12個月患者總生存率超90%的抗癌聯合療法；治療慢性HBV感染的表觀遺傳沉默劑進入臨牀…… | 一週盤點
▎藥明康德內容團隊編輯
本期看點
1. Cue Biopharma公司公佈了其兩款新型生物製品的積極臨牀數據，其中接受CUE-101聯用PD-1抑制劑pembrolizumab一線治療的HPV陽性複發性/轉移性頭頸部鱗狀細胞癌（R/M HNSCC）患者12個月時的總生存率爲91.3%。
2. 胸苷酸合成酶抑制劑NUC-3373聯用pembrolizumab在一項臨牀研究中使1名尿路上皮膀胱癌患者的靶病竈縮小了100%。
3. 用於治療慢性乙肝病毒（HBV）感染的表觀遺傳沉默劑TUNE-401在新西蘭獲批進入1b期臨牀試驗。
藥明康德內容團隊整理
CUE-101、CUE-102：公佈1期臨牀試驗的新數據
Cue Biopharma公司公佈其CUE-101治療頭頸癌和CUE-102治療WT1陽性癌症的1期臨牀試驗的積極新數據。CUE-101是該公司開發的一款基於白細胞介素-2（IL-2）的T細胞誘導劑，旨在選擇性調節和激活HPV陽性T細胞，以提高療效，同時減少傳統免疫療法的副作用。CUE-102是一種由兩個呈遞WT1肽的人白細胞抗原（HLA）分子、四個親和力減弱的IL-2分子和一個效應減弱的人免疫球蛋白G（IgG1）Fc結構域組成的新型生物製品，被開發作爲單一療法治療WT1陽性復發/轉移性癌症患者。
截至2024年9月11日的數據，接受CUE-101聯用PD-1抑制劑pembrolizumab一線治療的HPV陽性R/M HNSCC患者的客觀緩解率（ORR）爲46%，疾病控制率（DCR）爲75%，12個月時的總生存率爲91.3%，中位總生存期（OS）爲21.8個月。在歷史研究KEYNOTE-048中，pembrolizumab單藥治療的ORR爲19%，12個月時的總生存率爲51%，中位OS爲12.3個月。在本研究中，1例患者達到完全緩解（CR），10例患者達到部分緩解（PR），以及7例患者獲得了超過12周的持久疾病穩定（SD）。接受該一線聯合治療的PD-L1低表達患者的ORR爲50%。
截至2024年10月29日的數據，接受CUE-102單藥治療的晚期胰腺癌患者的DCR爲67%，其中包括腫瘤負荷減少40%的未確認的PR。有證據表明，WT1特異性CD8陽性T細胞受到了選擇性刺激和擴增，而非特異性CD8陽性T細胞的總數沒有明顯增加。
NUC-3373：公佈1b/2期聯合治療臨牀試驗數據
NuCana公司公佈了其正在進行的1b/2期模塊化研究的初步數據，模塊1研究評估了NUC-3373聯用PD-1抑制劑pembrolizumab治療晚期實體瘤患者的療效，模塊2研究評估了NUC-3373聯用多西他賽治療肺癌患者的療效。NUC-3373是一種胸苷酸合成酶抑制劑，由核苷類似物5-氟尿嘧啶衍生而來，可導致DNA損傷。
模塊1包括12名患有各種實體瘤、已用盡所有其他治療方案的患者，其中9例患者曾接受過PD-1/PD-L1抑制劑的治療。接受NUC-3373聯用pembrolizumab治療後，患者實現了顯著的腫瘤體積縮小，PFS得到延長。2名患者獲得了確認的PR，4例患者達到SD。在療效可評估人羣中，ORR爲22%，DCR爲67%。其中，1例尿路上皮膀胱癌患者接受聯合治療後靶病竈縮小了100%（非靶病竈依然存在），1例BRAF突變轉移性皮膚黑色素瘤患者的靶病竈縮小了81%。此外，NUC-3373聯合pembrolizumab的耐受性普遍良好。
模塊2包括4名非小細胞肺癌（NSCLC）或胸膜間皮瘤患者，這些患者在既往含化療方案中出現疾病進展或無法耐受。患者在接受NUC-3373聯用多西他賽治療後PFS得到延長，2例患者實現了長期的SD。
TUNE-401：在新西蘭獲批啓動1b期臨牀試驗
Tune Therapeutics公司宣佈，該公司已獲得新西蘭藥品和醫療器械安全局（Medsafe）的臨牀試驗申請（CTA） ，將推進其用於治療慢性HBV感染的表觀遺傳沉默劑TUNE-401進入1b期臨牀試驗。
TUNE-401是一款潛在"first-in-class"的表觀遺傳沉默劑，利用Tune Therapeutics的多功能、模塊化TEMPO平臺所開發。TUNE-401通過脂質納米顆粒（LNP）將編碼活性、HBV靶向的RNA直接遞送至肝細胞。在這些細胞內，所遞送的RNA被翻譯爲表觀沉默蛋白，靶向整合入宿主細胞的乙肝病毒DNA（intDNA）和共價閉合環狀DNA（cccDNA）。cccDNA是一種獨特、遊離的環狀染色體（episomes），可作爲病毒進行復制時的模板，是造成HBV患者多年持續感染的原因之一。臨牀醫生認爲，關閉這些cccDNA“病毒工廠”是實現HBV功能性治癒的必要前提。TUNE-401不涉及切割或編輯DNA，其導致產生的活性表觀沉默蛋白通過添加甲基基團與DNA結合，以抑制或失活病毒基因，同時保持人類基因的完整性。根據新聞稿，TUNE-401是首個獲批進入臨牀，用以治療常見傳染病的表觀遺傳療法。
KVA12123：公佈1/2期臨牀試驗數據
