Cutaneous melanoma: new advances in treatment

Foletto, Michele Ceolin; Haas, Sandra Elisa

doi:10.1590/abd1806-4841.20142540

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Review • An. bras. dermatol. 89 (2) • Mar-Apr 2014 • https://doi.org/10.1590/abd1806-4841.20142540 copy

Cutaneous melanoma: new advances in treatment^* * Work performed at the School of Pharmacy, Universidade Federal do Pampa (UNIPAMPA) - Uruguaiana (RS), Brazil.

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Cutaneous melanoma is a challenge to treat. Over the last 30 years, no drug or combination of drugs demonstrated significant impact to improve patient survival. From 1995 to 2000, the use of cytokines such as interferon and interleukin become treatment options. In 2011, new drugs were approved by the U.S. Food and Drug Administration, including peginterferon alfa-2b for patients with stage III disease, vemurafenib for patients with metastatic melanoma with the BRAF V600E mutation, and ipilimumab, a monoclonal antibody directed to the CTLA-4 T lymphocyte receptor, to combat metastatic melanoma in patients who do not have the BRAF V600E mutation. Both ipilimumab and vemurafenib showed results in terms of overall survival. Other trials with inhibitors of other genes, such as the KIT gene and MEK, are underway in the search for new discoveries. The discovery of new treatments for advanced or metastatic disease aims to relieve symptoms and improve patient quality of life.

Antibodies, monoclonal; Antibody specificity; Interferons; Melanoma; Therapeutics

