Ieramilimab

The March approval of Bristol Myers Squibb’s Opdualag (relatlimab and nivolumab) to treat unresectable or metastatic melanoma validated the newest checkpoint in the immuno-oncology arsenal. Since then, Regeneron, Merck, Immutep S.A. and more have been working hard to develop the next successful lymphocyte activation gene-3 (LAG-3) inhibitor. At the European Society of Medical Oncology (ESMO) Congress, Regeneron presented data from a combination of Libtayo (cemiplimab) and fianlimab, a LAG-3 inhibitor, in advanced melanoma. The Phase III study pits the combo against Merck’s Keytruda (pembrolizumab), with progression-free survival (PFS) as the primary endpoint. In two independent patient cohorts, the IO duo demonstrated greater than 60% response rates. One cohort saw a 62.5% overall response rate, six complete responses and 19 partial responses. The second had a 65% ORR with one CR and 25 PRs. Israel Lowy, M.D., Ph.D., SVP, translational and clinical sciences, oncology at Regeneron, spoke about the meaning of these data. “Combining LAG-3 and PD-1 inhibition has shown promise in advanced melanoma but achieving response rates above 50% has been challenging,” he said in a statement. A Phase III trial in first-line metastatic melanoma is currently enrolling, and Lowy said Regeneron “[looks] forward to opening additional trials with this combination in the near future.” Dr. Omid Hamid M.D., chief of research/immuno-oncology at The Angeles Clinic & Research Institute and primary investigator on the trial, referred to the consistency of the results. “With greater numbers of patients treated, we continue to see the same remarkable response rate of 63.8%,” he told BioSpace, adding that a LAG-3 dose 100x higher was still tolerable. No novel toxicities were seen and there were durable responses to therapy, he noted. In New Jersey, Merck is always looking for ways to augment the success of Keytruda. One of these is combining the blockbuster drug with favezelimab, its own anti-LAG-3 antibody. The tag-team is being studied in a Phase III trial versus standard of care in patients with previously treated metastatic PD-L1 positive colorectal cancer. And BMS is working just as hard to stay on top. The company is currently studying Opdualag in a Phase II trial for non-small cell lung cancer. Data from the NEOpredict-Lung trial were presented at ESMO. The winning melanoma combo showed early signs of efficacy in NSCLC, according to the abstract presented by principal investigator Dr. Martin Schuler of the University Hospital, Essen. Immutep is Building on LAG-3 Innovation Meanwhile, Immutep, founded by Frédéric Triebel, M.D., Ph.D., who discovered the LAG-3 immune control mechanism in 1990, is well on