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延长胰腺癌患者生命的泛KRAS疗法；效果优于标准治疗的多款小分子癌症组合疗法… | 一周盘点

药明康德 · 公众号 · 药品 · 2024-12-23 07:30

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▎药明康德内容团队编辑

本期看点

1. 用于治疗妇科癌症的小分子组合疗法（lunresertib+camonsertib）在1期临床试验中表现亮眼，近一半患者在24周时保持无疾病进展，效果优于当前的标准治疗。

2. 首个针对PI3Kα，具有突变体和异构体（isoform）选择性的别构抑制剂RLY-2608的首个人体试验数据获更新，接受该疗法联用fulvestrant作为2线治疗的特定乳腺癌患者的中位无进展生存期（PFS）为11.4个月，为现有标准治疗的两倍多。

3. 靶向KRAS突变肿瘤的癌症疫苗ELI-002 2P在一项1期临床试验中使KRAS基因突变驱动的胰腺癌患者的中位总生存期（OS）较历史对照组延长。

药明康德内容团队整理

Lunresertib+camonsertib：公布1期联合治疗扩展试验的数据

Repare Therapeutics公司宣布其MYTHIC临床1期妇科癌症扩展试验取得积极成果。该试验评估了在推荐2期剂量（RP2D）下，lunresertib和camonsertib（lunre+camo）联合疗法在携带lunre敏感性生物标志物的子宫内膜癌和铂耐药性卵巢癌（PROC）患者中的疗效。Lunresertib是一种潜在“first-in-class”的精准肿瘤学小分子PKMYT1抑制剂，通过调控细胞周期发挥抗癌作用。Camonsertib则是一款潜在“best-in-class”的ATR口服小分子抑制剂，ATR是DNA损伤应答通路的关键组成部分。

此次公布的数据显示，近一半妇科癌症患者在24周时保持无疾病进展，效果优于当前的标准治疗。截至2024年11月14日，妇科癌症扩展队列共有51名可评估患者。分析显示，在接受RP2D剂量的患者中，有73%患者的肿瘤缩小，31%患者达成缓解（16/51）。

▲MYTHIC试验疗效结果（图片来源：参考资料[7]）

RLY-2608：公布首个人体试验的新中期数据

Relay Therapeutics公司公布了其在研疗法RLY-2608首个人体试验的积极中期数据。RLY-2608是Relay Therapeutics开发针对PI3Kα突变体的选择性抑制剂。该激酶是所有癌症中最常出现突变的激酶之一，约在14%的实体瘤患者检测出PI3Kα的致癌突变。传统上，PI3Kα抑制剂的开发聚焦于蛋白的活性位点。然而，这些抑制剂缺乏对突变型PI3Kα的选择性，导致治疗效果欠佳。为了增强PI3Kα抑制剂的选择性，Relay Therapeutics解析了PI3Kα的全长蛋白冷冻电镜结构，以阐明野生型和突变型PI3Kα的构象差异，并利用这些见解支持RLY-2608的设计。新闻稿指出，RLY-2608是首个针对PI3Kα，具有突变体和异构体（isoform）选择性的别构抑制剂。

截至2024年11月4日的数据，携带PI3Kα突变的HR阳性/HER2阴性局部晚期或转移性乳腺癌患者接受RP2D的RLY-2608联合fulvestrant，2线治疗患者的中位PFS为11.4个月，是现有标准治疗的两倍多。在31例可测量疾病的患者中有12例达到部分缓解（PR），确认的客观缓解率（ORR）为39%；15例携带激酶突变且可测量疾病的患者中有10例达到PR，确认的ORR为67%。

ELI-002：公布1期临床试验数据

Elicio Therapeutics公司展示了其靶向KRAS突变肿瘤的癌症疫苗ELI-002 2P的1期临床试验的新结果。ELI-002是一种基于该公司淋巴结靶向两亲性（AMP）技术的癌症疫苗，在这项临床试验中使用的ELI-002 2P是ELI-002的两肽制剂，包含针对两种KRAS突变体的多肽抗原。入组患者为接受标准局部治疗后，仍有循环肿瘤DNA（ctDNA）和/或血清肿瘤生物标志物残留的KRAS基因突变驱动的结直肠癌（CRC）或胰腺导管癌（PDAC）患者，他们面临较高的疾病复发风险。

