Moving Beyond Steroids to Treat Immunotherapy Toxicity

Managing toxicities for patients on immunotherapy requires collaboration with specialists, who manage specific organ toxicities, explained Michael Postow, MD, chief, melanoma service, Memorial Sloan Kettering Cancer Center, during a presentation at ESMO Congress 2023.

Any organ in the body can get inflamed regardless of which immune checkpoint inhibitor is used to treat patients. “Everything can be enflamed from toxicity,” he said.

Immune checkpoint inhibition | Image credit: Masaki - stock.adobe.com

Steroids have been the first treatment to treat immunotherapy toxicity. While they do work, they can be harmful, Postow noted. Pooled data in melanoma showed no obvious detriment in objective response rate for patients receiving systemic immune-modulating agents,¹ but additional studies coming out have questioned that initial data. Other pooled data have shown a reduction in progression-free surviv al or overall survival with the high steroid doses (ie, more than 30 mg/day of prednisone within 2 months of PD-1 initiation) to treat toxicities in patients with melanoma.²

The results may differ tumor by tumor or depending on the outcome being looked at, Postow noted. In addition, whether the impact of steroids is similar on the combination of PD-L1 and CTLA-4 inhibitors remains to be seen.

To move beyond steroids, we need to understand why the toxicities are occurring, he said. There are 4 hypothesized mechanisms of toxicity:

1. Increased T-cell activity against antigens present in tumors and health tissue
2. Increased levels of inflammatory cytokines
3. Increased levels of preexisting autoantibodies
4. Enhanced complement-mediated inflammation due to direct binding of an anti–CTLA-4 antibody with CLTA-4 expressed on normal tissue

Myocarditis is one toxicity that is believed to be T-cell driven. Abatacept, a CTLA-4 agonist, with ruxolitinib, a Janus kinase inhibitor, was used to mitigate fatality rates of severe myocarditis as a result of treatment with immune checkpoint inhibitors.³ Fatality from myocarditis was 3% compared with a historical mortality rate of 60%.

“This does show we can do better with different immunomodulation and increased monitoring of the respiratory status in the context of this trial,” Postow said. “We can improve with new thinking on ways we can treat these toxicities.”

B cells, in addition to T cells, are thought to play a role in autoantibody production, which has been a problem. In an adapted immunotherapy trial, led by Postow, a lower baseline antibody rate was associated with greater toxicity.^4,5 In addition, a greater fold change of antibodies from baseline to week 6 was associated with greater toxicity.⁵ The trial included 60 patients receiving a modified combination of CTLA-4 and PD-1 inhibitors.

The data suggest that making antibodies after immune checkpoint blockade may be a bad thing for toxicities, Postow explained. This can be inhibited through the use of rituximab, plasmapheresis, or intravenous immunoglobulin and may successfully treat forms of this toxicity.⁶

There are also cytokines associated with skin toxicity, specifically IL-6 and IgE, and there are drugs that inhibit those targets. For instance, omalizumab targets IgE, and has been shown to improve rash and pruritus. “[This suggests] that perhaps we should think about drawing cytokine levels—if we can get them back quickly or at least in a research context—and then apply selective immunosuppressants that might be specifically relevant for that particular patient,” Postow said.

The most commonly blocked cytokine is tumor necrosis factor (TNF)-alpha, which is inhibited with infliximab. A recent review from Postow and colleagues argued for the earlier use of TNF-alpha blockade to reduce the dose and duration of corticosteroids.⁷

Ultimately, there is research into how to drive mechanistic-based toxicity management, but the data isn’t there yet, Postow said.

“We have a dearth of data in this area, and I think the big challenge is how do we generate this data together, recognizing prospective trials are incredibly difficult to do,” he said. “How do we prove that the mechanisms we’re inhibiting with these selective immunosuppressants are distinct from those involved with tumor immunity?”

Postow concluded with the note that the studies done so far have been short term in the first weeks or months of treatment, and there is a need for long-term data to monitor toxicities in survivorship.

References

1. Weber JS, Hodi FS, Wolchok JD, et al. Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J Clin Oncol. 2017;35(7):785-792. doi:10.1200/JCO.2015.66.1389

2. Bai X, Hu J, Betof Warner A, et al. Early use of high-dose glucocorticoid for the management of irAE is associated with poorer survival in patients with advanced melanoma treated with anti-PD-1 monotherapy. Clin Cancer Res. 2021;27(21):5993-6000. doi:10.1158/1078-0432.CCR-21-1283

3. Salem J-E, Bretagne M, Abbar B, et al. Abatacept/ruxolitinib and screening for concomitant respiratory muscle failure to mitigate fatality of immune-checkpoint inhibitor myocarditis. Cancer Discov. 2023;13(5):1100-1115. doi:10.1158/2159-8290.CD-22-1180

4. Postow MA, Goldman DA, Shoustari AN, et al. Adaptive dosing of nivolumab + ipilimumab immunotherapy based upon early, interim radiographic assessment in advanced melanoma (the ADAPT-IT study). J Clin Oncol. 2022;40(10):1059-1067. doi:10.1200/JCO.21.01570

5. Ghosh N, Postow MA, Zhu C, et al. Lower baseline autoantibody levels are associated with immune-related adverse events from immune checkpoint inhibition. J Immunother Cancer. 2022;10(1):e004008. doi:10.1136/jitc-2021-004008

6. Phillips GS, Wu J, Hellmann MD, et al. Treatment outcomes of immune-related cutaneous adverse events. J Clin Oncol. 2019;37(30):2746-2758. doi:10.1200/JCO.18.02141

7. Faleck DM, Dougan M, Tello M, Grossman JE, Moss AC, Postow MA. Accelerating the evolution of immune-related enterocolitis management. J Clin Oncol. 2023;41(17):3110-3115. doi:10.1200/JCO.22.02914