Carboplatin

北京时间9月8日晚上十一点半，WCLC大会的进入第二天的主席台口头报告环节，AK112一线治疗NSCLC的报告第一个出场，PPT亮出，头对头K药的PFS对照曲线和HR数据展现在台下以及线上的观众面前，所有人都沸腾了。  当之前投资者们还在讨论HR预期0.6是否给高了时，Harmoni2试验给了投资者巨大的超出预期的惊喜：HR值达到了0.5左右，头对头K药的对照PFS曲线非常漂亮。  这次，国产肺癌创新药在WCLC大会上“艳惊四座”，让全球医药界人士真正看到了中国创新药自研能力质的进步。 下一个时代，中国创新药将成为引领药物创新的中坚力量之一，十年饮冰的沉淀与努力，终于迎来了收获期。 01 AK112——惊艳全球的双抗弄潮儿 就在三个多月前，康方AK112（依沃西单抗）的Harmoni 1III期临床试验结果公布时，还引发了市场完全不同的解读，导致了康方股价经历了一场过山车，后来更加深度分析证明发生了数据解读上的巨大反转，康方又经历了一轮巨大的涨幅，AK112也迅速进入了商业化阶段：6月2日开出首张处方，到6月底短短一个月不到时间，其销售额达到了1.03亿元，向我们展示了一把“康方速度”。 如今，AK112再次给了众人一个超出预期的惊喜：WCLC大会上，当美国时间还在早上八点半时，中国时间是晚上十一点半，中国许多医药界人士和投资者正在深夜守着康方AK112一线治疗非小细胞肺癌的数据公布，看看是否能到达之前普遍预期的0.6-0.7，当PPT翻到那一页，大家看到了HR达到了0.51这个数字时，所有人都沸腾了。 关于AK112在一线治疗NSCLC临床数据上的解读，可以分两个维度来展开，一个是它头对头K药方面的数据，在一线用药上实现的质的飞跃；另一个是它作为一个双抗而言，与PD-1和VEFG两个单抗联用相比，是否具有显著的优势。 在第一个维度上，有了这一次头对头K药的试验，这个比较的结果是非常直观的。 患者基线上，AK112组198人，K药组200人，NSCLCIII期和IV期人数上基本相同，差距人数小于等于1，PD-L1 TPS指标上，≥50%亚组和＜50%亚组的人数也基本相同，差距小于等于2。不过，在脑转移上，K药组略多6人，但也不构成显著的差异。总体而言，患者基线方面，两组实现了较为完美的平行对照。 在最后试验结果上，mPFS曲线如图所示，非常具有差异化。K药的mPFS为5.82个月，而AK112达到了11.14个月，其相较于K药提升了5.3个月。而HR也达到了超预期的0.51。最后的ORR上，AK112的ORR达到了惊人的50%，而K药的数据为38.5%，DCR分别为89.9%和70.5%，同样有非常显著的差异化疗效。 从亚组上来看，重点应关注鳞癌亚组的数据，一方面是因为此前贝伐珠单抗这类VEGF单抗在进行NSCLC鳞癌临床时折戟沉沙，在II期临床试验中，8名贝伐珠单抗组患者死于严重的不良反应，如大咯血等，因此，VEGF类型抗体能不能用于鳞癌非常值得关注；另一方面，AK112的另一项III期临床——头对头替雷利珠单抗就是针对NSCLC鳞癌适应症。 而值得欣慰的是，在鳞癌的亚组中，AK112在疗效以及安全性方面均表现十分良好。疗效方面，其HR达到了0.48，还高于总的HR值。安全性方面亦然，鳞癌亚组中III级及以上不良反应发生率为22.2%，低于合并后大组AK112的数字29.4%；严重不良反应发生率上，鳞癌亚组中AK112的比率为18.9%，合并后大组的比例为20.8%，同样低于大组的比例。 也就是说，在鳞癌亚组中，AK112在疗效和安全性上的表现是强于非鳞癌亚组的。这是个非常具有里程碑意义的验证，给后期AK112头对头替雷利珠单抗治疗非小细胞肺癌鳞癌的III期临床预期打了一剂强心针。 而第二个维度来说，或许现在仍然没有特别明确的答案，可以说二者各有千秋，但有一点可以肯定的是，AK112相对于PD-1和VEGF两种单抗联用而言，做到了一项之前联用疗法所没有做到的事情：直接进入一线治疗广泛的一线NSCLC适应症。 会有人用LUNG-MAP S1800A临床试验举例子来非头对头比较AK112，但二者并不好比较，因为该试验中雷莫芦单抗联用K药治疗的是免疫检查点抑制剂耐药后的NSCLC患者。 而信达的Orient-31同理，它的联用主要针对的是EGFR-TKI治疗失败后的后线治疗情况。 倒是LEAP-007这项三期临床，是在用K药联用VEGF抑制剂仑伐替尼，用于NSCLC的一线治疗，可惜的是该项III期临床后来失败了。 目前能够进行类比的可能只有ABCP（PD-L1＋VEGF＋卡铂＋紫杉醇）四药联合疗法治疗非小细胞肺癌，但该疗法用药过多，且只能用于非鳞状非小细胞肺癌的适应症。而事实上它非头对头的数据也确实不如AK112，在ABCP对照BCP（除去PD-L1单抗）的结果中，HR值为0.62。当然，非头对头的比较仅用来参考，用来严谨对照不恰当。 这是目前来看的现状，两药联用的疗法目前还没有III期临床成功的案例，而四药联合虽然走力大砖飞的路线得到了一定的疗效，但无论是从适用性广泛角度考虑还是从疗效考虑，都不如AK112。 两药联用这种上个时代没有得到在一线治疗突破的瓶颈，如今已经被下一个时代的双抗降维打击，成功进入杀入一线治疗。至于许多人担心在如今一线EGFR TKI药物如此内卷的情况下，AK112在一线能否杀出重围这件事情，这就属于杞人忧天了。 目前肺腺癌中驱动基因未知的比例占比34%，肺鳞癌驱动基因未知的比例占比56%，驱动基因未知说明这个市场是小分子抑制剂还无法涉足的领域，而这个领域之前的一线大多是归K药这类PD-1单抗的，而之后，这一大块市场都将要被AK112降维打击。 从患者的角度来说，驱动基因阴性的患者依然有活下去的权利，他们依然需要更新一代的药物来进行前线治疗；从商业化的角度来说，一个EGFR突变养活了中国奥希替尼，伏美替尼和阿美替尼三个巨大单品去三分天下，如今AK112还没有同等疗效的药物去和它竞争驱动基因阴性的NSCLC市场，能触碰到的天花板将非常之高。 02 伏美替尼——艾力斯的宝藏单品 2024年上半年，艾力斯的销售额达到了15.76亿元，相比去年同期直接翻了一倍，在15.76亿元中，98.7%的营收皆由伏美替尼所贡献。这款第三代EGFR TKI成就了伏美替尼，也成就了海外权益所有者——ArriVent。 伏美替尼的尽管目前实现了半年超过15亿元的销售收入，且爬坡极为迅速，但其适应症拓展上还远远没有到瓶颈期，其EGFR 20外显子插入突变非小细胞肺癌的二线治疗和一线治疗都进入了注册性临床的状态，其一线疗法已经被FDA授予了突破性疗法认定，正在ArriVent那做的风生水起。 在这次WCLC大会中，它同样获得了一次在主席台上做口头汇报的机会，主要内容是关于一线治疗EGFR PACC突变非小细胞肺癌患者的研究（FURTHER），该研究目前在ArriVent管线中处于临床Ib期阶段，较为早期。当然，在EGFR突变类型中，PACC突变型占比并不算大，约占所有EGFR 突变的12%，其突变位于ATP结合口袋的内侧表面或螺旋C端，影响三代TKI的结合，奥希替尼在应对该类突变时效果尤其不好。 目前临床上，二代TKI可能是一个解决办法。二代TKI是夹在一代和三代中间的TKI抑制剂，典型的是阿法替尼，在一代的基础上可以抑制HER家族中的HER2和HER4，属于用泛性抑制HER家族的方式来达到一定解决一代耐药突变的效果。当时它带来了一代TKI耐药后的解决办法时也带来了严重的不良反应。 但二代处于一个非常尴尬的位置，二代tki的代表阿法替尼出现在2013年，但是两年后奥希替尼便横空出世，特异性抑制T90M，不仅作为后线疗法十分惊艳，安全性明显优于前面两代。