Retrospective Data Show Promise of Ipilimumab Plus PD-1/L1 Inhibitors in Resistant Melanoma


Patients with PD-1 inhibitor-resistant melanoma who were treated with ipilimumab plus anti–PD-1 therapy saw significantly better long-term responses than those on ipilimumab alone.

Ipilimumab (Yervoy) plus anti–PD-1/L1 therapy shows higher objective response rate (ORR) and longer progression-free and overall survival (OS) compared with ipilimumab alone for patients with advanced melanoma that is resistant to available PD-1/L1 inhibitors, according to a study published in The Lancet Oncology.

At the median follow-up of 22.1 months, the ORR was 31% with ipilimumab plus anti–PD-1/L1 therapy versus 13% for ipilimumab monotherapy (P <.0001). The median OS was 20.4 months (95% CI, 12.7-34.8) and 8.8. months (95% CI, 6.1-11.3) for the combination and ipilimumab monotherapy arms, respectively (HR 0.50; 95% CI, 0.38-0.66; P <.0001). The median progression-free survival (PFS) for ipilimumab plus anti–PD-1/L1 therapy was 3.0 months (95% CI, 2.6-3.6) compared with 2.6 months with ipilimumab alone (95% CI, 2.4-2.9; HR 0.69; 95% CI, 0.55-0.87; P = .0019).

This study included 355 patients with unresectable stage III or metastatic melanoma. Patients were treated between February 1, 2011, and February 6, 2020, of whom 162 received ipilimumab monotherapy and 193 received ipilimumab plus anti–PD-1/L1 therapy.

In a post-hoc analysis, the 1-year OS rate was 58% (95% CI, 51%-66%) in the ipilimumab plus anti–PD-1/L1 group with 73 deaths compared with ipilimumab monotherapy at 38% (95% CI, 31%-48%) and 89 deaths. The 1-year PFS rates at the analysis were 24% (95% CI, 19%-32%) and 12% (95% CI, 8%-19%), respectively.

Investigators found that factors associated with longer better ORR and long OS with the combination included male sex, an ECOG performance status of 0, and normal lactate dehydrogenase.

Patients in the subgroup who had a BRAF and NRAS wild-type melanoma, stage IV M1c or M1d disease, or elevated lactate dehydrogenase experienced longer PFS and OS with ipilimumab plus anti–PD-1/L1 therapy compared with ipilimumab alone.

Grade 3 or greater treatment-related adverse events (TREAs) occurred in about a third of patients in both groups. The most common events were diarrhea, colitis, and increased alanine aminotransferase or aspartate aminotransferase. In the ipilimumab monotherapy group, 1 death occurred 26 days after the last treatment from a colon perforation.

Eleven patients had grade 3/4 TREAs on anti–PD-1/L1 monotherapy before the study treatment, 5 of whom experienced events of grade 3/4 severity on study. Relapses of the same AEs occurred in 4 patients, all with grade 3 events.

“This cohort study suggests a substantial clinical benefit with the ipilimumab plus anti–PD-1 treatment over ipilimumab monotherapy in patients with advanced melanoma resistant to anti-PD-(L)1; however, although the study is large, these results need to be interpreted with caution given the retrospective and non-randomized nature of this study,” wrote the study investigators who were led by Ines Pires da Silva, PhD.


Pires da Silva I, Ahmed T, Reijers ILM, et al. Ipilimumab alone or ipilimumab plus anti-PD-1 therapy in patients with metastatic melanoma resistant to anti-PD-(L)1 monotherapy: a multicentre, retrospective, cohort study. Lancet Oncol. 2021;22(6):836-847. doi:10.1016/S1470-2045(21)00097-8

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