Targeted Therapies Yield Most Promising Results: A New Era in Melanoma Treatment Has Begun

Melanoma is one of the most frequent cancers; more than 2 million Americans are treated for skin cancer annually. However, in its earlier stages, it can be easily cured by removal of the skin lesion.¹ “Melanoma is on the surface of the skin, and therefore easily visible to patients, doctors, and other health professionals without the use of x-rays or invasive procedures,” said Lynn M. Schuchter, MD, professor of Medicine, University of Pennsylvania School of Medicine, Philadelphia. “Therefore, early detection is highly feasible. Most melanomas are cured with surgery because the melanoma is detected at an early stage of disease before melanoma cells have the potential to metastasize.” Schuchter explained, “Once melanoma metastasizes to distant sites, it is highly resistant to therapy.” Melanoma caused an estimated 8700 deaths in 2010.1

Chemotherapy for advanced disease has yielded poor 5-year survivals for patients with metastatic disease—16% of those with metastatic melanoma survive 5 years post-diagnosis.² Dacarbazine has long been the only drug approved by the FDA for treating metastatic melanoma, and it is often ineffective.³ In other words, the prognosis for patients whose melanoma has spread is generally poor, and very few therapies existed before 2011 that could make more than a marginal difference. Only recently have investigational products emerged that, alone or in combination, seem to yield positive responses in some patients.

Taking Advantage of the Body’s Immune Response

Melanoma is one of the few cancers that triggers the body’s immune response naturally.⁴ The problem is that the response is easily overwhelmed by the malignancy. Ipilimumab, which was approved by the FDA in March 2011, works by spurring the body’s immune system to attack the tumor. The melanoma pipeline comprises several examples of investigational agents that seek to enhance the immune response, including therapeutic vaccines.

Vaccines

OncoVEXGM-CSF. The therapeutic vaccine that is perhaps furthest along the pipeline is OncoVEXGM-CSF, which is customized to the patient by using his/ her own tumor antigens. This viral vaccine invades both healthy cells and melanoma cells, but it does not harm the healthy cells, only replicating within the malignant cells, according to the manufacturer, BioVex, which was acquired by Amgen in March 2011.⁵ The virus produces granulocyte-macrophage colony-stimulating factor (GM-CSF), which gathers dendritic cells, causing the rupture of the tumor cell. This releases GM-CSF and tumor-cell peptides into the local area. The dendritic cells collect the tumor-cell peptides, allowing the immune system to recognize and attack them.

In 2009, phase II testing of the vaccine in 50 patients with metastatic melanoma revealed overall survival at 2 years of 52%, and an objective response rate of 26% (stable disease rate of 20%).⁶ Phase III testing is currently under way, and this OPTiM trial is expected to be completed in June 2012 (ClinicalTrials.gov, NCT00769704). The OPTiM trial compares the vaccine with the use of GM-CSF administered subcutaneously in patients with stage III (b-c) and stage IV (M1a-c) disease.

Prophage (vitespen). Not all autologous vaccinebased therapies entering phase III trials have met with success. This vaccine (formerly known as Oncophage), which is developed using gp96 and other peptides from the patient’s own tumor, was found to not improve survival in patients with stage IV melanoma compared with any other choice of therapy. In this phase III trial, only patients with better prognostic characteristics who were injected with vitespen seemed to improve.⁷

MVax. In the case of MVax, from Avax Technologies, the phase II clinical trial results were encouraging, yet the phase III study was halted in 2010, not for safety reasons or poor outcomes, but because of a lack of capital. It is unclear as to when or if this phase III trial may be continued, or if an interim analysis of the study results will take place as planned.

“

Most melanomas are cured with surgery...[but] once melanoma metastasizes to distant sites, it is highly resistant to therapy. ”

—Lynn M. Schuchter, MD

Similarly, in 2005, CancerVax Corp halted its phase III trial of the vaccine Canavaxinin for latestage melanoma, not because of safety reasons, but because it had not shown any benefit over placebo.⁸

Schuchter commented that, “Current approaches to vaccine development are still a major challenge. Unless there is a whole new approach to melanoma vaccines, I am not optimistic about the future of vaccines for patients with melanoma."