此后就是奥希替尼横扫NSCLC EGFR突变的时代，二代也没来得及在这个适应症留下一些浓墨重彩。 （图源：明湛药学） 根据UNICORN研究，阿法替尼在面对PACC突变情况时有着不错的疗效。但如上文所述，二代TKI并不算是好的解决办法，它的心血管毒性一直是个棘手的问题，对于患者而言会造成非常大的副作用。 三代TKI的药王奥希替尼无法解决该突变带来的问题，而二代TKI能解决但毒性非常大，如今正是需要一款全新的三代TKI来重塑该突变治疗格局之时。 而此次WCLC大会上的数据，将给予伏美替尼非常大的赋能。此外，在目前该突变的竞争格局上，伏美替尼是走在了非常前列。 03 他雷替尼——脑转移的满分答案 他雷替尼作为一款ROS1 TKI，虽然没有EGFR TKI那样有着总量那么大的蛋糕，但其主打的就是差异化竞争，在自身的高垂度领域做出足够的独占性。由于ALK和ROS1的激酶活性区域有70%的相似性，因此许多ALK抑制剂会被用做ROS1突变患者的治疗。 但其中有一些状况ALK抑制剂并没有办法应对，例如脑转移患者血脑屏障的问题。尽管克唑替尼作为ROS1阳性一线疗法的有效率高达70-80%，mPFS达到了19.2个月。但克唑替尼无法通过血脑屏障，对于脑转移患者疗效较差。 而他雷替尼的横空出世，不仅是为了去改善脑转移患者的情况，更是为了改变ROS1突变患者的用药格局：开发专属于ROS1基因突变的靶向药物。 在TRUST-I研究中，他雷替尼用于一线治疗的cORR高达92.5%，而对于经克唑替尼治疗的患者，其cORR达到52.6%，可以说是ROS1领域针对克唑替尼耐药之后的全新一代TKI；而在脑转移方面，在可测量脑转移灶的患者、中，他雷替尼的颅内客观缓解率（IC-ORR）高达91.7%，颅内疾病控制率（IC-DCR）更是高达100%。这个数字，可以堪称是脑转移的满分答案。 基于关键临床II期TRUST-I研究的积极结果，他雷替尼两项NDA被NMPA授予优先审评资格，离商业化仅有一步之遥。 而在本次的WCLC大会中，将会公布TRUST-II(NCT04919811)的研究结果。在去年10月，葆元医药已经公布了其部分中期数据，一线治疗方面（16%接受过化疗），经确认的客观缓解率(cORR)达到了92%；对存在脑转移的患者，cORR为80%；而在21例接受过ROS1 TKI治疗的患者（52%接受过化疗）中，cORR也达到了57.1%；脑转移患者亚组的cORR更高，达到了62.5%；mPFS为11.7个月。 这项专门针对脑转移的小分子大杀器，一方面在ROS1抑制剂领域将要迭代原来的ALK抑制剂疗法，另一方面其对脑转移的特殊效果，也大大加深了其本身的竞争壁垒。 在商业化的路途上，这类单品属于护城河极深的那一类。 结语：本次WCLC大会，国产肺癌创新药的表现让医药界彻底沸腾了一把，扫除了一波之前情绪不振的阴霾。 在未来，中国针对肺癌这一大癌种的创新药还有非常多的迭代空间，例如即将到来的TROP2 ADC等药物，一方面各种新一代药物之间的联用是趋势，另一方面，这些新型疗法的出现也让突变基因阴性的患者有了更加多样性的选择。 下一个时代将会在联用过程中让ADC入局，这方面，上文提到的康方已经在准备它的ADC管线，而阿雷替尼的权益方之一信达更是ADC领域的大玩家。对于肺癌这个癌种而言，未来的趋势便是后线治疗手段越来越丰富，会有更多药物让突变基因阴性的患者获得更加长的无进展生存期。癌症慢病化的时代，终归会靠一线接一线的疗法给叠出来。 声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！ 长按关注本公众号  粉丝群/投稿/授权/广告等 请联系公众号助手 觉得本文好看，请点这里↓

September 18th Event in New York City to Include a Review of the Opportunity for Investigational Therapy IMNN-001 (IL-12) to Treat Advanced Ovarian Cancer and Clinical Development Timeline LAWRENCEVILLE, N.J., Sept. 09, 2024 (GLOBE NEWSWIRE) -- IMUNON, Inc. (NASDAQ: IMNN), a clinical-stage company in late-stage development with its DNA-mediated immunotherapy, will hold its first Ovarian Cancer R&D Day on September 18, 2024 at the Harvard Club (35 West 44th Street) in New York City. The event will feature presentations and updates on the development program for IMNN-001, Imunon’s investigational therapy currently in development for the treatment of ovarian cancer. Presentations from KOLs including clinical study investigators, immunology and biostatistics experts and company management will take place from 10:00 a.m. to 12:00 p.m. Eastern time, followed by lunch and informal conversations with presenters from 12:00 p.m. to 1:00 p.m. Eastern time. To RSVP for the event, please register here. Plans for the Ovarian Cancer R&D Day event follow IMUNON’s recent announcement of positive topline data from its randomized Phase 2 OVATION 2 Study of IMNN-001 showing that treatment was associated with an 11.1 month increase in median OS in the intent-to-treat population, representing a 35% improvement in survival among patients with advanced disease. The R&D Day program will include insights from thought leaders with expertise in ovarian cancer and immunology and principal investigators from IMNN-001 clinical studies. The agenda will include a review of the OVATION 2 Study results, assessments