Clinical utility of nivolumab in the treatment of advanced melanoma

Figures & data

Figure 1 One-year overall survival for patients with advanced-stage melanoma.

Note: Data from previous studies.^1,3,4

Table 1 Summary of nivolumab trials in advanced melanoma

Study	Phase	Study population	Treatment arms	Number of melanoma patients	ORR	OS and/or PFS	Grade 3+ AEs (related to immunotherapy)
Topalian et al (2012)^Citation44 (long-term follow-up in 2014^Citation5)	I	Advanced melanoma	Nivolumab monotherapy	104	28% (31% on long-term follow-up)	Median PFS: 3.7 months Median OS: 16.8 months	14% (pneumonitis 1%)
Weber et al (2013)^Citation32	I	Advanced melanoma with $10% positivity for gp100, NY-ESO-1, and/or MART-1	Nivolumab ± multipeptide vaccine	Total: 90 Ipi-naïve: 34 Ipi-refract: 56	25% (addition of vaccine did not alter response)	–	14% (pneumonitis 2%)
CheckMate 037 (Weber et al [2015])^Citation31	III	Advanced melanoma, refractory to ipilimumab, and BRAF inhibitor	Nivolumab vs ICC (dacarbazine or paclitaxel + carboplatin)	Total: 405 Nivo: 272 ICC: 133	Nivolumab: 32% ICC: 11%	Median PFS: 4.7 months (nivo) vs 4.2 months (ICC). HR: 0.82	Nivolumab: 9% ICC: 31%
Robert et al (2015)^Citation33	III	Advanced melanoma without BRAF mutation	Nivolumab vs dacarbazine	Total: 418	Nivolumab: 40%	Median PFS: 5.1 vs 2.2 months, favoring nivo (HR: 0.43, P<0.001)	Nivolumab: 12%
				Nivo: 210 Dacarbazine: 208	Dacarbazine: 14% (OR: 4.06, P<0.001)	OS at 1 year: 73% vs 42%, favoring nivo (HR: 0.42, P<0.001)	Dacarbazine: 18%
Wolchok et al (2013)^Citation34	I	Advanced melanoma	Nivo + ipi (concurrent or sequential)	Total: 86 Conc: 53 Sequential: 33	Concurrent: 40% (53% at MTD) Sequential: 20%	–	53% (most common: elevated lipase, transaminitis)
Postow et al (2015)^Citation47	II	Advanced melanoma, previously untreated	Nivo + ipi vs ipi alone	Total: 142	BRAF wild type: combo 61% vs ipi 11% (P<0.001) (data similar for BRAF mutant)	Median PFS (BRAF wild type): NR vs 4.4 months, favoring combo (HR 0.40, P<0.001)	Combo: 54% (most common: colitis, transaminitis)
				Combo: 95 Ipi alone: 47		Median PFS (BRAF mutant): 8.5 vs 2.7 months, favoring combo (HR 0.38)	Ipi alone: 24%
CheckMate 067 (Larkin et al [2015])^Citation48	III	Advanced melanoma, previously untreated	Nivo + ipi vs nivo alone vs ipi alone	Total: 945 Combo: 314 Nivo: 316 Ipi: 315	Combo: 58% Nivo alone: 44% Ipi alone: 19%	Median PFS: 11.5 months (combo) vs 6.9 months (nivo) vs 2.9 months (ipi). HR: 0.42, P<0.001 (for combo vs ipi)	Combo: 55% Nivo alone: 16% Ipi alone: 27%

Abbreviations: AEs, adverse events; conc, concurrent; HR, hazard ratio; ICC, investigator’s choice of chemotherapy; ipi, ipilimumab; MTD, maximum tolerated dose; nivo, nivolumab; NR, not reached; OR, odds ratio; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; refract, refractory.

