Advances in Melanoma Management
Advances in Melanoma Management
In 2006, an estimated 62,190 Americans will be diagnosed with cutaneous melanoma and 7910 will die from the disease. In the United States, cutaneous melanoma currently ranks 5th in incidence among both men and women. At the first annual Oncology World Congress, held in New York City, Drs. F. Stephen Hodi, Michael B. Atkins, and Patrick Hwu reviewed the literature and discussed new developments in melanoma management.
Immunotherapy
Patrick Hwu, MD, Chairman of Melanoma Medical Oncology at the M.D. Anderson Cancer Center (MDACC) reviewed new developments in melanoma immunotherapy.
Melanoma and renal cell carcinoma are 2 malignancies for which the immune system response is critical. The primary goals of immunotherapy are to upregulate the proinflammatory response, and thus to mobilize immune effector cells, and to downregulate the immune tolerance to cancer cells. Dr. Hwu discussed the use of proinflammatory cytokines, tumor vaccines, and adoptive cell therapies to stimulate the immune response.
Cytokine Therapy
Treatment with high-dose interleukin 2 (IL-2) has resulted in dramatic clinical outcomes, including significant tumor regression in patients with diffuse metastatic disease. High-dose IL-2 induced a response rate of 16% (95% confidence interval, 12% to 21%) with a 10% partial response (PR) and 6% complete response (CR) in patients with stage IV melanoma. Those patients who did respond, attained a prolonged response (median 5.9 months for PR, with the CR median response duration not yet reached). Nonetheless, response rates for IL-2 therapy are modest and toxicity is high. Dr. Hwu emphasized the need to better understand the molecular fingerprints of responders vs nonresponders and to develop immune therapies that are more effective and less toxic.
Vaccine Therapy
Vaccines are a promising but still experimental approach to treating melanoma. Unlike antibodies, which can only target extracellular proteins, T cells can recognize intracellular peptides, presented by major histocompatibility complex (MHC) molecules, within tumor cells. Possible tumor-specific targets for vaccine therapy include mutated proteins, oncogene products, and abnormal signaling proteins. A number of possible tumor antigen targets in melanoma have been explored and include MART-1, EphA2, adipophilin, SSX-2, NY-ESO-1gp100, Tyrosinase, ESO, CDK4, and TRP- and TRP-2.
Subsets of whole tumor vaccines include autologous vaccines, which are developed from each patient's tumor biopsy, and "off the shelf" allogeneic vaccines, which can be used in a variety of patients (eg, polyvalent cancer vaccine). Antigen-specific vaccines include peptide/protein plus adjuvant, recombinant viral, and DNA vaccines. Although the use of melanoma vaccines has resulted in greater numbers of circulating specific T cells, response rates have been poor. A pooled analysis of recombinant viral, peptide, and DNA vaccine clinical trials presented by Dr. Hwu showed an objective response in approximately 2% of patients with stage IV disease.
F. Stephen Hodi, MD, Assistant Professor of Medicine, Harvard Medical School, and Clinical Director of the Melanoma Program at the Dana-Farber Cancer Institute, Boston, Massachusetts, reviewed the results of clinical trials with melacine. Large prospective trials of melacine, an allogeneic melanoma cell lysate, for patients with stages II/III melanoma demonstrated a disease-free survival (DFS) benefit in the intent-to-treat population, but no overall survival benefit. However, analysis of responders linked certain HLA haplotypes with improved relapse-free survival. HLA-A2 and HLA-C3, in particular, were associated with disease-free and overall survival benefit.