of oncology clinical trial endpoints and a discussion of the potential role of IMNN-001 in the treatment of advanced ovarian cancer. In addition, IMUNON management will review next steps in the development program for IMNN-001 and the potential impact treatment could have on standard of care. Presenters during the R&D Day event will include (listed in order of presentations): Sid Kerkar, M.D., T cell biology review editor, Frontiers in Immunology. Dr. Kerkar will discuss the important role of IL-12 in treating cancer.William Bradley, M.D., Professor, Obstetrics and Gynecology, Gynecologic Oncology, Medical College of Wisconsin. Dr. Bradley will discuss the data highlighting the safety and efficacy of IMNN-001.L.J. Wei, Ph.D., Professor of Biostatistics, Harvard T.H. Chan School of Public Health. Dr. Wei will discuss the opportunity to combine PFS and OS to provide a clinically interpretable evaluation of the IMNN-001 treatment effect.Amir Jazaeri, M.D., Vice Chair for Clinical Research, Director, Gynecologic Cancer Immunotherapy Program, Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center. Dr. Jazaeri will discuss the ongoing Phase 1/2 study of IMNN-001 in combination with bevacizumab in advanced ovarian cancer, for which he serves as principal investigator, including the importance of minimal residual disease and early translational insights.Premal Thakker, M.D, David & Lynn Mutch Distinguished Professor of Obstetrics & Gynecology, Chief of Gynecologic Oncology, Interim Director of Gynecologic Oncology Clinical Research, Professor of Gynecologic Oncology, Washington University School of Medicine, and the OVATION 2 Study Chair. Dr. Thaker will discuss the OVATION 2 topline results and their clinical significance beyond the reported topline results. IMUNON executives at the R&D Day event will include: Stacy R. Lindborg, Ph.D., President and CEO, will provide an overview of treatment for women newly diagnosed with ovarian cancer and discuss how IMNN-001 has the potential to change the paradigm as well as planning for a Phase 3 registration study.Khursheed Anwar, Ph.D., Chief Scientific Officer, will review the company’s TheraPlas technology platform, among other topics. IMUNON strongly encourages in-person attendance to facilitate networking and direct engagement with speakers and management. For those unable to attend in person, a webcast will be available using the same registration link as above. OVATION 2 Study Topline Results OVATION 2 evaluated the dosing, safety, efficacy and biological activity of intraperitoneal administration of IMNN-001 in combination with neoadjuvant and adjuvant chemotherapy (NACT) of paclitaxel and carboplatin in patients newly diagnosed with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer. Treatment in the neoadjuvant period is designed to shrink the tumors as much as possible for optimal surgical removal after three cycles of chemotherapy. Following NACT, patients undergo interval debulking surgery, followed by three additional cycles of adjuvant chemotherapy to treat any residual tumor. This open-label study enrolled 112 patients who were randomized 1:1 and evaluated for safety and efficacy to compare NACT