Kineta公司公佈了其正在進行的1/2期臨牀試驗的最新進展，該試驗評估了其新型在研VISTA阻斷免疫療法KVA12123單藥或與PD-1抑制劑pembrolizumab聯用在晚期實體瘤患者中的治療效果。KVA12123是一種單克隆抗體療法，需每週輸注兩次。通過將獨特的表位與優化的IgG1 Fc區相結合，KVA12123單藥在臨牀前模型中顯示出強大的腫瘤生長抑制作用，且在臨牀試驗中沒有報告細胞因子釋放綜合徵（CRS）。KVA12123已被證明能降低VISTA靶點的風險，並提供了一種新的方法來解決腫瘤微環境中的免疫抑制問題，其作用機制與以T細胞爲重點的療法不同且互補。
截至2024年10月18日的數據，接受KVA12123單藥治療並至少進行了一次隨訪掃描的19例患者中，有13名實現了SD。在許多接受KVA12123單藥治療的患者中觀察到持久的臨牀結果，其中1名此前已接受過六線治療（包括免疫檢查點抑制劑治療）的NSCLC患者已保持SD狀態60周。在接受KVA12123聯合pembrolizumab治療並至少進行了一次隨訪掃描的9例患者中，1例粘液表皮樣癌患者獲得了PR，靶病竈縮小了54%，非靶病竈獲得了CR；1名免疫檢查點抑制劑治療後進展的腎細胞癌患者達到SD，靶病竈縮小了24%。安全性方面，KVA12123的耐受性良好，單藥或與pembrolizumab聯用在任何劑量水平上都未出現劑量限制性毒性（DLT）。
IDRX-42：公佈1/1b期臨牀試驗的新數據
IDRx公司公佈了其用於治療晚期胃腸道間質瘤（GIST）的在研口服小分子KIT酪氨酸激酶抑制劑IDRX-42的1/1b期臨牀試驗數據。IDRX-42旨在選擇性地靶向最常見的KIT突變形式，這些突變要麼驅動腫瘤細胞的初始生長、增殖和生存，要麼使腫瘤對現有療法產生耐藥性。
截至2024年9月30日的數據，87例中位治療線數爲四線、療效可評估患者的ORR爲29%，包括1例CR和24例PR。接受IDRX-42作爲二線治療患者的ORR爲53%（8/15），包括1例CR和7例PR，這些患者的中位PFS尚未達到。接受IDRX-42作爲三線治療的患者的中位PFS估計爲12.9個月。既往未使用過ripretinib、接受IDRX-42作爲≥四線治療的患者在推薦的1b期劑量下，其中位PFS估計爲11.0個月。此外，IDRX-42具有良好的安全性，在推薦的1b期劑量下，8%的患者減少了劑量，沒有因治療伴發不良事件而停藥的情況。
APV-527：公佈1期臨牀試驗數據
Alligator Bioscience公司和Aptevo Therapeutics公司公佈了APV-527用於治療可能表達腫瘤抗原5T4實體瘤患者的1期臨牀試驗數據。APV-527是一種靶向4-1BB和腫瘤抗原5T4的雙特異性抗體，僅在與4-1BB和5T4同時結合時纔有活性。
此次公佈的結果顯示，16例療效可評估的患者中有9例（56%）達到SD，其中，1例結腸癌患者已保持SD超過6個月。最長的SD持續時間發生在一名乳腺癌患者中，該患者進入研究時病情發生進展，目前病情保持穩定，且已參與研究超過11個月。安全性方面，APV-527在所有隊列中均表現出積極的安全性和耐受性，尚未觀察到嚴重的肝毒性。肝毒性是其他4-1BB靶向治療的常見副作用，可導致患者停藥。
ELI-002：公佈1期臨牀試驗的初步數據
Elicio Therapeutics公司公佈了其在研治療性癌症免疫療法ELI-002用於治療接受標準局部治療後仍有疾病復發風險的KRAS突變驅動實體瘤的1期臨牀試驗的初步結果。ELI-002由AMP修飾的KRAS突變體（mKRAS）肽段，和一種AMP修飾的免疫刺激寡核苷酸佐劑ELI-004組成，經皮下給藥靶向淋巴結。它能產生RAS特異性殺傷性T細胞，以攻擊術後殘留腫瘤細胞，有望延長癌症患者緩解並可預防未來複發。
初步數據表明，靶向KRAS突變體的T細胞反應持久且呈劑量依賴性，並誘導了針對患者特異性新抗原的反應。觀察到無病生存期（DFS）與T細胞反應強度之間存在相關性。此外，ELI-002的1期安全性及耐受性特徵依然良好，未觀察到DLT或CRS。
GUBamy：公佈1期臨牀試驗數據
Gubra公司公佈了長效胰澱素（amylin）類似物GUBamy在單劑量遞增（SAD）1期臨牀試驗中獲得的 。GUBamy耐受性良好，表現出良好的藥代動力學特徵，半衰期爲11天，支持每週一次的給藥方案。此外，單劑量的GUBamy劑量依賴性地降低體重，這一效果在試驗期間（6周）內持續存在。在所有高劑量組（3.5-6.0 mg）中，受試者在6周試驗期內的平均體重下降約3％，而安慰劑組的體重平均增長約1％。
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參考資料（可上下滑動查看）
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[24] GenVivo to Present Phase 1 Trial Results for GEN2, A Personalizing Gene Vector Therapy, at the 2024 Society for Immunotherapy of Cancer (SITC) Annual Meeting. Retrieved November 15, 2024, from https://genvivoinc.com/2024/11/08/genvivo-to-present-phase-1-trial-results-for-gen2-a-personalizing-gene-vector-therapy-at-the-2024-society-for-immunotherapy-of-cancer-sitc-annual-meeting/
