagues wrote. “Close follow-up and collaboration between oncologists and organ specialists is mandatory in managing such patients. This study raises the idea of immunosuppressive therapy being discontinued at ICI initiation in patients with inactive PAD, but further prospective studies are needed to draw firm conclusions.” – by Jason Laday
Disclosure: Cornec reports no relevant disclosures. Please see the full study for additional authors’ disclosures.
Perspective
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David A. McLain, MD, FACP, FACR
There has been an explosion of anti-cancer therapy with the use of immune checkpoint inhibitors, which are becoming standard of care for various cancers. The cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) with its ligand C80-CD86 and programmed cell death 1 (PD-1) with its ligands PD-L1 and PD-L2 are physiologic inhibitors of activated T-cells.
Blocking these immune checkpoints enhances the anti-tumor immune response, but may also break self-tolerance leading to immune-related adverse effects (IRAEs), which can be severe and are most common with anti-PD-1 and anti-CTLA-4 drugs. One drug called ipilimumab (Yervoy, Bristol-Myers Squibb) blocks CTLA-4, while two additional drugs — pembrolizumab (Keytruda, Merck) and nivolumab (Opdivo, Bristol-Myers Squibb) — target PD-1. A third drug, atezolizumab (Tecentriq, Genentech/Roche), targets PD-L1.
Considering these new therapies are being used widely, the researchers wanted to know what effect they would have on preexisting autoimmune disease (PAD). This is a very interesting, one-year retrospective, cohort, multicenter French study on the use of ICIs in patients with cancer and PAD since this subgroup had been excluded from ICI clinical trials. The researchers assessed adults with PAD receiving ICI for occurrence of PAD flare, other IRAE, and cancer response.
According to the researchers, flare of a PAD and/or an IRAE occurred in almost 75% of the patients. The flares of PAD, which occurred in 47%, were similar to previous flares and 70% were mild — 30%, however, were severe. Slightly more than half required an immunosuppressive to treat which was mostly corticosteroids but other immunosuppressives were used (for example, methotrexate, azathioprine or TNF inhibitor) .
Progression free survival (PFS) was shorter among patients receiving immunosuppression at ICI initiation (3.8 vs. 12 months, P<.006). The PFS interval was no different for “strong” immunosuppression (prednisone ≥15 mg/d or DMARDs) vs. “weak” immunosuppression (hydroxychloroquine or prednisone <15 mg/d).
The researchers concluded that patients with PAD have frequent reactions to ICI therapy but these reactions can be managed and the patients with PAD are good candidates for ICI. Their study also raises the question of whether immunosuppression should be stopped prior to ICI initiation.
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