To improve the response rates seen with vaccine alone, investigators have combined vaccine therapy with other methods of improving the anti-tumor immune response. Cytotoxic T lymphocyte-associated antigen (CTLA-4) is a membrane-bound molecule on cytotoxic, regulatory, and helper T cells that inhibits T cell proliferation and is important to maintaining peripheral tolerance to self-antigens. In a study by Attia and colleagues, patients with stage IV melanoma were vaccinated with 1 of 2 gp100 melanoma peptides and anti-CTLA-4 monoclonal antibody. Of 56 patients, 2 achieved CR (ongoing at 30 and 31 months, respectively) and 5 experienced PRs, for an overall objective response rate of 13%. And, a phase 1 trial by Ribas and colleagues of anti-CTLA-4 monotherapy resulted in a total response of 14% (4 of 29 patients), with 2 CRs and 2 PRs. In both studies, grade 3/4 toxicities consisted of autoimmune phenomena including colitis, dermatitis, vitiligo, panhypopituitarism, uveitis, and hyperthyroidism, which correlated with tumor response (PR and CR). In the latter study, patients who experienced autoimmune toxicity achieved a clinical response of 36% (5 of 14 patients), compared with only 5% (2 responses of 42 patients) of those without an autoimmune response(P = .008).
Lymphodepletion with chemotherapy followed by adoptive cell transfer with autologous activated tumor-specific T cells has improved response rates in refractory metastatic melanoma. A recent investigation by Dudley and associates evaluated 35 patients with metastatic melanoma who were given lymphodepleting, but not myeloablative chemotherapy, with cyclophosphamide/fludarabine followed by infusion with autologous tumor-reactive T cells and high-dose IL-2 therapy. An objective clinical response was achieved in 51% (18 of 35) of treated patients including 3 ongoing CRs and 15 PRs (mean duration of 11.5 ± 2.2 months).
In an attempt to improve response rates, investigators are currently evaluating the value of combining cytokine therapies, T cell therapy, and vaccines in patients with stage IV melanoma. Dendritic cell vaccination plus T cell infusion and IL-2 resulted in a more robust tumor response in mouse models. An investigation of combined immunotherapy is currently underway at MDACC to evaluate lymphodepleting chemotherapy with a combination of dendritic cell vaccination, T cell infusion, and IL-2.
Biochemotherapy
Michael B. Atkins, MD, Director of Cutaneous Oncology and Biologic Therapy Programs at Beth Israel Deaconess Medical Center, Boston, reviewed new developments in biochemotherapy. The combination of cisplatin-based cytotoxic therapy plus IL-2 based immunotherapy has been extensively studied over the past decade. Phase 2 trials and meta-analyses of cisplatin/IL-2-based biochemotherapy demonstrated positive results (50% RR, 10% CR, and 33% improvement in median survival time). In a prospective randomized phase 3 intergroup study (E3695); however, no statistically significant difference in response or survival was observed between the 2 treatment arms (cisplatin, vinblastine, dacarbazine, IL-2, and IFN alpha-2 vs dacarbazine alone).
Given the low toxicity profile of temozolomide (TMZ) and in an attempt to prevent CNS progression, many clinicians prefer to use TMZ rather than dacarbazine. A single institution study of temozolomide plus IL-2 biochemotherapy led to a 47% overall response rate (22 of 48 patients) with 7 CRs and 15 PRs. The TMZ/IL-2 group experienced a significantly lower rate of CNS progression (9% at 4 and 9 months, P = .001) vs those receiving dacarbazine/IL-2 (63% at median 6 months).
At the 2005 annual ASCO meeting, O'Day presented the results of a phase 2 multicenter trial evaluating maintenance biotherapy with IL-2 plus granulocyte macrophage colony-stimulating factor (GM-CSF) after induction biochemotherapy for stage IV melanoma. After biochemotherapy, 37% of patients responded (8% CR; 36% PR). Four patients responded to maintenance biotherapy (3 PR to CR; 1 stable disease to PR) and 5 patients (3 PR and 2 SD) were able to undergo complete resection of residual disease. The median time to progression (TTP) was 9 months (range, 7.8-12.0) and overall survival (OS) was 14 months (range, 11.5-15.4). However, 52 patients (39%) developed CNS progression.
Thus, maintenance biotherapy appeared to prolong TTP and improve OS, in contrast to results from multi-center trials of chemotherapy and biochemotherapy (eg, E3695), which failed to show any benefit. An intergroup adjuvant trial of concurrent biochemotherapy vs high-dose interferon (S0008) is currently ongoing. At this point, biochemotherapy is still an investigational treatment. High-dose IL-2 is the only immunotherapy currently indicated for patients with stage IV melanoma.
