New Therapies Emerge for Metastatic Melanoma

W

ith the emergence of new therapies targeted to specific drivers of melanoma and the approval of two new agents that demonstrate improvements in overall survival,^1,2 there appears to be fresh hope for improving outcomes in a cancer that, after metastasis, formerly left patients with very little hope. Today, the median survival of melanoma patients with distant metastases, according to the American Joint Committee on Cancer (AJCC) stage IV statistics, is less than one year.³

In March 2011, the FDA approved ipilimumab (Yervoy, Bristol-Myers Squibb), a monoclonal antibody that blocks cytotoxic T-lymphocyte antigen 4 (CTLA-4), for patients with metastatic melanoma.4 CTLA-4 is thought to play a role in preventing the immune system from fighting off cancer cells, and ipilimumab may allow the immune system to recognize, target, and attack melanoma cells.⁴

In August 2011, the BRAF inhibitor vemurafenib (Zelboraf, Genentech) was FDA-approved to treat patients with metastatic melanoma whose tumors express the BRAF^V600E mutation; the approval was granted on the basis of phase III trial evidence showing an improvement in overall survival. The drug was licensed along with a test, the Cobas 4800 BRAF V600 Mutation Test, to specifically identify the mutation that the drug targets.^2,5,6

Developments from ASCO 2012

This year’s annual meeting of the American Society of Clinical Oncology (ASCO) saw several important developments in the treatment of melanoma.

Results from the phase III METRIC trial of the oral investigational agent trametinib showed that the drug delayed tumor growth and extended survival in patients with advanced melanoma with BRAF mutations. Trametinib inhibits the protein MEK, which is part of the MAP kinase signaling pathway, of which BRAF is a component.⁷

Patients who had received up to one prior chemotherapy regimen were randomly assigned to treatment with trametinib (n=214) or standard chemotherapy (n=108; either dacarbazine or paclitaxel). Median progression- free survival (PFS) was 4.8 months in patients treated with trametinib versus 1.5 months in the chemotherapy group, a 55% reduction in the risk of progression. A total of 81% of patients in the trametinib group were alive after six months of follow-up compared with 67% of patients in the chemotherapy group. Side effects of trametinib were generally manageable; severe side effects included skin rash (7% of patients), eye problems (less than 1%), high blood pressure (12%), and reduced heart function (7%).⁷

Interim results of phase III BREAK-3 study presented at ASCO found that dabrafenib, an investigational oral drug that targets BRAF, reduced the risk of disease progression by 70% versus standard dacarbazine chemotherapy in patients with previously untreated, advanced melanoma with BRAF mutations. Estimated median PFS was significantly longer in the dabrafenib group compared with chemotherapy: 5.1 months versus 2.7 months. Overall survival data were not yet mature. The study authors noted that there appeared to be fewer cases of serious skin toxicities associated with dabrafenib treatment, including squamous cell carcinomas, than have been previously reported in trials of the approved BRAF inhibitor, vemurafenib.⁸

Two abstracts featured promising results from phase I studies. BMS-936558 is a fully human monoclonal antibody that blocks Programmed Death 1 (PD-1) protein, overcoming immune resistance and mediating tumor regression. Topalian and colleagues (abstract CRA2509) successfully demonstrated the clinical activity and safety of this agent in melanoma, renal cell carcinoma, and non-small cell lung cancer, and verified the importance of the PD-1 ligand (PDL1) as a potential predictive biomarker.⁹

A related phase I study (abstract 2510) established the safety and clinical activity of an anti-PD-L1 antibody, BMS-936559, in patients with solid tumors including melanoma, as well as the importance of the PD-1/PDL1 pathway as a target for cancer immunotherapy.¹⁰

The safety, activity, and immune correlates of anti- PD-1 antibody in cancer were detailed in the June 2 issue of The New England Journal of Medicine.¹¹ In the report, a total of 296 patients with advanced melanoma, nonsmall cell lung cancer, castrate-resistant prostate cancer, or renal cell or colorectal cancer received varying doses of anti-PD-1 antibody every two weeks in eight-week cycles for up to 12 cycles, until disease progression or complete response. Of 236 patients in whom response could be assessed, cumulative response rates at all doses were 28% among patients with melanoma, 18% in non-small cell lung cancer, and 27% in patients with renal cell cancer. Stable disease (≥24 weeks) was observed in six patients (6%) with melanoma as well as the other cancers under study. Twenty of 31 patients had responses that lasted more than one year.¹¹

