Fianlimab

▎药明康德内容团队编辑 在今年欧洲肿瘤内科学会（ESMO）大会中，百时美施贵宝（Bristol Myers Squibb）与再生元（Regeneron）分别公布其LAG-3靶向疗法与PD-1抑制剂组合作为一线疗法治疗晚期癌症的积极数据。分析显示，在两项独立的临床试验当中，PD-1/LAG-3靶向联合疗法在晚期非小细胞肺癌（NSCLC）与黑色素瘤患者中，皆展现近60%的客观缓解率（ORR），显示PD-1/LAG-3疗法用于广泛癌症治疗的潜力。 百时美施贵宝这次所公布的RELATIVITY-104是一项随机2期研究，旨在评估LAG-3靶向抗体relatlimab联合PD-1靶向抗体Opdivo（nivolumab）和化疗，与nivolumab联合化疗相比，作为IV期或复发性NSCLC患者一线疗法的疗效与安全性。 分析显示，在该试验第二部分的50名肿瘤PD-L1表达至少1%且组织学类型为非鳞状细胞的患者中，固定剂量relatlimab联合nivolumab加化疗组合实现了58%的ORR，而此数值在对照组中仅为39.6%。此外，relatlimab联合疗法组患者的中位无进展生存期为11.6个月，对照组为6.9个月。截至数据截止时，总体生存期数据仍不成熟。 美国FDA在2022年3月批准“first-in-class”疗法Opdualag上市。这款疗法由固定剂量的relatlimab与nivolumab组成，治疗罹患不可切除或转移性黑色素瘤的成人和儿童（12岁及以上）患者。值得一提的是，relatlimab是美国FDA批准的首款LAG-3抗体，也是近10年来针对全新免疫检查点获批的首款创新癌症免疫疗法。 百时美施贵宝即将开展临床3期试验RELATIVITY-1093，该研究旨在评估该PD-1/LAG-3联合化疗作为一线疗法，与Keytruda联合化疗相比的疗效与安全性。该研究将募集800名PD-L1表达率在1%至49%之间且组织学类型为非鳞状细胞的患者NSCLC患者。 另一方面，再生元也公布其LAG-3靶向抗体fianlimab联合PD-1靶向疗法Libtayo（cemiplimab）一线治疗黑色素瘤患者的1期试验数据。患有不可切除或转移性黑色素瘤的成年患者接受每3周一次1600毫克fianlimab和350毫克cemiplimab治疗，最长达24个月。 在平均23个月的随访中，接受fianlimab加cemiplimab联合疗法的98例患者的ORR高达57%（95% CI：47-67），完全缓解率（CR）为25%，中位无进展生存期（PFS）为24个月（95% CI：12-不可评估）。 再生元副总裁兼fianlimab全球项目负责人Mark Salvati博士在接受行业媒体Fierce Biotech采访时表示：“我们看到了药物出色的疗效持久性。随着时间的推移，患者的CR率从12%上升到25%，这在该领域几乎是史无前例的。” ▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放 参考资料： [1] LBA53 - Nivolumab (NIVO) plus relatlimab with platinum-doublet chemotherapy (PDCT) vs NIVO + PDCT as first-line (1L) treatment (tx) for stage IV or recurrent NSCLC: Results from the randomized phase II RELATIVITY-104 study. Retrieved September 16, 2024 from https://cslide.ctimeetingtech.com/esmo2024/attendee/confcal/session/calendar?q=relatlimab [2] 1097P - Long-term follow-up of advanced melanoma (unresectable/metastatic - aMel) patients (pts) treated with fianlimab (FIAN) + cemiplimab (CEMI): Results from blinded independent central review (BICR) efficacy assessment. Retrieved September 16, 2024 from https://cslide.ctimeetingtech.com/esmo2024/attendee/confcal_2/presentation/list?q=fianlimab+ [3] 'Cooking with gas': Regeneron sees its Opdualag rival as next big thing for treating solid tumors. Retrieved September 16, 2024 from https://www.fiercebiotech.com/biotech/cooking-gas-regenerons-opdualag-rival-companys-next-big-thing-solid-tumor-treatments 免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。 版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。 分享，点赞，在看，聚焦全球生物医药健康创新

Bristol Myers Squibb plans to “do a little bit more homework” as it works on the exact design of its phase 3 trial for Opdualag in PD-L1-high non-small cell lung cancer, Chief Medical Officer Samit Hirawat, M.D., said. More than two years after an initial FDA approval in melanoma, Bristol Myers Squibb is moving its PD-1/LAG-3 combo Opdualag into registrational testing in one of the most important oncology disease areas—first-line non-small cell lung cancer (NSCLC).The company has disclosed a phase 3 trial coded RELATIVITY1093 to evaluate Opdualag—a fixed combination of the PD-1 inhibitor Opdivo and the LAG-3 inhibitor relatlimab—plus chemotherapy in stage 4 or recurrent nonsquamous NSCLC cases with PD-L1 expression between 1% and 49%. The trial will adopt a higher dose of relatlimab than in Opdualag’s FDA-approved melanoma indication and will use Merck & Co.’s Keytruda and chemo as the comparator.Separately, BMS plans to initiate another phase 3 trial next year for Opdualag in first-line nonsquamous NSCLC patients with PD-L1 expressions of at least 50%, Chief Medical Officer Samit Hirawat, M.D., told Fierce Pharma in an interview.RELATIVITY1093 is ready to roll because “the signal is very clear” and the unmet medical need still exists in the PD-L1-low population, Hirawat said.“We don’t believe that the current standard of care is giving you the benefit of [progression-free survival] and overall response rate as what we have seen in our clinical trial,” Hirawat said. “So that is squarely a place where we wanted to go and fit and start the study as soon as possible.”In contrast, BMS is taking time to “do a little bit more homework” as it devises the exact design of its phase 3 for the PD-L1-high population, including on the utilization of chemotherapy, he said. When asked whether BMS is considering dividing the PD-L1-high population to focus on a subgroup based on eligibility for chemo, Hirawat said he’s “not ready to commit”  to such an approach. Development of Opdaulag has been “a slow march,” Hirawat acknowledged.