Table 2. FDA-Approved Therapies for Metastatic or Unresectable Stage III Melanoma Since 2011 and a Brief Summary of Pivotal Trials Leading to Corresponding FDA Approval, Focusing on OS Outcomes.
| Therapy | FDA approval year | Dose | Comparator | Trial name | Study phase | Primary end point | Statistically significant OS benefit | Indication or line of treatment in patients with metastatic or unresectable melanoma | Statistically and clinically significant outcomes from trials |
|---|---|---|---|---|---|---|---|---|---|
| Ipilimumab12 | 2011 | 3 mg/kg body weight IV every 3 wk | Gp100 | NA | 3 | OS | Yes | First line | Median OS 10.1 mo with ipilimumab vs 6.4 mo with Gp100 |
| Vemurafenib22 | 2011 | 960 mg PO BID | Dacarbazine | BRIM-3 | 3 | OS and PFS | Yes | Melanoma with BRAF V600E mutation (first line) | Median OS 13.6 mo with vemurafenib vs 9.7 mo with dacarbazine |
| Dabrafenib mesylate23,24,25 | 2013 | 150 mg PO BID | Dacarbazine | BREAK-3 | 3 | ORR and OS | Yes | Metastatic melanoma with BRAF V600E mutation (first line) | 5-y OS 24% with dabrafenib vs 22% with dacarbazine, but crossover to dabrafenib was allowed |
| Trametinib dimethyl sulfoxide26 | 2013 | 2 mg PO once a day | Dacarbazine or paclitaxel | METRIC | 3 | PFS and OS | Yes | Melanoma with BRAF V600 mutation (first line) | 6-mo OS 81% with trametinib vs 67% with dacarbazine or paclitaxel, including 47% patients with crossover to trametinib after progression |
| Pembrolizumab27,28 | 2014 | 10 mg/kg body weight every 2 or 3 wk | Ipilimumab (3 mg/kg) every 3 wk for 4 doses | KEYNOTE 006 | 3 | PFS and OS | Yes | First line | Median OS 32.7 mo with pembrolizumab vs 15.9 mo with ipilimumab |
| Nivolumab monotherapy29,30 | 2014 | 3 mg/kg body weight IV every 2 wk | Investigator's choice chemothrapy (dacarbazine, 1000 mg/m2 every 3 wk, or paclitaxel, 175 mg/m2, combined with carboplatin [area under the curve, 6] every 3 wk) | CheckMate 037 | 3 | Objective response | No | Second line (refractory to ipilimumab or a BRAF inhibitor) | Approval based on better response rate 32% with nivolumab vs 11% with chemotherapy |
| Nivolumab monotherapy31,32 | 2015 | 3 mg/kg body weight IV every 2 wk | Dacarbazine | CheckMate 066 | 3 | PFS and OS | Yes | Metastatic melanoma (first line) | 5-y OS 39% with nivolumab vs 17% with dacarbazine |
| Nivolumab with ipilimumab33,34 | 2015 | Nivolumab, 1 mg/kg every 2 wk, plus ipilimumab, 3 mg/kg every 2 wk, for 4 doses, followed by nivolumab, 3 mg/kg every 2 wk | Nivolumab (3 mg/kg every 2 or 3 wk) or ipilimumab (3 mg/kg every 3 wk for 4 doses) | CheckMate 067 | 3 | PFS and OS | Yes | Metastatic melanoma (first line) | Median OS 72.1 mo in combination vs 36.9 mo with nivolumab vs 19.9 mo with ipilimumab |
| Dabrafenib with trametinib35,36,37 | 2015 | Dabrafenib, 150 mg PO BID with trametinib, 2 mg once a day | Dabrafenib | COMBI-d | 3 | PFS | Yes | Melanoma with BRAF V600 mutation (first line) | Median OS 25.1 mo with combination vs 18.7 mo with dabrafenib; 3-y OS 45% with combination vs 32% with vemurafenib |
| Vemurafenib | COMBI-v | ||||||||
| Vemurafenib plus cobimetinib fumarate38,39 | 2015 | Vemurafenib, 960 mg PO BID, and cobimetinib fumarate, 60 mg once a day | Vemurafenib | coBRIM | 3 | PFS | Yes | Melanoma with BRAF V600 mutation (first line) | 5-y OS 31% with combination vs 26% with vemurafenib |
| Talimogene laherparepvec40,41,42 | 2015 | Intralesional first dose, 106 pfu/mL, then 108 pfu/mL every 2 wk starting 3 wk after first dose | GM-CSF | OPTiM | 3 | OS and DRR | No | Unresectable stage III or IV melanoma (first line) | DRR (>6 mo) 16.3% with talimogene laherparepvec vs 2.1% with GM-CSF |
| Encorafenib plus binimetinib43 | 2018 | Encorafenib, 450 mg PO once a day, plus binimetinib, 45 mg PO BID | Vemurafenib | COLUMBUS | 3 | PFS | Yes | Metastatic or unresectable melanoma with BRAF V600 mutation (first line) | Median OS 33.6 mo with combination vs 16.7 mo with vemurafenib |
| Atezolizumab plus cobimetinib and vemurafenib44 | 2020 | Cobimetinib, 60 mg PO once a day (d 1-21), plus vemurafenib, 720 mg PO BID plus IV atezolizumab, 840 mg, d 1 plus 15 d in 28-d cycles | Placebo with cobietinib and vemurafenib | IMspire150 | 3 | OS and PFS | No | Metastatic melanoma with BRAF V600 mutation (first line) | OS data not mature yet, approval based on PFS of 15.1 mo with combination vs 10.6 mo with placebo and cobietinib and vemurafenib |
| Relatlimab and nivolumab18 | 2022 | Relatlimab, 160 mg IV, and nivolumab, 480 mg IV in a fixed dose combination every 4 wk | Nivolumab, 480 mg IV every 4 wk | RELATIVITY-047 | 2/3 | PFS | No | Unresectable stage IIIa or metastatic melanoma (first line) | OS data not mature yet; median PFS 10.1 mo with combination vs 4.6 mo with nivolumab |
Abbreviations: BID, twice daily; BRAF, v-RAF murine sarcoma viral oncogene homologue B1; DRR, durable response rate; FDA, US Food and Drug Administration; GM-CSF, granulocyte-macrophage colony-stimulating factor; Gp100, glycoprotein 100; IV, intravenously; NA, not applicable; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; pfu, plaque-forming unit; PO, orally.
a
The stage of melanoma is per American Joint Committee on Cancer staging system for cancers.