[25] Sparian Biosciences Announces Results from the Phase 1 Clinical Trial of First in Class Novel Arylepoxamide Receptor (AEAr) Agonist Analgesic SBS-1000. Retrieved November 15, 2024, from https://www.globenewswire.com/news-release/2024/11/12/2979419/0/en/Sparian-Biosciences-Announces-Results-from-the-Phase-1-Clinical-Trial-of-First-in-Class-Novel-Arylepoxamide-Receptor-AEAr-Agonist-Analgesic-SBS-1000.html
[26] Spyre Therapeutics Announces Positive Interim Results from Phase 1 Healthy Volunteer Trial for SPY001, Its Novel Half-Life Extended anti-α4β7 Antibody for the Treatment of Inflammatory Bowel Disease, with a Half-Life of >90 Days Supporting the Potential for Both Q3M & Q6M Maintenance Dosing. Retrieved November 15, 2024, from https://www.prnewswire.com/news-releases/spyre-therapeutics-announces-positive-interim-results-from-phase-1-healthy-volunteer-trial-for-spy001-its-novel-half-life-extended-anti-47-antibody-for-the-treatment-of-inflammatory-bowel-disease-with-a-half-life-of-90-days-s-302302014.html
[27] Nuvectis Pharma Reports Encouraging NXP800 Interim Data Supporting Ongoing Enrollment in Phase 1b Study in Patients with Platinum-Resistant ARID1a-Mutated Ovarian Cancer. Retrieved November 15, 2024, from https://www.globenewswire.com/news-release/2024/11/14/2981017/0/en/Nuvectis-Pharma-Reports-Encouraging-NXP800-Interim-Data-Supporting-Ongoing-Enrollment-in-Phase-1b-Study-in-Patients-with-Platinum-Resistant-ARID1a-Mutated-Ovarian-Cancer.html
[28] Enlivex Announces the Dosing of the First Patient in a Phase I Clinical Trial Evaluating Allocetra in Patients with Psoriatic Arthritis. Retrieved November 15, 2024, from https://enlivex.com/investors/news-releases/enlivex-announces-the-dosing-of-the-first-patient-in-a-phase-i-clinical-trial-evaluating-allocetra-in-patients-with-psoriatic-arthritis/#:~:text=Nes-Ziona%2C%20Israel%2C%20Nov.%2014%2C%202024%20%E2%80%94%20Enlivex%20Therapeutics,an%20affected%20joint%20in%20patients%20with%20psoriatic%20arthritis.
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