US Pharm. 2012;37(11)(Oncology suppl):7-11.

ABSTRACT: Skin cancer is the most common cancer in the United States, causing about 2% of all cancer deaths. Basal cell carcinoma (BCC) is the most common type of skin cancer, but it is less life threatening than melanoma, which is the most deadly form. Few effective treatment options were available for patients with advanced metastatic melanoma for several decades. Over a 12-month period, the FDA unprecedentedly approved several new drugs for the treatment of skin cancer—vismodegib for advanced BCC and peginterferon alfa-2b, vemurafenib, and ipilimumab for metastatic melanoma. These novel immune and target therapeutic agents have changed the standard of care for skin cancer.

Skin cancer is the most common cancer in the United States, with over 2 million new diagnoses annually. This is more than the combined incidences of all other common human cancers, including breast, prostate, lung, and colon cancers. It is estimated that one in five Americans will develop skin cancer at some point in his or her lifetime.1

The most common malignant skin cancers are basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma (FIGURE 1).2 BCC is the most common type, accounting for 90% of all skin cancers. Although BCC is rarely life threatening, it can be highly disfiguring without treatment. As the second most common form of skin cancer, SCC is more malignant compared to BCC. It is reported that approximately 65% of SCCs were developed from actinic keratoses, the most common precancer. Compared to BCC and SCC, melanoma is less common, but it is the most deadly skin cancer with a growing mortality rate second only to that of lung cancer. The incidence of melanoma is escalating in the U.S., and one in every 50 Caucasians develops melanoma in his or her lifetime. Every hour, a person dies of melanoma in the U.S.3,4


Although there are many causes and risk factors for skin cancer, ultraviolet (UV) radiation from the sun and indoor tanning is the main cause.5 New evidence indicates that UV radiation is also immunosuppressive, which can significantly increase the risk of cancer development. Aging, family history, environmental factors, and genetic mutations can also significantly increase the risk of skin cancer. Skin cancer can also develop when malignant T lymphocytes affect the skin, which causes cutaneous T-cell lymphoma (CTCL), a slow-growing skin cancer that often takes many years to develop.6

Novel Therapeutic Agents Approved for Skin Cancer

As with other cancers, surgery, radiation therapy, and chemotherapy are three types of standard treatment for AK, melanoma, and nonmelanoma skin cancers (BCC, SCC). In addition, photodynamic therapy (PDT), which uses a combination of laser and photosensitizing chemicals such as porfimer sodium (Photofrin) to treat CTCL, has been approved by the FDA since 1988. Since the laser used to activate most photo-sensitizers cannot pass through thick tissues (>1 cm), PDT is usually used to treat local tumors on the skin or just under the skin, and it is not commonly used for large or metastatic tumors.7

In most cases, skin cancer is preventable by avoiding certain risk factors (e.g., sun exposure, ionizing radiation, arsenic ingestion, tanning beds) and curable if it is discovered and removed at an early stage by surgery, radiation therapy, PDT, or adjuvant chemotherapy. Patient education is essential in preventing the occurrence and recurrence of skin cancers. The regular use of sun protective clothing and sunscreens (SPF ≥30) is strongly recommended by the American Academy of Dermatology.2

Melanoma is one of the most deadly and difficult-to-treat cancers. The median life span for patients with advanced-stage melanoma is less than 1 year.8 The treatment options with overall survival benefit for metastatic melanoma were almost none until the recent approvals of new agents for immunotherapy and target therapy. Only 5% to 10% of patients with metastatic melanoma respond to conventional chemotherapy agents, such as dacarbazine (DTIC) and temozolomide (Temodar). Although high-dose interleukin-2 and peginterferon alfa-2b can increase response rates, they are commonly associated with severe toxicities.