plus IMNN-001 versus standard-of-care NACT. In accordance with the study protocol, patients randomized to the IMNN-001 treatment arm could receive up to 17 weekly doses of 100 mg/m2 in addition to NACT. As announced on July 30, 2024, highlights from patients treated with IMNN-001 plus standard-of-care in a first-line treatment setting include: An 11.1 month increase in median overall survival (OS) compared with standard-of-care alone in the intent-to-treat population (ITT).A hazard ratio in the ITT population of 0.74, which indicates a 35% improvement in survival.Among the approximately 90% of trial participants who received at least 20% of specified treatments per-protocol in both study arms, patients in the IMNN-001 arm had a 15.7 month increase in median OS, representing a further extension of life with a hazard ratio of 0.64, a 56% improvement in survival.For the nearly 40% of trial participants treated with a poly ADP-ribose polymerase (PARP) inhibitor, the hazard ratio decreased further to 0.41, with median OS in the IMNN-001 treatment arm not yet reached at the time of database lock, compared with median OS of 37.1 months in the standard-of-care treatment arm. About IMNN-001 Immunotherapy Designed using IMUNON's proprietary TheraPlas platform technology, IMNN-001 is an IL-12 DNA plasmid vector encased in a nanoparticle delivery system that enables cell transfection followed by persistent, local secretion of the IL-12 protein. IL-12 is one of the most active cytokines for the induction of potent anticancer immunity acting through the induction of T-lymphocyte and natural killer cell proliferation. IMUNON previously reported positive safety and encouraging Phase 1 results with IMNN-001 administered as monotherapy or as combination therapy in patients with advanced peritoneally metastasized primary or recurrent ovarian cancer, and completed a Phase 1b dose-escalation trial (the OVATION 1 Study) of IMNN-001 in combination with carboplatin and paclitaxel in patients with newly diagnosed ovarian cancer. About Epithelial Ovarian Cancer Epithelial ovarian cancer is the sixth deadliest malignancy among women in the U.S. There are approximately 20,000 new cases of ovarian cancer every year and approximately 70% are diagnosed in advanced Stage III/IV. Epithelial ovarian cancer is characterized by dissemination of tumor in the peritoneal cavity with a high risk of recurrence (75%, Stage III/IV) after surgery and chemotherapy. Since the five-year survival rates of patients with Stage III/IV disease at diagnosis are poor (41% and 20%, respectively), there remains a need for a therapy that not only reduces the recurrence rate, but also improves overall survival. The peritoneal cavity of advanced ovarian cancer patients contains the primary tumor environment and is an attractive target for a regional approach to immune modulation. About IMUNON IMUNON is a clinical-stage biotechnology company focused on advancing a portfolio of innovative treatments that harness the body’s natural mechanisms to generate safe, effective and durable responses across a broad array of human diseases, constituting a differentiating approach from conventional therapies. IMUNON is developing