Balstilimab

Five months after the FDA blocked its plans for accelerated approval, Agenus is moving ahead with discussions with potential pharma partners to chart a more conventional registrational path for its anti-CTLA-4 drug combo that has new Phase 2 data in advanced colorectal cancer. There are a variety of different partnership proposals on the table, with some focused on co-developing and others on financing, Agenus chief medical officer Steven O’Day told Endpoints News in an interview. “These negotiations are active — they’re moving forward,” he said. During its second-quarter earnings call last year, the company already indicated that it was looking for partnerships for botensilimab, which is combined with its PD-1 candidate balstilimab (BOT/BAL). According to data presented Saturday at the ASCO Gastrointestinal Cancers Symposium in San Francisco, the biotech’s 75 mg dose of botensilimab combined with balstilimab achieved a 19% objective response rate in patients with refractory microsatellite stable metastatic colorectal cancer that had spread to certain body parts but not the liver. This compares well with an ORR of zero for the control arm, which featured standard-of-care: Bayer’s Stivarga or Taiho Pharmaceutical’s Lonsurf. The 75 mg treatment cohort also achieved a 55% disease control rate. This means that more than half the patients treated with the combo were no longer progressing, O’Day said. Hello, Traci Lang You’re an essential part of the biopharma world. Share your voice on this important question to help shape our understanding of the industry. Can you help us out? Hello, Traci Lang You’re an essential part of the biopharma world. Share your voice on this important question to help shape our understanding of the industry. Can you help us out? The company has regulatory “alignment” to move forward with the 75 mg regimen in a Phase 3 trial with survival as a primary endpoint, he added. In July 2024, the FDA advised Agenus against pursuing accelerated approval for BOT/BAL based on data from previous Phase 1 and 2 studies in relapsed or refractory non-microsatellite instability-high colorectal cancer. The agency said that response rates in this population have not always translated to survival outcomes, adding it wanted to see a definitive survival study. Now that a Phase 3 is in the cards, Agenus has several options as to the specific subset of colorectal cancer patients it advances in, O’Day said. Other than the late-line setting, “we can also move into earlier-line metastatic colon and neoadjuvant” disease, he said. The company shared results from various BOT/BAL-based regimens in these other settings at ASCO GI. “But clearly the Phase 3 refractory [setting] is the most set up in terms of the work that’s been done with dose and contribution and a large database,” O’Day said. Agenus is no stranger to regulatory struggles. In 2021, the drugmaker withdrew its accelerated BLA for balstilimab in second-line cervical cancer shortly after the FDA cleared Merck’s Keytruda for full approval in the same setting. In August 2024, Bristol Myers Squibb turned its back on a pact with Agenus for a bispecific anti-TIGIT drug that featured more than $1 billion in potential milestones. Last month, the biotech launched a biologics manufacturing business to help it make money. In November, it had just $44.8 million in consolidated cash.

