The New Therapeutic Paradigm for Personalized Therapy of Melanoma

Sanjiv S. Agarwala, MD

Melanoma

The incidence of melanoma in the United States is increasing at an alarming rate (Figure 1).¹ In men, melanoma is increasing more rapidly than in any other cancer; in women, it is increasing more rapidly than any other cancer except lung cancer.² In 2012, an estimated 76,250 new cases of melanoma (44,250 in men and 32,000 in women) are expected in the United States, and 9180 people are expected to die of this cancer.³

More than 80% of melanoma patients present with localized disease, 10% to 13% with regional disease, and 2% to 5% with distant metastases.² The prognosis is excellent for patients who present with localized disease and primary tumors ?1.0 mm in thickness, with 5-year survival achieved in >90% of patients. However, survival rates range from 50% to 90% when the localized melanomas are >1.0 mm in thickness. When regional nodes are involved, survival rates are roughly halved. However, within stage III, 5-year survival rates range from 20% to 70%, depending primarily on the nodal tumor burden. Long-term survival in patients with stage IV disease is <10%.²

Systemic therapy is the primary treatment option for most patients with stage IV disease.2 For the past 30 years, there were no major advances in treatment for metastatic melanoma, and until recently people with the disease had few options.² However, the therapeutic landscape for metastatic melanoma is rapidly changing with the recent development of novel agents that have demonstrated better efficacy than traditional chemotherapy² (Figure 2). Importantly, melanomas can now be classified according to the underlying molecular aberrations that drive tumor progression, and these biomarkers are now being used in therapeutic practice.²

Chemotherapy
DTIC (dacarbazine) (Table 1) is the only FDA-approved chemotherapy agent for the treatment of stage IV melanoma. It is administered as an IV infusion.^4-6 Temozolomide is an oral chemotherapy agent that is considered an oral form of DTIC, but it is not approved by the FDA for the treatment of melanoma.^4,6

A number of combination therapies, including the Dartmouth regimen (DTIC, cisplatin, carmustine, and tamoxifen), have been used for the treatment of metastatic melanoma. However, a phase 3 study of 240 patients with stage IV melanoma compared the 4-drug Dartmouth regimen with single-agent DTIC and found no difference in survival time and only a small, statistically nonsignificant increase in tumor response for patients treated with the Dartmouth regimen (Figure 3).⁷

Immunotherapy
Interferon alpha-2b is the FDA-approved standard treatment for patients with metastatic melanoma, but interferon therapy is associated with significant adverse reactions in most patients. Interleukin-2 (IL-2) has been used for the treatment of melanoma with modest success for several decades, but many acute toxicities are associated with interleukin therapy, and extremely close monitoring is essential for safe administration.^8-10

Ipilimumab, a monoclonal antibody that binds to CTLA-4, was approved by the FDA on March 25, 2011, making it the first drug in 13 years to be approved for the treatment of melanoma. Approval was based on a randomized phase 3 trial of 676 patients with unresectable metastatic disease that progressed during systemic therapy.¹¹ Patients received ipilimumab 3 mg/kg plus a glycoprotein 100 peptide vaccine (gp100), ipi­limumab alone, or gp100 alone in a 3:1:1 ratio. Overall survival (OS) was significantly longer in patients receiving the combination (10.0 months; hazard ratio [HR] = 0.68 compared with gp100 alone; P<.001) or ipilimumab alone (10.1 months; HR = 0.66 compared with gp100 alone; P=.003) compared with those receiving gp100 alone (6.4 months). The best objective response rates were 5.7% for ipilimumab plus gp100, 10.9% for ipilimumab alone, and 1.5% for gp100 alone. Ipilimumab stimulates T cells and is associated with a substantial risk of immune-related reactions. Grade 3 or 4 immune-related adverse events occurred in 10% to 15% of patients treated with ipilimumab and in 3% of those treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events.¹¹

A second phase 3 study was conducted in 502 patients with previously untreated metastatic melanoma.12 OS was significantly longer in the group receiving ipi­limumab plus DTIC than in the group receiving DTIC plus placebo (11.2 months vs 9.1 months), and survival rates were higher for the group receiving ipilimumab-DTIC at 1-, 2-, and 3-year time points (Table 2). Grade 3 or 4 adverse events occurred in 56.3% of patients treated with ipilimumab plus DTIC versus 27.5% of those treated with DTIC and placebo (P<.001).

Ipilimumab is the first immunotherapy to show an OS advantage for patients with metastatic melanoma. An OS benefit was seen as a single agent compared with a vaccine and in combination with DTIC compared with DTIC alone, and the drug is effective for both frontline and second-line therapy. As yet, however, there is no confirmed biomarker to predict response to ipilimumab.