Allovectin-7. A plasmid that contains the genetic sequences for HLA-B7 and β2-microglobulin, Allovectin-7 is a receptor that activates T cells to provoke an immune response.⁹ This immunomodulator can be injected directly into the tumor lesion, which may help T-cell recognition of the malignancy and trigger attacks on these specific tumor cells.9 In phase II studies, Allovectin-7 injection in patients with recurrent or refractory advanced melanoma produced a 12% response rate, with a median duration of response of 13.8 months.¹⁰ The phase III AIMM trial was begun in 2007 and compares Allovectin-7 with dacarbazine or temozolomide in patients who had not been previously treated with chemotherapy (Clinical- Trials.gov, NCT00395070). This trial is scheduled for completion in the third quarter of 2012.

GSK2132231A. GSK2132231A is a recombinant fusion protein with potential immunostimulatory and antineoplastic properties that is derived from the melanoma antigen MAGE-3 and protein D from Hemophilus influenzae (it is also referred to as a MAGE-3 AS02B by the manufacturer). No clinical trial data using this agent have yet been made public, but a phase III trial called DERMA is ongoing to examine the use of GSK2132231A as adjuvant therapy for patients with resected melanoma (ClinicalTrials.gov, NCT00796445). Thirteen hundred patients will be enrolled, and the study is expected to be completed in December 2016.

Tremelimumab. This product, a fully human IgG2 monoclonal antibody targeted to CTLA-4, like ipilimumab, may summarize the key learning of research on melanoma to date: The shotgun approach to drug development in metastatic melanoma works poorly. In a previous phase III trial, tremelimumab failed to demonstrate a significant improvement in overall survival compared with temozolomide or dacarbazine in a cohort of patients without prior systemic treatment for their metastatic melanoma.¹¹ However, Pfizer came to an agreement with Switzerland’s Debiopharm to revive plans for a clinical trial of tremelimumab in patients with a biomarker indicating it would most likely be effective. Under this arrangement, Debiopharm would be responsible for funding and running the phase III trial (not yet under way).¹² In October 2011, Pfizer granted global rights to the product to MedImmune, a subsidiary of AstraZeneca, for development of this product for other indications.¹³

Ipilimumab. Approved in March 2011 for use in nonresectable or metastatic (untreated) melanoma, its manufacturer, Bristol-Myers Squibb (BMS), is conducting additional trials to determine if ipilimumab is also effective in untreated metastatic disease when combined with dacarbazine (ClinicalTrials.gov, NCT00324155) and if it is effective as adjuvant therapy in patients with high-risk stage III disease (ClinicalTrials. gov, NCT00636168). Randomized phase II data have demonstrated 65% 1-year survival and 23% 3-year survival for the ipilimumab dacarbazine combination in patients with chemotherapynaïve advanced disease.¹⁴

Ipilimumab is a fully human monoclonal antibody targeted to CTLA-4, a molecule known to negatively regulate the immune system.¹⁵ By inhibiting CTLA-4, ipilimumab can enhance the immune system’s T-cell response to tumor cells. In its pivotal 3-arm trial, another BMS agent, gp100 peptide vaccine, which was dubbed MDX- 1379, was used as the active control, despite the fact that no standard of care exists for this patient population. Patients were randomized to receive ipilimumab and gp100, gp100 and placebo, or ipilimumab and placebo. Compared with the median overall survival (OS) of the gp100 arm (6.4 mo), both ipilimumab-containing arms produced significant improvements, with a median OS of 10.0 months in the combination therapy arm (P <.001) and 10.1 months in the monotherapy arm (P =.003). In addition to these promising data, ipilimumab is also in phase III testing as an addition to dacarbazine chemotherapy for patients with untreated advanced melanoma (ClinicalTrials.gov, NCT00324155). Clinical trials have identified potential toxic liver effects.

There is no evidence that BMS is proceeding with the developmental program for MDX-1379.

Focusing on Melanoma Cell Targets

Much research in metastatic melanoma has involved testing of agents on specific melanoma cell targets or biomarkers. The targeted medication that has received the most attention, vemurafenib, was approved along with its companion diagnostic test in August 2011 to treat patients with metastatic (late-stage) or unresected (inoperable) melanoma in patients whose tumors express the BRAF gene’s V600E mutation, a driver of tumor growth. Other targets include c-kit, MEK, and Bcl-2 inhibitors. However, successful targeting is difficult, as demonstrated by Genta, which in May 2011 terminated its phase III trial and development program for the Bcl-2 inhibitor oblimersen (genasense) for the treatment of melanoma.¹⁶ On the other hand, GlaxoSmithKline’s GSK2118436, a BRAF inhibitor, has entered phase III testing (the first phase III study is scheduled to be completed in June 2012), which if successful in clinical trials won’t reach the market for some time (2014 at the earliest).