its non-viral DNA technology across its modalities. The first modality, TheraPlas®, is developed for the coding of cytokines and other therapeutic proteins in the treatment of solid tumors where an immunological approach is deemed promising. The second modality, PlaCCine®, is developed for the delivery of DNA-coded viral antigens that can elicit a strong immunological response. The Company’s lead clinical program, IMNN-001, is a DNA-based immunotherapy for the localized treatment of advanced ovarian cancer that has completed Phase 2 clinical studies. IMNN-001 works by instructing the body to produce safe and durable levels of powerful cancer-fighting molecules, such as interleukin-12 and interferon gamma, at the tumor site. Additionally, the Company has entered a first-in-human study of its COVID-19 booster vaccine (IMNN-101). IMUNON will continue to leverage these modalities and to advance the technological frontier of plasmid DNA to better serve patients with difficult-to-treat conditions. For more information, please visit www.imunon.com. Forward-Looking Statements IMUNON wishes to inform readers that forward-looking statements in this news release are made pursuant to the “safe harbor” provisions of the Private Securities Litigation Reform Act of 1995. All statements, other than statements of historical fact, including, but not limited to, statements regarding the timing for commencement of a Phase 3 trial of IMNN-001, the timing and outcome of the Company’s End-of-Phase 2 meeting with the FDA, the timing and enrollment of the Company’s clinical trials, the potential of any therapies developed by the Company to fulfill unmet medical needs, the market potential for the Company’s products, if approved, the potential efficacy and safety profile of our product candidates, and the Company’s plans and expectations with respect to its development programs more generally, are forward-looking statements. We generally identify forward-looking statements by using words such as “may,” “will,” “expect,” “plan,” “anticipate,” “estimate,” “intend” and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances). Readers are cautioned that such forward-looking statements involve risks and uncertainties including, without limitation, uncertainties relating to unforeseen changes in the course of research and development activities and in clinical trials, including the fact that interim results are not necessarily indicative of final results; the uncertainties of and difficulties in analyzing interim clinical data; the significant expense, time and risk of failure of conducting clinical trials; the need for IMUNON to evaluate its future development plans; possible actions by customers, suppliers, competitors or regulatory authorities; and other risks detailed from time to time in IMUNON’s filings with the Securities and Exchange Commission. IMUNON assumes no obligation, except to the extent required by law, to update or supplement forward-looking statements that become untrue because of subsequent events, new information or otherwise. Contacts: IMUNONLHA Investor RelationsDavid GaieroKim Sutton Golodetz978-376-6352212-838-3777dgaiero@imunon.comkgolodetz@lhai.com # # #