Biochemotherapy
Biochemotherapy is the combination of chemotherapy and biological agents. Recent studies have shown that outcomes in patients treated with biochemotherapy are no better than outcomes in patients treated with combination chemotherapy. In a phase 3 randomized study, biochemotherapy (cisplatin, vinblastine, DTIC, IL-2, and interferon alpha-2b) produced a slightly higher response rate and progression-free survival (PFS) than cisplatin, vinblastine, and dacarbazine (CVD) alone, but it was not associated with either improved quality of response or OS, and biochemotherapy was substantially more toxic than CVD.¹³ Other studies that attempted to decrease the toxicity of biochemotherapy by administering subcutaneous outpatient IL-2 did not show a substantial benefit of biochemo­therapy versus chemo­therapy alone.^14-16 A meta-analysis also showed that although biochemotherapy improved overall response rates, there was no survival benefit for patients with metastatic melanoma.¹⁷

Targeted Therapy
Melanoma is not 1 disease. Evidence increasingly shows that melanoma is not 1 malignant disorder but rather a family of distinct molecular diseases.¹ Exposure to the sun is generally accepted as a major causative factor of melanoma; however, the role of exposure to ultraviolet light is complex. For example, in light-skinned people, the group that is predominantly affected by melanoma, tumors are most common on areas that are intermittently exposed to the sun, such as the trunk, arms, and legs, rather than on areas that are chronically exposed to the sun, such as the face. A small proportion of melanomas arise without obvious exposure to ultraviolet light, because they affect sites that are relatively or absolutely protected, such as the palms and soles (acral melanoma), and mucosal membranes.¹⁸

Curtin and colleagues examined 102 melanomas from 4 groups in which the degree of exposure to ultraviolet light differed: 18 melanomas from skin with chronic sun-induced damage and 18 melanomas from skin without such damage; 28 melanomas from palms, soles, and subungual (acral) sites; and 18 mucosal melanomas, and genetic analysis showed significant differences in the distribution of genetic mutations in BRAF, NRAS, and KIT among the 4 groups (Figure 4).¹⁸

Vemurafenib, a selective inhibitor of the activated BRAF V600E gene, a gene found in 70% of malignant melanomas,¹⁹ was approved by the FDA in August 2011 for both first- and second-line treatment of unresectable or metastatic melanoma with a V600E mutation in the BRAF gene, as detected by an FDA-approved test. The cobas 4800 BRAF V600 Mutation Test, a companion diagnostic test to determine the tumor mutational status, received approval along with the agent.

The FDA approval of vemurafenib in previously untreated patients was based on an international, randomized, open-label trial in 675 subjects.²⁰ Patients were randomized to receive either vemurafenib orally twice daily or DTIC IV on day 1 every 3 weeks. Treatment continued until disease progression, unacceptable toxicity, and/or consent withdrawal.

The major efficacy outcome measures were OS and investigator-assessed PFS. The overall response rate was 48% in the vemurafenib arm versus 5% in the DTIC arm. There were 2 complete responses and 104 partial responses in the vemurafenib arm, and all 12 responses in the DTIC arm were partial responses. The median PFS was 5.3 months in the vemurafenib arm versus 1.6 months in the DTIC arm. Skin complications were frequently associated with the agent: 18% of vemurafenib-treated patients developed cutaneous squamous cell carcinoma or keratoacanthoma that required simple excision, while 12% experienced grade 2 or 3 photosensitivity skin reactions. Arthralgia was the most common (21%) noncutaneous side effect.

The FDA approval of vemurafenib in patients who received prior systemic therapy was based on a single-arm, multicenter phase 2 study in 132 patients.21 The confirmed best overall response rate was 53%; 6% with a complete response and 47% with a partial response. The median time to response was 1.4 months, with 75% of responses occurring by month 1.6 of treatment. The median duration of response was 6.5 months. Median survival was 15.9 months. Secondary skin lesions were detected in 26% of patients.

Imatinib, a tyrosine kinase inhibitor that is FDA approved as therapy for gastrointestinal stromal tumors and chronic myeloid leukemia, is under investigation as a treatment for patients with metastatic melanomas with c-KIT aberrations.^22-24 In a phase 2 study of 43 patients with a median follow-up time of 12 months, the median PFS was 3.5 months, and the 6-month PFS rate was 36.6%. Ten patients (23.3%) achieved partial responses, and 13 patients (30.2%) achieved stable disease. The 1-year OS rate was 51.0%.²⁴

The New Therapeutic Paradigm for Personalized Therapy of Melanoma
The most important first step in treating a patient with metastatic melanoma today is to test the tumor, at least for BRAF status, and then choose a therapy based on BRAF status (Figure 5). If the tumor is BRAF positive (ie, mutant), vemurafenib is probably the best choice. If it is BRAF positive, and vemurafenib therapy has failed, then ipilimumab or IL-2 can be tried. If the tumor is BRAF negative (ie, wild-type), choices include ipilimumab, IL-2, or a clinical trial. It is important to always consider clinical trials.