截至2024年9月24日的数据，接受剂量为0.1 mg至10.0 mg ELI-002 2P治疗的25名患者的中位无复发生存期（mRFS）为16.3个月。PDAC亚组（n=20）的mRFS为15.3个月，CRC亚组（n=5）为16.3个月，与全体队列一致。全体研究队列及PDAC亚组的中位OS均为28.9个月，优于历史PDAC对照组，CRC亚组（n=5）尚未达到mOS。在大多数患者中观察到KRAS突变特异性T细胞的扩增以及肿瘤生物标志物减少。安全性方面，ELI-002 2P耐受性良好，未观察到3级/4级治疗相关不良事件、剂量限制性毒性（DLT）或细胞因子释放综合征（CRS）。

Soquelitinib：公布1期临床试验的中期数据

Corvus Pharmaceuticals公司公布了其小分子白细胞介素-2诱导的T细胞激酶（ITK）抑制剂soquelitinib用于治疗中度至重度特应性皮炎的1期临床试验的中期数据。ITK是一种主要表达于T细胞中的酶，在T细胞和自然杀伤（NK）细胞的免疫功能中起重要作用。通过抑制ITK，soquelitinib有望抑制自身免疫和炎症反应。

此次公布的结果显示，在评估患者疾病程度和严重性的EASI评分上，soquelitinib组患者的改善优于安慰剂组。Soquelitinib组在第28天和第58天时的EASI评分分别降低了55.9%和69.1%，而安慰剂组分别为27.0%和19.1%。此外，soquelitinib组达到湿疹面积和严重度指数较基线减少50%（EASI 50）、EASI 75和EASI 90的患者比例也明显高于安慰剂组。Soquelitinib组患者EASI评分获得改善的时间表明，其疗效从第8天开始显现，并在整个研究期间持续。安全性方面，soquelitinib具有良好的安全性和有效性。这些结果支持soquelitinib在特应性皮炎中的持续开发，并展示了ITK抑制作为治疗其他免疫疾病潜在新作用机制的可能性。

▲队列1的疗效数据（图片来源：参考资料[10]）

PDC*lung01：公布1/2期临床试验的新数据

PDC*line Pharma公司公布了其现货型治疗性候选癌症疫苗PDC*lung01的1/2期临床试验中最后一批患者的主要临床结果。该研究旨在评估PDC*lung01单药或与抗PD-1治疗联用，用于治疗非小细胞肺癌（NSCLC）患者的效果。浆细胞样树突状细胞（PDC）系是一种有效的专业抗原呈递细胞系，能够激发和增强患者的抗肿瘤细胞毒性CD8阳性T细胞，并能与抗PD-1治疗协同作用。PDC*lung01是由7种活性组分组成的细胞悬液，由辐照的人PDC细胞系制成，装载着多种肿瘤抗原。

此次公布的结果显示，在PD-L1表达≥50%的IV期NSCLC患者中，与单独使用PD-1抑制剂pembrolizumab相比，PDC*lung01联用pembrolizumab显示出具有临床意义的获益，并具有温和的安全性特征。在42例可评估的患者中，高剂量PDC*lung01疫苗联用pembrolizumab的确认的ORR为55%，达到了试验的预定目标，中位PFS为8.9个月。此外，联合治疗组中更强的免疫反应与更长的PFS显著相关。

BHV-1300：公布1期临床试验数据

Biohaven公司公布了其皮下给药的在研蛋白降解剂BHV-1300的积极1期临床试验结果。BHV-1300在选择性清除目标IgG（IgG1、IgG2和IgG4）方面具有独特优势，同时保留IgG3水平。IgG3在对抗细菌、寄生虫和病毒中发挥关键作用。BHV-1300的设计目标是避免与其他IgG降低方法相关的广泛免疫抑制，同时在治疗自身免疫性疾病的过程中允许免疫系统对潜在感染做出反应。

此次公布的结果显示，BHV-1300在给药后的数小时内即导致IgG逐步降低，并在为期四周的研究期间内维持了药效。BHV-1300在最低剂量下将目标IgG水平降低了60%。BHV-1300在整个1期研究中表现出良好的安全性和耐受性，未观察到对白蛋白或肝功能的临床显著影响，也未见胆固醇水平升高。此外，血浆IgG3水平在研究的第4周末仍得到维持，有助于确保健康的免疫效应功能。所有不良事件（AEs）均为轻度，任何与药物相关的不良事件均已解决，且无因药物相关不良事件而中断治疗的情况。