These data, together with similarly impressive results for the anti-PD-L1 antibody, also reported in the June 2 issue of The New England Journal of Medicine,¹² demonstrate that immunotherapy agents with “wide applicability” “…have broken the ceiling of durable tumor response rates of 10 to 15% (the highest rate of antitumor activity of the many immunotherapy approaches tested in the clinic for the treatment of cancer during the past 30 years..” according to a concurrent Journal editorial.¹³

Other immunotherapeutic approaches in late-stage development include T-VEC, formerly OncoVEXGMCSF, an oncolytic herpes simplex virus type 1 encoding granulocyte macrophage colony-stimulating factor (GMCSF). This agent is formulated for direct injection into accessible melanoma lesions. According to an abstract presented at ASCO, results from a randomized phase III clinical trial in patients with unresectable Stage IIIb, IIIc, and IV melanoma are expected in 2012.^14,15

Systemic immunotherapy Allovectin7 (veligene alloplasmid, Vical) is undergoing a phase III clinical trial comparing Allovectin-7 alone vs chemotherapy alone in patients with stage III or stage IV melanoma (active). The estimated completion date for the trial is June 2012.¹⁶

References:

1. 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.

2. 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.

3. Balch CM, Gershenwald JE, Soong SJ, et al. Final version of 2009 AJCC melanoma staging and classification. J Cin Oncol. 2009;27:6199-6206.

4. Yervoy [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2011.

5. Zelboraf [package insert]. San Francisco, CA: Genentech USA, Inc; 2011.

6. U.S. Food & Drug Administration. FDA approves Zelboraf and companion diagnostic test for late-stage skin cancer. August 17, 2011. Available at: http://www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm268241.htm

7. Robert C, Flaherty KT, Hersey P, et al. METRIC Phase 3 study: Efficacy of trametinib (T), a potent and selective MEK inhibitor (MEKi), in progression-free survival (PFS) and overall survival (OS), compared with chemotherapy (C) in patients (pts) with BRAF V600E/K mutant advanced or metastatic melanoma (MM). J Clin Oncol. 2012;30(suppl: abstr LBA8509).

8. Hauschild A, Grob JJ, Demidov LV. Phase III, randomized, open-label, multicenter trial (BREAK-3) comparing the BRAF kinase inhibitor dabrafenib (GSK2118436) with dacarbazine (DTIC) in patients with BRAFV600E-mutated melanoma. J Clin Oncol. 2012;30(suppl; abstr LBA8500).

9. Topalian SL, Brahmer JR, Hodi, FS, et al. Anti-PD-1 (BMS-936558, MDX-1106) in patients with advanced solid tumors: clinical activity, safety, and a potential biomarker for response. J Clin Oncol. 2012;30(suppl; abstr CRA2509).

10. Tykodi SS, Brahmer JR, Hwu W-J, et al. PD-1/PD-L1 pathway as a target for cancer immunotherapy: Safety and clinical activity of BMS-936559, and anti-PD-L1 antibody, in patients with solid tumors. J Clin Oncol. 2012;30(suppl; abstr 2510).

11. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012. Published online June 2, 2012. DOI: 10.1056/NEJMoa1200690.

12. Brahmer JR, Tykodi SS, Chow LQM, et al. Safety and activity of anti—PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012. Published online June 2, 2012. DOI: 10.1056/NEJMoa1200694.

13. Ribas A. Tumor immunotherapy directed at PD-1. N Engl J Med. 2012. Published online June 2, 2012. DOI:10.1056/NEJMe1205943.

14. Kaufman H, Wagner VJ, Goldsweig H, Yao B, Coffin R. OPTiM: A randomized phase III trial to evaluate the efficacy and safety of talimogene laherparepvec (T-VEC) compared with subcutaneously (sc) administered GM-CSF for the treatment (tx) of unresectable stage IIIb, IIIc, and IV melanoma. J Clin Oncol. 2012;(suppl; abstr 95193).

15. ClinicalTrials.gov. Efficacy and safety study of OncoVEXGM-CSF compared to GM-CSF in melanoma. Available at: http://clinicaltrials. gov/ct2/show/NCT00769704?term=OncoVEX+GM-csf&rank=4. Accessed May 28, 2012.

16. ClinicalTrials.gov. A phase 3 pivotal trial comparing Allovectin-7® alone vs chemotherapy alone in patients with stage 3 or stage 4 melanoma. Available at: http://clinicaltrials.gov/ct2/show/ NCT00395070. Accessed May 28, 2012.