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E-45. Small cell lung cancer: Targeting minimal residual disease
s55
E-45. Small Cell Lung Cancer:TargetingMinimal ResidualDisease Lee M. Krug Clinical
Assistant
Attending
Physician,
Memorial
The outcome for patients with small cell lung cancer has improved marginally over the last 20 years. Standard chemotherapy regimens yield high response rates and some cures when combined with thoracic irradiation in limited stage patients. Nonetheless, SCLC has a high relapse rate due to drug resistance. This has resulted in continued poor survival for most patients. Developing ways to maintain response after induction chemotherapy or chemoradiotherapy has been a major research focus. The lack of an assay capable of measuring residual disease limits our ability to gauge the risk for relapse or to assess the efficacy of therapy in this setting. At this time all patients are considered at high risk and the challenge is to maintain their remission status. The chemosensitivity of SCLC logically supports the use of maintenance chemotherapy or high dose treatments as a way to attack residual metastatic disease. However, trials using more chemotherapy have generally resulted in more toxicity with no improvement in survival. In 13 randomized trials of maintenance chemotherapy, only one showed an overall survival advantage, five showed improvements only in subgroups of patients, and one showed a shorter survival with continued treatment [ 11. At least 36 studies of high dose chemotherapy with autologous bone marrow or stem cell rescue have been reported [2,3]. In these trials, only a small fraction of patients can complete the high dose chemotherapy due to co-morbid illnesses or toxicity, treatment related mortality is significant, and survival remains poor. In order to change outcomes in SCLC substantially, new approaches are needed. The matrix metalloproteinase (MMP) inhibitors are a novel class of drugs that were tested in SCLC patients as a potential therapy aimed at maintaining remission, but unfortunately yielded disappointing results in phase III trials. MMPs are a class of over 30 extracellular enzymes that degrade connective tissue and play an important role in bone development, wound healing, and vascular remodeling. Several inhibitors of these enzymes have been developed to decrease the cell migration responsible for metastatic spread. Dr. Shepherd reported the results of a phase III NCICEORTC trial in which 532 patients with small cell lung cancer who completed initial therapy were randomized to receive marimastat, a broad-spectrum MMP inhibitor, or placebo [4]. There was no difference between the marimastat and placebo groups with regards to overall survival or progression free survival. Furthermore, myalgias and arthralgias necessitated dose reduction or drug discontinuation in 33% and 32% of the patients receiving marimastat. The results of this trial, as well as the early discontinuation of a similar trial with BAY 12-9566, raise doubts as to the efficacy of this class of agents in SCLC, though specific inhibition of other MMPs could be explored. At Memorial Sloan-Kettering, we are attempting to take advantage of unique epitopes present on SCLC to develop vaccines. One potential target identified is the ganglioside GD3 expressed on cells of neuroectodermal origin. Using an anti-idiotype approach, the mouse monoclonal antibody BEC2 was developed against the binding region of the mouse monoclonal antibody R24 which binds to GD3. A pilot study was performed in which
Sloan-Kettering
Cancer
Center;
New York, NI:
USA
1.5 patients with SCLC who had a major response to induction chemotherapy were immunized with BEC2. BCG was also added as an immunologic adjuvant [5]. Of the 13 evaluable patients, all developed anti-BEC2 antibodies (HAMA). Five patients had measurable anti-GD3 IgM antibody and 3 of those patients developed IgG antibodies. Median overall survival was 21 months; median time to relapse was 11 months in the extensive stage group and had not been reached in the limited stage group (>47 months). These results were a significant improvement when compared to two historical control groups treated at our center, and prompted an international phase III trial in SCLC patients with limited disease and a complete or partial response after initial therapy (the SILVA trial, lead by the EORTC). This trial completed accrual in October, 2002. Currently, we are also testing the immunogenicity of vaccines against other targets in SCLC such as GM2, Fucosyl GM1 [6,7], Globo H, and polysialic acid [S]. In order to optimize the likelihood of immunologic effect, we plan to combine the vaccines into a polyvalent vaccine. Only new strategies will improve outcomes for SCLC patients. Eligible individuals should enroll in clinical trials after chemotherapy and irradiation. References [I I Sculier, J. P., Berghmans, T., Castaigne, C., Lute, S., Sotiriou, C., Vermylen, P. and