American Society for Clinical Oncology (ASCO) June 2010 Update

The annual meeting of ASCO was attended by more than 30,000 clinical oncologists and basic cancer researchers. This report summarizes key presentations on melanoma with a focus on therapy (immunotherapy, chemotherapy and therapy with small molecule inhibitors). This is a very technical report and should be used only to obtain information on the topics covered at the annual ASCO meeting.

Download a PDF version of the 2010 ASCO Melanoma Therapies Presentation Summary.

I. Immunotherapy

In the past 30 years, randomized clinical trials of various immunotherapies have repeatedly failed to demonstrate an improvement in overall survival in patients with advanced melanoma, which is extremely difficult to treat. However, recently, a novel approach using an immunomodulatory agent (Ipilimumab or Ipi) induced promising clinical responses in metastatic melanoma patients.

Immunomodulators activating T cells

T cells are predominantly found in the blood and tissues, including tumors. In their activated state, T cells may destroy tumor cells. Several modulators may activate T cells and are therefore candidates for immunotherapy.

1. Ipilimumab (Ipi)

   For the first time, a drug has shown a survival advantage in advanced melanoma. Ipi is a monoclonal antibody that binds to CTLA-4, an inhibitory molecule on T lymphocytes. T lymphocytes are blood cells that may be highly effective in inhibiting cancer growth. When CTLA-4 on T lymphocytes binds to CD80 on tumor antigen-presenting cells (APC), activation of the T cells by tumor antigen, and thus the capacity of the T cells to destroy tumor cells expressing the antigen, is inhibited (see figure). When Ipi binds to CTLA-4 on T cells, the brake is released and T cells can become activated and destroy tumor cells.

   A total of 676 melanoma patients at 125 centers in 13 countries were randomized to receive Ipi, Ipi plus a vaccine, or the vaccine alone. All patients had been pre-treated for metastatic melanoma. Ipi was given intravenously at 3mg/kg body weight every 3 weeks for 4 doses. Overall median survival was improved from 6.4 months with the vaccine alone to 10 months in both Ipi arms. These differences were statistically significant. 1-year survival was 44-46% in the Ipi-treated patients vs. 25% in the vaccine alone group. 2-year survival was 22-24% in the Ipi-treated patients vs. 14% in the vaccine-alone arm. Two thirds of the patients receiving Ipi had immune-related adverse events, compared with one third of patients receiving the vaccine alone. Immune-related events usually were reversible and rarely required steroid treatment. There were some treatment-related deaths (most of them due to gastro-intestinal perforation and sepsis) in all arms of the study. Results of this trial were published in the New England Journal of Medicine in June 2010.

   The study was sponsored by Bristol-Myers Squibb, and the company expects to seek regulatory approval of Ipi in advanced melanoma this year.
   
    

2. Anti-CD40 antibody

   Similar to Ipi, anti-CD40 antibody activates T lymphocytes via removing a blockade. As CD40 is also expressed by B lymphocytes, which can destroy tumor cells by producing cytotoxic antibodies, anti-CD40 antibody can also activate B cells. This clinical trial included only 21 patients of various tumor types, including 3 melanoma patients, and showed no objective clinical responses. However, immune responses induced by the antibodies were promising and warrant further controlled trials, especially as all patients were pre-treated with cortisone which may have decreased patients’ immune functions. The trial was presented by P.W. Johnson at the Southampton Experimental Cancer Medical Center, Southampton, UK.

3. Anti-PD1 antibody

   PD1 is another T cell-inhibitory molecule. Antibody to PD1 was administered to 38 melanoma patients. 18 of the patients had objective clinical responses. This trial was presented by M. Sznol at the Yale Cancer Center, New Haven.

Cytokines

Cytokines are another group of immunomodulatory proteins that are produced by peripheral blood and bone marrow cells. Cytokines may directly stimulate or inhibit the function of various effector cells (T cells, B cells, scavenger cells such as monocytes and macrophages, or antigen-presenting cells) and thus they may either stimulate or inhibit the capacities of these cells to destroy tumors. Two cytokines – interleukin-2 and interferon-alpha, are approved for the treatment of metastatic melanoma.

1. Interleukin (IL)-2

   This cytokine has been used for the treatment of melanoma with modest success for several decades. In recent trials, IL-2 has been combined with other cytokines, such as GM-CSF (granulocyte, macrophage, colony stimulating factor). However, clinical response rates were not increased by adding GM-CSF to IL-2. This trial was presented by J. Lutzky, Mount Sinai Comprehensive Cancer Center, Miami Beach.

2. Interferon (IFN)-alpha

   One year of IFN-alpha treatment is the FDA approved standard for patients with metastatic melanoma. As this treatment induces significant adverse reactions in most patients, an abbreviated treatment regimen of 12 weeks was evaluated for clinical efficacy. This treatment was as efficacious as the prolonged 1 year treatment. This trial was presented by R.J. Sullivan, Beth Israel Deaconess Medical Center, Boston.