“We didn’t straight away jump into [a] phase 3 trial in non-small cell lung cancer after we saw the melanoma data, which used to happen in the prior I-O world, because we really need to define how LAG-3 works, what the combinations would be and what the indication should be.” ESMO RELATIVITY-104 readout BMS’ latest decision is based on results from the phase 2 RELATIVITY-104 trial conducted in patients with previously untreated stage 4 or recurrent NSCLC. The trial did not include any enrollment criteria around levels of PD-L1 present in patients’ tumors. The story refers to the combo as Opdualag even though the dosage strengths of nivolumab and relatlimab evaluated in the trial are different from those in Opdualag’s FDA-approved melanoma indication.Among  PD-L1-negative patients enrolled in the part 2 efficacy portion of the trial (see table below for detailed data), the addition of relatlimab—at the 360-mg dose as selected from part 1—to Opdivo and chemo led to a slightly higher overall response rate (ORR), but the LAG-3-containing regimen performed slightly worse on progression-free survival (PFS), according to results shared at the European Society of Medical Oncology Congress 2024. Similarly, in patients with squamous disease, the Opdualag regimen showed a higher ORR but a shorter median PFS time.In terms of patients’ life expectancy, benefits of Opdualag were observed only in PD-L1-positive patients and in those with nonsquamous disease, Hirawat said.In PD-L1-low patients, those who took Opdualag and chemo showed an ORR of 60.7% and a median PFS of 9.8 months, whereas the Opdivo-chemo group experienced an ORR of 30% and PFS of 5.5 months, according to Hirawat.In PD-L1-high patients, Opdualag and chemo delivered an ORR of 54.5% and a median PFS of 13.8 months, versus 46.4% and 7.1 months for Opdivo and chemo.Among nonsquamous patients with PD-L1-positive tumors, the median PFS was 11.6 months for the LAG-3 group and 6.9 months for control, translating into a 45% reduction in the risk of progression or death.BMS took into consideration data from part 1 of the trial and also benchmarked all results with findings from other published trials, Hirawat said.RELATIVITY-104 Part 2 (Girard et al/ESMO24) Opdualag + chemoOpdivo + chemoORR (%)mPFS (mo)ORR (%)mPFS (mo)PD-L1-negative505.644.85.8PD-L1-low60.79.8305.5PD-L1-high54.513.846.47.1Squamous60.85.655.35.8Nonsquamous46.78.338.56 Shifting lung cancer landscape Previously, in the landmark KEYNOTE-189 trial conducted in first-line nonsquamous NSCLC. Keytruda and chemo led to a median PFS of 11.3 months in PD-L1-high patients and 9.4 months in PD-L1-low patients, according to an updated analysis published last year.BMS is advancing Opdualag into phase 3 testing as the NSCLC ground rapidly shifts under its feet. In LAG-3 alone, a phase 2/3 study that’s comparing the addition of Regeneron’s fianlimab on top of the company’s PD-1 inhibitor Libtayo and chemotherapy in advanced NSCLC is currently underway in phase 2. Regeneron has some early data at ESMO24 suggesting fianlimab might be better than BMS’ relatlimab in melanoma and is determined to prove that with an ongoing head-to-head phase 3 trial.Beyond the LAG-3 class, Akeso and Summit Therapeutics’ PD-1/VEGF bispecific antibody ivonescimab just beat Keytruda monotherapy in a head-to-head China phase 3 in first-line, PD-L1-positive NSCLC. Summit has already launched a phase 3 trial pitting ivonescimab and chemo against Keytruda and chemo in first-line squamous NSCLC.Merck, AstraZeneca and Gilead Sciences are developing their TROP2 antibody-drug conjugates in first-line NSCLC, too. BMS has recently in-licensed an EGFRxHER2 bispecific ADC from China’s SystImmune. The drug is being evaluated in NSCLC and breast cancer. On the flip side, the New Jersey pharma just terminated a deal for Agenus’ TIGITxCD96 bispecific antibody following multiple failures in the TIGIT class.“Each and every clinical trial is a step forward, not a step backward,” Hirawat said, “because it gives us an insight into how the landscape is evolving and what is to be learned.”