Paesmans, M. Maintenancechemotherapyfor small cell lung cancer:a critical review of the literature. Lung Cancer, 19: 141.151, 1998. [21 Elias, A. D., Ayash, L., Frei III, E., Skarin, A. T., Hunt, M., Wheeler, C., Schwartz, G., Mazanet, R., Tepler, I., Eder, J. P., McCauley, M., Herman, T., Schnipper, L. and Antman, K. H. Intensive combined modality therapy for limited-stage small-cell lung cancer. J. Natl. Cancer Inst., 85: 559.566, 1993. [31 Kmg, L. M., Grant, S. C., Miller, V. A., Ng, K. K. and Kris, M. G. Strategies to eradicate minimal residual disease in small cell lung cancer: High-dose chemotherapy with autologous bone marrow transplantation, matrix metalloproteinase inhibitors, and BEC2 plus BCG vaccination. Semin. Oncol., 5 (suppll5): 55-61, 1999. [41 Shepherd, F. A., Giaccone, G., Seymour, L., Debruyne, C., Bezjak, A., Hirsh, V., Smylie, M., Rubin, S., Martins, H., Lament, A., Krzakowski, M., Sadura, A. and Zee, B. Prospective, randomized, double-blind, placebo-controlled trial of marimastat after response to first-line chemotherapy in patients with small-cell lung cancer: a trial of the National Cancer Institute of CanadaClinical Trials Group and the European Organization for Research and Treatment of Cancer. J. Clin. Oncol., 20: 4434-4439.2002. [51 Grant, S. C., Kris, M. G., Houghton, A. N. and Chapman, I? B. Long survival of patients with small cell lung cancer after adjuvant treatment with the anti-idiotypic antibody BEC2 plus Bacillus Calmette-Guerin. Clinical Cancer Research, 5: 1319-1323, 1999. [61 Krug, L. M., Ragupathi, G., Livingston, P. O., Tyson, L., Hood, C., Baez, V, Danishefsky, S. J., Miller, V. A., Ng, K., Gomez, J. and Kris, M. G. Pilot trial of a synthetic fucosyl-GM1 ganglioside vaccine in patients with small cell lung cancer (SCLC). Proc. Am. Sot. Clin. Oncol., 21: Abstr 1218,2002. [71 Dickler, M. N., Ragupathi, G., Liu, N. X., Musselli, C.. Martino, D. J., Miller, V. A., Kris, M. G., Brezicka, F., Livingston, P. 0. and Grant, S. C. Immunogenicity of a Fucosyl-GMl-Keyhole Limpet Hemocyanin conjugate vaccine in patients with small cell lung cancer. Clinical Cancer Research, 5: 2773. 2779, 1999. 181 Ng, K. K., Kris, M. G., Miller, V. A., Kmg, L. M., Michaelson, N., Livingston, P. O., Ragupathi, G. and Jennings, H. Vaccination with polysialic acid-KLH or N-propionylated polysialic acid-KLH conjugate plus QS-21 in patients with small cell lung cancer after a major response to therapy. Proc. Am. Sot. Clin. Oncol., abstr 2644, 2001.
E-45. Small Cell Lung Cancer:TargetingMinimal ResidualDisease Lee M. Krug Clinical
Assistant
Attending
Physician,
Memorial
The outcome for patients with small cell lung cancer has improved marginally over the last 20 years. Standard chemotherapy regimens yield high response rates and some cures when combined with thoracic irradiation in limited stage patients. Nonetheless, SCLC has a high relapse rate due to drug resistance. This has resulted in continued poor survival for most patients. Developing ways to maintain response after induction chemotherapy or chemoradiotherapy has been a major research focus. The lack of an assay capable of measuring residual disease limits our ability to gauge the risk for relapse or to assess the efficacy of therapy in this setting. At this time all patients are considered at high risk and the challenge is to maintain their remission status. The chemosensitivity of SCLC logically supports the use of maintenance chemotherapy or high dose treatments as a way to attack residual metastatic disease. However, trials using more chemotherapy have generally resulted in more toxicity with no improvement in survival. In 13 randomized trials of maintenance chemotherapy, only one showed an overall survival advantage, five showed improvements only in subgroups of patients, and one showed a shorter survival with continued treatment [ 11. At least 36 studies of high dose chemotherapy with autologous bone marrow or stem cell rescue have been reported [2,3]. In these trials, only a small fraction of patients can complete the high dose chemotherapy due to co-morbid illnesses or toxicity, treatment related mortality is significant, and survival remains poor. In order to change outcomes in SCLC substantially, new approaches are needed. The matrix metalloproteinase (MMP) inhibitors are a novel class of drugs that were tested in SCLC patients as a potential therapy aimed at maintaining remission, but unfortunately yielded disappointing results in phase III trials. MMPs are a class of over 30 extracellular enzymes that degrade connective tissue and play an important role in bone development, wound healing, and vascular remodeling. Several inhibitors of these enzymes have been developed to decrease the cell migration responsible for metastatic spread. Dr. Shepherd reported the results of a phase III NCICEORTC trial in which 532 patients with small cell lung cancer