IMP761：公布1期临床试验的初步数据

Immutep公司公布了其潜在“first-in-class”LAG-3激动剂IMP761在含安慰剂对照、双盲的首个人体1期临床试验中获得的初步积极安全性数据。LAG-3免疫检查点被认为是治疗类风湿性关节炎、1型糖尿病和多发性硬化等多种自身免疫性疾病的重要靶点。IMP761这款潜在“first-in-class”的激动性LAG-3抗体旨在通过增强LAG-3的抑制功能，平衡免疫系统，抑制导致多种自身免疫性疾病的自身抗原特异性记忆T细胞，从而从根本上解决多种自身免疫性疾病的病因。新闻稿指出，IMP761是全球首款LAG-3激动性抗体。此次公布的结果显示，在健康受试者中，前三个单次递增剂量队列中均未观察到与治疗相关的不良事件。

INX-315：公布1/2期临床试验的中期数据

Incyclix Bio公司公布了其选择性细胞周期蛋白依赖性激酶2（CDK2）抑制剂INX-315的1/2期临床试验的中期数据，该试验针对对CDK4/6抑制剂耐药的雌激素受体（ER）阳性、HER2阴性乳腺癌或CCNE1扩增的实体瘤。此次公布的结果显示，INX-315在单剂量递增试验中的安全性和耐受性良好，并显示出抗肿瘤活性。30例疗效可评估患者中有3例达到了PR，19例为疾病稳定（SD）。

Gedatolisib：公布1b期联合治疗试验数据

Celcuity公司公布了其PI3K/mTOR抑制剂gedatolisib联用palbociclib和来曲唑/氟维司群治疗HR阳性、HER2阴性晚期或转移性乳腺癌患者的1b期临床试验结果。初治患者队列的中位OS为77.3个月（95% CI，50.3-89.0），既往接受过CDK4/6抑制剂治疗患者队列的中位OS为33.9个月（95% CI，17.8-52.3）。

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参考资料（可上下滑动查看）

[1] Elicio Therapeutics Presents Updated Results from ELI-002 Phase 1 AMPLIFY-201 Study at ESMO Immuno-Oncology Congress 2024. Retrieved December 12, 2024, from https://www.globenewswire.com/news-release/2024/12/12/2996042/0/en/Elicio-Therapeutics-Presents-Updated-Results-from-ELI-002-Phase-1-AMPLIFY-201-Study-at-ESMO-Immuno-Oncology-Congress-2024.html

[2] PDC*line Pharma presents primary clinical results from phase I/II trial on PDC*lung01 cancer vaccine at ESMO-IO 2024. Retrieved December 12, 2024, from https://www.pdc-line-pharma.com/news/pdcline-pharma-presents-primary-clinical-results-phase-iii-trial-pdclung01-cancer-vaccine-esmo

[3] Biohaven Reports Positive Phase 1 Degrader Data, Achieving Deep Targeted IgG Reductions in the Lowest Subcutaneous Dose Tested; Announces NDA Submission for Troriluzole in SCA and Provides Other Key Program Updates. Retrieved December 16, 2024, from https://ir.biohaven.com/news-releases/news-release-details/biohaven-reports-positive-phase-1-degrader-data-achieving-deep

[4] Immutep Announces Initial Safety Data from First-in-Human Phase I Trial Evaluating IMP761. Retrieved December 17, 2024, from https://www.globenewswire.com/news-release/2024/12/17/2998188/0/en/Immutep-Announces-Initial-Safety-Data-from-First-in-Human-Phase-I-Trial-Evaluating-IMP761.html

[5] Incyclix Bio Announces Interim Clinical Data from the Phase 1/2 Clinical Trial of INX-315 in Patients with CDK4/6 Inhibitor Resistant ER+/HER2- Breast Cancer or CCNE1-Amplified Solid Tumors. Retrieved December 17, 2024, from https://www.globenewswire.com/news-release/2024/12/13/2996733/0/en/Incyclix-Bio-Announces-Interim-Clinical-Data-from-the-Phase-1-2-Clinical-Trial-of-INX-315-in-Patients-with-CDK4-6-Inhibitor-Resistant-ER-HER2-Breast-Cancer-or-CCNE1-Amplified-Solid.html