GSK1120212. Another targeted agent, GSK1120212, is an inhibitor of the MEK1 and MEK2 (MEK1/2) enzymes, preventing Raf-dependent MEK phosphorylation, resulting in antitumor effects in early-stage trials.¹⁷ This GlaxoSmithKline product is the subject of multiple clinical trials for different oncology indications. For melanoma, it is being tested in an open-label, randomized Phase III study comparing GSK1120212 with chemotherapy (either dacarbazine or paclitaxel) in up to 297 patients with stage IIIc or stage IV malignant cutaneous melanoma (all having a BRAF mutation—positive tumor). This trial is not scheduled for completion until September 2012 (ClinicalTrials.gov, NCT01245062).

Vemurafenib. Developed by Plexxicon and Roche, this BRAF V600E inhibitor seems to be effective¹⁸— in some cases, dramatically effective&mdash;for patients with this mutation, although its effects seem to wane after a period of time.¹⁹

In previous studies, vemurafenib had induced response rates of 50% and more in patients with metastatic melanoma who have the BRAF V600E mutation. In the phase III BRIM3 study, this oral agent (960 mg bid) was compared with intravenous dacarbazine (1000 mg/m2 of body surface area) every 3 weeks as monotherapy in 675 previously untreated patients with stage IIIC or IV melanoma.

After 6 months of treatment, vemurafenib demonstrated an OS of 84% compared with 64% in the dacarbazine group. In the interim analysis for OS and final analysis for progession-free survival (PFS), vemurafenib demonstrated a 63% relative reduction in risk of death from melanoma compared with dacarbazine. Response rates were 48% for vemurafenib and 5% for dacarbazine (P <.001). In addition, the risk of the composite endpoint, death, or disease progression was 74% lower in the vemurafenib group (P <.001).¹⁸

However, this agent is not without significant side effects. Thirty-eight percent of the study population taking vemurafenib required dose adjustments to alleviate side effects such as photosensitivity skin reactions, arthralgia, and fatigue.¹⁸

Although this study did not report long-term follow-up, there is anecdotal evidence that patients who benefit from vemurafenib may not experience a recurrence for 7 months to 2 years or more.¹⁹

With the recent progress in treating metastatic melanoma using targeted therapies like ipilimumab and vemurafenib, might combination approaches of these 2 agents be next in line for clinical trials? Samjiv S. Agarwala, MD, at St. Luke’s Cancer Center in Bethlehem, Pennsylvania, said, “Combination therapy would be an interesting research approach given the differences between ipilimumab (low response rate, prolonged duration) and vemurafenib (high response rate, possibly less durable).” Agarwala pointed out, however, that “Future trials with other agents in combination should address specific biomarkers.”

A study to test this combination of vemurafenib and ipilimumab is listed on ClinicalTrials.gov but is not currently under way. Additionally, it is expected that the use of vemurafenib will be tested in coming years in a phase IIII study as adjunctive therapy in patients with metastatic melanoma.

Conventional Chemotherapy

There are few positive data to report on conventional chemotherapeutic agents in the treatment of metastatic melanoma. One agent in development, tasisulam, has run into safety problems in phase III testing.

Tasisulam. Tasisulam is an acyl-sulfonamide compound that induces apoptosis through the mitochondrial-mediated cell death pathway. In phase II trials, 47% of patients taking tasisulam experienced some level of disease control, and a 2.6-month PFS (median) as second-line treatment of patients with unresectable or metastatic melanoma.²⁰ This was not a controlled trial. In December 2010, the SUMMIT-1 phase III registration trial of tasisulam versus paclitaxel stopped recruiting patients with metastatic melanoma because of 12 patient deaths that were potentially associated with the medication.²¹

There is no further word from the manufacturer (Eli Lilly) whether dosing will be changed for continued enrollment or whether the trial has been discontinued permanently.

Conclusions

Although the late-stage pipeline for melanoma seems bustling, most of the interest is occurring around ipilimumab and vemurafenib, which have been approved for their initial indications.

The success of these 2 agents in treating metastatic melanoma may encourage more drug development activity for targeted therapy, according to Agarwala. “I believe it will spur more drug development, as we are still a long way off from curing patients and the encouraging results seen so far have at least opened the door to even more effective drugs in the future,” he remarked. “I believe the results with vemurafenib and ipilimumab are proof of principal trials that show these approaches are effective. Now let’s move that up a notch and find drugs or combinations with even greater efficacy.”

Table. Drug Pipeline for Melanoma Products.

