（中国医学科学院肿瘤医院石远凯教授与英国巴特斯癌症研究所Jude Fitzgibbon教授）

 

 

石远凯教授：肿瘤治疗现已进入分子靶向治疗和免疫治疗时代，分子靶向治疗时代标志性的单克隆抗体药物就是CD20单抗-利妥昔单抗，全球第一个有明确靶点的抗肿瘤单克隆抗体，自1997年被美国FDA批准上市之后的20多年时间里，在淋巴瘤治疗上显示了非常良好的疗效。在滤泡淋巴瘤、弥漫大B细胞淋巴瘤等CD20阳性的淋巴瘤中，CD20单抗与传统的化学药物治疗相结合组成新的免疫化疗治疗方案，显著提高了这部分患者的生存，已经成为标准的治疗方案，改变了传统的治疗理念，为患者带来了临床获益。在分子靶向药物的发展历程当中，具有非常重要的意义。

 

 

石远凯教授：HLX01是上海复宏汉霖公司研发的利妥昔单抗，从I期到III期临床试验，严格按照中国《生物类似药研发与评价技术指导原则（试行）》进行了临床研究。III期临床试验是在弥漫大B细胞淋巴瘤中，应用H-CHOP对比R-CHOP进行的前瞻性、多中心、双盲的临床试验，主要研究终点是6周期化疗的最佳缓解率。研究结果显示，H-CHOP对比R-CHOP在最佳客观缓解率上高度的相似，达到了我们预先设定的统计学的主要研究终点，安全性和药代动力学特性相似。与R-CHOP方案相比，H-CHOP方案的安全性以及药物毒副反应的发生率及程度，两者之间都没有统计学差异。因此，国家药监局在今年的2月22日批准HLX 01上市，成为中国第一个生物类似药。HLX 01对于中国弥漫大B细胞淋巴瘤患者而言，又多了一个治疗选择来造福患者。

 

 

 

Fitzgibbon教授：首先，我想说的是淋巴瘤的困境和研究工作，我们可以看到，通过引入抗CD20单抗，淋巴瘤的治疗尤其是弥漫性大B细胞淋巴瘤和滤泡性淋巴瘤有了革命性的进步。我们认为在过去的20年里，随着利妥昔单抗的引入和现在新的利妥昔单抗生物类似药HLX 01的出现，弥漫性大B细胞淋巴瘤和滤泡性淋巴瘤的治疗生存率得到显著提高。显然，引入生物类似药是很重要的，而且我认为用同样的严格程度来检测这种药物是很重要的。这就是现在汉利康（HLX 01）研发过程中一直严格遵循的。因此，当像利妥昔单抗这样的药物专利到期时，它为我们提供了一个机会，新的同类药物可以占领市场并以与过去利妥昔单抗相同的疗效和成效造福患者。

 

石远凯教授：生物类似药的疗效和安全性一直是研发者和临床医生关注的核心问题，因此在研发过程中应该严格遵照国家相关的法律法规和技术指导原则进行相关研究，务必达到相关行业技术标准和要求。

 

 

 

Fitzgibbon教授：个人认为二代测序的应用为我们提供了一个巨大的机会来确定特定的基因突变和基因表达变化，并了解弥漫性大B细胞淋巴瘤和滤泡性淋巴瘤的特性。相信未来的免疫疗法会非常有效和个体化。肿瘤微环境及靶向微环境的治疗是弥漫性大B细胞淋巴瘤和滤泡性淋巴瘤亟待解决的问题。显然，靶向微环境的治疗与现有治疗方法相结合很可能产生较好的疗效。目前有一种观念认为，表观遗传学突变在淋巴瘤中非常常见，它们可能削弱了免疫系统的防御作用，肿瘤细胞依赖这种方式不被杀灭，针对这方面的治疗和现有治疗方法的结合可以更好地起到抑制肿瘤细胞的作用。当前，我们仍处于抗CD20免疫疗法结合化疗作为弥漫大B细胞淋巴瘤标准治疗方案的时代，这也是我们目前所能利用的各种治疗方法的基础。

 

 

Editors note: The European Society for Medical Oncology (ESMO) 2019 Congress was held on 27 Sept to 01 October in Barcelona， many researches on biosimilar were presented in the conference， and the update research of HLX01 drew attention of public. HLX01(Brand name Hanlikang) is a recently approved biosimilar of Rituximab injection by NMPA. As the first biosimilar drug approved in China， HLX01 undoubtedly starts the show of China’s biosimilar drugs. We invited Prof. Yuankai Shi from Tumor Hospital of the Chinese Academy of Medical Sciences and Prof. Jude Fitzgibbon from Barts Cancer Institute to discuss therapeutic efficacy of HLX01 and the management of quality control in biosimilar drug development.

