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Immune-related adverse events do not impact melanoma survival, time to treatment failure
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Patients with melanoma treated with ipilimumab often experience immune-related adverse events; however, these events do not appear to impact patient survival or time to treatment failure, according to retrospective study results.
Ipilimumab (Yervoy, Bristol-Myers Squibb) sometimes activates an immune response against normal tissue, resulting in immune-related adverse events (irAEs) such as diarrhea, rash, hepatitis and hypophysitis.
Paul B. Chapman, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center and professor of medicine at Weill Cornell Medical College, and colleagues suspected the incidence of irAEs might be higher than indicated by the NCI’s Common Terminology Criteria for Adverse Events definition of grade 3 irAEs, and that a higher percentage of patients may require immunosuppressive treatment.
Based on that suspicion, Chapman and colleagues conducted a study to evaluate the incidence and treatment of irAEs in 298 patients (median age, 65 years) treated with standard-dose ipilimumab in a real-world setting outside of a clinical trial between 2011 and 2013.
From this cohort, 85% of the patients experienced an irAE of any grade and 19% of the population discontinued their therapy because of an irAE.
Thirty-one percent of the patients experienced a grade 3 or worse adverse event, the most common of which was diarrhea (14%). Researchers noted previous reports of grade 3 irAEs in patients treated with ipilimumab for melanoma range from 6% to 19%.
“Although this wide range of scoring might suggest that there are significant regional differences in how patients tolerate ipilimumab, we think it is more likely that this indicates that even with a standardized grading system, toxicity evaluations vary among investigators and global regions,” Chapman and colleagues wrote.
Overall, 35% of the patients required a systemic corticosteroid treatment for an irAE and 10% also needed anti-tumor necrosis factor alpha therapy.
“This is more than twice the rate of grade 3 [or worse] toxicity reported in clinical trials with ipilimumab at the 3 mg/kg dose,” Chapman and colleagues wrote. “This is probably explained by our group’s experience regarding when to abandon less intensive therapies (eg, diet manipulation or budesonide for colitis) and our readiness to use systemic corticosteroids early in the course of irAEs.”
Estimated time to treatment failure (TTF) — defined as the initiation of a new treatment or death — was 5.7 months (95% CI, 5.1-6.4). The estimated median OS was 16.5 months (95% CI, 12.6-21.1), and 39% (95% CI, 33-46) of patients achieved 2-year OS.
Additionally, 12% of the population experienced long-term disease control without additional anti-melanoma therapy.
After excluding patients who died or were lost to follow-up before week 14, researchers conducted an additional analysis of 36 patients to assess the impact of irAEs on OS and TTF. Results showed no difference in OS or TTF when patients were stratified based on occurrence of an irAE. Further, OS and TTF did not significantly differ when researchers stratified patients according to administration of systemic corticosteroids to treat irAEs.
“We found that neither the occurrence of irAEs (no matter the grade) nor the use of systemic corticosteroids was associated with OS or TTF, which is consistent with the observation from Ascierto et al, [J Transl Med. 2014;doi:10.1186/1479-5876-12-116.]” Chapman and colleagues wrote. “However, we cannot rule out the possibility that a specific irAE might be associated with a worse (or better) OS or TTF. On the basis of our data and that of the Italian group, we believe that patients and physicians should not be concerned that irAEs requiring systemic immunosuppression will compromise the therapeutic benefit.” – by Anthony SanFilippo
Disclosure: Chapman reports honoraria, travel accommodations and research funding from and consultant/advisory roles with Bristol-Myers Squibb, Daiichi Sankyo, Genentech/Roche, GlaxoSmithKline, Momenta Pharmaceuticals and Provectus. Please see the full study for a list of all other researchers’ relevant financial disclosures.
Perspective
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Brent A. Hanks, MD, PhD
The availability of the immunotherapeutic agents, ipilimumab (Yervoy, Bristol-Myers Squibb), pembrolizumab (Keytruda, Merck) and nivolumab (Opdivo, Bristol-Myers Squibb), have revolutionized the management of advanced melanoma, providing a subset of these patients with durable clinical benefit. At the same time, there is often a cost associated with the use of these agents in the form of immune-related adverse events (irAEs). As the indications for these agents expand to include other solid tumor malignancies and combinatorial immunotherapeutic regimens are introduced into our armamentarium, the time spent managing these irAEs is likely to only increase. It is clear, therefore, that improved recognition of these irAEs as well as an intimate understanding of their recommended management algorithms are important for treating patients with active immune-based therapies.
This point is emphasized by the manuscript reported by Horvat and colleagues, which describes a single-institution experience of 298 patients with advanced melanoma who underwent treatment with ipilimumab off study at the standard dose of 3 mg/kg. The authors report that this ‘real world’ patient population exhibits a higher incidence of grade 3/4 irAEs (38%) compared with 19% of 511 patients involved in the landmark phase 3 clinical trial that led to the FDA approval of ipilimumab for the treatment of patients with advanced melanoma. Although this difference in the prevalence of more severe irAEs is likely related to variations in toxicity grading between studies, it cannot be completely ruled out that regional differences in checkpoint inhibitor response rates and toxicities may exist, particularly in light of recent preclinical findings suggesting a potential role of the gut microbiota influencing checkpoint inhibitor response rates.
Interestingly, Horvat and colleagues show that 35% of their patients required systemic corticosteroid therapy and that 30% of these patients went on to require additional immunosuppressive therapies, such as infliximab (Remicade, Janssen). These rates are probably reflective of this group’s experience with irAEs and their earlier recognition of the need for corticosteroid therapy as well as the understanding that the use of Tumor Necrosis Factor-alpha blocking agents is likely associated with a superior benefit–risk ratio relative to prolonged steroid therapy in this patient population. As opposed to prior studies that have recognized an association between clinical benefit and the development of irAEs, this report did not find any significant association between the development irAEs and OS or time to treatment failure. The reason for this discrepancy is unclear, however, they note that the use of immunosuppressive therapies for the treatment of irAEs in their patient population did not negatively influence overall clinical outcome. These findings reinforce previous reports indicating that neither the oncologist nor the patient should be concerned about these agents interfering with the efficacy of their overall treatment regimen. Overall, this manuscript emphasizes the point that practicing oncologists should remain vigilant about the development irAEs while treating patients with immunotherapeutic agents and that the use of immunosuppressive agents in the ‘real world’ setting is unlikely to negatively impact the course of their disease.
References:
Attia P, et al. J Clin Oncol. 2005;doi:10.1200/JCO.2005.06.205.
Downey SG, et al. Clin Cancer Res. 2007;doi:10.1158/1078-0432.CCR-07-0187.
Hodi FS, et al. N Engl J Med. 2010;doi:10.1056/NEJMoa1003466.
Lutzky J, et al. Abstract 9034. Presented at: ASCO Annual Meeting; May 29-June 2, 2009; Orlando, Fla.
Sivan A, et al. Science. 2015;doi:10.1126/science.aac4255.
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