Targeted Products Yield Most Promising Results

, ,
Evidence-Based Oncology, February, Volume 18, Issue SP1

A New Era in Targeted 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 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.” It 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 is the only drug approved by the US Food and Drug Administration (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 trigger the body’s immune response naturally. 4 The problem is that the response is easily overwhelmed by the malignancy. Ipilimumab, which was approved in March 2011 by the FDA, 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 their 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 was 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

(vitaspen).

Not all autologous vaccine-based 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 by the physician. In this phase III trial, only patients with better prognostic characteristics who were injected with vitaspen 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.

Similarly, in 2005, CancerVax Corphalted its phase III trial of the vaccine Canavaxini for late-stage melanoma not because of safety reasons but because it had not shown any benefit over placebo.8

Schuchter commented that overall, “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 specific 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 (ClinicalTrials .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 currently enrolling patients 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 non-resectable or metastatic (untreated) melanoma, its manufacturer, Bristol-Myers Squibb, 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 chemotherapy-naïve 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 months), 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 (Gentasense) 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 (eitherdacarbazine 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 Trial Number NCT01245062).

Vemurafenib.

Developed by Plexxicon and Roche, this BRAF V600E inhibitor seems to be effective18—in some cases, dramatically effective—for patients with this mutation, though 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 end point, 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 be next in line for clinical trials? Samjiv S. Agarwala, MD, at St. Luke’s Cancer Center 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 Clinical- Trials.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 of the few, tasisulam, has run into safety problems in phase III testing.

Tasisulam. Tasisulam is an acyl-sulfonamide compound which 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 Dr 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.”

PIPELINE PERSPECTIVE

Interview With Maria Lopes, MD, MS , Chief Medical Officer, AMC Health

Q. How are payers evaluating the value of newer, targeted melanoma therapies, such as ipilimumab and vemurafenib?

ML:

As with other oncology agents, payers are evaluating new therapies primarily on the basis of the clinical trial data with efficacy and safety. We’re using the label indication/appropriate use as defined by National Comprehensive Cancer Network to define coverage criteria. Since ipilimumab is an infused agent, it is covered through the medical benefit. Vemurafenib, an oral drug, may be managed through the pharmacy benefit. This may result in implications for patient cost share and pharmacy management.

Ipilimumab is administered intravenously over 90 minutes every 3 weeks, a total of 4 doses and $120,000. The marginal benefit in overall survival (OS) is 3.6 months, compared with GP vaccine and a marginal OS benefit of 2.1 months in the group receiving ipilimumab in combination with dacarbazine versus dacarbazine alone. Ipilimumab was approved with a companion diagnostic test for a biomarker to help in patient selection.

In contrast, vemurafenib is an oral agent given twice daily, with an FDA-approved diagnostic kit and a total estimated treatment cost of $37,000 to $56,400 for the average treatment duration of 4 to 6 months. Overall survival data are not yet available but trends in a favorable direction. To the extent that there is a biomarker associated with the drug to assist in identifying those who will have the highest likelihood to benefit from its use, the BRAF mutation is a requirement that will be incorporated into the prior authorization consideration for approval and will hopefully add to improved outcomes and provide clinically meaningful OS.

Q: Are they game changers for patients with metastatic melanoma?

ML:

The goal of new treatments will be to enhance meaningful OS. With targeted therapy, the ability to identify who can benefit most from a treatment will hopefully lead to not only statically significant changes in OS but clinically meaningful OS (OS >6 months) versus best standard of care and go beyond progression-free survival and risk of recurrence to justify coverage and value. As we compare outcomes, it will become increasingly more important to payers, providers, and members to examine value as the margin of OS, safety in the context of the episode treatment cost, and how this compares with existing treatment options.

Q: From a payer’s viewpoint, what are the most important clinical (or clinically based) outcomes that help you determine the value of an oncological medication? A re these outcomes generally being tested and reported by the manufacturers?

ML:

As a payer, the end point with the most meaning to me is OS. The future of personalized medicine in oncology will require an evidence-based approach to define the best sequence of treatment options based on individual genomic patterns, and to deliver better efficacy, safety, or cost, which will define a rational treatment/pathway approach to available treatment options. That will require identifying through biomarkers/compendium diagnostics those who can benefit most from specific agents or combination therapies, by adding meaningful improvements in OS.

Q: Therapeutic vaccines are featured prominently in the melanoma pipeline. H ow can lessons learned from vaccines like sipuleucel-T (Provenge) be applied to understanding the value of these investigational immunostimulatory products?

ML:

Provenge tested the concept of value. Although it came with a unique mechanism of action, using autologous immunotherapy, the price was simply too high for the OS survival benefit. From the clinical trials, the median OS for patients receiving Provenge was 25.8 months compared with 21.7 months in the control group, at an episode treatment cost of more than $94,000. Despite this, the Centers for Medicare & Medicaid Services approved the drug for coverage and NCCN’s Prostate Panel added Provenge as a category 1 treatment recommendation for patients with castration-resistant prostate cancer. As a result, Provenge is covered by most payers despite the modest marginal value.

Q: In oncology research most investigational agents are being tested not as monotherapies but in combined use with approved treatments. W hen trying to address value on a health tech assessment committee, how do these additive regimens complicate the calculation of cost-effectiveness?

ML:

When comparing treatment options, it is important to keep in mind how the combinations will not only add to cost and possibly side effects, but in the real world, how we can control waste and noncompliance, if the agents are not being taken as prescribed.

