Landmark trials leading to US FDA approvals of ICIs for the treatment of unresectable/advanced/metastatic cutaneous melanoma.
| Trial and US FDA approval date | Key inclusion criteria | Study arms* | Key outcomes | Treatment-related adverse events |
| (NCT00094653)5
March, 2011 Note: first-line ipilimumab monotherapy is no longer considered standard of care in this setting | HLA-A*0201–positive with unresectable stage III or IV melanoma progressed on a prior regimen for metastatic disease containing one or more of the following: dacarbazine, temozolomide, fotemustine, carboplatin, or IL-2 | Ipilimumab (n=137)† gp100 vaccine (n=136) | ORR: 10.9% vs 1.5% (p=0.001); CR 1.5% vs 0%; DCR 28.5% vs 11.0% PFS: median 2.86 vs 2.76 months (HR 0.64; p<0.001) OS: median 10.1 vs 6.4 months (HR 0.66; p=0.003); 12-month 45.6% vs 25.3% | Grade 3–4 irAE: 14.5% vs 3.0% Grade 5: 3.1% vs 1.5% |
| KEYNOTE-002 (NCT01704287)106 September, 2014 | Progressive disease within 24 weeks after ≥2 ipilimumab doses and, if BRAFV600 mutated, previous treatment with a BRAF or MEK inhibitor or both | Pembrolizumab 2 mg/kg (n=180) Pembrolizumab 10 mg/kg (n=181) ICC with paclitaxel plus carboplatin, paclitaxel, carboplatin, dacarbazine, or temozolomide (n=179) | ORR: 21% vs 25% vs 4% Median PFS: 2.9 (HR vs ICC 0.57; 95% CI 0.45 to 0.73, p<0.0001) vs 2.9 (HR vs ICC 0.50; 95% CI 0.39 to 0.64, p<0.0001) vs 2.7 months Median DOR: 3.7 vs 5.4 vs 2.6 months | Grade 3–4: 11% vs 14% vs 26% Grade 5: 0% for all arms |
| CheckMate 069 (NCT01927419)115 October, 2015‡ | Advanced melanoma with no prior systemic therapy for unresectable or metastatic disease | Ipilimumab plus nivolumab (n=72 patients with BRAF wild-type disease)§¶ Ipilimumab (n=37 patients with BRAF wild-type disease) § | ORR: 59.7% vs 10.8% (p<0.0001); CR 16.7% vs 0%; DCR 73.6% vs 43.2% PFS: median 8.9 vs 4.7 months (HR 0.40, 95% CI 0.22 to 0.71; p=0.0012) | Grade 3–4 (for BRAF WT and MT): 51.1% vs 19.6% |
| CheckMate 066 (NCT01721772)108 November, 2015 | Unresectable, previously untreated stage III or IV BRAF wild-type melanoma | Nivolumab (n=210) Dacarbazine (n=208) | ORR: 40.0% vs 13.9% (p<0.001); CR 7.6% vs 1.0%; DCR 56.7% vs 36.1% PFS: median 5.1 vs 2.2 months (HR 0.43; 95% CI 0.34 to 0.56; p<0.001) OS: median NR vs 10.8 months (HR 0.42; 99.79% CI 0.25 to 0.73, p<0.001); 1-year 72.9% vs 42.1% | Grade 3–4: 11.7% vs 17.6% Grade 5: 0% for both arms |
| KEYNOTE-006 (NCT01866319)137 December, 2015 | Unresectable stage III or IV melanoma and no more than one previous systemic therapy for advanced disease | Pembrolizumab** (n=277) Ipilimumab (n=278) | ORR: 32.9% vs 11.9% (p<0.001); CR 6.1% vs 1.4% PFS: median 4.1 mo vs 2.8 months (HR 0.58; 95% CI 0.47 to 0.72; p<0.001) OS: median NR in any arm (HR 0.69; 95% CI 0.52 to 0.90; p=0.0036); 12-month 68.4% vs 58.2% | Grade ≥3: 10.1% vs 19.9% Grade 5: 0% vs 0.4% |