who completed initial therapy were randomized to receive marimastat, a broad-spectrum MMP inhibitor, or placebo [4]. There was no difference between the marimastat and placebo groups with regards to overall survival or progression free survival. Furthermore, myalgias and arthralgias necessitated dose reduction or drug discontinuation in 33% and 32% of the patients receiving marimastat. The results of this trial, as well as the early discontinuation of a similar trial with BAY 12-9566, raise doubts as to the efficacy of this class of agents in SCLC, though specific inhibition of other MMPs could be explored. At Memorial Sloan-Kettering, we are attempting to take advantage of unique epitopes present on SCLC to develop vaccines. One potential target identified is the ganglioside GD3 expressed on cells of neuroectodermal origin. Using an anti-idiotype approach, the mouse monoclonal antibody BEC2 was developed against the binding region of the mouse monoclonal antibody R24 which binds to GD3. A pilot study was performed in which
Sloan-Kettering
Cancer
Center;
New York, NI:
USA
1.5 patients with SCLC who had a major response to induction chemotherapy were immunized with BEC2. BCG was also added as an immunologic adjuvant [5]. Of the 13 evaluable patients, all developed anti-BEC2 antibodies (HAMA). Five patients had measurable anti-GD3 IgM antibody and 3 of those patients developed IgG antibodies. Median overall survival was 21 months; median time to relapse was 11 months in the extensive stage group and had not been reached in the limited stage group (>47 months). These results were a significant improvement when compared to two historical control groups treated at our center, and prompted an international phase III trial in SCLC patients with limited disease and a complete or partial response after initial therapy (the SILVA trial, lead by the EORTC). This trial completed accrual in October, 2002. Currently, we are also testing the immunogenicity of vaccines against other targets in SCLC such as GM2, Fucosyl GM1 [6,7], Globo H, and polysialic acid [S]. In order to optimize the likelihood of immunologic effect, we plan to combine the vaccines into a polyvalent vaccine. Only new strategies will improve outcomes for SCLC patients. Eligible individuals should enroll in clinical trials after chemotherapy and irradiation. References [I I Sculier, J. P., Berghmans, T., Castaigne, C., Lute, S., Sotiriou, C., Vermylen, P. and Paesmans, M. Maintenancechemotherapyfor small cell lung cancer:a critical review of the literature. Lung Cancer, 19: 141.151, 1998. [21 Elias, A. D., Ayash, L., Frei III, E., Skarin, A. T., Hunt, M., Wheeler, C., Schwartz, G., Mazanet, R., Tepler, I., Eder, J. P., McCauley, M., Herman, T., Schnipper, L. and Antman, K. H. Intensive combined modality therapy for limited-stage small-cell lung cancer. J. Natl. Cancer Inst., 85: 559.566, 1993. [31 Kmg, L. M., Grant, S. C., Miller, V. A., Ng, K. K. and Kris, M. G. Strategies to eradicate minimal residual disease in small cell lung cancer: High-dose chemotherapy with autologous bone marrow transplantation, matrix metalloproteinase inhibitors, and BEC2 plus BCG vaccination. Semin. Oncol., 5 (suppll5): 55-61, 1999. [41 Shepherd, F. A., Giaccone, G., Seymour, L., Debruyne, C., Bezjak, A., Hirsh, V., Smylie, M., Rubin, S., Martins, H., Lament, A., Krzakowski, M., Sadura, A. and Zee, B. Prospective, randomized, double-blind, placebo-controlled trial of marimastat after response to first-line chemotherapy in patients with small-cell lung cancer: a trial of the National Cancer Institute of CanadaClinical Trials Group and the European Organization for Research and Treatment of Cancer. J. Clin. Oncol., 20: 4434-4439.2002. [51 Grant, S. C., Kris, M. G., Houghton, A. N. and Chapman, I? B. Long survival of patients with small cell lung cancer after adjuvant treatment with the anti-idiotypic antibody BEC2 plus Bacillus Calmette-Guerin. Clinical Cancer Research, 5: 1319-1323, 1999. [61 Krug, L. M., Ragupathi, G., Livingston, P. O., Tyson, L., Hood, C., Baez, V, Danishefsky, S. J., Miller, V. A., Ng, K., Gomez, J. and Kris, M. G. Pilot trial of a synthetic fucosyl-GM1 ganglioside vaccine in patients with small cell lung cancer (SCLC). Proc. Am. Sot. Clin. Oncol., 21: Abstr 1218,2002. [71 Dickler, M. N., Ragupathi, G., Liu, N. X., Musselli, C.. Martino, D. J., Miller, V. A., Kris, M. G., Brezicka, F., Livingston, P. 0. and Grant, S. C. Immunogenicity of a Fucosyl-GMl-Keyhole Limpet Hemocyanin conjugate vaccine in patients with small cell lung cancer. Clinical Cancer Research, 5: 2773. 2779, 1999. 181 Ng, K. K., Kris, M. G., Miller, V. A., Kmg, L. M., Michaelson, N., Livingston, P. O., Ragupathi, G. and Jennings, H. Vaccination with polysialic acid-KLH or N-propionylated polysialic acid-KLH conjugate plus QS-21 in patients with small cell lung cancer after a major response to therapy. Proc. Am. Sot. Clin. Oncol., abstr 2644, 2001.