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转移性葡萄膜黑色素瘤患者接受tebentafusp治疗的总生存获益
Overall Survival Benefit with Tebentafusp in Metastatic Uveal Melanoma


Paul Nathan ... 肿瘤 • 2021.09.23

双特异性抗体再创佳绩,转移性葡萄膜黑色素瘤死亡风险减半

 

李宜桐,魏文斌*

首都医科大学附属北京同仁医院眼科;首都医科大学眼科学院

*通讯作者

 

葡萄膜黑色素瘤是成人眼内发病率最高的原发性恶性肿瘤,其中有12%~49%的患者在确诊后10年内会发生远处转移1。由于葡萄膜黑色素瘤突变负荷较低2,且具有特殊的免疫豁免机制3,目前免疫检查点抑制剂4、肿瘤疫苗5和过继T细胞治疗6效果均不甚理想。一旦发生远处转移,患者中位生存期不足1年7。迫切需要对mUM有效的药物阻止疾病进展,延长患者生存期。

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摘要


背景

葡萄膜黑色素瘤是一种不同于皮肤黑色素瘤的疾病,具有较低的肿瘤突变负荷,转移性葡萄膜黑色素瘤患者的1年总生存率约为50%。目前尚无数据证明患者接受全身性治疗后的总生存获益。tebentafusp是一种双特异性蛋白,由亲和力增强的T细胞受体与抗CD3效应体融合而成,可将T细胞重定向为靶向糖蛋白100阳性细胞。

 

方法

在此项开放标签的3期试验中,我们以2∶1的比例将既往未经治疗的HLA-A*02:01阳性转移性葡萄膜黑色素瘤患者随机分组,两组分别接受tebentafusp(tebentafusp组)或研究者所选治疗方案(帕博利珠单抗、伊匹木单抗或达卡巴嗪单药治疗)(对照组),并根据乳酸脱氢酶水平进行分层。主要终点是总生存期。

 

结果

共计378例患者被随机分配至tebentafusp组(252例患者)或对照组(126例患者)。在意向治疗人群中,tebentafusp组和对照组的1年总生存率分别为73%和59%(死亡的风险比,0.51;95%置信区间[CI],0.37~0.71;P<0.001)。tebentafusp组的无进展生存率也显著高于对照组(6个月,31% vs. 19%;疾病进展或死亡的风险比,0.73;95% CI,0.58~0.94;P=0.01)。tebentafusp组最常见的治疗相关不良事件是细胞因子介导的事件(因T细胞活化)和皮肤相关事件(因糖蛋白100阳性黑色素细胞),包括皮疹(83%)、发热(76%)和瘙痒(69%)。前三次或前四次给药后,这些不良事件的发生率降低,严重程度减轻,并且很少导致试验治疗停药(2%)。无治疗相关死亡的报告。

 

结论

在既往未经治疗的转移性葡萄膜黑色素瘤患者中,tebentafusp治疗与对照治疗相比延长了患者的总生存期(由Immunocore资助,在ClinicalTrials.gov注册号为NCT03070392,在EudraCT注册号为2015-003153-18)。





作者信息

Paul Nathan, M.D., Ph.D., Jessica C. Hassel, M.D., Piotr Rutkowski, M.D., Ph.D., Jean-Francois Baurain, M.D., Ph.D., Marcus O. Butler, M.D., Max Schlaak, M.D., Ryan J. Sullivan, M.D., Sebastian Ochsenreither, M.D., Reinhard Dummer, M.D., John M. Kirkwood, M.D., Anthony M. Joshua, M.D., Ph.D., Joseph J. Sacco, M.D., Ph.D., Alexander N. Shoushtari, M.D., Marlana Orloff, M.D., Josep M. Piulats, M.D., Ph.D., Mohammed Milhem, M.D., April K.S. Salama, M.D., Brendan Curti, M.D., Lev Demidov, M.D., Lauris Gastaud, M.D., Cornelia Mauch, M.D., Ph.D., Melinda Yushak, M.D., M.P.H., Richard D. Carvajal, M.D., Omid Hamid, M.D., Shaad E. Abdullah, M.D., Chris Holland, M.S., Howard Goodall, M.D., and Sophie Piperno-Neumann, M.D. for the IMCgp100-202 Investigators*
From Mount Vernon Cancer Centre, Northwood (P.N.), the Clatterbridge Cancer Centre NHS Foundation Trust, Wirral (J.J.S.), the University of Liverpool, Liverpool (J.J.S.), and Immunocore, Abingdon (S.E.A., C.H., H.G.) — all in the United Kingdom; the Department of Dermatology and the National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg (J.C.H.), the Department of Dermatology and Allergy, University Hospital, Ludwig Maximilian University of Munich, Munich (M.S.), the Department of Hematology and Oncology, Charité–Comprehensive Cancer Center (S.O.), Berlin, and the Department of Dermatology and the Center for Integrated Oncology, University Hospital Cologne, Cologne (C.M.) — all in Germany; Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland (P.R.); Institut Roi Albert II des Cliniques Universitaires Saint-Luc and Université Catholique de Louvain, Brussels (J.-F.B.); Princess Margaret Cancer Centre, Toronto (M.O.B.); Massachusetts General Hospital Cancer Center, Boston (R.J.S.); the Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland (R.D.); Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh (J.M.K.); Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia (M.O.); Kinghorn Cancer Centre, Saint Vincent’s Hospital, Darlinghurst, NSW, Australia (A.M.J.); Memorial Sloan Kettering Cancer Center (A.N.S.) and Irving Medical Center, Columbia University (R.D.C.) — both in New York; Institut d’Investigació Biomèdica de Bellvitge–Centro de Investigación Biomédica en Red de Oncología, Institut Català d’Oncologia, Barcelona (J.M.P.); University of Iowa Hospitals and Clinics, Iowa City (M.M.); Duke University, Durham, NC (A.K.S.S.); Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR (B.C.); N.N. Blokhin Cancer Research Center, Moscow (L.D.); Centre Antoine Lacassagne, Nice (L.G.) and Institut Curie, Paris Sciences and Letters Research University, Paris (S.P.-N.) — both in France; Winship Cancer Institute, Emory University, Atlanta (M.Y.); and the Angeles Clinic and Research Institute, a Cedars–Sinai Affiliate, Los Angeles (O.H.). Address reprint requests to Dr. Nathan at the Mount Vernon Cancer Centre, Northwood HA6 2RN, United Kingdom, or at p.nathan@nhs.net. *A complete list of investigators in the IMCgp100-202 trial is provided in the Supplementary Appendix, available at NEJM.org.