Unfortunately, all of these conventional treatments have had minimal impact on overall survival of patients with metastatic melanoma until recent progress was made in immunotherapy and target therapy.8,9 The concept of immunotherapy is to modulate the key checkpoints of regulatory mechanisms for the immune system and to boost it to recognize and attack tumor cells. The strategy of target therapy is to use molecular targeting agents to block and interfere with the process of tumor growth and progression. The targets can be any molecules that are essential for tumor growth and progression, such as tumor growth factors, angiogenic stimulators, specific receptors, enzymes, and signal transduction pathways.10-12

During the past decade, immunological and target therapies for cancer treatment have gained tremendous progress against most cancers. However, there were no significant advances in clinical research for the treatment of skin cancer, particularly for advanced melanoma, until recently.10 Over a 12-month period, the FDA unprecedentedly approved vismodegib (Erivedge) for the treatment of advanced BCC and peginterferon alfa-2b (Sylatron), vemurafenib (Zelboraf), and ipilimumab (Yervoy) for malignant melanoma (TABLE 1). Many of these breakthrough therapeutic agents are the first in their class. (Note that Sylatron is a pegylated dosage form of an older drug and will not be discussed.) This rapid and unprecedented approval of several novel agents for skin cancer is likely to post a challenge to clinicians to educate themselves and their patients about the efficacy, safety, and proper use of these agents.11-13


Inhibiting Hedgehog Signaling in Advanced Basal Cell Carcinoma

Originally identified during a large-scale screening of genes required for patterning of the early embryo in Drosophila flies, Hedgehog signaling is one of the key cellular signal transduction pathways that is crucial for the early development of most animals. Evidence indicates that Hedgehog signaling plays an essential regulator role in cell growth, cell differentiation, and organ formation during human embryonic development. It regulates the interaction between epithelial and mesenchymal interactions in many tissues during embryogenesis.14

In humans, there are at least three secretive Hedgehog proteins: Desert hedgehog (Dhh), Indian Hedgehog (Ihh), and Sonic hedgehog (Shh). These extracellular hedgehog proteins bind to transmembrane PTCH receptors (Patched1 and Patched2) to relieve their inhibition on another adjacent transmembrane receptor, SMO (Smoothened). When SMO is activated, it initiates the Hedgehog signaling cascade to active Gli transcription factors (finger transcription factors mediating the Hedgehog downstream signaling pathways) to directly and indirectly activate other signal transduction pathways to promote cellular growth, including angiogenesis.14

Hedgehog signaling is generally inactive in most normal adult tissue, but it remains active in some organs to regulate the proliferation and maintenance of stem cells. Abnormal constitutive activation of the Hedgehog pathway has been defined in the development of skin, lung, breast, and prostate cancers. Constitutively activating mutation in components of Hedgehog signaling has been reported in over 90% of BCC. Most basal cell tumors have loss of function mutation of PTCH receptors, or, to a lesser extent, constitutively activating mutation of SMO receptors. Clinical evidence also indicates that the Hedgehog signaling pathway is involved in the pathogenesis of skin cancers other than BCC, such as SCC, melanoma, and Merkel cell carcinoma. Thus, specifically blocking the Hedgehog pathway is a promising drug target to treat a wide range of malignancies, especially BCC.14

Vismodegib (Erivedge): In January 2012, the FDA approved vismodegib, the first drug targeting Hedgehog signaling, for the treatment of advanced BCC or for locally advanced BCC that has recurred following surgery or when patients are not candidates for surgery or radiation. Vismodegib blocks the activation of Hedgehog signaling by competitively inhibiting the SMO receptors. The drug is also undergoing clinical trials for a wide range of other malignancies, such as metastatic colorectal cancer, small cell lung cancer, advanced stomach cancer, and pancreatic cancer.15

Vismodegib was approved by the FDA based on the objective response rates (ORR)—not overall survival—from an international, single-arm, multicenter, open-label, two-cohort trial conducted in 104 patients with either metastatic BCC (mBCC) (n = 33) or locally advanced BCC (laBCC) (n = 71). The confirmed ORR for the mBCC arm was 30.3% (95% CI, 15.6-48.2), and the confirmed ORR for the laBCC arm was 42.9% (95% CI, 30.5-56.0). The median response duration for both arms was 7.6 months.16