Adjuvant Chemotherapy for Advanced-Stage Melanoma
Stephen Hodi, MD, also presented an overview of adjuvant therapy for advanced-stage melanoma. Prognostic factors that should prompt the oncologist to consider adjuvant therapy include the depth of the primary tumor, the presence of ulceration, and lymph node status. The goal of adjuvant treatment is to improve survival in high risk patients. Yet, most adjuvant clinical trials have been underpowered and include a heterogeneous patient population, making clinical interpretation difficult. Dr. Hodi reviewed adjuvant therapies under investigation or in clinical practice including vaccines, interferon, and GM-CSF. Only the latter 2 approaches are discussed here.
Interferon
Currently, there is no standard of care for patients with stage III melanoma, and oncologists disagree regarding the use of interferon in this population. Adjuvant interferon alpha 2B (IFN) is the most utilized and best studied agent for stage III melanoma, but it offers no survival benefit and is associated with a high toxicity profile.
A pooled analysis of Eastern Cooperative Oncology Group (ECOG) and intergroup trials of high dose IFN in stage IIB and III melanoma has improved relapse-free survival vs observation alone. However, no impact on overall survival has been demonstrated. Dr. Hodi posited that IFN should be considered one potential standard of therapy in patients with stage III disease, especially those at high risk. He encouraged discussing treatment issues including toxicity and quality of life with each patient.
Granulocyte Macrophage Colony-Stimulating Factor
Another agent being studied is GM-CSF, which stimulates the immune system, thus leading to antigen presentation. Biopsy of intralesionally administered GM-CSF has shown immune infiltration, demonstrating its ability to stimulate the immune response. GM-CSF was associated with limited toxicity and an overall survival benefit. Prospective studies of GM-CSF in stage IV/NED (no evidence of disease, patients surgically rendered disease-free) are needed. The current standard of care in stage III/IV NED is observation, but enrolling patients in clinical trials is highly recommended.
Although these reports confirm the extensive investigation of new therapies for melanoma including temozolomide, anti-CLA-4 antibodies, adoptive cell transfer, and the combinations of various agents (biochemotherapy and combined immunotherapy), results have been modest. Unfortunately, the prognosis for patients with advanced melanoma continues to be dismal, with palliation the mainstay of therapy. Further investigation of these agents alone and in combination is needed and patient participation in clinical trials is critical.
References
In 2006, an estimated 62,190 Americans will be diagnosed with cutaneous melanoma and 7910 will die from the disease. In the United States, cutaneous melanoma currently ranks 5th in incidence among both men and women. At the first annual Oncology World Congress, held in New York City, Drs. F. Stephen Hodi, Michael B. Atkins, and Patrick Hwu reviewed the literature and discussed new developments in melanoma management.
Immunotherapy
Patrick Hwu, MD, Chairman of Melanoma Medical Oncology at the M.D. Anderson Cancer Center (MDACC) reviewed new developments in melanoma immunotherapy.
Melanoma and renal cell carcinoma are 2 malignancies for which the immune system response is critical. The primary goals of immunotherapy are to upregulate the proinflammatory response, and thus to mobilize immune effector cells, and to downregulate the immune tolerance to cancer cells. Dr. Hwu discussed the use of proinflammatory cytokines, tumor vaccines, and adoptive cell therapies to stimulate the immune response.
Cytokine Therapy
Treatment with high-dose interleukin 2 (IL-2) has resulted in dramatic clinical outcomes, including significant tumor regression in patients with diffuse metastatic disease. High-dose IL-2 induced a response rate of 16% (95% confidence interval, 12% to 21%) with a 10% partial response (PR) and 6% complete response (CR) in patients with stage IV melanoma. Those patients who did respond, attained a prolonged response (median 5.9 months for PR, with the CR median response duration not yet reached). Nonetheless, response rates for IL-2 therapy are modest and toxicity is high. Dr. Hwu emphasized the need to better understand the molecular fingerprints of responders vs nonresponders and to develop immune therapies that are more effective and less toxic.