Placing a Heavy Burden Melanoma Devastating to Patients...and Society

In 2011, over 70,000 Americans are expected to be diagnosed with melanoma and nearly 8800 will die of this disease.1 Melanoma represents a modest fractio —approximately 4%—of all newly diagnosed cancers in the United States, but the economic burden of this disease is substantial. One recent study examined the annual direct costs of caring for melanoma patients in the United States who were at least 65 years of age, reporting the annual cost to be $249 million.2 However, this drastically underestimates the actual economic burden of this disease because (1) only direct costs were measured (indirect costs were ignored), and (2) the patient population was restricted to those 65 years or older, which accounts for only 41% of the total melanoma patient population.3

A study published in 2009 used a comprehensive model of melanoma-related expenses to illustrate how costs differ at the distinct stages of disease, owing to the need for specific medical interventions and other healthcare expenditures.4 Using this model to quantify the average melanoma healthcare costs per person for the 5 years after melanoma diagnosis at each particular stage, the authors reported that these healthcare costs increase dramatically with the stage of disease. They demonstrated that, for the earliest stage disease (in situ melanoma), 5-year expenditures were only $4648. This increased substantially with each later stage of disease. For example, patients with stage IA disease incurred costs of $11,115, and those with stage IIA disease had 5-year costs totaling $29,620. For patients with stage III or IV disease, however, average healthcare costs in the 5 years post-diagnosis increased sharply—to over $150,000. Not surprisingly, the relative distribution of costs among healthcare expenditures varied significantly by stage. Patients with in situ melanoma spent the bulk of their expenditures on treatment of the primary lesion (52%) and surveillance costs (27%). In contrast, patients with metastatic melanoma spent only 2% of their total expenditures on the treatment of the primary lesion and nothing on surveillance, but they used 73% on workup and treatment for metastatic disease and 9% on terminal care costs. When costs were grouped by intervention, the treatment of a metastatic tumor was by far the most expensive outlay, costing $116,294. However, adjuvant therapy with interferon-alpha for highrisk melanoma was also quite expensive, with a cost of $75,955. Among the most expensive single-item expenditures were radiation therapy ($15,999), surgical removal of a skin tumor ($7150), and hospitalization for neutropenic fever ($1535-$1800 per day).

Another way to measure economic burden of a disease is to examine productivity lost as a result of a disease. The Centers for Disease Control and Prevention (CDC) has published a study quantifying the productivity loss associated with melanoma. The authors reported that, on average, a person with melanoma loses 20.4 years of potential life as a result of the melanoma, which is almost 4 years more than that lost for malignant cancers as a whole.5 Furthermore, the average melanoma patient will experience a lifetime earnings loss of $413,370 caused by his or her cancer diagnosis. This translates into an estimated annual US productivity loss due to melanoma of $3.5 billion (in 2006 US dollars). Productivity losses were not spread evenly among all ethnicities, however. Total productivity losses per person were lowest among non-Hispanic whites ($409,814) and highest among Hispanics ($545,795).5 There were also gender differences, with women having lower per-person productivity losses ($401,046) than men ($441,903).

Taken together, these data demonstrate that melanoma is not only a physically devastating disease, but that it can also place a heavy economic burden both on the patients and society at large.

References

1. American Cancer Society. Cancer Facts & Figures 2011. Atlanta, GA: American Cancer Society; 2011.

2. Seidler AM, Pennie ML, Veledar E, Culler SD, Chen SC. Economic burden of melanoma in the elderly population: population-based analysis of the Surveillance, Epidemiology, and End Results (SEER)--Medicare data. Arch Dermatol. 2010;146(3):249-256.

3. National Cancer Institute. SEER stat fact sheets: Melanoma of the skin. http://seer.cancer.gov/ statfacts/html/melan.html. Accessed November 9, 2011.

4. Alexandrescu DT. Melanoma costs: a dynamic model comparing estimated overall costs of various clinical stages. Dermatol Online J. 2009;15(11):1. http://dermatology.cdlib.org/1511/originals/melanoma_costs/alexandrescu.html. Accessed November 9, 2011.

5. Ekwueme DU, Guy GP Jr, Li C, Rim SH, Parelkar P, Chen SC. The health burden and economic costs of cutaneous melanoma mortality by race/ethnicity-United States, 2000 to 2006. J Am Acad Dermatol. 2011;65(5)(suppl 1):S133-S143.Funding Source: None

Author Disclosures: Mr Mehr reports receiving payment for involvement in the preparation of this article.The other authors (JK, MPZ) report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Authorship Information: Concept and design (JK, MPZ); acquisition of data (SRM, MPZ); analysis and interpretation of data (SRM, MPZ); drafting of the manuscript (JK, SRM, MPZ); critical revision of the manuscript for important intellectual content (JK, SRM, MPZ); and sidebar development (SRM).

(In “Melanoma Pipeline” section): Maria Lopes, MD, MS

Author Affiliation: AMC Health, New York, NY.

Funding Source: None

Author Disclosure: Dr Lopes reports receiving consulting fees for participation in the development of this article.

Authorship Information: Interview quotes (ML).

1. American Cancer Society: Cancer Facts & Figures 2010. Atlanta, GA: American Cancer Society; 2010 (www.cancer.org/Research/CancerFacts- Figures/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. http://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 colony-stimulating 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 tumorderived 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(TM) in patients with stage III and stage IV melanoma. CBS Business Network.http://findarticles.co/p/articles/mi_pwwi/is_200603/ai_n16114123/. Published March 2006. Accessed June 8, 2011.

9. Vical: Allovectin-7®. Vical Web site. http://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 [TMZ] or dacarbazine [DTIC]) in patients with advanced melanoma (abstract). 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. http://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. http://www.thepharmaletter.com/file/107799/astrazeneca-unit-in-licenses-pfizer-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. http://www.drugs.com/clinical_trials/phase-3-trialgenasense-advanced-melanoma-does-not-showsignificant-increase-overall-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. http://www.medscape.com/viewarticle/734208. Published December 14, 2010. Accessed June 14, 2011.