 

 

Prof. Yuankai Shi: Oncotherapy has entered the decade of target therapy and immunotherapy. As the first target specific monoclonal antibody drug worldwide， Rituximab， the CD20-targeted antibody， has been widely known as the represent drug of molecular targeted therapy. After being approved by FDA， Rituximab has shown ideal therapeutic effect in lymphoma in more than 20 years. As to CD20+ lymphoma like follicular lymphoma and diffuse large B-cell lymphoma treatment， the combine of anti-CD20 antibody and chemotherapy， known as immunochemotherapy， has significantly improved the survival of patients and become a standard regimen. It not only benefits the patients， also alters the classical therapeutic concept. Therefore， Rituximab means a lot to the development of molecular targeted therapy.

 

 

Prof. Yuankai Shi: HLX01 is a biosimilar of Rituximab developed by Shanghai Henlius Biotech. During clinical trail from Phase I to Phase III， development of HLX01 is stictly regulated by “Guideline for R&D and evaluation of biosimilar drug (trail version)”of NMPA. Phase III trail of HLX01 is a double-blind， multi-centered prospective study comparing with R-CHOP on diffuse large B-cell lymphoma， and the primary end point is remission rate after 6 cycles of therapy. The result showed H-CHOP is highly similar to R-CHOP on ORR， which reached the primary end point， meanwhile the safety and phamacokenetic character is also similar. H-CHOP is also not statistically different to R-CHOP in degree nor occurance rate of adverse effect. So HLX01 got market authorization from NMPA on February 22 this year， and became the first biosimilar in China. For diffuse large B-cell lymphoma patients in China， apparently they got a new optimal choice of therapy.

 

 

 

Professor Jude Fitzgibbon: First of all， I’d like to say the dilemma and research work in lymphoma， like we can see that the treatment of lymphoma has been revoluntionized by the introduction of anti-CD20 therapies， specifically in the areas of diffuse large B cell lymphoma and then follicular lymphoma. And we do think in the last 15 or so years， the survival has changed significantly based on the introduction of rituximab and now the new anti-CD20 therapy called HLX 01 and specifically that’s appropriate for the treatment of diffuse large B cell lymphoma and follicular lymphoma. Clearly introduction of biosimilar drug is important and as well clearly I think it’s essential that this one is tested with the same degree of rigor. And that’s exeactly what’s happening at the present time. So it provides us an opportunity when drugs like Rituximab come off patent where new buy similars can take over and be utilized with the same efficacy and success that rituximab has had in the past.

 

Prof. Yuankai Shi: Efficacy and safety of biosimilar drugs are always concerned by researchers and clinicians， so the development of new biosimilars has to be always strictly regulated by related guidelines， and associated technical standards also have to be fully met.

 

 

Professor Jude Fitzgibbon: So I think the use of next-generation sequencing has provide us with a huge opportunity to identity specific gene mutations and specific changes of gene expressions and special understand of personality of both diffuse large B cell lymphoma and follicular lymphoma. I think going forward that immuno-thrapies have been very efficacious and soli concerto . I think the targeting of human micro-environment is an open question of diffuse large B cell lymphomaand follicular lymphoma. And clearly I think their efficacy is most likely to have an effect in combination with our therapies. Specifically I think there is a notion at the present time that epigenetic mutations which are very common theme in lymphomas. They might provide an opportunity to actually weaken the immunity that tumor cell has its cloak of an invincibility that tumor cell might have to rely for and this therapy could actually work better. Clearly I think we are on the stage at the present time where immuno-therapy with anti-CD20 therapy still be the standard care that would actually be more really at the backbone of therapies we could utilize at the present time.