[6] Repare Therapeutics Announces Positive Results of the Lunresertib and Camonsertib Combination from the MYTHIC Phase 1 Gynecologic Expansion Clinical Trial. Retrieved December 13, 2024, from https://ir.reparerx.com/news-releases/news-release-details/repare-therapeutics-announces-positive-results-lunresertib-and

[7] MYTHIC Lunresertib and Camonsertib Clinical Data Update. Retrieved December 13, 2024 from https://ir.reparerx.com/static-files/92c4a8df-f6db-41f4-9505-bfa866768880

[8] Relay Therapeutics Announces Updated Interim Data for RLY-2608 + Fulvestrant Demonstrating Continued Maturation of Clinically Meaningful Progression Free Survival. Retrieved December 13, 2024 from https://ir.relaytx.com/news-releases/news-release-details/relay-therapeutics-announces-updated-interim-data-rly-2608

[9] Celcuity Presents Overall Survival Data from Phase 1b Study Evaluating Gedatolisib in Combination with Palbociclib and Endocrine Therapy at the 2024 San Antonio Breast Cancer Symposium. Retrieved December 13, 2024 from https://www.globenewswire.com/news-release/2024/12/11/2995280/0/en/Celcuity-Presents-Overall-Survival-Data-from-Phase-1b-Study-Evaluating-Gedatolisib-in-Combination-with-Palbociclib-and-Endocrine-Therapy-at-the-2024-San-Antonio-Breast-Cancer-Sympo.html

[10] Corvus Pharmaceuticals Announces Interim Data from Placebo-Controlled Phase 1 Clinical Trial of Soquelitinib for Atopic Dermatitis. Retrieved December 18, 2024 from https://www.globenewswire.com/news-release/2024/12/18/2998957/0/en/Corvus-Pharmaceuticals-Announces-Interim-Data-from-Placebo-Controlled-Phase-1-Clinical-Trial-of-Soquelitinib-for-Atopic-Dermatitis.html

[11] Blue Lake Biotechnology Reports Additional Promising Clinical Data from Ongoing Pediatric Clinical Study of Intranasal RSV Vaccine BLB201. Retrieved December 19, 2024, from https://www.bluelakebiotechnology.com/news/blue-lake-reports-additional-data-from-blb201-rsv-ph1-2

[12] DLX-159 Nominated as Third Developmental Candidate, Broadening the Company’s Portfolio of Novel Neuroplastogens. Retrieved December 19, 2024, from https://www.delixtherapeutics.com/news/delix-presents-full-results-from-phase-1-trial/

[13] Kynexis Announces Positive Topline Results from Phase 1 Study of KYN-5356, a Potential Treatment for Cognitive Impairment Associated with Schizophrenia. Retrieved December 19, 2024, from https://www.globenewswire.com/news-release/2024/12/17/2998058/0/en/Kynexis-Announces-Positive-Topline-Results-from-Phase-1-Study-of-KYN-5356-a-Potential-Treatment-for-Cognitive-Impairment-Associated-with-Schizophrenia.html

[14] ExeGi Pharma Positive Topline Results in EXE-346 PROF Phase 1b Study. Retrieved December 19, 2024, from https://www.prnewswire.com/news-releases/exegi-pharma-positive-topline-results-in-exe-346-prof-phase-1b-study-302333867.html

[15] TransCode Therapeutics Announces Safety Review Committee Approval of Opening Third Cohort and Preliminary Results from First Cohort in Phase 1 TTX-MC138 Clinical Trial. Retrieved December 19, 2024, from https://www.prnewswire.com/news-releases/transcode-therapeutics-announces-safety-review-committee-approval-of-opening-third-cohort-and-preliminary-results-from-first-cohort-in-phase-1-ttx-mc138-clinical-trial-302334447.html

[16] Verastem Oncology Provides a Clinical Update for RAMP 203 Trial in Advanced KRAS G12C Mutant Non-Small Cell Lung Cancer. Retrieved December 19, 2024, from https://investor.verastem.com/news-releases/news-release-details/verastem-oncology-provides-clinical-update-ramp-203-trial