Table 2 Summary of PD-L1 correlative work across nivolumab trials

Study	Definition of PD-L1 positivity (by IHC)	Antibody clone used	Number of PD-L1-positive patientsa	ORR in PD-L1-positive patients	ORR in PD-L1-negative patients
Topalian et al (2012)^Citation44	≥5% of tumor cells	5H1	25/42 (60%)	9/25 (36%)	0/17 (0%)
Weber et al (2013)^Citation32	≥5% of tumor cells	28-8	12/44 (27%)	8/12 (67%)	6/32 (19%)
	≥1% of tumor cells		23/44 (52%)	9/23 (39%)	5/21 (23%)
CheckMate 037 (Weber et al [2015])^Citation31	≥5% of tumor cells	28-8	77/164 (47%)	NR/77 (43.6%)	NR/87 (20.3%)
Robert et al (2015)^Citation33	≥5% of tumor cells	28-8	74/210 (35%)	NR/74 (52.7%)	NR/136 (33.1%)
Wolchok et al (2013)^Citation34	≥5% of tumor cells	28-8	21/56 (38%)	Concurrent: 6/13 (46%) Sequential: 4/8 (50%)	Concurrent: 9/22 (41%) Sequential: 1/13 (8%)
Postow et al (2015)^Citation47	≥5% of tumor cells	28-8	35/118 (30%)	Combination: 14/24 (58%) Ipi alone: 2/11 (18%)	Combination: 31/56 (55%) Ipi alone: 1/27 (4%)
CheckMate 067 (Larkin et al [2015])^Citation48	≥5% of tumor cells	28-8	223/843 (26%)	Combination: NR/68 (72%) Nivo alone: NR/80 (58%) Ipi alone: NR/75 (21%)	Combination: NR/210 (55%) Nivo alone: NR/208 (41%) Ipi alone: NR/202 (18%)

Note:

a Reflects only patients who were PD-L1 evaluable.

Abbreviations: IHC, immunohistochemistry; ipi, ipilimumab; nivo, nivolumab; NR, not reached; ORR, objective response rate; PD, programmed death.

ChapmanPBEinhornLHMeyersMLPhase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanomaJ Clin Oncol19991792745275110561349

 PubMed Web of Science ®Google Scholar

HodiFSO’DaySJMcDermottDFImproved survival with ipilimumab in patients with metastatic melanomaN Engl J Med2010363871172320525992

 PubMed Web of Science ®Google Scholar

RobertCKaraszewskaBSchachterJImproved overall survival in melanoma with combined dabrafenib and trametinibN Engl J Med20153721303925399551

 PubMed Web of Science ®Google Scholar

TopalianSLHodiFSBrahmerJRSafety, activity, and immune correlates of anti-PD-1 antibody in cancerN Engl J Med2012366262443245422658127

 PubMed Web of Science ®Google Scholar

TopalianSLSznolMMcDermottDFSurvival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumabJ Clin Oncol201432101020103024590637

 PubMed Web of Science ®Google Scholar

WeberJSKudchadkarRRYuBSafety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanomaJ Clin Oncol201331344311431824145345

 PubMed Web of Science ®Google Scholar

WeberJSD’AngeloSPMinorDNivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trialLancet Oncol201516437538425795410

 PubMed Web of Science ®Google Scholar

RobertCLongGVBradyBNivolumab in previously untreated melanoma without BRAF mutationN Engl J Med2015372432033025399552

 PubMed Web of Science ®Google Scholar

WolchokJDKlugerHCallahanMKNivolumab plus ipilimumab in advanced melanomaN Engl J Med2013369212213323724867

 PubMed Web of Science ®Google Scholar

PostowMAChesneyJPavlickACNivolumab and ipilimumab versus ipilimumab in untreated melanomaN Engl J Med20153722006201725891304

 PubMed Web of Science ®Google Scholar

LarkinJChiarion-SileniVGonzalezRCombined nivolumab and ipilimumab or monotherapy in untreated melanomaN Engl J Med20153731233426027431

 PubMed Web of Science ®Google Scholar