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. 2024 Mar 28;10(5):612–620. doi: 10.1001/jamaoncol.2023.7333

Table 1. Descriptions of Studies of Neoadjuvant Immune Checkpoint Inhibitors in Patients With High-Risk Resectable Melanoma.

Study Design Drugs Patients, No. Melanoma stage Melanoma type Treatment-naive patients, No.a End points Key clinical observations
Amaria et al,13 2018 Randomized, phase 2
  • Group 1: nivolumab, 3 mg/kg every 14 d (4 doses)

  • Group 2: ipilimumab, 3 mg/kg + nivolumab, 1 mg/kg every 21 d (3 doses)

  • All patients receive 13 doses of adjuvant nivolumab

23 IIIB, IIIC, IIID, and IV Cutaneous only; no mucosal or acral melanoma 19 Response rates; trAE; immune correlate of responses
  • Improved RFS, DMFS, and OS noted in patients with pCR

  • Improved RFS, PFS, DMFS, and OS with DCPI (not statistically significant)

Blank et al,10 2018 Randomized feasibility study, phase 1B
  • Group 1: ipilimumab 3 mg/kg + nivolumab 1 mg/kg (every 3 wk); adjuvant treatment (4 cycles after surgery)

  • Group 2: neoadjuvant treatment (2 cycles before surgery and 2 cycles after surgery)

20 IIIB and IIIC Cutaneous 20
  • Primary: feasibility, safety, immune-activating capability

  • Secondary: trAE; response; RFS, correlatives

  • No relapse in those who had pathologic response

  • Relapse rate of 80% within the first 2 y

  • RFS and OS may be better with neoadjuvant DCPI

Huang et al,14 2019 Single arm, phase 1B Pembrolizumab, 200-mg single dose, in neoadjuvant setting; surgery; and adjuvant therapy with pembrolizumab 29 Clinical stage III, resectable stage IV Cutaneous; excluded mucosal or uveal 29 Response
trAE; biomarkers
  • Major pathologic response correlates with 100% DFS at 2 y

  • T-reg proliferation was associated with poor RFS

Rozeman et al,15 2019 Randomized clinical trial, phase 2
  • Group 1: ipilimumab, 3 mg/kg + nivolumab 1 mg/kg every 21 d for 2 cycles

  • Group 2: ipilimumab, 1 mg/kg + nivolumab, 3 mg/kg, every 21 d for 2 cycles

  • Group 3: ipilimumab, 3 mg/kg every 3 wk for 2 cycles followed by nivolumab every 2 wk for 2 cycles

89 Stage III NR NR trAE within first 12 wk; radiologic response at 6 wk; pathologic response at 6 wk
  • 2-y RFS was significantly higher for those with a pathologic response

  • Low TMB and low IFN-γ are associated with the lowest survival and pathologic response rate

  • High TMB + high IFN-γ were associated with the best pathologic response and EFS rate

Amaria et al,16 2022 Single arm Nivolumab, 480 mg + relatlimab, 160 mg intravenously 4 wk for 2 doses; surgery; and 10 doses of nivolumab, 480 mg + relatlimab, 160 mg, every 4 wk 30 IIIB to IIID, M1a (completely resected) NR 29 (1 Patient received BRAF/MEK inhibitors before this study)
  • Primary: pCR

  • Secondary: trAE/safety; response rate; correlative studies

  • 1-y and 2-y RFS was significantly higher in patients with pathologic response

  • Increase in immune cell infiltration and decrease in M2 macrophage were associated with higher pathologic response

Reijers et al,17 2022 Single arm Ipilimumab, 1 mg/kg, and nivolumab, 3 mg/kg for 3 wk, 2 cycles
Pathologic assessment of ILND, TLND, and adjuvant therapy based on pathologic response
99 Stage III with clinically palpable nodes NR NR
  • Primary: RFS at 24 mo; rate of pathologic pCR, pnCR, pNR in the ILND, radiologic response, toxic effects

  • Secondary: long-term RFS; correlative studies

  • MPR in ILND was associated with better RFS and DMFS

  • ILND, TLND, and adjuvant therapy had better patient outcomes than no therapy

  • TLND omission improved reduced surgical morbidity and better HRQoL

Patel et al,18 2023 Randomized clinical trial, phase 2
  • Group 1: pembrolizumab, 200 mg, 3 wk for 3 doses before surgery, then surgery, followed by 14 more doses

  • Group 2: surgery, followed by pembrolizumab, 200 mg, 3 wk for 17 cycles

313 Stage IIIB to IIID, and IV (completely resected) Cutaneous (296 patients); mucosal (4 patients); and acral (9 patients) NR
  • Primary: EFS

  • Secondary: trAE; response rates; surgical resection

  • EFS was significantly better in the neoadjuvant group

Abbreviations: DCPI, dual checkpoint inhibition; DFS, disease-free survival; DMFS, distant metastasis-free survival; EFS, event-free survival; HRQoL, health-related quality of life; IFN-γ, interferon-gamma; ILND, index lymph node dissection; MPR, major pathologic response; NR, not reported; OS, overall survival; pCR, pathologic complete response; pnCR, pathologic near-complete response; pNR, pathologic nonresponse; RFS, relapse-free survival; T-reg, regulatory T cells; TLND, total lymph node dissection; TMB, tumor mutation burden; trAE, treatment-related adverse events.

a

No systemic treatment history.