Vaccine Therapy
Vaccines are a promising but still experimental approach to treating melanoma. Unlike antibodies, which can only target extracellular proteins, T cells can recognize intracellular peptides, presented by major histocompatibility complex (MHC) molecules, within tumor cells. Possible tumor-specific targets for vaccine therapy include mutated proteins, oncogene products, and abnormal signaling proteins. A number of possible tumor antigen targets in melanoma have been explored and include MART-1, EphA2, adipophilin, SSX-2, NY-ESO-1gp100, Tyrosinase, ESO, CDK4, and TRP- and TRP-2.
Subsets of whole tumor vaccines include autologous vaccines, which are developed from each patient's tumor biopsy, and "off the shelf" allogeneic vaccines, which can be used in a variety of patients (eg, polyvalent cancer vaccine). Antigen-specific vaccines include peptide/protein plus adjuvant, recombinant viral, and DNA vaccines. Although the use of melanoma vaccines has resulted in greater numbers of circulating specific T cells, response rates have been poor. A pooled analysis of recombinant viral, peptide, and DNA vaccine clinical trials presented by Dr. Hwu showed an objective response in approximately 2% of patients with stage IV disease.
F. Stephen Hodi, MD, Assistant Professor of Medicine, Harvard Medical School, and Clinical Director of the Melanoma Program at the Dana-Farber Cancer Institute, Boston, Massachusetts, reviewed the results of clinical trials with melacine. Large prospective trials of melacine, an allogeneic melanoma cell lysate, for patients with stages II/III melanoma demonstrated a disease-free survival (DFS) benefit in the intent-to-treat population, but no overall survival benefit. However, analysis of responders linked certain HLA haplotypes with improved relapse-free survival. HLA-A2 and HLA-C3, in particular, were associated with disease-free and overall survival benefit.
To improve the response rates seen with vaccine alone, investigators have combined vaccine therapy with other methods of improving the anti-tumor immune response. Cytotoxic T lymphocyte-associated antigen (CTLA-4) is a membrane-bound molecule on cytotoxic, regulatory, and helper T cells that inhibits T cell proliferation and is important to maintaining peripheral tolerance to self-antigens. In a study by Attia and colleagues, patients with stage IV melanoma were vaccinated with 1 of 2 gp100 melanoma peptides and anti-CTLA-4 monoclonal antibody. Of 56 patients, 2 achieved CR (ongoing at 30 and 31 months, respectively) and 5 experienced PRs, for an overall objective response rate of 13%. And, a phase 1 trial by Ribas and colleagues of anti-CTLA-4 monotherapy resulted in a total response of 14% (4 of 29 patients), with 2 CRs and 2 PRs. In both studies, grade 3/4 toxicities consisted of autoimmune phenomena including colitis, dermatitis, vitiligo, panhypopituitarism, uveitis, and hyperthyroidism, which correlated with tumor response (PR and CR). In the latter study, patients who experienced autoimmune toxicity achieved a clinical response of 36% (5 of 14 patients), compared with only 5% (2 responses of 42 patients) of those without an autoimmune response(P = .008).
Lymphodepletion with chemotherapy followed by adoptive cell transfer with autologous activated tumor-specific T cells has improved response rates in refractory metastatic melanoma. A recent investigation by Dudley and associates evaluated 35 patients with metastatic melanoma who were given lymphodepleting, but not myeloablative chemotherapy, with cyclophosphamide/fludarabine followed by infusion with autologous tumor-reactive T cells and high-dose IL-2 therapy. An objective clinical response was achieved in 51% (18 of 35) of treated patients including 3 ongoing CRs and 15 PRs (mean duration of 11.5 ± 2.2 months).
