Hoai‐Thu Thai, Nadia Gaudel-Dedieu, M. Cerou, Bernard Sebastien, H. Velde, D. Semiond, C. Veyrat‐Follet
{"title":"基于模型的方法评估Isatuximab (Isa)治疗复发/难治性多发性骨髓瘤(RRMM)的月给药方案","authors":"Hoai‐Thu Thai, Nadia Gaudel-Dedieu, M. Cerou, Bernard Sebastien, H. Velde, D. Semiond, C. Veyrat‐Follet","doi":"10.1158/1538-7445.AM2021-1372","DOIUrl":null,"url":null,"abstract":"Introduction: Isa is a CD38 monoclonal antibody with multiple modes of action for killing tumor cells. Isa, in combination with pomalidomide and dexamethasone (Pd), is approved for the treatment of adult pts with RRMM who have received ≥2 prior therapies including lenalidomide and a proteasome inhibitor. This study characterized the relationship between serum M-protein kinetics and progression free survival (PFS) in RRMM pts from the Phase 3 ICARIA-MM study, and simulated expected PFS outcomes when switching to a hypothetical monthly Isa dosing regimen after 6 months. Methods: A joint model of serum M-protein dynamics and PFS was developed using data from 256 pts. Pts received Isa intravenously, 10 mg/kg once weekly (QW) for 4 weeks (wks), then every other wk (Q2W) for 28-day cycles plus standard Pd (Isa-Pd) or Pd alone (control). A tumor growth inhibition model described serum M-protein kinetics under treatment effects of Isa-Pd or Pd alone; Isa exposure was predicted using individual PK parameters from the population PK analysis (Fau, PAGE Congress, 2019) and Pd exposure was predicted from K-PD model using dosing history. Trial simulations were performed using individual PK/PD parameters of ICARIA-MM pts. Results: The joint model identified instantaneous changes (slope) in serum M-protein as the best on-treatment predictor for PFS and identified baseline pt characteristics impacting serum M-protein kinetics (serum albumin and serum β2 microglobulin on the baseline serum M-protein levels and the non-IgG type on the serum M‐protein growth rate, the serum M-protein slope) and PFS (presence of plasmacytomas). Non-IgG MM pts have similar behavior on serum M-protein kinetics for the first 60 wks even with higher exposure and similar PFS vs IgG MM pts supporting non-dose adjustment based on IgG status. Clinical trial simulation of the Isa-Pd regimen showed that switching pts on treatment at 6 months to a monthly Isa regimen would shorten the median time to progression (TTP) by 4.1 wks and median PFS by 2.3 wks (14.03 to 13.45 months). Based on TTP criteria, pts with no risk of earlier progression while switching to a monthly Isa regimen (57.7%) tend to have lower baseline tumor burden (lower serum M-protein and lower percent of bone marrow plasma cell) and better prognostic factors (higher glomerular filtration rate, higher albumin, lower β2 microglobulin). At 6 months, 85% of these pts had predicted stable ≥VGPR status. Conclusions: Trial simulations support the approved Isa 10 mg/kg QW/Q2W regimen and show that switching to a monthly Isa regimen after 6 months may reduce clinical benefit in the overall population. However, some pts with good prognosis (low tumor burden, low ISS stage, good renal function) and obtaining stable ≥VGPR status by 6 months may switch to a monthly regimen after 6 months without compromising disease progression risk; this hypothesis will be tested in a prospective clinical trial. Citation Format: Hoai-Thu Thai, Nadia Gaudel-Dedieu, Marc Cerou, Bernard Sebastien, Helgi van de Velde, Dorothee Semiond, Christine Veyrat-Follet. Model based approach to evaluate Isatuximab (Isa) monthly dosing regimen in relapsed/refractory multiple myeloma (RRMM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1372.","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Abstract 1372: Model based approach to evaluate Isatuximab (Isa) monthly dosing regimen in relapsed/refractory multiple myeloma (RRMM)\",\"authors\":\"Hoai‐Thu Thai, Nadia Gaudel-Dedieu, M. Cerou, Bernard Sebastien, H. Velde, D. Semiond, C. Veyrat‐Follet\",\"doi\":\"10.1158/1538-7445.AM2021-1372\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Introduction: Isa is a CD38 monoclonal antibody with multiple modes of action for killing tumor cells. Isa, in combination with pomalidomide and dexamethasone (Pd), is approved for the treatment of adult pts with RRMM who have received ≥2 prior therapies including lenalidomide and a proteasome inhibitor. This study characterized the relationship between serum M-protein kinetics and progression free survival (PFS) in RRMM pts from the Phase 3 ICARIA-MM study, and simulated expected PFS outcomes when switching to a hypothetical monthly Isa dosing regimen after 6 months. Methods: A joint model of serum M-protein dynamics and PFS was developed using data from 256 pts. Pts received Isa intravenously, 10 mg/kg once weekly (QW) for 4 weeks (wks), then every other wk (Q2W) for 28-day cycles plus standard Pd (Isa-Pd) or Pd alone (control). A tumor growth inhibition model described serum M-protein kinetics under treatment effects of Isa-Pd or Pd alone; Isa exposure was predicted using individual PK parameters from the population PK analysis (Fau, PAGE Congress, 2019) and Pd exposure was predicted from K-PD model using dosing history. Trial simulations were performed using individual PK/PD parameters of ICARIA-MM pts. Results: The joint model identified instantaneous changes (slope) in serum M-protein as the best on-treatment predictor for PFS and identified baseline pt characteristics impacting serum M-protein kinetics (serum albumin and serum β2 microglobulin on the baseline serum M-protein levels and the non-IgG type on the serum M‐protein growth rate, the serum M-protein slope) and PFS (presence of plasmacytomas). Non-IgG MM pts have similar behavior on serum M-protein kinetics for the first 60 wks even with higher exposure and similar PFS vs IgG MM pts supporting non-dose adjustment based on IgG status. Clinical trial simulation of the Isa-Pd regimen showed that switching pts on treatment at 6 months to a monthly Isa regimen would shorten the median time to progression (TTP) by 4.1 wks and median PFS by 2.3 wks (14.03 to 13.45 months). Based on TTP criteria, pts with no risk of earlier progression while switching to a monthly Isa regimen (57.7%) tend to have lower baseline tumor burden (lower serum M-protein and lower percent of bone marrow plasma cell) and better prognostic factors (higher glomerular filtration rate, higher albumin, lower β2 microglobulin). At 6 months, 85% of these pts had predicted stable ≥VGPR status. Conclusions: Trial simulations support the approved Isa 10 mg/kg QW/Q2W regimen and show that switching to a monthly Isa regimen after 6 months may reduce clinical benefit in the overall population. However, some pts with good prognosis (low tumor burden, low ISS stage, good renal function) and obtaining stable ≥VGPR status by 6 months may switch to a monthly regimen after 6 months without compromising disease progression risk; this hypothesis will be tested in a prospective clinical trial. Citation Format: Hoai-Thu Thai, Nadia Gaudel-Dedieu, Marc Cerou, Bernard Sebastien, Helgi van de Velde, Dorothee Semiond, Christine Veyrat-Follet. Model based approach to evaluate Isatuximab (Isa) monthly dosing regimen in relapsed/refractory multiple myeloma (RRMM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. 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引用次数: 0
摘要
Isa是一种CD38单克隆抗体,具有多种杀伤肿瘤细胞的作用模式。Isa联合泊马度胺和地塞米松(Pd)被批准用于治疗既往接受过2种以上治疗(包括来那度胺和蛋白酶体抑制剂)的成年RRMM患者。本研究描述了来自ICARIA-MM 3期研究的RRMM患者血清m蛋白动力学与无进展生存期(PFS)之间的关系,并模拟了6个月后切换到假设的每月Isa给药方案时的预期PFS结果。方法:利用256例患者的数据建立血清m蛋白动力学和PFS联合模型。患者静脉注射Isa,每周一次(QW), 10mg /kg,持续4周(周),然后每隔一周(Q2W), 28天周期加标准Pd (Isa-Pd)或单独Pd(对照组)。肿瘤生长抑制模型描述了Isa-Pd或单独Pd治疗作用下的血清m蛋白动力学;使用群体PK分析中的个体PK参数预测Isa暴露(Fau, PAGE Congress, 2019),使用K-PD模型预测Pd暴露,使用给药历史。使用ICARIA-MM pts的个体PK/PD参数进行试验模拟。结果:联合模型确定了血清M蛋白的瞬时变化(斜率)是治疗期间PFS的最佳预测指标,并确定了影响血清M蛋白动力学的基线pt特征(血清白蛋白和血清β2微球蛋白对基线血清M蛋白水平的影响,非igg类型对血清M蛋白生长速率、血清M蛋白斜率的影响)和PFS(浆细胞瘤的存在)。非IgG MM患者在前60周的血清m蛋白动力学上具有相似的行为,即使在较高的暴露水平下也是如此,并且类似的PFS与IgG MM患者支持基于IgG状态的非剂量调整。