扫描二维码 可查看更多内容 编者按 2025年美国临床肿瘤学会胃肠道肿瘤研讨会（ASCO GI 2025）将于美国东部标准时间1月23日至25日举行。作为胃肠道肿瘤领域最高水平的世界级学术盛会之一，为全球胃肠道肿瘤领域的专家学者提供了深入交流与合作的机会。北京时间2025年1月22日上午，ASCO GI官网公布了除LBA摘要外其他全部摘要内容，其中结直肠癌领域的两项快速口头报告研究备受瞩目。两项研究（摘要19及23）分别从早期和晚期CRC的微卫星状态出发，为免疫治疗的精准化和个性化管理提供了重要参考。现将内容整理如下，以飨读者。 研究一 单周期帕博利珠单抗新辅助治疗Ⅰ~Ⅲ期MMR缺陷型结肠癌的疗效分析：RESET-C研究结果 摘要号：19 背景 近年来，免疫检查点抑制剂在治疗MMR缺陷型（dMMR）结直肠癌方面取得了显著进展。然而，最佳治疗方案及其疗程尚无明确结论。 方法 RESET-C（NCT05662527）是一项Ⅱ期、单臂、多中心研究，旨在评估单周期帕博利珠单抗（Pembrolizumab）新辅助治疗可切除Ⅰ~Ⅲ期dMMR结肠癌患者的疗效和安全性。纳入标准为年龄≥18岁、无新辅助治疗指征以及ECOG评分为0或1的患者。患者在入组后接受一周期帕博利珠单抗（4 mg/kg，最大剂量400 mg）治疗，并在3~5周内接受手术。术前通过血液检查、CT扫描及结肠镜以评估肿瘤反应。主要终点为病理完全缓解率（pCR）。次要终点包括手术并发症、安全性、主要病理反应（Mandard标准下TRG 1或2级）以及无病生存期（DFS）。 结果 2023年2月至2024年3月期间，共有85例患者入组。患者的中位年龄为74岁（IQR：68~79），72%为女性，60%为临床Ⅲ期患者。所有患者均接受了帕博利珠单抗治疗，其中84例患者接受了手术，1例Ⅰ期患者选择不接受手术。研究结果显示，pCR率为44%（37/84；95%CI：33~55），主要病理反应率为57%（48/84；95%CI：46~68）。Ⅰ~Ⅱ期患者的pCR率显著高于Ⅲ期患者（61% vs. 33%；P=0.02）。 手术相关并发症共计41例，发生在31例患者中（37%；95% CI：27~48）。其中，8例为Clavien-Dindo 3a级及以上的严重并发症，包括3例吻合口瘘和2例术后30天内死亡病例。 在85例患者中，7例（8%；95%CI：3~16）出现了3级不良事件，其中3例与治疗相关。未观察到4级或5级不良事件。关于内镜评估的临床完全缓解（cCR）与pCR的相关性数据，以及预计于2025年1月公布的1年DFS数据，将在后续报道中进一步公布。 结论 单周期新辅助帕博利珠单抗治疗在局限性dMMR结肠癌患者中显示出有效性和安全性。对于大多数临床Ⅰ~Ⅱ期患者，单周期治疗足以达到pCR。 研究二 无肝转移的MSS型转移性结直肠癌中Botensilimab联合或不联合Balstilimab治疗的Ⅱ期研究初步结果 摘要号：23 背景 Botensilimab（BOT）是一种Fc增强型抗CTLA-4抗体，旨在改善Fcγ受体介导的效应功能，并将免疫治疗（I-O）的适用范围扩展至包括微卫星稳定型（MSS）转移性结直肠癌（mCRC）等对传统免疫治疗反应较差的肿瘤类型。本研究为一项随机、开放标签的Ⅱ期研究（NCT05608044），初步评估了BOT单药或联合Balstilimab（BAL，抗PD-1抗体）治疗无肝转移的MSS mCRC患者的疗效和安全性。研究的主要终点为RECIST 1.1标准评估的客观缓解率（ORR）以及安全性。 方法 研究共纳入234例患者构成意向治疗（ITT）人群，随机分配至以下治疗组：BOT（最高4剂）75 mg或150 mg每6周（Q6W）一次；BOT 75 mg或150 mg （Q6W）联合BAL 240 mg每2周（Q2W）一次（最长2年）；或标准治疗（SOC，瑞戈非尼或曲氟尿苷/替匹拉西）。 结果 患者的中位年龄为58岁（23~90岁），50%为男性，39%为直肠癌患者，44%为三线及以上治疗的患者，43% ECOG评分为1。基因检测显示，58%为KRAS突变型，4%为NRAS突变型，83%接受过贝伐珠单抗治疗。所有患者均通过局部检测确认为MSS和/或pMMR。各组间基线特征总体均衡，但部分特征存在差异，包括从转移性确诊到入组的中位时间（各组均为30个月，SOC组为45个月）以及腹膜转移的发生率（各组均为34%，BOT 75 mg / BAL 240 mg组为42%，SOC组为27%）。截至2024年7月29日，中位随访时间为9.8个月。 疗效和安全性关键数据如表1所示，SOC组的3级及以上治疗相关不良事件（TRAEs）发生率最高，其次为BOT联合BAL组，再次为BOT单药组，且与剂量相关。治疗相关的免疫介导性腹泻/结肠炎（imDC）可控，在BOT 150 mg / BAL 240 mg组中发生率最高。未观察到新的安全信号，也未发生治疗相关死亡病例。 表1.不同治疗组的关键疗效和安全性数据 结论 在本研究中，BOT联合BAL组的总体ORR高于BOT单药组，其中BOT 75 mg / BAL 240 mg组的ORR最高，且毒性低于BOT 150 mg / BAL 240 mg组。与既往数据一致，SOC组未观察到客观缓解，而BOT联合BAL组的多数缓解持续存在，与Ⅰ期研究中观察到的缓解程度相似。疗效区别于既往的单纯免疫治疗组合和SOC组，本研究达成了明确药物剂量及各成分疗效贡献的研究目标，将支持未来在全球Ⅲ期研究中进一步对BOT 75 mg / BAL 240 mg组与SOC组进行比较评估。  滑动查看原文： Single-cycle neoadjuvant pembrolizumab in patients with stage I-III MMR-deficient colon cancer: Final analysis of the RESET-C study. Camilla Qvortrup|Copenhagen University Hospital - Rigshospitalet Abstract：19 Background: Neoadjuvant treatment with immune checkpoint inhibitors has shown remarkable responses in patients with deficient mismatch repair (dMMR) colorectal cancer. However, the optimal choice and duration of treatment have yet to be established. Methods: RESET-C (NCT05662527) was an investigator-initiated, phase II, single-arm, multicenter study investigating the efficacy and safety of single-cycle neoadjuvant pembrolizumab in 85 patients with resectable stage I-III dMMR colon cancer. Additional inclusion criteria were ≥ 18 years of age, no indication for neoadjuvant therapy, and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. After inclusion, patients received one cycle of pembrolizumab 4mg/kg (maximum 400mg) and underwent surgery within three to five weeks. A tumor-response evaluation was done before surgery, including blood samples, a computed tomography scan of the chest and abdomen, and a colonoscopy. The primary endpoint was the pathological complete response (pCR) rate according to Mandard tumor regression grading (Clopper-Pearson method). Secondary endpoints included surgical complications, safety of pembrolizumab, major pathological response (Mandard tumor regression grade 1 or 2), and disease-free survival. Results: Between February 2023 and March 2024, 85 patients were included. The median age was 74 years (IQR, 68-79), 72% were women, and 60% had clinical stage III disease. All patients received pembrolizumab, and 84 patients proceeded to surgery. One patient with stage I disease decided not to undergo surgery. A pCR rate of 44% (37/84; 95% CI, 33-55) and a major pathological response rate of 57% (48/84; 95% CI, 46~68) were found. A significantly higher pCR rate was seen in