its way to presenting a host of data at upcoming cancer conferences. Immutep is developing eftilagimod alpha (efti) across a range of oncology and autoimmune indications, including metastatic breast cancer, NSCLC and head and neck squamous cell carcinoma (HNSCC). A combination of efti and Keytruda is being assessed in the Phase II TACTI-002 trial in first-line NSCLC. Results presented at ESMO’s s European Lung Cancer Congress 2022 showed the duo led to an ORR of 6% and a disease control rate of 36%. The ORR was even stronger at 38.6%. In an interview with BioSpace, CEO Marc Voigt said these results “doubled or tripled” those seen with Keytruda monotherapy. “This opens the door for late-stage development,” he said. Immutep expects additional data from the trial in the fourth quarter of this year. At ESMO’s Breast Cancer Congress in May, the company presented “significant data” from the Phase IIb AIPAC trial, made up of 227 patients with HER2-negative/HR-positive metastatic breast cancer. Immutep reported a statistically significant increase in innate and adaptive immune response biomarkers, monocyte and CD8 T cell counts and serum CXCL10 levels. Absolute lymphocyte count was demonstrated in the efti group, but not the placebo cohort. Voigt shared that Immutep has “the chance to move forward” to Phase III in both NSCLC and metastatic breast cancer. PD-1 inhibitors like Keytruda and Opdivo (nivolumab) have shown formidable success since the mid-2010s. LAG-3, an MHC class II ligand structurally and genetically related to CD4, is generating excitement because the inhibition of this gene can enable them to work in more patients. A Unique Mechanism of Action While BMS, Merck and Regeneron are focused on blocking LAG-3 on the T cell to keep it active, Voigt said Immutep is putting a different spin on it. “We are touching the other side of the interaction in MHC class II,” he said. “We activate the antigen-presenting cells to boost the immune system on a broader scale.” While Keytruda boosts the T cell response, “we are working on the antigen-presenting cells which are involved in generating more CD8 and CD4 T cells and more NK cells,” he explained. In this way, Voigt continued, there are “potentially more targets for anti-PD-1 to work on.” Aside from Merck, Immutep has programs partnered with Pfizer and GSK and has out-licensed an antagonist antibody targeting LAG-3, LAG525, to Novartis. Efti has also attracted the attention of the Maria Skłodowska-Curie National Research Institute in Warsaw, Poland. On Sept. 6, Immutep announced an investigator-initiated Phase II trial assessing efti in combination with Keytruda and radiotherapy in the neoadjuvant setting in up to 40 patients with select soft tissue