Sir Peter MacCallum Cancer Centre Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.
Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, New South Wales, Australia.
J Immunother Cancer. 2022 Jul;10(7). doi: 10.1136/jitc-2022-004668.
Acral melanoma is a rare melanoma subtype with poor prognosis. Importantly, these patients were not identified as a specific subgroup in the landmark melanoma trials involving ipilimumab and the anti-programmed cell death protein-1 (PD-1) agents nivolumab and pembrolizumab. There is therefore an absence of prospective clinical trial evidence regarding the efficacy of checkpoint inhibitors (CPIs) in this population. Acral melanoma has lower tumor mutation burden (TMB) than other cutaneous sites, and primary site is associated with differences in TMB. However the impact of this on the effectiveness of immune CPIs is unknown. We examined the efficacy of CPIs in acral melanoma, including by primary site.
Patients with unresectable stage III/IV acral melanoma treated with CPI (anti-PD-1 and/or ipilimumab) were studied. Multivariable logistic and Cox regression analyses were conducted. Primary outcome was objective response rate (ORR); secondary outcomes were progression-free survival (PFS) and overall survival (OS).
In total, 325 patients were included: 234 (72%) plantar, 69 (21%) subungual and 22 (7%) palmar primary sites. First CPI included: 184 (57%) anti-PD-1, 59 (18%) anti-PD-1/ipilimumab combination and 82 (25%) ipilimumab. ORR was significantly higher with initial anti-PD-1/ipilimumab compared with anti-PD-1 (43% vs 26%, HR 2.14, p=0.0004) and significantly lower with ipilimumab (15% vs 26%, HR 0.49, p=0.0016). Landmark PFS at 1 year was highest for anti-PD-1/ipilimumab at 34% (95% CI 24% to 49%), compared with 26% (95% CI 20% to 33%) with anti-PD-1 and 10% (95% CI 5% to 19%) with ipilimumab. Despite a trend for increased PFS, anti-PD-1/ipilimumab combination did not significantly improve PFS (HR 0.85, p=0.35) or OS over anti-PD-1 (HR 1.30, p=0.16), potentially due to subsequent therapies and high rates of acquired resistance. No outcome differences were found between primary sites.
While the ORR to anti-PD-1/ipilimumab was significantly higher than anti-PD-1 and PFS numerically higher, in this retrospective cohort this benefit did not translate to improved OS. Future trials should specifically include patients with acral melanoma, to help determine the optimal management of this important melanoma subtype.
肢端黑色素瘤是一种预后较差的罕见黑色素瘤亚型。重要的是，这些患者在涉及伊匹单抗和抗程序性细胞死亡蛋白 1（PD-1）药物纳武单抗和帕博利珠单抗的重要黑色素瘤试验中并未被确定为特定亚组。因此，关于这群患者中检查点抑制剂（CPIs）的疗效缺乏前瞻性临床试验证据。肢端黑色素瘤的肿瘤突变负担（TMB）低于其他皮肤部位，并且原发部位与 TMB 存在差异。然而，这对免疫 CPIs 的有效性的影响尚不清楚。我们研究了 CPIs 在肢端黑色素瘤中的疗效，包括按原发部位。
研究了接受 CPIs（抗 PD-1 和/或伊匹单抗）治疗的不可切除的 III/IV 期肢端黑色素瘤患者。进行了多变量逻辑和 Cox 回归分析。主要结局是客观缓解率（ORR）；次要结局是无进展生存期（PFS）和总生存期（OS）。
共纳入 325 例患者：234 例（72%）为足底，69 例（21%）为甲下，22 例（7%）为手掌原发部位。首次 CPI 包括：184 例（57%）抗 PD-1，59 例（18%）抗 PD-1/伊匹单抗联合治疗和 82 例（25%）伊匹单抗。与抗 PD-1 相比，初始抗 PD-1/伊匹单抗的 ORR 明显更高（43%比 26%，HR 2.14，p=0.0004），而伊匹单抗的 ORR 明显更低（15%比 26%，HR 0.49，p=0.0016）。抗 PD-1/伊匹单抗治疗的 1 年标志性 PFS 最高，为 34%（95%CI 24%至 49%），而抗 PD-1 为 26%（95%CI 20%至 33%），伊匹单抗为 10%（95%CI 5%至 19%）。尽管 PFS 有增加的趋势，但抗 PD-1/伊匹单抗联合治疗并未显著改善 PFS（HR 0.85，p=0.35）或 OS（HR 1.30，p=0.16）优于抗 PD-1，这可能是由于后续治疗和高获得性耐药率所致。在原发部位之间未发现结局差异。
虽然抗 PD-1/伊匹单抗的 ORR 明显高于抗 PD-1，且 PFS 数值更高，但在这项回顾性队列研究中，这一益处并未转化为改善 OS。未来的试验应特别纳入肢端黑色素瘤患者，以帮助确定这种重要的黑色素瘤亚型的最佳治疗方法。
