Published: 19 September 2016. Authors: ESMO Guidelines Committee
This update refers to the Cutaneous melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Dummer R, Hauschild A, Lindenblatt N, et al. Ann Oncol (2015) 26 (suppl 5): v126-v132.
Treatment of systemic metastatic disease (stage IV)
In a double-blinded prospective randomised trial, nivolumab was compared with ipilimumab and the ipilimumab/nivolumab combination. Nivolumab monotherapy compared to ipilimumab was scored with an ESMO Magnitude of Clinical Benefit Scale (MCBS) score of 4, as it resulted in a statistically and clinically significant progression-free survival (PFS) benefit, without increased toxicity. The nivolumab+ipilimumab combination was scored with an ESMO-MCBS score of 2, the lower score reflecting the presence of only PFS data as well as the increased toxicity of the combination. Programmed death ligand 1 (PD-L1) expression may be a relevant marker in this context, however data are not available nor mature for the ESMO-MCBS scoring of the nivolumab+ipilimumab combination compared to ipilimumab in the PD-L1-negative melanoma subgroup of patients.
For patients with metastatic melanoma, treatment options for first-line setting include the anti-PD-1 antibody nivolumab which showed a clinically and statistically significant PFS benefit over ipilimumab, with a high MCBS score of 4 [II, B].
Therapy | Disease setting | Trial | Control | Absolute survival gain | HR (95% CI) | QoL/toxicity | MCBS score** |
---|---|---|---|---|---|---|---|
Nivolumab, a PD-1 checkpoint inhibitor | Unresectable stage III or IV melanoma, 1st line setting |
Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma [1] Phase III NCT01844505 |
Ipilimumab, in previously untreated patients with unresectable stage III or IV melanoma. Control PFS: 2.9 months |
PFS gain: 4.0 months |
PFS HR: 0.57 (0.43-0.76) |
Improved toxicity profile | 4 (Form 2b) |
Nivolumab (a PD-1 checkpoint inhibitor) + ipilimumab (a CTLA-4 checkpoint inhibitor) | Unresectable stage III or IV melanoma, 1st line setting |
Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma [1] Phase III NCT01844505 |
Ipilimumab, in previously untreated patients with unresectable stage III or IV melanoma. Control PFS: 2.9 months |
PFS gain***: 8.6 months |
PFS HR: 0.42 (0.31-0.57) |
Deteriorated toxicity profile | 2 (Form 2b) |
Nivolumab (a PD-1 checkpoint inhibitor) + ipilimumab (a CTLA-4 checkpoint inhibitor) |
Unresectable stage III or IV melanoma, 1st line setting. Pre-specified subgroup of PD-L1-negative melanoma |
Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma [1] Phase III NCT01844505 |
Ipilimumab, in previously untreated patients with unresectable stage III or IV melanoma. Control PFS: 2.9 months |
PFS gain: 8.3 months |
PFS HR: Not available |
Not available | Not available |
*EMA approvals in 2016 to end August 2016.
**ESMO-MCBS version 1.0 [2]
***Gain > nivolumab alone was only observed with PD-L1 positive melanoma
CI, confidence interval; QoL, quality of life; PD-1, programmed death 1; PFS, progression-free survival; HR, hazard ratio; CTLA-4, cytotoxic T-lymphocyte-associated antigen 4; EMA, European Medicines Agency; PD-L1, programmed death-ligand 1