[17] NMD Pharma Announces Publication of Phase 1 Clinical Trial Data Evaluating NMD670 in Healthy Volunteers in the Journal Clinical Pharmacology & Therapeutics. Retrieved December 19, 2024, from https://www.globenewswire.com/news-release/2024/12/19/2999511/0/en/NMD-Pharma-Announces-Publication-of-Phase-1-Clinical-Trial-Data-Evaluating-NMD670-in-Healthy-Volunteers-in-the-Journal-Clinical-Pharmacology-Therapeutics.html

[18] Enterome Presents Encouraging Initial Clinical Data on EO4010 in Colorectal Cancer at ESMO IO 2024. Retrieved December 19, 2024, from https://www.enterome.com/news-events/enterome-presents-encouraging-initial-clinical-data-on-eo4010-in-colorectal-cancer-at-esmo-io-2024/

[19] Plus Therapeutics Presents Positive ReSPECT-LM Phase 1 Interim Data for Breast Cancer Patients with Leptomeningeal Metastases at the 2024 San Antonio Breast Cancer Symposium. Retrieved December 19, 2024, from https://www.globenewswire.com/news-release/2024/12/17/2998156/0/en/Plus-Therapeutics-Presents-Positive-ReSPECT-LM-Phase-1-Interim-Data-for-Breast-Cancer-Patients-with-Leptomeningeal-Metastases-at-the-2024-San-Antonio-Breast-Cancer-Symposium.html

[20] Krystal Biotech Announces Initial Clinical Update for Rare Respiratory Disease Programs KB408 and KB407 Including Early Clinical Evidence of Gene Delivery to the Lung of AATD Patients and Increase in Lung AAT to Therapeutic Levels. Retrieved December 19, 2024, from https://www.globenewswire.com/news-release/2024/12/12/2996139/0/en/Krystal-Biotech-Announces-Initial-Clinical-Update-for-Rare-Respiratory-Disease-Programs-KB408-and-KB407-Including-Early-Clinical-Evidence-of-Gene-Delivery-to-the-Lung-of-AATD-Patie.html

[21] Kiromic BioPharma Reports 32% Decrease in Tumor Volume Eight Months Post-Treatment in Fourth Patient Enrolled in Deltacel-01. Retrieved December 19, 2024, from https://ir.kiromic.com/news-releases/news-release-details/kiromic-biopharma-reports-32-decrease-tumor-volume-eight-months

[22] Tenaya Therapeutics Reports Promising Early Data from MyPEAK™-1 Phase 1b/2 Clinical Trial of TN-201 for Treatment of MYBPC3-Associated Hypertrophic Cardiomyopathy. Retrieved December 19, 2024, from https://www.globenewswire.com/news-release/2024/12/17/2998112/0/en/Tenaya-Therapeutics-Reports-Promising-Early-Data-from-MyPEAK-1-Phase-1b-2-Clinical-Trial-of-TN-201-for-Treatment-of-MYBPC3-Associated-Hypertrophic-Cardiomyopathy.html

[23] ViGeneron Announces FDA Clearance of IND for Novel mRNA Trans-Splicing Gene Therapy VG801 to Treat Stargardt Disease and Other ABCA4-Linked Retinal Dystrophies. Retrieved December 18, 2024, from https://www.globenewswire.com/news-release/2024/12/18/2999005/0/en/ViGeneron-Announces-FDA-Clearance-of-IND-for-Novel-mRNA-Trans-Splicing-Gene-Therapy-VG801-to-Treat-Stargardt-Disease-and-Other-ABCA4-Linked-Retinal-Dystrophies.html

[24] Aurion Biotech Announces Positive Topline Data for Phase 1/2 Clinical Trial of AURN001, an Allogeneic Cell Therapy Product Candidate for the Treatment of Corneal Edema Secondary to Corneal Endothelial Dysfunction. Retrieved December 19, 2024, from https://aurionbiotech.com/aurion-biotech-announces-positive-data-for-phase_1-2_trial/

[25] Sensorion Reports Data in the Audiogene Phase 1/2 Gene Therapy Clinical Trial. Retrieved December 19, 2024, from https://s27.q4cdn.com/232015521/files/doc_news/2024/12/2024-12-SENS_SENS501Results_ENG_FinalVersion.pdf

[26] Krystal Biotech Announces Early Evidence of Monotherapy Activity in Heavily Pre-Treated Patients with Advanced Non-Small Cell Lung Cancer. Retrieved December 19, 2024, from https://ir.krystalbio.com/news-releases/news-release-details/krystal-biotech-announces-early-evidence-monotherapy-activity

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