Aims

Induction ipilimumab and nivolumab followed by maintenance nivolumab improve overall survival compared with ipilimumab alone in patients with advanced melanoma, but immune-related adverse events (irAE) occur commonly. The need for induction discontinuation because of irAE and the relationship between irAE and survival in non-trials patients are unclear.

Materials and methods

Patients with unresectable stage III–IV melanoma receiving first-line combination immunotherapy at one of six centres between December 2017 and February 2020 outside of trials were identified retrospectively. Landmark 12-week Kaplan–Meier analyses and log-rank tests were used to evaluate associations between discontinuation of induction therapy on overall survival and time to treatment failure (TTF). Multivariable analysis of factors influencing overall survival and TTF was undertaken.

Results

Among 95 patients, the median age was 62 years, 38.9% had Eastern Cooperative Oncology Group performance status ≥1 and 22.1% had brain metastases. The median follow-up for the whole cohort was 19.8 months by the reverse Kaplan–Meier method. Any grade and grade 3–4 irAE were noted in 78.9% and 44.2% of the cohort, respectively. 44.2% of patients completed induction immunotherapy, whereas 41.1% did not due to irAE. Twelve-week landmark overall survival and TTF were similar in patients who completed induction versus those who did not due to irAE. On multivariable analysis, any grade irAE (versus none) was associated with longer overall survival (hazard ratio = 0.35, 95% confidence interval 0.15–0.82, P = 0.02) and TTF (hazard ratio = 0.38, 95% confidence interval = 0.17–0.81, P = 0.01). Grade 3–4 irAE correlated with longer TTF (hazard ratio = 0.45, 95% confidence interval = 0.20–1.01, P = 0.05).

Conclusion

In this population-based cohort, discontinuation of induction immunotherapy as a result of irAE did not adversely affect overall survival or TTF. irAE observed during ipilimumab and nivolumab induction were associated with improved survival outcomes.

中文翻译：

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在基于人群的队列中停用 Ipilimumab 和 Nivolumab 治疗晚期黑色素瘤后的生存结果

宗旨

与单独使用易普利姆玛相比，在晚期黑色素瘤患者中，诱导易普利姆玛和纳武单抗继以维持纳武单抗可提高总生存率，但免疫相关不良事件 (irAE) 经常发生。由于 irAE 导致的诱导终止的必要性以及 irAE 与非试验患者生存率之间的关系尚不清楚。

材料和方法

回顾性确定了 2017 年 12 月至 2020 年 2 月期间在试验之外的六个中心之一接受一线联合免疫治疗的不可切除的 III-IV 期黑色素瘤患者。具有里程碑意义的 12 周 Kaplan-Meier 分析和对数秩检验用于评估停止诱导治疗与总生存期和治疗失败时间 (TTF) 之间的关联。对影响总生存期和 TTF 的因素进行了多变量分析。

结果

在 95 名患者中，中位年龄为 62 岁，38.9% 的东部肿瘤协作组体能状态≥1，22.1% 有脑转移。通过反向 Kaplan-Meier 方法，整个队列的中位随访时间为 19.8 个月。队列中分别有 78.9% 和 44.2% 出现任何级别和 3-4 级 irAE。44.2% 的患者完成了诱导免疫治疗，而 41.1% 不是由于 irAE。完成诱导的患者与未因 irAE 导致的患者的 12 周标志性总生存期和 TTF 相似。在多变量分析中，任何级别的 irAE（与无）都与更长的总生存期（风险比 = 0.35，95% 置信区间 0.15-0.82，P = 0.02）和 TTF（风险比 = 0.38，95% 置信区间 = 0.17- 0.81，P= 0.01）。3-4 级 irAE 与更长的 TTF 相关（风险比 = 0.45，95% 置信区间 = 0.20-1.01，P = 0.05）。

结论

在这个基于人群的队列中，由于 irAE 导致的诱导免疫治疗中止不会对总生存期或 TTF 产生不利影响。在 ipilimumab 和 nivolumab 诱导期间观察到的 irAE 与改善的生存结果相关。