Early initiation of corticosteroid during immune checkpoint inhibitor treatment may hamper efficacy, according to US and Australian researchers
While corticosteroids are commonly used to manage immune-related adverse effects (irAEs), there is uncertainty about their impact on immunotherapy efficacy, they wrote in in the Journal for ImmunoTherapy of Cancer.
Their study therefore reviewed survival outcomes and objective response rates (ORR) for 247 metastatic cancer patients who received corticosteroids concurrently with checkpoint inhibitors at a US cancer centre.
The agents used were PD-1/PD-L1 immunotherapy (nivolumab, pembrolizumab, atezolizumab, or durvalumab) with or without the combination of CTLA-4 inhibitor, ipilimumab.
The study found that patients who started corticosteroids within two months of checkpoint inhibitors had shorter progression-free survival (median PFS: 14.9 versus 2.8 months, adjusted HR: 0.30, P < 0.0001) and overall survival (median OS: 25.0 versus 6.4 months, adjusted HR: 0.34, P < 0.0001) periods than those who started corticosteroids after two months.
They also had a reduced ORR compared with those who started corticosteroids later (14.7% versus 39.8%, P < 0.001).
Figures were adjusted for possible confounding factors such as immune-related adverse events (irAEs), drug type, tumour type and presence of brain metastases.
“Interestingly we found that, unlike the timing of initiation of corticosteroids, higher total steroid dosage did not impact outcomes of patients treated with CPIs,” the study authors said.
They noted that previous studies had suggested corticosteroids do not impact checkpoint inhibitor outcomes. However, these had compared corticosteroid versus non-corticosteroid use, which “may be confounded by higher rates of irAEs in patients that receive corticosteroids and a known association of irAEs with higher response rates to CPIs”.
In the current study, the differences in outcomes were consistent across all indications for corticosteroids, including both irAEs and non-irAE uses.
Other studies showed corticosteroids had similar negative effects on checkpoint inhibitor efficacy. However, these looked at the effects of baseline corticosteroids at the time of CPI initiation.
There were several possible mechanisms to explain why corticosteroids might impact the efficacy of immunotherapy, the authors said. Corticosteroids could be immunosuppressive on both the innate and adaptive immune system by inducing effector T-cell apoptosis and impairing maturation of dendritic cells. They have also been shown to inhibit the production of important effector T-cell cytokines such as interleukin-2 (IL-2) and interferon-gamma.
Preclinical studies had also described how corticosteroids preferentially suppress naïve T cells, which are important for initiation of an anti-tumour immune response.
The study authors said oncologists should be cognisant that early steroid use could reduce checkpoint inhibitor efficacy, but acknowledged that corticosteroids were an important and necessary treatment for certain complications from cancer and from immunotherapy.
“Along with previously reported data demonstrating inferior outcomes with baseline corticosteroid, our results support judicious use of corticosteroid early in the course of [checkpoint inhibitor] treatment,” they concluded.