Target Therapies for Melanoma

Missed early diagnosis and staging, rapid progress and wild metastasis, considerable heterogeneity, and frequent drug resistance are some of the reasons that melanoma, especially advanced metastatic melanoma, is one of the most difficult malignancies to treat. Most of the standard chemotherapy, radiotherapy, and even biological therapies, such as interleukin and interferon, have failed to significantly improve the overall survival for patients with advanced melanoma. The new strategy is to target the specific mutations at the molecular level to slow or block the process of tumor growth and metastasis.17 Since the genetic mutations in melanoma tumors are heterogeneous, it is important to separate the patient population based on their genetic profiles and to individualize the treatment. Thus, pharmacogenomics plays an important role in target therapy to define genetic subgroups that will respond to the specific treatment.18

Vemurafenib (Zelboraf): In August 2011, the FDA approved vemurafenib, a selective low-molecular-weight oral kinase inhibitor of the mutated BRAFV600E serine-threonine kinase, which is found in 60% to 70% of malignant melanomas and in a significant percentage of other cancers, such as colorectal cancer. Vemurafenib is indicated for the treatment of unresectable or metastatic melanoma with the BRAFV600E mutation, as detected by an FDA-approved test, such as the Cobas 4800 BRAF V600 Mutation Test. It is not recommended for use in patients with wild-type BRAF melanoma.19

BRAF (B-RAF) is a member of the RAF kinase gene family (BRAF, ARAF1, and RAF1), which is one of the key downstream effectors of active KRAS in the MAP kinase pathway activated by mutations or a tyrosine kinase receptor ligand, such as epithelial growth factor (EGF). RAF activates MEK kinase (MAP kinase extracellular signal transduction kinase), which activates its downstream effector ERK (extracellular signal-regulated kinase) (FIGURE 2). The RAS-RAF-MEK-ERK signal transduction cascade associated with receptor tyrosine kinase plays an important role in the induction, maintenance, and progression of many cancers, including melanoma.20,21


Clinical evidence has documented that about 70% of melanoma cases have BRAF mutations.21 In addition, the BRAFV600E mutation (a mutation at position 600 of the BRAF gene, which replaces valine by glutamic acid) is the most common BRAF mutation, accounting for more than 90% of these mutations. The BRAFV600E mutation results in constitutively activated BRAF proteins in the absence of growth factors, which activates the cascade of the RAS-RAF-MEK-ERK signaling pathway and significantly contributes to the growth and progress of melanoma tumors.21

The FDA approval of vemurafenib was based on the clinical evidence of significant improvement in overall survival (OS) and progression-free survival (PFS) in treatment-naïve, BRAFV600E mutation–positive, unresectable or metastatic melanoma in a randomized, open-label phase III clinical trial (n = 675). At 6 months, 36% of patients in the control arm with the traditional standard treatment of dacarbazine died, while only 16% of patients in the vemurafenib arm died. The hazard ratio of OS is 0.44 (95% CI, 0.33-0.59). Furthermore, vemurafenib also significantly improved PFS with a hazard ratio of 0.26 (95% CI, 0.20-0.33). The confirmed, investigator-assessed best overall response rate (ORR) was also significantly improved with 48.4% (95% CI, 41.6%-55.2%) in the vemurafenib arm compared to 5.5% (95% CI, 2.8%-9.3%) in the dacarbazine arm.22

Novel Immunologic Therapies for Melanoma

The concept of immunologic therapy is to treat malignant tumors using the body’s own immune-defensive system through strengthening or training the host immune system to reject and destroy the abnormal tumor growth. It was discovered that the antigen CTLA-4 (cytotoxic T-lymphocyte-associated antigen 4) found on T cells has a negative regulatory effect on T-cell activation, which stops the immune system from attacking cancer cells. There was also evidence that blocking antibody to CTLA-4 combined with a cancer vaccine releases the physiological brake on the immune system and elicits a potent immune attack at tumors. This indicated that CTLA-4 can be a potential target for immune therapy of many human tumors.23,24

