Immune landscape of melanoma: Tumor microenvironment, resistance mechanisms, and predictive biomarkers

Table 1 Ongoing or recently completed clinical trials of emerging combination strategies in melanoma (ClinicalTrials.gov database)

Combination therapy	NCT ID	Phase	Status	Mechanism/intervention
Nivolumab + relatlimab (anti-LAG-3)	NCT03470922	III	Active, not recruiting	Dual checkpoint blockade (PD-1 + LAG-3)
Spartalizumab (anti-PD-1) + LAG525 (anti-LAG-3)	NCT03365791	II	Completed	Dual checkpoint blockade
Cemiplimab (anti-PD-1) + fianlimab (anti-LAG-3)	NCT03005782	I/II	Active, not recruiting	Dual checkpoint blockade
Nivolumab + BMS-986253 (anti-IL-8)	NCT03400332	I/II	Recruiting	Inhibition of pro-tumoral chemokine IL-8
Pembrolizumab + STING agonist (MK-1454)	NCT03010176	I	Recruiting	Activation of innate immune cGAS-STING pathway
Nivolumab + oncolytic virus RP1	NCT03767348	II	Recruiting	Oncolytic virus combined with PD-1 blockade

NCT ID: National clinical trial identifier; LAG-3: Lymphocyte-activation gene 3; PD-1: Programmed death-1; IL-8: Interleukin-8; STING: Stimulator of interferon genes; cGAS: Cyclic GMP-AMP synthase.

Table 2 Major published clinical trials evaluating combination therapies in advanced melanoma

Combination therapy	Study	Phase	Population	Key outcomes	Ref.
Nivolumab + ipilimumab	CheckMate 067	III	Untreated advanced melanoma	ORR: Approximately 57%; 5-year OS: Approximately 52%	[64,163]
Relatlimab + nivolumab	RELATIVITY-047	II/III	Untreated advanced/metastatic melanoma	PFS: 10.1 months vs 4.6 months (vs nivolumab alone)	[164]
Pembrolizumab + T-VEC (oncolytic virus)	MASTERKEY-265	I-b/III	Unresectable advanced melanoma	ORR: Approximately 62% in phase I-b; phase III did not confirm benefit	[133,165]
Dabrafenib + trametinib + pembrolizumab	KEYNOTE-022	II	BRAF V600-mutant advanced melanoma	Median PFS: 16.9 months vs 10.7 months	[166]
Atezolizumab + vemurafenib + cobimetinib	IMspire150	III	BRAF V600-mutant advanced melanoma	Median PFS: 15.1 months vs 10.6 months	[167]

T-VEC: Talimogene laherparepvec; BRAF: B-Raf proto-oncogene; ORR: Objective response rate; OS: Overall survival; PFS: Progression-free survival.