Date Updated

Company

Product

Mechanism of Action

Indication(s)

Stage

Licensee/ Partner(s)

PDUFA Datea

11/11/2011

AB Science

Masitinib

Tyrosine kinase inhibitor/ c-kit inhibitor

Melanoma stage III or IV

Phase III

N/A

N/A

11/11/2011

Celgene

ABI-007 (paclitaxel derivative)

Antimicrotubule agent

Metastatic melanoma in treatment-naïve patients

Phase III

N/A

N/A

1/11/2011

Agenus (formerly Antigenics, Inc)

Prophage (vitespen)

Vaccine

Melanoma stage IV

Phase IIIa

N/A

N/A

11/11/2011

AVAX Technologies

MVax

Vaccine

In combination with low-dose interleukin-2 in patients with stage IV melanoma

Phase III

N/A

N/A

11/11/2011

Bayer AG

Nexavar (sorafenib)

Raf kinase inhibitor/ vascular endothelial growth factor receptor inhibitor

In combination with standard chemotherapies after receiving 1 prior therapy of dacarbazine or temozolomide in patients with stage III or IV melanoma

Phase III

Onyx Pharmaceutical

N/A

11/11/2011

Amgen

OncoVEXGM-CSF

Vaccine

In combination with GM-CSF in patients with metastatic melanoma

Phase III

N/A

N/A

11/11/2011

Bristol-Myers Squibb Co

Yervoy (ipilimumab)

Monoclonal antibody

Unresectable or metastatic melanoma

FDA approval 3-25-11

N/A

—

11/11/2011

Bristol-Myers Squibb Co

Yervoy (ipilimumab)

Monoclonal antibody

Prevent recurrence after complete resection of high-risk stage III melanoma

Phase III

N/A

N/A

11/11/2011

Bristol-Myers Squibb Co

Yervoy (ipilimumab)

Monoclonal antibody

Ipilimumab plus temozolomide in metastatic melanoma

Phase III

N/A

N/A

11/11/2011

Eli Lilly & Co

Tasisulam

N/A

Metastatic melanoma

Phase III

N/A

N/A

11/11/2011

GlaxoSmithKline

GSK1120212

MEK inhibitor

Patients with stage III or IV malignant melanoma previously treated with or without a BRAF inhibitor

Phase III

N/A

N/A

11/11/2011

GlaxoSmithKline

GSK2118436

BRAF protein kinase inhibitor Previously treated

BRAF-mutant metastatic melanoma

Phase III

N/A

N/A

11/11/2011

GlaxoSmithKline

GSK2132231A

MAGE-A3 vaccine

Adjuvant therapy in patients with resected melanoma

Phase III

N/A

N/A

11/11/2011

Merck & Co, Inc

Temodar (temozolomide)

Cytotoxic alkylating agent

Stage IV metastatic melanoma

Phase III

N/A

N/A

11/11/2011

Merck & Co, Inc

Temodar (temozolomide)

Cytotoxic alkylating agent

In combination with radiation therapy to the brain in treating patients with stage IV melanoma

Phase III

European Organization for Research and Treatment of Cancer, National Cancer Institute

N/A

11/11/2011

Novartis AG

Tasigna (nilotinib)

Tyrosine kinase inhibitor

Metastatic and/or inoperable melanoma harboring a c-kit mutation

Phase III

N/A

N/A

11/11/2011

Pfizer

Tremelimumab

Monocolonal antibody

Treatment-naïve patients with surgically incurable metastatic melanoma

Phase III

Debiopharm

N/A

11/11/2011

Roche Holdings Ltd

Zelboraf (vemurafenib)

BRAF protein kinase inhibitor

BRAF V600 mutation-positive metastatic melanoma

FDA approval 8-17-11

Plexxicon

—

11/11/2011

Roche Holdings Ltd

Zelboraf (vemurafenib)

BRAF protein kinase inhibitor

BRAF V600 mutation-positive advanced melanoma with brain metastases

Phase II

Plexxicon

N/A

5/27/2011

Vical

Allovectin-7

Tumor suppression gene therapy

In combination with dacarbazine in patients with stage III or IV melanoma

Phase III

N/A

N/A

N/A indicates not available; PDUFA, Prescription Drug User Fee Act.

^aNo further clinical trial or regulatory submission activity since 2008.

