Expanded Options for the Treatment of Melanoma

Newly approved drugs represent marked advances in treatment for this rare but deadly disease, and they were deemed to be among the top game changers in oncology in 2011.

Last year proved to be a significant milestone for advances in the treatment of melanoma with the FDA approval of 3 new drugs to treat this rare but deadly form of skin cancer. Bristol-Myers Squibb’s Yervoy (ipilimumab) was approved in March 2011, Merck’s Sylatron (peginterferon alfa-2b) was approved in April 2011, and Roche’s Zelboraf (vemurafenib) was approved in August 2011.^1-3 These newly approved drugs represent marked advances in treatment and were deemed to be among the top game changers in oncology in 2011.⁴

OVERVIEW OF MELANOMA^5-8

Melanoma is a cancer that develops from cells called melanocytes, which make the brown pigment of the skin referred to as melanin. Melanoma can occur on any location on the skin but is most likely to appear on the trunk in males and on the legs in females in addition to common sites such as the face and neck. Because of the melanin, melanoma tumors are likely to be black or brown, although they can also be flesh colored, pink, red, purple, blue, or white. Melanoma is typically caused by intense occasional ultraviolet light exposure.

Although melanoma accounts for less than 5% of all skin cancers, it is among the most deadly. The American Cancer Society Estimates that in 2012 about 76,000 new melanomas will be diagnosed and approximately 9100 people are expected to die of melanoma. The rate of melanoma is highest among those in their 80s; however, melanoma can occur at almost any age and is one of the more common cancers in young adults.

Self-exam is critical to spotting melanoma and it is important to check skin frequently (at least once per month) for any changes in the size, shape, or color of spots on the skin (Table). Any changes or unusual markings should be brought to the attention of a physician. A skin biopsy is typically used to determine if melanoma is present. The prognosis of melanoma can be predicted and staged based on the following: the depth of the tumor, presence or absence of ulceration, and whether or not there are lymph nodes involved at the time of diagnosis. Patients with stage I melanoma have a 5-year survival rate of >90% while those that present with metastatic disease have a 5-year survival rate of <20%.

TREATMENT OF MELANOMA⁸

Treatment of early-stage melanoma consists of surgery to remove the local tumor. Removal of local lymph nodes can also be considered. Because surgery is the mainstay of treatment for melanoma, pharmacotherapy is typically only used for patients with advanced melanoma. Dacarbazine, interleukin-2, carboplatin, and paclitaxel have been used with somewhat limited success for advanced-stage melanoma. Although each of the agents approved for melanoma in 2011 has a unique and specific indication, the FDA approvals of Yervoy (ipilimumab), Sylatron (peginterferon alfa-2b), and Zelboraf (vemurafenib) represent needed additional options in the treatment of melanoma.

Yervoy (ipilimumab)^1,9,10

On March 25, 2011, the FDA announced the approval of the monoclonal antibody ipilimumab for the treatment of unresectable or metastatic melanoma. Ipilimumab was the first agent shown to increase survival time in patients with advanced melanoma.

Iplimumab is a targeted T-cell antibody. It blocks cytoxic T-lymphocyte associated antigen-4 (CTLA-4), an antigen on the surface of T-cells which acts to inhibit T-cell activity. By blocking CTLA-4, T-cells can be activated to attack cancer cells associated with melanoma.

The FDA based its approval of iplimumab on a phase III, randomized, doubleblind active control study in 676 patients with stage III or stage IV melanoma who had previously received treatment. As there is currently no otherSpecialtyPharmacyTimes.com Specialty Pharmacy Times | 08.12 n 29 accepted standard of care for advanced metastatic melanoma, the active control in this study was the experimental cancer vaccine gp100. Gp100 has been shown to induce immune response and increase the efficacy of interleukin-2 and ipilimumab. The study was designed to show if treatment with iplimumab, either alone or in combination with gp100, improved survival compared with treatment with gp100 alone in patients with metastatic melanoma who had undergone previous treatment. The study design consisted of ipilimumab dosed at 3 mg/kg and infused intravenously over 90 minutes every 3 weeks for 4 treatments.

The primary end point was median overall survival, which showed that treatment with iplimuab+gp100 or ipilimumab alone led to a statistically significant increase in median overall survival versus gp100 alone (10 months [95% CI, 8.5-11.5], 10.1 months [95% CI, 8.0- 13.8], and 6.4 months [95% CI, 5.5-8.7], respectively). The effect of iplimumab on survival was independent of age, sex, disease stage, or previous interleukin therapy. The most common reason for discontinuation during the study was disease progression.