sarcoma (STS). Immutep expects to dose the first patient in the first half of 2023 with initial interim data expected in Q4 2024. This trial will be efti’s first test in the neoadjuvant setting, Triebel told BioSpace. “The current successes of efti plus pembro (Keytruda) in the first- and second-line metastatic disease settings encourage us to ‘climb the ladder’ and test the same combo in early disease,” he said. Triebel added that “immunotherapeutic approaches should be used at the earliest possible stage of the disease” in STS. LAG-3: The Possibilities Hamid concurred, saying he sees LAG-3 combinations "moving into the adjuvant and the neoadjuvant field quickly to show response and benefit.” He also discussed the potential of the LAG-3/PD-1 combination to improve two other immunotherapy approaches: Tumor-infiltrating lymphocytes (TIL) therapy and immune-mobilizing monoclonal TCRs against cancer (ImmTAC). Hamid pointed to Immunocore’s IMC-F106C, a PRAME×CD3 ImmTAC therapy, as an example. Immunocore presented data at ESMO demonstrating doses of the drug were clinically active and showed “consistent and robust interferon gamma induction” – a specific marker of T cell activation. Durable responses were observed in two of six patients with cutaneous melanoma; two of four patients with ovarian cancer; and three of six patients with tebentafusp-naïve uveal melanoma. Hamid said LAG-3 “is the best backbone to future triplet trials in melanoma.”

诺华肺癌产品版图清晰可见：商业化产品以小分子靶向药物为主，在研管线瞄准KRAS等热门靶点，同时布局了免疫药物联用领域；还积极尝试通过商业化合作达成替雷利珠单抗（tislezumab）及欧司珀利单抗（ociperlimab） 在全球主要市场的权益。日前，诺华的非小细胞肺癌药物卡马替尼 (capmatinib）先后获准在海南博鳌乐城和粤港澳大湾区落地，这使人们的视线又一次关注到诺华研发管线布局。诺华在2021年公布的在研创新药管线中，共有70款新分子实体（NMEs）项目，65个项目处于后期开发阶段，100个项目处于早期开发阶段。过去6年，获FDA突破性疗法认定的项目达23个，管线中约85%的项目为first-in-class产品。实体肿瘤领域覆盖乳腺癌、肺癌、黑色素瘤以及肾癌等癌种。在肺癌领域，诺华目前在中国已商业化的产品主要以小分子靶向药物为主，包括二代ALK抑制剂塞瑞替尼（ceritinib）、BRAF/MEK抑制剂达拉非尼（dabrafenib）/曲美替尼（trametinib），本月诺华也在WCLC更新了达拉非尼/曲美替尼在中国BRAF突变非小细胞肺癌人群中的注册研究数据，复制了全球多中心研究数据结果。其在研管线覆盖了多个热门靶点，包括KRAS、SHP2及耐药基因NRF2/KEAP1。此外，管线还拓展到了免疫药物领域。NIS793是一款潜在first-in-class的TGF-β中和抗体，可调控肿瘤微环境，逆转免疫抑制和纤维化；LAG-3免疫球蛋白埃拉利单抗具有在联用中增加PD-1单药疗效的潜力。未来3～5年内诺华肺癌领域的数个产品有望在中国上市。capmatinib：针对METex14跳跃突变，2024年有望中国获批卡马替尼是一种口服、选择性、ATP竞争性的c-Met激酶抑制剂，对c-Met具有高度选择性，能有效抑制c-Met依赖性肿瘤细胞的增殖和迁移，并能有效诱导细胞凋亡。与其他c-Met抑制剂相比，对METex14的抑制力最高。MET突变或扩增是肺癌治疗领域的关注热点之一。METex14跳跃突变的分子机制主要是METex14跳跃，导致c-Cbl酪氨酸结合位点丢失，从而引起蛋白酶体介导的MET蛋白降解率降低，使MET信号持续激活，最终导致肿瘤发生。METex14跳突在晚期NSCLC中的突变率约为3%~4%，被认为是NSCLC中的致癌驱动突变。同时，METex14跳跃突变与疾病的不良预后有关，与没有MET突变的患者相比，生存期更差。目前，卡马替尼已在多个国家和地区获批，包括欧盟、美国、日本、瑞士和中国香港。在已上市的所有c-MET 抑制剂中，卡马替尼唯一获得FDA常规获批资格，在中国已获准在海南博鳌乐城和粤港澳大湾区使用。目前，卡马替尼还正在中国开展II期临床试验。JDQ-443：进入全球Ⅲ期，中国加入全球同步研发计划目前的临床实践表明，肺癌中的主要基因突变包括EGFR、ALK、HER2、ROS1、MET 14外显子（METex14）跳跃突变、BRAF、KRAS、RET等。