Isa- pd方案的临床试验模拟显示,将6个月治疗的患者转换为每月一次的Isa方案将缩短中位进展时间(TTP) 4.1周,中位PFS缩短2.3周(14.03至13.45个月)。基于TTP标准,转换为每月一次Isa方案时无早期进展风险的患者(57.7%)往往具有较低的基线肿瘤负担(较低的血清m蛋白和较低的骨髓浆细胞百分比)和较好的预后因素(较高的肾小球滤过率,较高的白蛋白,较低的β2微球蛋白)。6个月时,85%的患者预测稳定的≥VGPR状态。结论:试验模拟支持已批准的Isa 10 mg/kg QW/Q2W方案,并显示在6个月后切换到每月Isa方案可能会降低总体人群的临床获益。然而,一些预后良好(肿瘤负荷低、ISS分期低、肾功能良好)且在6个月前获得稳定的≥VGPR状态的患者,在不降低疾病进展风险的情况下,可以在6个月后改用月度方案;这一假设将在前瞻性临床试验中得到验证。引文格式:Hoai-Thu Thai, Nadia Gaudel-Dedieu, Marc Cerou, Bernard Sebastien, Helgi van de Velde, Dorothee Semiond, Christine veyratt - follet。基于模型的方法评价Isatuximab (Isa)治疗复发/难治性多发性骨髓瘤(RRMM)的月给药方案[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志,2021;81(13 -增刊):摘要第1372期。
Abstract 1372: Model based approach to evaluate Isatuximab (Isa) monthly dosing regimen in relapsed/refractory multiple myeloma (RRMM)
Introduction: Isa is a CD38 monoclonal antibody with multiple modes of action for killing tumor cells. Isa, in combination with pomalidomide and dexamethasone (Pd), is approved for the treatment of adult pts with RRMM who have received ≥2 prior therapies including lenalidomide and a proteasome inhibitor. This study characterized the relationship between serum M-protein kinetics and progression free survival (PFS) in RRMM pts from the Phase 3 ICARIA-MM study, and simulated expected PFS outcomes when switching to a hypothetical monthly Isa dosing regimen after 6 months. Methods: A joint model of serum M-protein dynamics and PFS was developed using data from 256 pts. Pts received Isa intravenously, 10 mg/kg once weekly (QW) for 4 weeks (wks), then every other wk (Q2W) for 28-day cycles plus standard Pd (Isa-Pd) or Pd alone (control). A tumor growth inhibition model described serum M-protein kinetics under treatment effects of Isa-Pd or Pd alone; Isa exposure was predicted using individual PK parameters from the population PK analysis (Fau, PAGE Congress, 2019) and Pd exposure was predicted from K-PD model using dosing history. Trial simulations were performed using individual PK/PD parameters of ICARIA-MM pts. Results: The joint model identified instantaneous changes (slope) in serum M-protein as the best on-treatment predictor for PFS and identified baseline pt characteristics impacting serum M-protein kinetics (serum albumin and serum β2 microglobulin on the baseline serum M-protein levels and the non-IgG type on the serum M‐protein growth rate, the serum M-protein slope) and PFS (presence of plasmacytomas). Non-IgG MM pts have similar behavior on serum M-protein kinetics for the first 60 wks even with higher exposure and similar PFS vs IgG MM pts supporting non-dose adjustment based on IgG status. Clinical trial simulation of the Isa-Pd regimen showed that switching pts on treatment at 6 months to a monthly Isa regimen would shorten the median time to progression (TTP) by 4.1 wks and median PFS by 2.3 wks (14.03 to 13.45 months). Based on TTP criteria, pts with no risk of earlier progression while switching to a monthly Isa regimen (57.7%) tend to have lower baseline tumor burden (lower serum M-protein and lower percent of bone marrow plasma cell) and better prognostic factors (higher glomerular filtration rate, higher albumin, lower β2 microglobulin). At 6 months, 85% of these pts had predicted stable ≥VGPR status. Conclusions: Trial simulations support the approved Isa 10 mg/kg QW/Q2W regimen and show that switching to a monthly Isa regimen after 6 months may reduce clinical benefit in the overall population. However, some pts with good prognosis (low tumor burden, low ISS stage, good renal function) and obtaining stable ≥VGPR status by 6 months may switch to a monthly regimen after 6 months without compromising disease progression risk; this hypothesis will be tested in a prospective clinical trial. Citation Format: Hoai-Thu Thai, Nadia Gaudel-Dedieu, Marc Cerou, Bernard Sebastien, Helgi van de Velde, Dorothee Semiond, Christine Veyrat-Follet. Model based approach to evaluate Isatuximab (Isa) monthly dosing regimen in relapsed/refractory multiple myeloma (RRMM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1372.