Transcript 슬라이드 1
Sipuleucel-T Immunotherapy for CastrationResistant Prostate Cancer Philip W. Kantoff, M.D., Celestia S. Higano, M.D., Neal D. Shore, M.D., E. Roy Berger, M.D., Eric J. Small, M.D., David F. Penson, M.D., Charles H. Redfern, M.D., Anna C. Ferrari, M.D., Robert Dreicer, M.D., Robert B. Sims, M.D., Yi Xu, Ph.D., Mark W. Frohlich, M.D., and Paul F. Schellhammer, M.D. N Engl J Med 2010;363:411-22 R1 Kang Sung-wook / prof. Kim Si-young BACKGROUND Prostate cancer the most common cancer among men in the United States the second leading cause of death from cancer in men Metastatic castration-resistant prostate cancer median survival : 12.2 to 21.7 months Docetaxel : a median survival benefit of 2 to 3 months, as compared with mitoxantrone and prednisone. BACKGROUND Sipuleucel-T active cellular immunotherapy : autologous peripheral-blood mononuclear cells (PBMCs), including antigen-presenting cells (APCs) PA2024 : recombinant fusion protein consists of a prostate antigen, prostatic acid phosphatase, that is fused to GM-CSF Two studies 1st : reduction in the risk of death of 41% 2nd : not statistically significant No significant effect on the time to disease progression (the primary end point) METHODS - Patients Eligibility criteria metastatic castration-resistant prostate cancer expected survival of at least 6 months any Gleason score, asymptomatic or minimally symptomatic disease Serum PSA ≥ 5ng/ml, testosterone < 50ng/dl progressive disease on imaging studies or PSA measurements Exclusion criteria ECOG performance status ≥ 2, visceral metastases pathologic long-bone fractures, spinal cord compression treatment within the previous 28 days : systemic glucocorticoids, external-beam radiation, surgery, initiated or discontinued bisphosphonate therapy treatment with more than two chemotherapy regimens or chemotherapy within the previous 3 months METHODS - Randomization and Treatment Patients stratifing Primary Gleason grade : ≤3 or ≥4 The number of bone metastases : ≤5, 6 to 10 or >10 Bisphosphonate use : yes or no Treatment premedication : acetaminophen, antihistamine sipuleucel-T or placebo iv during 60 minutes Sipuleucel-T : culturing APCs for 36 to 44 hours at 37°C with media containing PA2024 Placebo : at 2 to 8°C without PA2024 Disease progression monitoring : CT, bone scanning METHODS - Others Adverse Events grade with the National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 3.0 Primary end point overall survival the time from randomization until death from any cause Secondary end point objective disease progression increase of at least 50% diameters for index lesions new appearance or unequivocal progression of nonindex lesions at least two new lesions on bone scanning new pathologic fracture or spinal cord compression METHODS - Others Statistical methods Two-sided Wald’s test : To analyze The primary end point of overall survival Stratified, unadjusted Cox model and log-rank test : To assese the treatment effect Primary Cox model : To determination of prostate-cancer–specific survival Inverted Kaplan–Meier technique : To estimate median follow-up time RESULTS Sipuleucel-T Death Median survival Placebo 210/341(61.6%) 121/171(70.8%) 25.8months 21.7months Adjusted hazard ratio for death : 0.78 (P= 0.03) median survival 4.1 months longer 23.0% 31.7% The median time to objective disease progression Sipuleucel-T group : 14.6 weeks (3.7 months) Placebo group : 14.4 weeks (3.6 months) hazard ratio = 0.95 (P = 0.63) The results of the median time to clinical disease progression was similar hazard ratio = 0.92 (P = 0.40) PA2024 PAP (prostatic acid phosphatase) Sipuleucel-T Placebo Ab titer > 400 100/151(66.2%) 2/70(2.9%) T-cell proliferation 46/63(73.0%) 4/33(12.1%) Ab titer > 400 43/151(28.5%) 1/70(1.4%) T-cell proliferation 15/55(27.3%) 2/25(8.0%) PA2024 or PAP Ab titer > 400 at any time survival benefit (P<0.001 and P = 0.08) PA2024 or PAP T-cell proliferation responses at week 6 No survival difference These events occurred within 1 day after infusion and resolved within 1 to 2 days (except groin pain ) CONCLUSION Sipuleucel-T prolonged survival among men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer. No significant effect on the time to objective disease progression was observed. The treatment was associated with infusional adverse events, including fever and chills, which were mainly grade 1 or 2 in severity.