Therapy	Disease Stage	Goal	Trial	Results	Reference
IL-2 (1998)	IV or recurrent melanoma	Determine the short- and long-term efficacy and toxicity of high-dose IL-2	n = 70 → 600,000 or 720,000 IU/kg (IV). Cycle repeated after 6-9 days	n = 43 / PFS 8.9 months	(19)
				n = 12 / PFS 12 months
				The results are more lasting for the patients with good pulmonary, heart and kidney function
	IV or recurrent melanoma, without previous treatment	Determine the antitumor efficacy of IL-2	n = 24 → 30 mg/kg (IV) for 8 weeks	n = 9 / PFS 8 weeks	(21)
				n = 2 / PFS 16 weeks
				Response rate is lower and efficacy in terms of response rate is comparable to conventional therapies such as DTIC.
IFNa-2b (1995) ESTG-1684	IIB, IIC or III (with or without lymph node involvement) or recurrent melanoma	Determine the anti-tumor efficacy of high-dose IFNa-2b	n = 143 → 20 million IU/m2, 5 days a week for 4 weeks, followed by 10 million IU/m2, three times a week for 48 weeks	The analysis of 7 years of study showed that on average 1-1.7 years to PFS and 2.8-3.8 years to OS	(24)
IFNa-2b (1995) ESTG-1684		Determine the anti-tumor efficacy of high-dose IFNa-2b		First agent to show significant OS benefit (more pronounced benefit in patients with lymph node involvement).	(24)
IFN-PEGa-2b (2011) EORTC 18991	IIB, IIC or III (with or without lymph node involvement) or recurrent melanoma	Determine the anti-tumor efficacy of higher doses of PEG-IFNa-2b	n = 1256 / n = 627 → 6 Hg/kg weekly for 8 weeks, followed by 3 Hg/kg weekly for 5 years	PEG-IFNa-2b → the risk of recurrence and death in 7% of patients at 4 years and 13% for patients with nodal disease.	(27)
		Determine the anti-tumor efficacy of low-dose PEG- IFNa-2b	n = 1388 → half received 10 million IU/m2, 5 days a week for 4 weeks, followed by 5 million IU/m2, three times a week for 2 years	During 2 years of analysis, the results of PFS were better with the use of high medication doses.	(28)
Biochemother apy	III, IV or recurrent melanoma	Determine whether the combination of chemotherapy and immunotherapy might have better efficacy	Patients were randomized to receive cisplatin, vin- blastine, and DTIC (CVD) alone or simultaneously with IL-2 and IFNa-2b	Those who received IL-2 and IFN-2b showed the slightly higher response rate and PFS than the group that received CVD alone.	(30)
Biochemother apy	III, IV or recurrent melanoma			There was no increase in OS or durable responses.	(30)
Ipilimumab (2011)	III, IV or recurrent melanoma	Evaluate the median OS of patients who received an ipilimumab-containing regimen as compared with a group that received the gp100 vaccine alone	n = 403 → ipilimumab 3 mg/kg + gp100 peptide vaccine	Median OS in ipilimumab + gp100 group = 10 months	(33)
			n = 137 → ipilimumab 3 mg/kg	Median OS with ipilimumab alone = 10.1 months
			n = 136 → gp100 vaccine peptide	Median OS with gp100 alone = 6.4 months
		Evaluate the average OS with different doses of ipilimumab	n = 73 → 10 mg/kg	OS was 11% at 10 mg/kg, 4.2%	(34)
			n = 72 → 3 mg/kg
			n = 72 → 0.3 mg/kg
			every 3 weeks for 4 months by IV infusion	at 3 mg/kg and 0% at 0.3 mg/kg.
				Ipilimumab proved more effective at a dose of 10 mg/kg.
Vemurafenib (2011)	III, IV or recurrent melanoma, without	Evaluate average OS with vemurafenib	n = 337, 960 mg vemurafenib orally twice daily	After 6 months, OS was 84% for vemurafenib and 64% for DTIC	(36)
Vemurafenib (2011)	treatment previous	Evaluate average OS with vemurafenib	n = 338 → 1,000 mg/nv* of DTIC, IV, once every 3 weeks	Vemurafenib showed a 63% relative reduction in the risk of death (OS) and 74% in the risk of progression (PFS) as compared with DTIC	(36)
Dabrafenib	III or IV, without previous treatment	Evaluate the antitumor efficacy of dabrafenib, another BRAF inhibitor	Patients were randomized to receive dabrafenib (n = 187) or DTIC (n = 63)	Average PFS was 5.1 months with dabrafenib versus 2.7 months with DTIC.	(39)
Dabrafenib	III or IV, without previous treatment			70% → in risk of progression or death compared with DTIC	(39)
Trametinib	III or IV	Cause a stronger response against the cancer and prevent resistance to treatment, as patients who use vemurafe-nib eventually develop resistance.	n = 125 → varying doses of dabrafenib / trameti-nib	Average PFS was 10.8 months in this group, and 15 of 24 patients (63%) achieved either CR or PR. This dosage (150/2 mg) is being assessed in a phase III randomized trial	(40)
Trametinib	III or IV		Most PFS was achieved in 24 patients receiving 150 mg dabrafenib twice daily and 2 mg trametinib once daily		(40)
Imatinib	III or IV	Ascertain the effectiveness of imatinib for melanoma with Kit gene mutation	n = 28 → 400 mg of imatinib twice daily	The durable overall response rate was 16%, with a median time to progression of 12 weeks, and mean OS 46.3 weeks.	(41)
			n = 43 → 400 mg daily until disease progression or unacceptable toxicity to a mean of 12 months	41.9% (n=18) CR	(42)
				30.2% (n=13) SD
				23.3% (n=10) PR

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E-mail: revista@sbd.org.br

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[1] MAILING ADDRESS: Sandra Elisa Haas, Universidade Federal do Pampa - UNIPAMPA Br 472, Km 592, CP 118, 97500-970 - Uruguaiana - RS, Brazil. E-mail: sandra.haas@gmail.com

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Cutaneous melanoma: new advances in treatment* * Work performed at the School of Pharmacy, Universidade Federal do Pampa (UNIPAMPA) - Uruguaiana (RS), Brazil.

Cutaneous melanoma: new advances in treatment^* * Work performed at the School of Pharmacy, Universidade Federal do Pampa (UNIPAMPA) - Uruguaiana (RS), Brazil.