In an attempt to improve response rates, investigators are currently evaluating the value of combining cytokine therapies, T cell therapy, and vaccines in patients with stage IV melanoma. Dendritic cell vaccination plus T cell infusion and IL-2 resulted in a more robust tumor response in mouse models. An investigation of combined immunotherapy is currently underway at MDACC to evaluate lymphodepleting chemotherapy with a combination of dendritic cell vaccination, T cell infusion, and IL-2.
Biochemotherapy
Michael B. Atkins, MD, Director of Cutaneous Oncology and Biologic Therapy Programs at Beth Israel Deaconess Medical Center, Boston, reviewed new developments in biochemotherapy. The combination of cisplatin-based cytotoxic therapy plus IL-2 based immunotherapy has been extensively studied over the past decade. Phase 2 trials and meta-analyses of cisplatin/IL-2-based biochemotherapy demonstrated positive results (50% RR, 10% CR, and 33% improvement in median survival time). In a prospective randomized phase 3 intergroup study (E3695); however, no statistically significant difference in response or survival was observed between the 2 treatment arms (cisplatin, vinblastine, dacarbazine, IL-2, and IFN alpha-2 vs dacarbazine alone).
Given the low toxicity profile of temozolomide (TMZ) and in an attempt to prevent CNS progression, many clinicians prefer to use TMZ rather than dacarbazine. A single institution study of temozolomide plus IL-2 biochemotherapy led to a 47% overall response rate (22 of 48 patients) with 7 CRs and 15 PRs. The TMZ/IL-2 group experienced a significantly lower rate of CNS progression (9% at 4 and 9 months, P = .001) vs those receiving dacarbazine/IL-2 (63% at median 6 months).
At the 2005 annual ASCO meeting, O'Day presented the results of a phase 2 multicenter trial evaluating maintenance biotherapy with IL-2 plus granulocyte macrophage colony-stimulating factor (GM-CSF) after induction biochemotherapy for stage IV melanoma. After biochemotherapy, 37% of patients responded (8% CR; 36% PR). Four patients responded to maintenance biotherapy (3 PR to CR; 1 stable disease to PR) and 5 patients (3 PR and 2 SD) were able to undergo complete resection of residual disease. The median time to progression (TTP) was 9 months (range, 7.8-12.0) and overall survival (OS) was 14 months (range, 11.5-15.4). However, 52 patients (39%) developed CNS progression.
Thus, maintenance biotherapy appeared to prolong TTP and improve OS, in contrast to results from multi-center trials of chemotherapy and biochemotherapy (eg, E3695), which failed to show any benefit. An intergroup adjuvant trial of concurrent biochemotherapy vs high-dose interferon (S0008) is currently ongoing. At this point, biochemotherapy is still an investigational treatment. High-dose IL-2 is the only immunotherapy currently indicated for patients with stage IV melanoma.
Adjuvant Chemotherapy for Advanced-Stage Melanoma
Stephen Hodi, MD, also presented an overview of adjuvant therapy for advanced-stage melanoma. Prognostic factors that should prompt the oncologist to consider adjuvant therapy include the depth of the primary tumor, the presence of ulceration, and lymph node status. The goal of adjuvant treatment is to improve survival in high risk patients. Yet, most adjuvant clinical trials have been underpowered and include a heterogeneous patient population, making clinical interpretation difficult. Dr. Hodi reviewed adjuvant therapies under investigation or in clinical practice including vaccines, interferon, and GM-CSF. Only the latter 2 approaches are discussed here.
Interferon
Currently, there is no standard of care for patients with stage III melanoma, and oncologists disagree regarding the use of interferon in this population. Adjuvant interferon alpha 2B (IFN) is the most utilized and best studied agent for stage III melanoma, but it offers no survival benefit and is associated with a high toxicity profile.
A pooled analysis of Eastern Cooperative Oncology Group (ECOG) and intergroup trials of high dose IFN in stage IIB and III melanoma has improved relapse-free survival vs observation alone. However, no impact on overall survival has been demonstrated. Dr. Hodi posited that IFN should be considered one potential standard of therapy in patients with stage III disease, especially those at high risk. He encouraged discussing treatment issues including toxicity and quality of life with each patient.