| CheckMate 067 (NCT01844505)116 January, 2016 | Stage III (unresectable) or stage IV melanoma and no prior systemic treatment for advanced disease | Ipilimumab plus nivolumab (n=313) ¶ Ipilimumab (n=311) Nivolumab (n=313) | ORR: 57.6% (ipi/nivo) vs 19.0% (ipi) vs 43.7% (nivo); CR 11.5% (ipi/nivo) vs 2.2% (ipi) vs 8.9% (nivo) PFS: median 11.5 (ipi/nivo; HR vs ipi 0.42 [99.5% CI 0.31 to 0.57; p<0.001]) vs 6.9 (nivo; HR vs ipi 0.57 [99.5% CI 0.43 to 0.76; p<0.001]) vs 2.9 months (ipi) | Grade 3–4: 55% (ipi/nivo) vs 27.3% (ipi) vs 16.3% (nivo) Grade 5: 0% (ipi/nivo) vs 0.3% (ipi) vs 0.3% (nivo) |
| IMspire150 (NCT02908672)122 July, 2020 | Unresectable stage IIIC–IV, BRAFV600-mutated melanoma | Atezolizumab plus vemurafenib plus cobimetinib (n=256) Vemurafenib plus cobimetinib (n=258) | ORR: 66.3% vs 65%; CR 15.7% vs 17.1% Median DOR: 21.0 vs 12.6 months PFS: median 15.1 vs 10.6 months (HR 0.78; 95% CI 0.63 to 0.97, log-rank p=0.025) OS: HR 0.85; 95% CI 0.64 to 1.11; log-rank p=0.23 | Grade 3–4: 79% vs 73% Grade 5: 0.8% vs 0.4% |
| RELATIVITY-047 (NCT03470922)42 March, 2022 | Previously untreated advanced melanoma | Nivolumab plus relatlimab (n=355) Nivolumab (n=359) | PFS: 10.1 vs 4.6 months (HR 0.75, 95% CI 0.6 to 0.9; p=0.0055); 12-month 47.7% vs 36% OS: median NR vs 34.1 months (HR 0.80; 95% CI 0.64 to 1.01) | Grade 3–4: 18.9% vs 9.7% Grade 5: 0.8% vs 0.6% |
Information presented in this table is based on investigator reviewed data available at the time of each corresponding US FDA approval. Experimental arm data are listed first and in the order in which they appear in the study arms column.
*Therapy-matched placebos are not reported here. With the exception of KEYNOTE-002, patients enrolled in the above trials had not received prior treatment with ICIs.
†gp100 is an HLA-A*0201-restricted melanoma-associated peptide vaccine. gp100 and ipilimumab (dosed at 3 mg/kg) were administered every 3 weeks for up to four (induction) treatments, with re-induction available to eligible patients. Data from a third trial arm, ipilimumab plus gp100, are not reported here as there was no OS difference between the two ipilimumab-containing arms (HR 1.04; p=0.76).
‡Note: this US FDA approval was for BRAF wild-type disease only and was subsequently approved for BRAF-unselected advanced disease in 2016 based on the results of CheckMate 067.
§Patients with BRAFV600-mutated disease were included in this study but are not reported here due to small sample size.
¶Ipilimumab was dosed at 3 mg/kg combined with nivolumab 1 mg/kg every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks.
**Pembrolizumab was administered at a dose of 10 mg/kg every 3 weeks. Data from a third trial arm, pembrolizumab 10 mg/kg administered every 2 weeks, are not reported here.
CI, confidence interval; CR, complete response; DCR, disease control rate (complete and partial responses plus stable disease); DOR, duration of response; HR, hazard ratio; ICC, investigator’s choice chemotherapy; ICI, immune checkpoint inhibitor; IL, interleukin; ipi, ipilimumab; irAE, immune-related adverse event; MT, mutated; nivo, nivolumab; NR, not reached; ORR, objective response rate (complete plus partial response); OS, overall survival; PFS, progression-free survival; US FDA, United States Food and Drug Administration; WT, wildtype.