Furthermore, a small, preliminary clinical study (n = 9) indicated that CTLA-4–based target therapy can boost the clinical benefits of certain cancer vaccines in patients with metastatic melanoma or metastatic ovarian cancer. The widespread death of cancer cells and the number of immune system cells were significantly increased in those patients who received a certain cancer vaccine and MDX-CTLA-4, a locking antibody for CTLA-4.25

Ipilimumab (Yervoy): In March 2011, the FDA approved ipilimumab, the human monoclonal antibody blocking CTLA-4, to treat unresectable or metastatic melanoma. This was the first drug approved for the treatment of advanced metastatic melanoma in 13 years. This approval was based on the clinical evidence that ipilimumab significantly improved OS for patients with unresectable or metastatic melanoma.26

In a randomized, double-blind, double-dummy phase III clinical trial, 676 patients with unresectable or metastatic melanoma previously treated with one or more of the following drugs—aldesleukin, dacarbazine, temozolomide, fotemustine, or carboplatin—were randomized into three arms.27 In Arm 1, 403 patients were treated with ipilimumab in combination with gp100, an investigational peptide vaccine with incomplete Freund’s adjuvant. In Arm 2, 137 patients received ipilimumab monotreatment. In Arm 3, 136 patients received gp100 mono-treatment. Compared to Arm 3, the OS was significantly improved in Arm 1 with a hazard ratio of 0.66 (95% CI, 0.51-0.87) and in Arm 2 with a hazard ratio of 0.68 (95% CI, 0.55-0.85). The median OS was 10 months (95% CI, 8.0-13.8) in Arm 1, 10 months (95% CI, 8.5-11.5) in Arm 2, and 6 months (95% CI, 5.5-8.7) in Arm 3. In addition, the ORR was 5.7% (95% CI, 3.7%-8.4%) in Arm 1; 10.9% (95% CI, 6.3%-17.4%) in Arm 2; and 1.5% (95% CI, 0.2%-5.2%) in Arm 3. Thus, ipilimumab monotherapy significantly improved the OS and ORR for patients with unresectable or metastatic melanoma.27


Conclusion

The recent FDA approvals of new drugs for the treatment of advanced BCC and malignant melanoma represent the latest historic breakthrough of target and immunologic therapies for skin cancer. Vismodegib is the first approved drug in the class of Hedgehog inhibitors, and vemurafenib is the first drug approved by the FDA to target BRAFV600E signaling. Furthermore, ipilimumab is the first drug approved to use a novel approach to elicit immune attack on tumor cells by blocking CTLA-4. (The safety profiles of these agents are reviewed in TABLE 2.) Phase I and phase II clinical trials are ongoing to study the safety and efficacy of an ipilimumab and vemurafenib combination to treat metastatic melanoma with the BRAFV600E mutation.28 These cutting-edge, novel drug targets and therapeutic strategies have not only significantly advanced the treatment for metastatic melanoma, but they have also shed light on the potential application of these drugs in other devastating cancers.