Granulocyte Macrophage Colony-Stimulating Factor
Another agent being studied is GM-CSF, which stimulates the immune system, thus leading to antigen presentation. Biopsy of intralesionally administered GM-CSF has shown immune infiltration, demonstrating its ability to stimulate the immune response. GM-CSF was associated with limited toxicity and an overall survival benefit. Prospective studies of GM-CSF in stage IV/NED (no evidence of disease, patients surgically rendered disease-free) are needed. The current standard of care in stage III/IV NED is observation, but enrolling patients in clinical trials is highly recommended.
Although these reports confirm the extensive investigation of new therapies for melanoma including temozolomide, anti-CLA-4 antibodies, adoptive cell transfer, and the combinations of various agents (biochemotherapy and combined immunotherapy), results have been modest. Unfortunately, the prognosis for patients with advanced melanoma continues to be dismal, with palliation the mainstay of therapy. Further investigation of these agents alone and in combination is needed and patient participation in clinical trials is critical.
References
American Cancer Society. Cancer Facts & Figures 2006. Available at: http://www.cancer.org/downloads/STT/CAFF2006PWSecured.pdf. Accessed March 1, 2006.
Atkins MB, Lotze MT, Dutcher JP, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999;17:2105-2116. Abstract
Sondak VK, Sosman JA. Results of clinical trials with an allogenic melanoma tumor cell lysate vaccine: Melacine. Semin Cancer Biol. 2003;13:409-415. Abstract
Vasu C, Prabhakar BS, Holterman MJ. Targeted CTLA-4 engagement induces CD4+CD25+CTLA-4high T regulatory cells with target (allo)antigen specificity. J Immunol. 2004;173:2866-2876. Abstract
Taylor PA, Noelle RJ, Blazar BR. CD4(+)CD25(+) immune regulatory cells are required for induction of tolerance to alloantigen via costimulatory blockade. J Exp Med. 2001;193:1311-1318. Abstract
Takahashi T, Tagami T, Yamazaki S, et al. Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med. 2000;192:303-310. Abstract
Attia P, Phan GQ, Maker AV, et al. Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol. 2005;23:6043-6053. Abstract
Ribas A CL, Lopez-Berestein G, Pavlov D, et al. Antitumor activity in melanoma and anti-self responses in a phase i trial with the anti-cytotoxic t lymphocyte-associated antigen 4 monoclonal antibody CP-675,206. J Clin Oncol. 2005;23:8968-8977. Abstract
Dudley ME, Wunderlich JR, Yang JC, et al. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol. 2005;23:2346-2357. Abstract
Lou Y, Wang G, Lizee G, et al. Dendritic cells strongly boost the antitumor activity of adoptively transferred T cells in vivo. Cancer Res. 2004;64:6783-6790. Abstract
Atkins MB, Lee S, Flaherty LE, et al. A prospective randomized phase III trial of concurrent biochemotherapy (BCT) with cisplatin, vinblastine, dacarbazine (CVD), IL-2 and interferon alpha-2b (IFN) versus CVD alone in patients with metastatic melanoma (E3695): An ECOG-coordinated intergroup trial. Proc Am Soc Clin Oncol. 2003. Abstract 2847
Atkins MB, Gollob JA, Sosman JA, et al. A phase II pilot trial of concurrent biochemotherapy with cisplatin, vinblastine, temozolomide, interleukin 2, and IFN-alpha 2B in patients with metastatic melanoma. Clin Cancer Res. 2002;8:3075-3081. Abstract
O'Day. A phase II multi-center trial of maintenance biotherapy (MBT) after induction concurrent biochemotherapy (BCT) for patients (Pts) with metastatic melanoma (MM). Proc Am Soc Clin Oncol; 2005. Abstract 7503
Kirkwood JM, Manola J, Ibrahim J, Sondak V, Ernstoff MS, Rao U. A pooled analysis of eastern cooperative oncology group and intergroup trials of adjuvant high-dose interferon for melanoma. Clin Cancer Res. 2004;10:1670-1677. Abstract
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