其中，KRAS是三种RAS同种型中最常见的突变，KRASG12C突变发生在大约13%的肺腺癌、4%的结肠肿瘤和较小部分的其他癌种中。诺华的靶向药物JDQ-443是一款口服KRASG12C抑制剂，相较于其他同类型产品，其优势在于结构的唯一性，并且直接与C12残基结合，将KRAS不可逆地稳定在受GDP抑制的非活跃状态中。该品种目前正在开展全球多中心III期临床试验，是与多西他赛在局部晚期或转移性KRASG12C突变NSCLC患者中的比较研究。JDQ-443在今年AACR上公布了Ib/II期研究数据：按照推荐剂量200mg BID服用JDQ433后，82%以上的NSCLC患者平均靶点占有率超过90%，ORR为57%，且无≥3级AE。上述结果初步证明JDQ443具有良好的早期疗效和安全性。不可逆共价抑制导致了较强的选择压力和多种不同耐药机制的趋同进化是KRASG12C抑制剂耐药的主要机制，应对策略之一是联合治疗。KRAS抑制剂与SHP2抑制剂联合是NSCLC的一个重要研发方向。SHP2是一种由 PTPN11 基因编码的非受体蛋白酪氨酸磷酸酶，通过调节MAPK 信号通路参与细胞生长和分化，在程序性细胞死亡和调节肿瘤微环境细胞功能中发挥着重要作用。这里靶向SHP2的目的在于阻断RTK驱动的肿瘤信号通路，联合JDQ-443后能防止RAS/MAPK通路的反馈再激活。诺华的TNO155是一种口服型SHP2变构抑制剂，今年的AACR大会上，诺华也报道了JDQ-443联合TNO155的数据。一位患有KRASG12C突变的十二指肠乳头状癌的58岁女性，在接受JDQ-443联合TNO155治疗两个周期后，肿瘤的最长直径之和减少了44.2%，实现了部分缓解。这显示出TNO155与KRASG12C抑制剂之间的协同作用，但目前样本量还比较少，期待后续更多的有效性数据。MGY825：针对耐药基因NRF2/KEAP1诺华另一款靶向药物MGY825，针对耐药基因NRF2/KEAP1。NRF2/KEAP1在NSCLC中的突变率很高，约20%的肺腺癌及30%的肺鳞癌存在突变。NRF2基因翻译的蛋白主要是调节因子，KEAP1基因翻译的蛋白则可以敏感感知氧化还原变化。目前有一些证据表明NRF2/KEAP1信号通路是癌症进展、转移和药物耐药的关键驱动因素。约20%的肺腺癌及30%的肺鳞癌存在KEAP1/NRF2突变，突变频率仅次于TP53基因和KRAS基因。EGFR基因突变的NSCLC患者，KEAP1/NRF2发生突变的概率是7%，往往与靶向药物耐药相关，患者表现为很快出现病情进展，临床研究数据提示，存在KEAP1/NRF2突变的患者对免疫治疗不敏感。MGY825目前正在开展一项I期临床试验，研究的是MGY825在携带NFE2L2/KEAP1/CUL3突变的晚期NSCLC成人患者中的安全性和耐受性。NIS793：潜在FIC靶向TGF-β的中和抗体与以上几个品种不同的是，NIS793是一款免疫药物。转化生长因子β（TGF-β）信号通路主要通过调节细胞的生长、增殖、分化、迁移和凋亡等过程，参与介导组织与器官的正常生长和发育、机体的免疫反应等生物过程，具有抑癌和促癌的双重作用。它可诱导癌前细胞凋亡，抑制癌细胞增殖；而当肿瘤发展到晚期时，肿瘤细胞可以通过抑制TGF‐β通路或使自身产生TGF‐β耐受作用，此时的TGF‐β反而促进肿瘤细胞发生TMT，促进其浸润和转移。TβRII（TGF‐β的二型受体）的一级结构中包含一段10个连续的腺嘌呤核苷酸区域，该区域发生突变的概率高，在结直肠癌、乳腺癌、肺癌和前列腺癌中都有发现。TGF-β还是许多肿瘤纤维化包膜形成和维持的关键因素，这种纤维化被认为会限制标准护理化疗的疗效。NIS793是一款潜在的first-in-class全人源抗TGF-β IgG2单克隆抗体，可抑制肿瘤细胞的TGF-β通路，并调控肿瘤微环境，逆转免疫抑制和纤维化。ClinicalTrials网站显示，诺华正在全球范围内开展多项NIS793的临床试验，涉及的适应症包括转移性胰腺导管腺癌、转移性结直肠癌、肺癌等。其中，NIS793治疗胰腺导管腺癌的研究已进入到III期临床阶段。在中国，NIS793开发的第一个临床适应症为晚期胰腺癌，后续研究将继续探索在非小细胞肺癌、乳腺癌、肝细胞癌、胰腺癌、结直肠癌等癌种的应用。LAG-525:  布局多种联合治疗方案，提升抗肿瘤效果淋巴细胞活化基因3（LAG-3）又称为CD233，是一种I/型跨膜蛋白，主要在活化的T细胞、NK细胞、B细胞和浆细胞样DC中表达。诺华的埃拉利单抗（ieramilimab）（LAG-525）是一种人源化LAG-3免疫球蛋白，可抑制LAG-3与MHC-II分子的相互作用。今年2月，诺华发表了LAG-525联合或不联合PD-1在晚期恶性肿瘤患者中的I/II期试验结果。在I期试验中，研究结果显示，截至2018年1月15日，不管是单药治疗还是与PD-1单抗联合使用，LAG-525均具有良好的耐受性；而LAG-525单药的抗肿瘤活性有限，在联合组中则观察到了一定抗肿瘤活性。在II期试验中，截至2020年6月1日，NSCLC组的患者共有42名，其中3位未接受过抗PD-1/L1治疗的患者观察到部分缓解。业内对LAG-3与PD-1的联用尝试中，已初步证实该联用方案可能增加PD-1单药的疗效。在2022年ASCO年会上，Immutep公司的可溶性LAG-3蛋白Eftilagimod alpha与Keytruda联用用于晚期NSCLC治疗的研究公布了最新研究结果：在114名入组受试者中，ORR达到38.6%，DCR为73.7%，并且在PD-L1无表达或低表达的患者群体中，这一组合疗法也达到了28.1%的ORR。而如果不筛选PD-L1高表达的患者，Keytruda单药疗法治疗NSCLC患者的缓解率只有20%，这说明可溶性LAG-3蛋白有可能通过激活免疫细胞的反应，增强Keytruda的疗效。近年诺华也积极布局新兴技术平台，公司目前已拥有领先的5大技术平台，包括靶向蛋白质降解技术、细胞疗法、基因疗法、放射性配体疗法以及RNA疗法。诺华布局肺癌研发管线多年，在NSCLC研发布局中发力分子靶向治疗，多靶点协同。在治疗领域格局不断变化的当下，靶向小分子类药物能够穿透血脑屏障在晚期患者治疗地位不可撼动，耐药谱将变得极其碎片化和复杂，仍需更多的新型药物及组合方案。（本文仅供医疗卫生专业人士参考；MCC号TML22082073有效期至2023年8月24日，资料过期，视同作废。）总第1689期访问研发客网站可浏览更多文章www.PharmaDJ.com