Serious immune-related adverse events were associated with iplimumab therapy, prompting the FDA to require a REMS program for drug approval, which Bristol-Myers Squibb has developed and implemented. Iplimumab prescribing information includes a boxed warning stating that potentially life-threatening immune-mediated reactions can affectany organ system but most commonly include enterocolitits, hepatitis, dermatitis, neuropathy, and endocrinopathy. Immune reactions were mostly seen during treatment with iplimumab, but some occurred weeks to months after drug discontinuation. Patients should be assessed for signs and symptoms of immune-mediated reactions and have blood chemistries, including liver function tests and thyroid function tests, at baseline and before each ipilimumab dose. Discontinuation of ipilimumab and initiation of high-dose corticosteroids are recommended for severe immune reactions.

Sylatron (peginterferon alfa-2b)^2,11-13

On March 29, 2011, the FDA approved Sylatron (peginterferon alfa-2b) for the adjuvant treatment of melanoma with microscopic or gross nodal involvement within 84 days of definitive surgical resection, including complete lymphadenectomy. Peginterferon alfa-2b first gained approval in the United States in 2001 under the trade name PegIntron for the treatment of chronic hepatitis C in combination with ribavirin at an adult dose of 1.5 mcg/kg/week. The FDA-approved dosing for Sylatron use in melanoma is 6 mcg/kg/week subcutaneously for 8 doses, followed by 3 mcg/kg/week subcutaneously for up to 5 years.

The FDA approval was granted based on a single open-label, multi-center trial that enrolled 1256 patients who had been adequately surgically resected for their primary cutaneous melanoma and affected regional lymph nodes. These patients were randomized in a 1:1 ratio to receive either treatment with Sylatron or observation for 5 years. Patients were assessed for local and regional recurrence or distant metastases every 3 months for the first 2 years and then every 6 months through the end of the trial. The primary efficacy end point was relapse-free survival (RFS) and was defined as the time to the earliest of local or regional recurrence, distant metastases, or death. There were 696 relapse events in the study. The estimated median RFS was 34.8 months for the Sylatron arm and 25.5 months in the observational arm (HR 0.82, CI, 0.71-0.96, p = 0.011). There were 525 deaths during the course of the study and there were no differences in the overall survival rate detected between the 2 treatment groups.

The most common adverse reactions seen with Sylatron therapy were fatigue, increased alanine transaminase, increased aspartate aminotransferase, pyrexia, headache, anorexia, myalgia, nausea, chills, and injection site reactions. A total of 33% of patients treated with Sylatron in the clinical trial discontinued therapy due to adverse reactions. Peginterferon alfa-2b can cause life-threatening or fatal neuropsychiatric reactions which may include suicide, suicidal and homicidal ideation, depression, and an increased risk of relapse of recovering drug addicts. Sylatron should be permanently discontinued if the patient develops new onset ventricular arrhythmia, cardiovascular decompensation, new or worsening retinopathy or other serious ocular adverse reactions, if there is evidence of severe (grade 3) hepatic injury or hepatic decompensation (Child-Pugh score >6 [class B and C]), or if the patient develops hypothyroidism, hyperthyroidism, or diabetes mellitus that cannot be effectively managed.

Zelboraf (vemurafenib)^3,14,15

On August 17, 2011, the FDA approved vemurafenib for the treatment of patients with unresectable or metastatic melanoma with the BRAF^V600E mutation as detected by an FDA-approved test. Confirmation of BRAF^V600E mutation-positive melanoma using an FDA-approved test is required before treatment with vemurafenib. Vemurafenib is not recommended for use in patients with wildtype BRAF melanoma. Vemurafenib approved dosing is 960 mg orally twice daily administered approximately 12 hours apart, with or without a meal.

One of the studies that the FDA considered consisted of 337 patients who were assigned to vemurafenib 960 mg twice daily and 338 who were assigned to dacarbazine 1000 mg/m2 intravenous every 3 weeks. It was found that overall survival was significantly improved in patients receiving vemurafenib compared with those receiving dacarbazine. The median survival of patients receiving vemurafenib had not yet been reached at the data cutoff point (95% CI, 9.6 months, not reached) and was 7.9 months (95% CI, 7.3-9.6) for those patients receiving dacarbazine. Progression-free survival was also significantly improved in patients treated with vemurafenib compared with dacarbazine. The median progression-free survival was 5.3 months (95% CI, 4.9-6.6) for vemurafenib and 1.6 months (95% CI, 1.6-1.7) in the dacarbazine arm.