 

参考文献

1. Jager MJ, Shields CL, Cebulla CM, et al. Uveal melanoma. Nat Rev Dis Primers 2020;6:24-24.

2. Coupland SE, Lake SL, Zeschnigk M, Damato BE. Molecular pathology of uveal melanoma. Eye (Lond) 2013;27:230-242.

3. Milam RW, Daniels AB. Uveal melanoma. In: Riker AI, ed. Melanoma: a modern multidisciplinary approach. Copenhagen: Springer International Publishing, 2018:273-312.

4. van der Kooij MK, Speetjens FM, van der Burg SH, Kapiteijn E. Uveal versus cutaneous melanoma: same origin, very distinct tumor types. Cancers (Basel) 2019;11:845-845.

5. Buder K, Gesierich A, Gelbrich G, Goebeler M. Systemic treatment of metastatic uveal melanoma: review of literature and future perspectives. Cancer Med 2013;2:674-686.

6. Rantala ES, Hernberg M, Kivelä TT. Overall survival after treatment for metastatic uveal melanoma: a systematic review and meta-analysis. Melanoma Res 2019;29:561-568.

7. Carvajal RD, Schwartz GK, Tezel T, Marr B, Francis JH, Nathan PD. Metastatic disease from uveal melanoma: treatment options and future prospects. Br J Ophthalmol 2017;101:38-44.

8. Kujala E, Mäkitie T, Kivelä T. Very long-term prognosis of patients with malignant uveal melanoma. Invest Ophthalmol Vis Sci 2003;44:4651-4659.

9. Lorenzo D, Piulats JM, Ochoa M, et al. Clinical predictors of survival in metastatic uveal melanoma. Jpn J Ophthalmol 2019;63:197-209.

10. Weis E, Salopek TG, McKinnon JG, et al. Management of uveal melanoma: a consensus-based provincial clinical practice guideline. Curr Oncol 2016;23(1):e57-e64.

11. Khoja L, Atenafu EG, Suciu S, et al. Meta-analysis in metastatic uveal melanoma to determine progression free and overall survival benchmarks: an international rare cancers initiative (IRCI) ocular melanoma study. Ann Oncol 2019;30:1370-1380.

12. Liddy N, Bossi G, Adams KJ, et al. Monoclonal TCR-redirected tumor cell killing. Nat Med 2012;18:980-987.

13. Lowe KL, Cole D, Kenefeck R, OKelly I, Lepore M, Jakobsen BK. Novel TCR-based biologics: mobilising T cells to warm ‘cold’ tumours. Cancer Treat Rev 2019;77:35-43.

14. Bossi G, Buisson S, Oates J, Jakobsen BK, Hassan NJ. ImmTAC-redirected tumour cell killing induces and potentiates antigen cross-presentation by dendritic cells. Cancer Immunol Immunother 2014;63:437-448.

15. Boudousquie C, Bossi G, Hurst JM, Rygiel KA, Jakobsen BK, Hassan NJ. Polyfunctional response by ImmTAC (IMCgp100) redirected CD8+ and CD4+ T cells. Immunology 2017;152:425-438.

16. Middleton MR, McAlpine C, Woodcock VK, et al. Tebentafusp, a TCR/Anti-CD3 bispecific fusion protein targeting gp100, potently activated antitumor immune responses in patients with metastatic melanoma. Clin Cancer Res 2020;26:5869-5878.

17. Sacco JJ, Carvajal R, Butler MO, et al. 64MO A phase (ph) II, multi-center study of the safety and efficacy of tebentafusp (tebe) (IMCgp100) in patients (pts) with metastatic uveal melanoma (mUM). Ann Oncol 2020;31:S1442-S1443.

18. Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 2009;15:7412-7420.

19. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-655.

20. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-247.

21. Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant 2019;25:625-638.

22. Gordon Lan KK, Demets DL. Discrete sequential boundaries for clinical trials. Biometrika 1983;70:659-663.

23. O’Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics 1979;35:549-556.

24. Maurer W, Bretz F. Multiple testing in group sequential trials using graphical approaches. Stat Biopharm Res 2013;5:311-320.

25. Lin DY, Wei LJ, Ying Z. Checking the Cox model with cumulative sums of martingale-based residuals. Biometrika 1993;80:557-572.

26. Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 inhibition. N Engl J Med 2017;377:2500-2501.

27. Piulats JM, Espinosa E, de la Cruz Merino L, et al. Nivolumab plus ipilimumab for treatment-naïve metastatic uveal melanoma: an open-label, multicenter, phase II trial by the Spanish Multidisciplinary Melanoma Group (GEM-1402). J Clin Oncol 2021;39:586-598.

28. Pelster MS, Gruschkus SK, Bassett R, et al. Nivolumab and ipilimumab in metastatic uveal melanoma: results from a single-arm phase II study. J Clin Oncol 2021;39:599-607.

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