Because not every patient is a candidate for immunotherapy, and not all patients are BRAF positive, chemotherapy will still play a role in the new therapeutic paradigm, but probably as a single agent in second- or third-line therapy.

Based on these new considerations, a good first-line choice for treating Case 1 would be vemurafenib, with ipilimumab as second-line treatment. A good first-line choice for treating Case 2 would be ipilimumab, with high-dose IL-2 as second-line treatment.

According to the National Comprehensive Cancer Network guidelines, “Although approval of ipilimumab and vemurafenib has significantly altered the initial management of patients with stage IV melanoma, each agent has unique limitations. For ipilimumab, there is the potential for serious autoimmune toxicity, clinical responses may take months to become apparent, and the overall response rate is less than 20%. However, when responses are seen, they can be quite durable. Vemurafenib, on the other hand, is associated with a 40% to 50% response rate in patients with a V600 mutated BRAF gene, and responses may be seen in days to weeks after starting the drug. Unfortunately, the median duration of response is only 5 to 6 months. The success of these 2 agents has prompted a new wave of questions regarding their use in the adjuvant setting, augmenting response by combining them with cytotoxic chemotherapy, and defining mechanisms of drug resistance. The pace of change underscores the importance of participating in a clinical trial whenever possible.â€�²

References

1. Romano E, Schwartz GK, Chapman PB, et al. Treatment implications of the emerging molecular classification system for melanoma. Lancet Oncol. 2011;12:913-922.
2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Melanoma. Version 2.2013. www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf. Accessed November 16, 2012.
3. American Cancer Society. Cancer Facts & Figures 2012. Atlanta, GA: American Cancer Society; 2012. www.cancer.org/acs/groups/content/@epi demiologysurveilance/documents/document/acspc-031941.pdf. Accessed November 16, 2012.
4. Melanoma Research Foundation. Melanoma Treatment. www.me lanoma.org/learn-more/melanoma-101/melanoma-treatment. Accessed November 9, 2012.
5. Serrone L, Zeuli M, Sega FM, et al. Dacarbazine-based chemotherapy for metastatic melanoma: thirty-year experience overview. J Exp Clin
   Cancer Res. 2000;19:21-34.
6. Middleton MR, Grob JJ, Aaronson N, et al. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol. 2000;18:158-166.
7. Chapman PB, Einhorn LH, Meyers ML, et al. Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol. 1999;17:2745-2751.
8. Rosenberg SA, Yang JC, Topalian SL, et al. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA. 1994;271:907-913.
9. Atkins MB, Lotze MT, Dutcher JP, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999;17:2105-2116.
10. Atkins MB, Kunkel L, Sznol M, et al. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am. 2000;6(suppl 1):S11-S14.
11. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363: 711-723.
12. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364: 2517-2526.
13. Atkins M, Hsu J, Lee S, et al. Phase III trial comparing concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin-2, and interferon alfa-2b with cisplatin, vinblastine, and dacarbazine alone in patients with metastatic malignant melanoma (E3695): a trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol. 2008;26:5748-5754.
14. Bajetta E, Del Vecchio M, Nova P, et al. Multicenter phase III randomized trial of polychemotherapy (CVD regimen) versus the same chemotherapy (CT) plus subcutaneous interleukin-2 and interferon alpha2b in metastatic melanoma. Ann Oncol. 2006;17:571-577.
15. Keilholz U, Punt CJ, Gore M, et al. Dacarbazine, cisplatin, and interferon-alfa-2b with or without interleukin-2 in metastatic melanoma: a randomized phase III trial (18951) of the European Organisation for Research and Treatment of Cancer Melanoma Group. J Clin Oncol. 2005;23:6747-6755.
16. Ridolfi R, Chiarion-Sileni V, Guida M, et al. Cisplatin, dacarbazine with or without subcutaneous interleukin-2, and interferon alpha-2b in advanced melanoma outpatients: results from an Italian multicenter phase III randomized clinical trial. J Clin Oncol. 2002;20:1600-1607.
17. Ives NJ, Stowe RL, Lorigan P, et al. Chemotherapy compared with biochemotherapy for the treatment of metastatic melanoma: a meta-analysis of 18 trials involving 2,621 patients. J Clin Oncol. 2007;25:5426-5434.
18. Curtin JA, Busam K, Pinkel D, et al. Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol. 2006;24:4340-4346.
19. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363:809-819.
20. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507-2516.
21. Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012;366:707-714.
22. Carvajal RD, Antonescu CR, Wolchok JD, et al. KIT as a therapeutic target in metastatic melanoma. JAMA. 2011;305:2327-2334.
23. Guo J, Si L, Kong Y, et al. Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. J Clin Oncol. 2011;29:2904-2909.
24. Hodi FS, Friedlander P, Corless CL, et al. Major response to imatinib mesylate in KIT-mutated melanoma. J Clin Oncol. 2008;26:2046-2051.

Related Articles