3. GM-CSF

   This cytokine statistically significantly improved disease-free survival of metastatic melanoma patients with minimal toxicity. This trial was presented by D.H. Lawson, Winship Cancer Institute of Emory University, Atlanta.

4. IL-21

   The trial with IL-21 in metastatic melanoma patients received much attention at the meeting as there has been no clinical experience with this cytokine in the past. The overall response rates of 22% and median progression-free survival of 5.19 months compared very favorably with historical controls and patients treated in other trials with Ipilimumab. This trial was presented by T.M. Petrella, Odette Cancer Center, Toronto, Canada.

Vaccines

All melanoma vaccine trials presented at the meeting were in their initial phases (Phase I or II) and therefore the clinical efficacy is currently unclear. In the past, melanoma vaccines have not shown clinical benefits in double blind, randomized phase III trials in melanoma patients.

1. Melanoma peptides

   Peptides are short sequences of proteins that may specifically stimulate T cells to destroy tumor cells. 174 Stage IV melanoma patients received combinations of various melanoma peptide vaccines with the aim of enhancing cytotoxic anti-tumor responses of T lymphocytes. Objective tumor regression was observed in 5% of the patients. This trial was presented by C. Slingluff, University of Virginia, Charlottesville.

2. DNA vaccines

   DNA or RNA encoding tumor proteins/antigens may be injected directly into patients or loaded onto antigen-presenting cells, such as dendritic cells. This induces the production of a tumor antigen which eventually may lead to the activation of immune effector cells destroying tumors.

   • 4 of 18 melanoma patients had objective clinical responses to DNA vaccines encoding two different melanoma antigens (Melan-A and tyrosinase). This trial was presented by J.S. Weber, Lee Moffitt Cancer Center, Tampa.
   • 40 patients received antigen presenting cells (dendritic cells) loaded with RNA encoding various melanoma antigens. 14 patients had objective clinical responses. This trial was presented by S. Wilgenhof, UZ Brussel, Brussels, Belgium.
3. Dendritic cell vaccines
   • 64 metastatic melanoma patients received peptide or tumor cell-pulsed dendritic cell vaccines.
   • 14% of the patients are alive 5-11 years after vaccination.
   • Median overall survival was 17 months.

   This trial was presented by A.K. Palucka, Baylor Institute for Immunology Research, Dallas. Three long-term observation trials with CanVax plus BCG (D. Morton) melanoma oncolysate (M. Wallack) or GM2 (P. Livingston) showed no significant overall survival advantage of the treated patients.

Monoclonal antibodies to melanoma antigens

Monoclonal antibodies (Mab) are artificially produced by B lymphocytes in culture. As they are derived from a single B cell (monoclonal) they all bind to the same antigen on tumor cells. Using various mechanisms, Mab may destroy tumor cells.

1. Mab to GPNMB

   A monoclonal antibody to a melanoma-associated glycoprotein (GPNMB) and coupled to a toxin was administered to 117 stage III/IV melanoma patients with overall response rates of 15-20%. This trial was presented by O. Hamid, The Angeles Clinic and Research Institute, Santa Monica.

2. Rituximab

   Rituximab is a monoclonal antibody directed to an antigen (CD20) shared by normal and malignant blood cells and melanoma cells. Nine stage IV melanoma patients were treated with the antibody. After 2 years, 6 patients are still disease-free and all 9 patients are still alive. This treatment seems superior to standard treatments used for historical controls, although larger randomized and controlled studies are needed to convincingly demonstrate efficacy of the antibody. This trial was presented by S.N. Wagner, Medical University of Vienna, Austria.

II. Chemotherapy

Chemotherapy is often used as first line treatment for metastatic melanoma. This form of therapy rarely induces long-term survival and in many patients is accompanied by unacceptable toxicities.

Dacarbazine (DTIC)

DTIC has been the standard chemotherapeutic agent for treatment of melanoma, but durable responses are rare and toxicity of this treatment modality is not uncommon. Recently, preclinical studies in animals have shown superiority of combined immune/chemotherapy vs. either therapy alone.

Thus, DTIC was combined with a monoclonal antibody (Ramucirumab) which has anti-angiogenic (inhibits blood vessel sprouting) activity for treatment of metastatic melanoma patients. Control patients received either DTIC or Ramucirumab alone. Combination therapy may be associated with improved 6 month progression-free survival compared to monotherapy. This trial was presented by R.D. Carvajal, Memorial Sloan-Kettering Cancer Center, New York.

Similarly, 40 advanced melanoma patients were treated with this kind of combination therapy with promising therapeutic outcome. This trial was presented by A. diPietro, European Institute of Oncology, Milan, Italy.

DTIC was also combined with a small molecule inhibitor which targets a growth-activating pathway in melanoma cells and sensitizes the cells to the action of chemotherapeutic agents. Progression-free survival of the patients compared favorably to historical controls. This trial was presented by A.P. Algazi, UCSF, San Francisco.

