Systematic review evidence
Immunotherapy is now standard treatment for most patients with unresectable stage III and stage IV melanoma. Antibodies targeting the CTLA-4 and PD-1 checkpoints on activated T-cells have significant activity to shrink melanoma, and induce and durable responses and prolong survival. Immunotherapy is now considered first-line for most patients with unresectable stage III and stage IV melanoma.
Evidence included from outside the systematic review is identified with an asterisk (*) following the reference.
Three randomised controlled studies have been conducted with the anti-CTLA4 antibody ipilimumab. The first two showed a survival benefit for either ipilimumab monotherapy (3mg/kg) (HR 0.66 vs gp100 vaccine, median overall survival [OS] 10.1 months) or ipilimumab combined with DTIC (3mg/kg) (HR 0.72 vs DTIC, median OS 11.2 months). A third trial of ipilimumab at two doses (10mg/kg vs 3mg/kg) showed benefit with the higher dose (HR 0.84, median OS 15.7 months).
Toxicity is frequent with ipilimumab, but manageable, largely reversible and rarely fatal. Immune-related adverse events (irAE) occurred in 60% of patients on ipilimumab at 3mg/kg, and 15–20% had grade 3–4 toxicity. Higher dosing of ipilimumab (10mg/kg) or in combination with chemotherapy (DTIC) resulted in greater toxicity (grade 3 in 34% and 42%, respectively) with no increase longer-term efficacy in the case of the DTIC combination, and insufficient increase in longer-term efficacy when balanced against toxicity for the 10mg/kg dose. As such these are not approved and should not be used in the clinic.
A pooled analysis of approximately 1800 patients on ipilimumab trials demonstrated an OS plateau at approximately 20% at 3 years that persisted to 10 years.*
Anti-PD-1 antibodies, alone and in combination with ipilimumab
There have been three randomised phase III trials of the anti-PD-1 antibodies pembrolizumab and nivolumab in patients with advanced melanoma, demonstrating superiority over chemotherapy and ipilimumab monotherapy. Combination ipilimumab and nivolumab therapy appears more effective but more toxic than anti-PD1 monotherapy.
Nivolumab has been shown to be superior to chemotherapy (DTIC) in BRAF wild-type patients, with a higher response rate (40% vs 14%), and superior OS (HR 0.43, 1-year 73%, 2-year 58%).* Nivolumab and pembrolizumab have each been proven to be superior to ipilimumab, with higher response rates, superior OS (HR 0.69 pembro vs ipi, HR 0.57 nivo vs ipi) and less toxicity (see below). In the pembrolizumab trial, treatment duration was two years and 91% of patients remain in disease control after a median of nine months follow-up time from cessation.*
Combination ipilimumab (3mg/kg) and nivolumab (1mg/kg) has been studied in a single phase III trial of the combination versus nivolumab versus ipilimumab (CheckMate 067). While the trial was only powered to compare the nivolumab containing arms to ipilimumab, combination therapy had a numerically higher response rate (58% vs 44%) and numerically superior OS (HR 0.85, 3-year OS 58% vs 52%) than nivolumab. The greatest benefit of combination was seen in the PD-L1 negative, BRAF mutant melanoma and elevated LDH subgroups.
PD-1 antibodies as monotherapy were well tolerated, with grade 3+ irAEs occurring in approximately 15%, and only 4–8% of patients discontinued treatment for toxicity. In contrast, 55% had grade 3+ irAEs with combination therapy, and 36% discontinued due to toxicity. While there have been no trials comparing nivolumab and pembrolizumab, cross-trial comparisons suggest similar efficacy and toxicity. Studies exploring PD-1 antibodies in combination with lower doses of ipilimumab are underway in the hope that efficacy may be maintained with lower toxicity.
Trials using various cutoffs and scoring techniques demonstrate that PD-L1 expression does influence the response rate and PFS with PD-1 monotherapy, with higher expression correlating with higher efficacy.* Negative staining does not preclude benefit and should not exclude patients from receiving PD-1 monotherapy. Early phase trials have demonstrated higher response rates and superior PFS when immunotherapy is used first-line compared to later lines,* including in BRAF mutant patients. In contrast, BRAF inhibitors have been shown to have consistent response rates and PFS when used any line.*
In patients who progress on PD-1 antibodies, ipilimumab and combination ipilimumab and nivolumab has been shown to have efficacy in retrospective series.* Similarly, toxicity with one class of inhibitor does not preclude use of another, and selected patients with autoimmune disease have been shown to be safely treated with both ipilimumab or PD-1 antibodies as monotherapy.*
Evidence summary table
|First-line/upfront anti-PD1 immunotherapy with nivolumab or pembrolizumab improves the progression-free survival (PFS) and overall survival (OS) compared with ipilimumab monotherapy, regardless of BRAF mutation status. First-line nivolumab improves the PFS and OS compared with dacarbazine chemotherapy (3-year landmark OS nivo vs chemo 56% vs 68%, HR 0.69 [95% CI 0.44–1.07]) in patients whose melanoma is BRAF wild-type.||II||, , |
|First-line/upfront combined therapy with nivolumab and ipilimumab improves the response rate, PFS (3-year landmark PFS combi vs ipi 39% vs 10%, HR 0.43, p<0.001) and OS (3-year landmark OS combi vs ipi 58% vs 34%, HR 0.55, p<0.001) compared with ipilimumab monotherapy, regardless of BRAF mutation status.||II||, |
|First-line/upfront combined therapy with nivolumab and ipilimumab improves the response rate and PFS compared with nivolumab monotherapy 3-year landmark PFS combi vs nivo 39% vs 32%, HR 0.78 [95% CI 0.64–0.96]), regardless of BRAF mutation status of melanoma.||II||, |
|Ipilimumab monotherapy or in combination with chemotherapy (dacarbazine) improves the PFS and OS compared with gp100 or dacarbazine, respectively. Ipilimumab at a dose of 10mg/kg improves the OS compared with ipilimumab at a dose of 3mg/kg.||II||, , |
Next section: Targeted therapies (MEK and BRAF inhibitors)
See the Summary of all recommendations section for all recommendations and practice points.
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