REFERENCES

1. Rogers HW, Weinstock, MA, Harris AR, et al. Incidence estimate of nonmelanoma skin cancer in the United States, 2006. Arch Dermatol. 2010;146:283-287.
2. Melanoma skin cancer overview. American Cancer Society. www.cancer.org/Cancer/SkinCancer-Melanoma/OverviewGuide/index. Accessed February 15, 2012.
3. Watson M, Johnson CJ, Chen VW, et al. Melanoma surveillance in the United States: overview of methods. 2011. J Am Acad Dermatol. 2011;65(5 suppl 1):S6-S16.
4. Criscione, VD, Weinstock MA, Naylor MF, et al. Actinic keratoses natural history and risk of malignant transformation in the Veterans Affairs Tropical Tretinoin Chemoprevention Trial. Cancer. 2009;115:2523-2530.
5. Zhang M, Qureshi AA, Geller AC, et al. Use of tanning beds and incidence of skin cancer. J Clin Oncol. 2012;30:1588-1593.
6. Lansigan F, Foss FM. Current and emerging treatment strategies for cutaneous T-cell lymphoma. Drugs. 2010;70:273-286.
7. Vrouenraets MB, Visser GW, Snow GB, van Dongen GA. Basic principles, applications in oncology and improved selectivity of photodynamic therapy. Anticancer Res. 2003;23:505-522.
8. Amaria RN, Lewis KD, Gonzalez R. Therapeutic options in cutaneous melanoma: latest developments. Ther Adv Med Oncol. 2011;3:245-251.
9. Grob JJ, Jouary T, Dréno B, et al. Adjuvant therapy with pegylated interferon alfa-2b (36 months) versus low-dose interferon alfa-2b (18 months) in melanoma patients without macro-metastatic nodes: EADO trial. J Clin Oncol. 2010;28(suppl):LBA8506.
10. Márquez-Rodas I, Martín Algarra S, Avilés Izquierdo JA, et al. A new era in the treatment of melanoma: from biology to clinical practice. Clin Transl Oncol. 2011;13:787-792.
11. Natarajan N, Telang S, Miller D, Chesney J. Novel immunotherapeutic agents and small molecule antagonists of signalling kinases for the treatment of metastatic melanoma. Drugs. 2011;71:1233-1250.
12. Drugs approved for skin cancer. National Cancer Institute. Updated January 30, 2012. www.cancer.gov/cancertopics/druginfo/skincancer. Accessed February 15, 2012.
13. Magliano MP, Hebrok M. Hedgehog signalling in cancer formation and maintenance. Nat Rev Cancer. 2003;3:903-911.
14. Ng JM, Curran T. The Hedgehog’s tale: developing strategies for targeting cancer. Nat Rev Cancer. 2011;11:493-501.
15. De Smaele E, Ferretti E, Gulino A. Vismodegib, a small-molecule inhibitor of the hedgehog pathway for the treatment of advanced cancers. Curr Opin Investig Drugs. 2010;11:707-718.
16. Erivedge (vismodegib) package insert. South San Francisco, CA: Genentech; January 2012.
17. Eggermont AM, Robert C. New drugs in melanoma: it’s a whole new world. Eur J Cancer. 2011:47:2150-2157.
18. Feng X, Brazill B, Pearson D. Therapeutic application of pharmacogenomics in oncology: selective biomarkers for cancer treatment. US Pharm. 2011;36(11)(Oncology suppl):5-12.
19. Zelboraf (vemurafenib) package insert. South San Francisco, CA: Genentech; August 2011.
20. Haass NK, Smalley KS. Melanoma biomarkers: current status and utility in diagnosis, prognosis, and response to therapy. Mol Diagn Ther. 2009;13:283-296.
21. Dhomen N, Marais R. New insight into BRAF mutations in cancer. Curr Opin Genetics Dev. 2007;17:31-39.
22. 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.
23. Sotomayor EM, Borrello I, Tubb E, et al. In vivo blockade of CTLA-4 enhances the priming of responsive T cells but fails to prevent the induction of tumor antigen-specific tolerance. Proc Natl Acad Sci. 1999;96:11476-11481.
24. Sharma P, Wagner K, Wolchok JD, Allison JP. Novel cancer immunotherapy agents with survival benefit: recent successes and next steps. Nat Rev Cancer. 2011;11:805-812.
25. Hodi FS, Mihm MC, Soiffer RJ, et al. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci. 2003;100:4712-4717.
26. Yervoy (ipilimumab) package insert. Princeton, NJ: Bristol-Myers Squibb; March 2011
27. 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.
28. Ph I/II ipilimumab vemurafenib combo. www.clinicaltrials.gov. Accessed October 9, 2012.

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