patients with stage I-II (20/33) versus stage III (17/51) disease (61% vs 33%; p=0.02). A total of 41 surgical complications were seen in 31 patients (37%; 95% CI, 27-48). Of these, eight complications were Clavien-Dindo grade 3a or above, including three patients with anastomotic leakages and two deaths within 30 days. The patients who died were aged 80 and 81, had ECOG performance status 1, and clinical stage IIIB and IIIC disease, respectively. Seven out of 85 patients (8%; 95% CI, 3-16) experienced grade 3 adverse events, three of which were treatment-related. No grade 4 or 5 adverse events were registered. Finally, data on the association between endoscopically evaluated clinical complete response and pCR, along with the 1-year disease-free survival rate expected in January 2025, will be reported. Conclusions: A single cycle of neoadjuvant pembrolizumab was efficacious and safe in patients with localized dMMR colon cancer. For most patients with clinical stage I-II disease, a single cycle sufficed to achieve pCR. Preliminary results from a randomized, open-label, phase 2 study of botensilimab (BOT) with or without balstilimab (BAL) in refractory microsatellite stable metastatic colorectal cancer with no liver metastases (MSS mCRC NLM). Marwan Fakih|Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center Abstract：23 Background: BOT is an Fc-enhanced, multifunctional anti-CTLA 4 antibody designed to improve Fc gamma receptor-mediated effector functions and extend the reach of I-O to tumor types such as MSS mCRC. Here we present preliminary data from a randomized, open-label, phase 2 study in patients (pts) with MSS mCRC NLM treated with BOT ± BAL (anti-PD 1; NCT05608044). The study aimed to inform dose and contribution of components based on the primary endpoint of objective response rate (ORR) by RECIST 1.1 per investigator, and safety, and was not powered for statistical comparisons between arms. Methods: A total of 234 pts (intent-to-treat [ITT]) were randomized to BOT (up to 4 doses) 75 or 150 mg every 6 wks (Q6W), BOT 75 or 150 mg Q6W plus BAL 240 mg Q2W (up to 2 years), or standard of care (SOC; regorafenib or trifluridine/tipiracil). Results: Median age was 58 yrs (range 23—90), 50% male, 39% rectal, 44% 3L+, 43% ECOG 1, 58% KRAS mutant, 4% NRAS mutant, 83% prior bev, all MSS and/or pMMR by local testing. Key characteristics were well balanced with some exceptions including median time from diagnosis of metastatic disease to study entry (30 mos across arms; 45 mos SOC) and presence of peritoneal metastases (34% across arms; 42% 75 mg BOT / 240 mg BAL; 27% SOC). As of July 29, 2024, median follow-up was 9.8 mos. Key efficacy and safety data are shown (Table). Image based endpoints by blinded independent review, as well as overall survival will be reported in the future. Grade ≥3 treatment-related adverse events (TRAEs) were highest with SOC followed by BOT + BAL combination, and then BOT monotherapy, with dose dependency. Treatment-related immune-mediated diarrhea/colitis (imDC) was manageable and highest with 150 mg BOT / 240 mg BAL. No new safety signals and no treatment-related deaths occurred. Conclusions: The study met the objectives of informing dose and contribution of components. Overall ORR was higher with BOT + BAL vs BOT monotherapy. ORR was highest with 75 mg BOT / 240 mg BAL with less toxicity as compared to 150 mg BOT / 240 mg BAL. Consistent with published data, there were no objective responses in SOC whereas most responses seen with BOT + BAL were ongoing, similar to the durable responses observed in the ph1 study. These responses are differentiated from previous I-O-only combinations and SOC, supporting further investigation of 75 mg BOT / 240 mg BAL vs SOC in a planned global ph3 trial. （来源：肿瘤瞭望消化时讯） 声 明 凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。