Department of Internal Medicine, Division of Hematology, Medical Oncology, and Palliative Care, University of Wisconsin, Madison, WI, United States.
Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI, United States.
Front Immunol. 2022 Jul 6;13:860421. doi: 10.3389/fimmu.2022.860421. eCollection 2022.
Standard combination ipilimumab/nivolumab (I/N) is given as 4 induction doses for advanced stage melanoma followed by nivolumab single-agent maintenance therapy. While many patients receive less than 4 doses due to immune-related toxicities, it is unclear if fewer doses of I/N may still provide long term clinical benefit. Our aim is to determine if response assessment after 1 or 2 doses of I/N can predict long-term survival and assess if fewer doses of I/N can lead to similar survival outcomes.
We performed a retrospective analysis on a cohort of patients with advanced melanoma who w0ere treated with standard I/N. Cox regression of progression-free survival (PFS) and overall survival (OS) models were performed to assess the relationship between response after 1 or 2 doses of I/N and risk of progression and/or death. Clinical benefit response (CBR) was assessed, defined as SD (stable disease) + PR (partial response) + CR (complete response) by imaging. Among patients who achieved a CBR after 1 or 2 doses of I/N, a multivariable Cox regression of survival was used to compare 1 or 2 vs 3 or 4 doses of I/N adjusted by known prognostic variables in advanced melanoma.
199 patients were evaluated. Patients with CBR after 1 dose of I/N had improved PFS (HR: 0.16, 95% CI 0.08-0.33; p<0.001) and OS (HR: 0.12, 0.05-0.32; p<0.001) compared to progressive disease (PD). Patients with CBR (vs PD) after 2 doses of I/N also had improved PFS (HR: 0.09, 0.05-0.16; p<0.001) and OS (HR: 0.07, 0.03-0.14; p<0.001). There was no survival risk difference comparing 1 or 2 vs 3 or 4 doses of I/N for PFS (HR: 0.95, 0.37-2.48; p=0.921) and OS (HR: 1.04, 0.22-4.78; p=0.965).
Early interval imaging with response during induction with I/N may be predictive of long-term survival in advanced stage melanoma. CBR after 1 or 2 doses of I/N is associated with favorable survival outcomes, even in the setting of fewer I/N doses received. Further studies are warranted to evaluate if electively administering fewer combination I/N doses despite tolerance in select patients may balance the benefits of therapy while decreasing toxicities.
标准的伊匹单抗/纳武单抗（I/N）联合方案用于晚期黑色素瘤，给予 4 个诱导剂量，然后进行纳武单抗单药维持治疗。由于免疫相关毒性，许多患者接受的剂量少于 4 个，但尚不清楚较少剂量的 I/N 是否仍能提供长期临床获益。我们的目的是确定 I/N 治疗 1 或 2 个剂量后的反应评估是否可以预测长期生存，并评估较少剂量的 I/N 是否可以导致相似的生存结果。
我们对接受标准 I/N 治疗的晚期黑色素瘤患者进行了回顾性分析。对无进展生存期（PFS）和总生存期（OS）模型进行 Cox 回归分析，以评估 I/N 治疗 1 或 2 个剂量后的反应与进展和/或死亡的风险之间的关系。采用影像学评估临床获益反应（CBR），定义为 SD（稳定疾病）+PR（部分缓解）+CR（完全缓解）。在 I/N 治疗 1 或 2 个剂量后达到 CBR 的患者中，采用多变量 Cox 回归分析比较 1 或 2 个剂量与 3 或 4 个剂量的 I/N 对晚期黑色素瘤中已知预后变量的生存影响。
共评估了 199 例患者。与疾病进展（PD）相比，I/N 治疗 1 个剂量后达到 CBR 的患者 PFS（HR：0.16，95%CI 0.08-0.33；p<0.001）和 OS（HR：0.12，0.05-0.32；p<0.001）均得到改善。I/N 治疗 2 个剂量后达到 CBR（与 PD 相比）的患者 PFS（HR：0.09，0.05-0.16；p<0.001）和 OS（HR：0.07，0.03-0.14；p<0.001）也得到改善。I/N 治疗 1 或 2 个剂量与 3 或 4 个剂量相比，PFS（HR：0.95，0.37-2.48；p=0.921）和 OS（HR：1.04，0.22-4.78；p=0.965）的生存风险无差异。
在晚期黑色素瘤中，I/N 诱导期内的早期间隔成像与长期生存相关。I/N 治疗 1 或 2 个剂量后的 CBR 与有利的生存结果相关，即使接受的 I/N 剂量较少。需要进一步的研究来评估在某些患者中选择较少剂量的联合 I/N 是否可以平衡治疗的益处，同时减少毒性，尽管存在耐受性。