Temozolomide

Temozolomide has shown equal efficacy to DTIC in phase III (randomized and controlled) trials with response rates of 5-20%. Temozolomide was combined with a monoclonal antibody that blocks angiogenesis (growth of blood vessels) in 66 stage IV melanoma patients. >35% of the patients showed clinical responses at 12 weeks of treatment. This trial was presented by R. Dummer, University Hospital, Zurich, Switzerland.

III. Therapy with small molecule inhibitors

Small molecule inhibitors are chemical compounds that bind to structures on tumor cells (e.g. kinases) that are essential for tumor growth. Binding may lead to tumor growth arrest and even tumor cell destruction. There was a consensus that a combination of several inhibitors targeting different kinases is needed to achieve better clinical responses in future trials.

Mutated BRAF inhibitor

Mutated BRAF is exclusively expressed by tumor and not normal cells and is therefore the most attractive of all small molecule inhibitors presented at the meeting. This mutation is expressed by approximately 60% of melanomas. The drug was tested in multi-center trials and overall has shown a 70-80% response rate in advanced patients.

New England Journal of Medicine (August 2010) details a multicenter trial in which 55 patients received escalating doses of the drug. Ten of 16 patients who had the BRAF gene mutation had a partial response to the drug, meaning the tumor shrank by at least 30%, while one had a complete response, with the tumor disappearing altogether. Among 32 patients with BRAF-mutated melanoma in the second phase of the study, 24 had a partial response and two had a complete response. PLX4032 is slated for FDA approval in 2011 for treatment of metastatic melanoma. Of some concern is the induction of squamous cell carcinomas in some of the treated patients, although these tumors were relatively benign. As tumors recurred in most patients treated with PLX4032, in recent trials this drug is combined with the immunomodulator Ipi (see above).

GSK2118436 caused >20% tumor decrease in 18 out of 30 metastatic melanoma patients. This drug also induced squamous cell carcinomas in some patients. This trial was presented by R. Kefford, University of Sydney, Australia.

BRAF inhibitor

Sorafenib raised high hopes for treatment of melanoma patients, but extensive clinical testing of the drug alone or in combination with chemotherapy has yielded disappointing results. This trial was presented by K. Flahery, Massachusetts General Hospital Cancer Center, Boston.

MEK inhibitor

AZD6244 is a selective MEK inhibitor and showed clinical activity in 5 of 8 patients with BRAF mutations, but not in patients lacking the mutation. This trial was presented by S.P. Patel, M.D. Anderson Cancer Center, Houston.

Sunitinib

Sunitinib inhibits several kinases and was administered to 36 locally advanced or metastatic melanoma patients with a clinical response rate of 33%. This trial was presented by L. Decoster, Oncologisch Centrum, Universitair Ziekenhuis, Brussels, Belgium.

Imatinib

Imatinib inhibits KIT oncogene and was administered to 67 metastatic melanoma patients with KIT mutations or amplification. 15 patients had objective clinical responses. This trial was presented by J. Guo, Beijing Cancer Hospital, Beijing, China.

In a preliminary trial, 6 melanoma patients (acral, mucosal or chronic sun damage melanoma) with KIT mutations or amplifications were treated with Imatinib and 2 had clinical responses. This trial was presented by D.R. Minor, The Angeles Clinic and Research Institute, Los Angeles.

Prognostic melanoma markers

The availability of melanoma markers that would predict response to therapy could greatly enhance the success rate of these therapies.

1. Melanoma-associated genes in peripheral blood
   Presence of melanoma-associated genes in peripheral blood was a good predictor for clinical outcome in patients treated with biochemotherapy or interferon. This trial was presented by J.A. Sosman, Vanderbilt University Medical Center, Nashville.
2. Circulating angiopoietin
   Angiopoietin level in the blood is a useful marker for metastatic melanoma patients compared to healthy individuals. This trial was presented by R. Mouawad, Salpetriere Hospital, University of Paris, Paris, France.
3. Nestin
   High expression of nestin in circulating melanoma cells might represent an index for poor prognosis in metastatic melanoma patients. This trial was presented by A. Fusi, Charite, Berlin, Germany.
4. Interleukin 10
   High IL-10 production in melanoma cells was associated with worse prognosis in stage III melanoma patients receiving autologous tumor cell vaccine. This trial was presented by Mahipa, Thomas Jefferson University, Philadelphia.
5. Cox-2
   Cox-2 expression by melanoma cells was associated with worse clinical outcome. This trial was presented by A. Minisini, University and General Hospital, Udine, Italy.
6. Macrophage markers
   Macrophages are scavenger blood cells and express several molecules shared with melanoma cells. Expression of these markers by melanomas is strongly associated with poor survival. This trial was presented by T.O. Jensen, Aarhus University Hospital, Aarhus, Denmark.
7. Nras mutations
   Nras mutations in melanoma are associated with decreased survival. This trial was presented by B.A. Devitt, Peter MacCallum Cancer Centre, East Melbourne, Australia.