Association of Immune-Related Adverse Events, Hospitalization, and Therapy Resumption With Survival Among Patients With Metastatic Melanoma Receiving Single-Agent or Combination Immunotherapy

Abstract

ImportanceImmune-related adverse events (irAEs) due to immune checkpoint blockade (ICB) have been shown to be positively associated with survival. Among patients with metastatic melanoma, evidence supporting this association has been conflicting, while ipilimumab-nivolumab combination ICB has been examined only in small clinical cohorts.ObjectiveTo examine the association between irAEs and survival among patients with metastatic melanoma, in particular for those receiving combination ICB.Design, Setting, and ParticipantsA retrospective cohort of 492 consecutive patients with metastatic melanoma treated with ICB at 2 tertiary and 4 regional cancer centers in Alberta, Canada, from August 1, 2013, to May 31, 2020, was observed. Patients were aged 18 years or older with metastatic melanoma agnostic to primary site, who received 1 or more doses of an anti–programmed cell death protein 1 agent as single or combination ICB. Clinically significant irAEs requiring systemic corticosteroids and/or treatment delay were captured. To minimize immortal time bias, only patients surviving 12 weeks after ICB initiation were included in survival analyses. Statistical analysis was conducted on December 10, 2021.ExposuresDevelopment of irAEs requiring systemic corticosteroids and/or treatment delay.Main Outcomes and MeasuresThe primary outcome was overall survival (OS), with the association of irAE development with OS assessed via Kaplan-Meier and Cox proportional hazards regression analyses. The association of hospitalization for irAEs and ICB resumption after irAE with OS was examined.ResultsAmong 492 patients, the median age of those with irAEs was 61.8 years (IQR, 52.9-72.1 years), and the median age of those without irAEs was 65.5 years (IQR, 56.5-76.9 years), while sex distribution was comparable (137 of 198 men [69.2%] with irAEs vs 183 of 294 men [62.2%] without irAEs). There was an association between irAEs and OS both in the overall cohort (with irAEs: median OS, 56.3 months [95% CI, 38.2 months to not evaluable] vs without irAEs: median OS, 18.5 months [95% CI, 14.4-23.2 months]; P < .001) and in the 124 patients (25.2%) receiving combination ICB (with irAEs: median OS, 56.2 months [95% CI, 52.2 months to not evaluable] vs without irAEs: median OS, 19.0 months [95% CI, 6.6 months to not evaluable]; P < .001). Hospitalization for irAE did not alter this positive association with OS compared with outpatient treatment (median OS, not evaluable [95% CI, 31.5 months to not evaluable] vs median OS, 52.2 months [95% CI, 35.2 months to not evaluable]; P = .53), while resumption of ICB was associated with longer OS than not resuming ICB (median, 56.3 months [95% CI, 40.8 months to not evaluable] vs 31.5 months [95% CI, 21.0 months to not evaluable]; P = .009). A favorable independent association of irAEs with OS was confirmed in multivariable analysis (hazard ratio for death, 0.382 [95% CI, 0.254-0.576]; P < .001).Conclusions and RelevanceThis study suggests an association between irAEs and OS for patients with metastatic melanoma, including those treated with combination ICB and those with severe irAEs requiring hospitalization. The potential benefit associated with ICB resumption after irAEs warrants further investigation.

Immunotherapy Resumption/Rechallenge in Melanoma Patients after Toxicity: Do We Have Another Chance?

“…This is an important reason to support the idea of re-using this treatment despite the toxicity. In a study explained earlier [ 53 ], the patients under rechallenge had a better OS than those who were not retreated after toxicity. An Italian work [ 55 ] carried out a systematic review of studies that reported the efficacy and safety of ICI rechallenge.…”

“…A recent retrospective study published in December 2022 [ 53 ] examined the association between irAEs and survival in metastatic melanoma patients and included a sub-analysis of overall survival (OS) in patients hospitalized for an irAE and then resumed ICI treatment. They defined resumption after an irAE as a patient who received ≥1 cycle of ICI after withholding ICI for irAEs.…”

Treatment-Free Survival After Nivolumab vs Pembrolizumab vs Nivolumab-Ipilimumab for Advanced Melanoma

“…The longer TFS seen for patients receiving combination nivolumab-ipilimumab therapy may be associated with a more durable initial period of disease control, permitting SSAC therapy withdrawal, or the development of treatment-limiting adverse events followed by a treatment-free interval. These immune-related adverse events have been shown to be an established treatment biomarker of the likely benefit from ICI therapy . However, the subset of patients included in the combination nivolumab-ipilimumab cohort also had a lower ECOG status, were younger, and were more likely to be BRAF V600E variant positive, all of which may have been associated with the trend toward improved TFS in this group.…”

“…Furthermore, previous analyses had further stratified TFS based on the presence of immune-related adverse events into TFS with toxic effects and TFS without toxic effects, which could not be replicated in this cohort. Therefore, it is possible that, although patients receiving combination nivolumab-ipilimumab experienced longer TFS, a greater portion of this time was spent with additional toxic effects, as was seen in previous clinical trial analyses . Another limitation is the lack of information regarding choice of SSAC therapy for patients included in this analysis, which may have provided additional context for interpreting differences in duration receiving SSAC therapy seen in this study.…”

“…These immune-related adverse events have been shown to be an established treatment biomarker of the likely benefit from ICI therapy. 13 However, the subset of patients included in the combination nivolumab-ipilimumab cohort also had a lower ECOG status, were younger, and were more likely to be BRAF V600E variant positive, all of which may have been associated with the trend toward improved TFS in this group.…”