The most common adverse reactions (≥30%) in patients treated with vemurafenib were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, and nausea. Cutaneous squamous cell carcinomas (cuSCC), including squamous cell carcinomas of the skin, were detected in approximately 24% of patients treated with vemurafenib. CuSCCs were managed with excision in clinical trials, and patients were able to continue treatment without dose adjustment. A Medication Guide must be dispensed to inform health care professionals and patients of vemurafenib’s potential risks.

References

1. FDA approves new treatment for a type of late-stage skin cancer [Yervoy]. United States Food and Drug Administration, March 25, 2011. Available at http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm1193237.htm. Accessed June 27, 2012.

2. FDA Approves Merck's Sylatron (peginterferon alfa-2b) for Injection, a New Adjuvant Treatment for Melanoma with Microscopic or Gross Nodal Involvement. Drugs.com, April 11, 2011. Available at http://www.drugs.com/newdrugs/fda-approves-merck-s-sylatron-peginterferon-alfa-2b-new-adjuvant-melanoma-microscopic-gross-nodal-2602.html Accessed June 27, 2012.

3. FDA approves Zelboraf and companion diagnostic test for late-stage skin cancer. United States Food and Drug Administration, August 17, 2011. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm268241.htm Accessed June 27, 2012.

4. 2011 Top Game Changers in Oncology. Medscape, November 23, 2011 Available at http://www.medscape.com/viewarticle/754136 Accessed June 27, 2012.

5. Melanoma Skin Cancer. American Cancer Society, January 11, 2012. Available at http://www.cancer.org/acs/groups/cid/documents/webcontent/003120-pdf.pdf Accessed July 2, 2012.

6. Melanoma. Skin Cancer Foundation. Available at http://www.skincancer.org/skin-cancer-information/melanoma Accessed July 2, 2012.

7. Moles: Signs and Symptoms. American Academy of Dermatology. Available at http://www.aad.org/skin-conditions/dermatology-a-to-z/moles/signs-symptoms. Accessed July 2, 2012.

8. Malignant Melanoma. Medscape Reference, April 12, 2012. Available at http://emedicine.medscape.com/article/280245-overview#showall Accessed July 2, 2012.

9. Hoodi SF et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010; 363:876-878. Available at http://www.nejm.org/doi/full/10.1056/NEJMoa1003466. Accessed July 2, 2012.

10. Yervoy prescribing information. March 2011. Bristol-Myers Squibb. Princeton, New Jersey. Available at http://packageinserts.bms.com/pi/pi_yervoy.pdf. Accessed July 2, 2012.

11. Sylatron Prescribing Inforamation. Schering Corporation, 2011. Available at http://www.merck.com/product/usa/pi_circulars/s/sylatron/sylatron_pi.pdf Accessed July 2, 2012.

12. Long Term Pegylated Interferon Alfa-2b Therapy in Stage III Melanoma Demonstrated Significant and Sustained Impact on Relapse-Free Survival. Medical News Today, July 12, 2008. Available at http://www.medicalnewstoday.com/articles/114772.php Accessed July 2, 2012.

13. PegIntron Prescribing Information. Schering Corporation, 2011. Available at http://www.spfiles.com/pipeg-intron.pdf Accessed July 2, 2012.

14. Zelboraf Prescribing Information. Hoffman-LaRoche, August 2011. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202429s000lbl.pdf Accessed July 2, 2012.

15. Vemurafenib. US Food and Drug Administration, August 17, 2011. Available at http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm268301.htm Accessed July 2, 2012.

The above information is a selective summary of publicly available information and is accurate as of the date of writing. Please consult the sources for complete reference information. The views expressed in this article are those of the author alone and not of Managed Health Care Associates, Inc. Any patient care, treatment, dosing, or other decisions related to the subject matter of this article should be based on an independent evaluation of the patient’s condition and medical history by his/her treating physician.

About the Author

Stacey Ness, PharmD, RPh, MSCS, has worked in both national specialty pharmacy and payer organizations and has experience in clinical management, adherence and persistency programs, as well as chronic disease cost optimization strategies. Dr. Ness is active in the Consortium of Multiple Sclerosis Centers, Academy of Managed Care Pharmacy, National Home Infusion Association, and Hematology and Oncology Pharmacy Association, and has served on the Minnesota Medicaid Drug Formulary Committee since 2008. She is a multiple sclerosis certified specialist and currently serves as the director of specialty clinical services at Managed Health Care Associates, Inc, a health care services organization based in Florham Park, NJ. Dr. Ness is associate editor of Specialty Pharmacy Times.