LYL-797

Lyell Immunopharma’s recently acquired CAR-T doesn’t appear to impress Wall Street. The company said Tuesday that its dual-targeting CD19/CD20 CAR-T called LYL314 induced 22 responses in a cohort of 25 patients with large B cell lymphoma, for an overall response rate of 88%. Eighteen, or 72%, of the 25 patients achieved a complete response in the Phase 1/2 trial. But investors weren’t convinced. The company’s stock price $LYEL fell about 8% on Tuesday. And in an investor call Tuesday morning, analysts questioned executives on why they’re only pursuing patients who have not previously received CAR-Ts, since Lyell is positioning LYL314 as a better option than other CD19 CAR-T therapies like Gilead’s Yescarta, Bristol Myers Squibb’s Breyanzi and Novartis’ Kymriah. The therapy, previously known as IMPT-314, was acquired by Lyell last year in its $30 million upfront buyout of ImmPACT Bio. Lyell CEO Lynn Seely believes the goal of the program is to build on existing complete response rates and improve durability of treatments. “It makes more sense to treat more patients sooner with the best therapy,” she said on the call. The data come from an ongoing study of LYL314, looking at patients with large B cell lymphoma in the third- or later-line setting. Patients had a median follow-up of nine months. Lyell is banking on this therapy after most of its other programs have sputtered. In conjunction with last year’s ImmPACT acquisition, the company halted development of almost all pipeline programs, including its former lead therapy LYL797, a ROR1-targeting CAR-T. There were no reports of a severe side effect called cytokine release syndrome (CRS) among all 51 patients treated across all cohorts. CRS is a response that occurs when immune cells go into overdrive and cause excess inflammation. The company intends to advance LYL314 in this setting and has launched the PiNACLE trial, aiming to enroll 120 patients. Lyell is also moving forward in the second-line setting, with a pivotal trial set to launch by the beginning of next year. In an initial slice of 11 second-line patients, Lyell said it saw 10 patients respond, and six achieve a complete response.

近日，默沙东公布了其ROR1—ADC药物zilovertamab vedotin+R-CHP作为弥漫性大b细胞淋巴瘤（DLBCL）一线治疗方案的Ⅱ期临床初步数据—wavine -007，结果显示，该联合方案在两个剂量组中均实现了100%的完全缓解。 一位BMO Capital Markets分析师称，数据非常有竞争力，但未来安全性是个问题。 疗效惊艳，安全可疑 Zilovertamab vedotin是一款靶向ROR1—ADC，是默沙东2020年收购VelosBio公司获得的资产，该试验评估了不同剂量zilovertamab vedotin联合R-CHP用以未经治疗DLBCL患者的安全性与有效性。共有36名患者入组，中位随访时间为17.6个月。 试验结果显示，1.75mg/kg和2.25mg/kg剂量组的CR分别为100%，2.0mg/kg的CR略低，为93.3% 。截至数据统计时，全部患者还未达到中位缓解持续时间（DOR）。基于该结果，默沙东将1.75mg/kg作为zilovertamab vedotin的III期临床的推荐剂量。 Zilovertamab vedotin取得高CR率的另一面是令人担忧的安全性问题。 该项临床中，有58%的患者出现3-4级治疗相关不良事件，11%的患者出现了严重的治疗相关不良事件，1.75mg/kg组所有患者均完成了治疗，而2.25mg/kg和2.0mg/kg剂量组分别有1例患者停药。 从目前的响应率来看，zilovertamab vedotin的疗效还是非常惊艳，不过鉴于患者样本量较少，在更大规模的Ⅲ期临床中能不能维持这样的响应以及不良事件是否会升级仍值得关注。 两款CAR-T的失足 ROR1是一种典型的肿瘤胚胎蛋白，通常只存在于胚胎细胞的早期发育阶段，而在成体细胞中一般不表达，但是它被癌细胞利用后会促进癌细胞的生长和扩散。目前ROR1已被发现在多种肿瘤中高表达，包括各类白血病、非霍奇金淋巴瘤、乳腺癌、肺癌及卵巢癌。有介于这种在肿瘤和正常组织之间的高度差异化表达，ROR1成为一种潜力靶点。围绕ROR1的开发汇集了CAR-T，双抗/多抗，ADC等多种技术路线。 ROR1作为ADC的一种潜力开发靶点被广泛注意到是在2020年，基石药业、默沙东、勃林格殷格翰先后通过授权/并购获得ROR1 ADC药物的相关权益。 整体来看，最快的是Oncternal公司ROR1单抗Zilovertamab，进入Ⅲ期临床阶段。根据已披露的的Ⅰ/Ⅱ期临床，表达P53突变/del(17p)的CLL患者获得100%的无进展生存期（PFS），持续48个月。但是在2023年4月，Oncternal取消了Zilovertamab的优先级，关闭了其针对MCL的Ⅲ期临床和Ⅰ/Ⅱ期临床。 目前已有ROR1靶向药的临床数据公布有限，就已经已有的临床数据来看，ROR1是一个安全风险比较高的靶点，两款ROR1  CAR-T皆因此折戟。 2024年6月，Lyell的ROR1 CAR-T疗法LYL797在三阴乳腺癌（TNBC）的I期临床报告了发生了一例死亡事件，还有22%的患者出现肺炎相关的剂量限制毒性，最常见的严重程度为3级或更高。4个月后，Lyell便宣布停止对LYL797的开发。Lyell的首席执行官Lynn Seely在电话会议上表示，LYL797遇到了安全问题，并且没有足够的治疗窗口。 无独有偶，另一家ROR1开发公司Oncternal也报告了ROR1 CAR-T（ONCT-808）临床发生死亡案例，并且还预期ONCT-808治疗会发生不良事件。ONCT-808的临床开发已经停止，该公司正在考虑战略替代方案。 参考出处 https://www.biospace.com/drug-development/merck-touts-100-complete-response-rate-for-anti-ror1-adc-as-first-line-lymphoma-treatment https://www-merck-com.libproxy1.nus.edu.sg/news/mercks-investigational-zilovertamab-vedotin-in-combination-with-r-chp-demonstrates-complete-response-rate-of-100-at-1-75-mg-kg-dose-in-phase-2-trial-of-previously-untreated-patients-with-diff/