References

1. American Cancer Society: Cancer Facts & Figures 2010. Atlanta, GA: American Cancer Society; 2010 (www.cancer.org/Research/CancerFactsFigures/index). Accessed May 30, 2011.
2. National Cancer Institute: Surveillance Epidemiology and End Results stat fact sheets: Melanoma. Bethesda, MD: National Cancer Institute; 2010 (http://seer.cancer.gov/statfacts/html/melan.html). Accessed May 30, 2010.
3. 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(9): 2745-2751.
4. Crowley NJ, Seigler HF. Possibilities of immunotherapy and gene therapy for malignant melanoma. Semin Surg Oncol. 1993;9(3):273-278.
5. Oncovex. BioVex. www.oncovexgmcsf.com/clinicians.html. Published April 2011. Accessed June 1, 2011.
6. Senzer NN, Kaufman HL, Amatruda T, et al. Phase II clinical trial of a granulocyte-macrophage colonystimulating factor-encoding, second-generation oncolytic herpes virus in patients with unresectable metastatic melanoma [published online ahead of print November 2, 2009]. J Clin Oncol. 2009;27(34): 5763-5771.
7. Testori A, Richards J, Whitman E, et al. Phase III comparison of vitespen, an autologous tumor-derived heat shock protein gp96 peptide complex vaccine, with physician’s choice of treatment for stage IV melanoma: the C-100-21 Study Group. J Clin Oncol. 2008;26(6):955-962.
8. CancerVax announces results of phase 3 clinical trials of canvaxin in patients with stage III and stage IV melanoma. CBS Business Network. http://findarticles.com/p/articles/mi_pwwi/is_200603/ai_n16114123/. Published March 2006. Accessed June 8, 2011.
9. Vical: Allovectin-7. Vical Web site. www.vical.com/products/cancer-immunotherapies/allovectin/default.aspx. Published 2010. Accessed June 8, 2011.
10. Bedikian AY, Richards J, Kharkevitch D, et al. A phase 2 study of high-dose Allovectin-7 in patients with advanced metastatic melanoma. Melanoma Res. 2010;20(3):218-226.
11. Ribas A, Hauschild A, Kefford R, et al. Phase III, open-label, randomized, comparative study of tremelimumab (CP-675,206) and chemotherapy (temozolomide or dacarbazine) in patients with advanced melanoma. J Clin Oncol. 2008;26(15S) (suppl):LBA9011.
12. Pfizer and Debiopharm collaborate to co-develop investigational compound tremelimumab (CP-675,206) in advanced melanoma [press release]. Pfizer. www. pharmiweb.com/pressreleases/pressrel.asp?ROW_ID=13572. Published January 7, 2010. Accessed June 14, 2011.
13. AstraZeneca unit in-licenses Pfizer drug candidate tremelimumab. The Pharma Letter. www.thepharmaletter.com/file/107799/astrazeneca-unit-in-licensespfizer- drug-candidate-tremelimumab.html. Published October 4, 2011. Accessed November 11, 2011.
14. Hersh E, Weber J, Powderly J, et al. Long-term survival of patients (pts) with advanced melanoma treated with ipilimumab with or without dacarbazine. J Clin Oncol. 2009;27:15s(suppl);abstr 9038.
15. Parry RV, Chemnitz JM, Frauwirth KA, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol. 2005;25(21):9543-9553.
16. Phase 3 trial of Genasense in advanced melanoma does not show significant increase in overall survival [press release]. Genta. www.drugs.com/clinical_trials/phase-3-trial-genasense-advancedmelanoma-does-not-show-significant-increaseoverall-survival-11831.html. Published May 23, 2011. Accessed June 14, 2011.
17. Gilmartin AG, Bleam MR, Groy A, et al. GSK1120212 (JTP-74057) is an inhibitor of MEK activity and activation with favorable pharmacokinetic properties for sustained in vivo pathway inhibition. Clin Cancer Res. 2011;17(5):989-1000.
18. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation [published online ahead of print June 5, 2011]. N Engl J Med. 2011;364(26)2507-2516. doi:10.1056/NEJMoa1103782.
19. Pollack A. Drugs show promise slowing advanced melanoma. New York Times. June 6, 2011:A1, A11.
20. Kirkwood JM, Gonzalez R, Reintgen DS, et al. A phase II study of tasisulam sodium (LY573636) as second-line treatment for patients with unresectable or metastatic melanoma. J Clin Oncol. 2010;28:15s(suppl);abstr 8541.
21. Nelson R. Lilly suspends study of tasisulam for metastatic melanoma. Medscape. www.medscape.com/viewarticle/734208. Published December 14, 2010. Accessed June 14, 2011.