Recent I-O Trials
最新免疫腫瘤學試驗
The anti-TIGIT class — once hailed as the most promising next-generation immune checkpoint therapy after PD-1/PD-L1 — has suffered a series of high-profile clinical failures spanning multiple companies, cancer types, and drug molecules. The latest casualty is belrestotug (GSK/iTeos), terminated in May 2025.
Anti-TIGIT 類藥物曾被譽為繼 PD-1/PD-L1 後最具潛力的下一代免疫檢查點療法，卻在多家公司、多種癌症類型及多個藥物分子中接連遭遇重大臨床失敗。最新受害者是 belrestotug（GSK/iTeos），已於 2025 年 5 月終止。
| Company | Drug | Trial(s) | Cancer Type | Phase | Outcome | 公司 | 藥物 | 試驗 | 癌症類型 | 期別 | 結果 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Roche | Tiragolumab | SKYSCRAPER-01, -02, -14 | NSCLC, SCLC, HCC | Phase III | FAILED | ||||||
| Merck (MSD) | Vibostolimab (MK-7684A) | KEYVIBE-008, -010 | NSCLC, SCLC | Phase III | FAILED + Safety | ||||||
| BeiGene | Ociperlimab | AdvanTIG-302 | NSCLC | Phase III | TERMINATED | ||||||
| GSK / iTeos | Belrestotug (EOS-448) | GALAXIES Lung-201, H&N-202 | NSCLC, HNSCC | Phase II | FAILED — May 2025 | ||||||
| Gilead / Arcus | Domvanalimab | STAR-221, ARC-10 | Gastric, NSCLC | Phase III | FAILED / Pivoting | ||||||
| AstraZeneca | Rilvegostomig (anti-TIGIT × PD-1 bispecific) | 9 ongoing Phase III trials | Multiple | Phase III | ACTIVE |
The GALAXIES Lung-201 Phase II trial evaluated belrestotug + dostarlimab (a PD-1 inhibitor) vs. dostarlimab monotherapy in first-line PD-L1-high NSCLC. While the primary endpoint — objective response rate (ORR) — showed clinically meaningful improvement, the critical secondary endpoint of progression-free survival (PFS) was not met. Simultaneously, the GALAXIES H&N-202 head and neck trial fell short of ORR. Both GSK and iTeos terminated all belrestotug cohorts, halted enrollment in the already-launched Phase III GALAXIES Lung-301, and dissolved the collaboration.
GALAXIES Lung-201 二期試驗評估 belrestotug + dostarlimab 對比 dostarlimab 單藥治療一線 PD-L1 高表達 NSCLC。客觀緩解率（ORR）雖達標，但關鍵的無進展生存期（PFS）次要終點未達標。同時，H&N-202 頭頸癌試驗亦未達 ORR。GSK 與 iTeos 終止所有試驗組，停止已啟動的三期 GALAXIES Lung-301，並解散合作。iTeos 目前正尋求戰略替代方案。
Tiragolumab misses OS endpoint in NSCLC and SCLC Phase III studies. The first major warning signal for the anti-TIGIT class.
Tiragolumab 在 NSCLC 和 SCLC 三期研究中未達 OS 終點，為該類藥物的首個重大警訊。
KEYVIBE trial halted for futility in SCLC; elevated immune-related adverse events (irAEs) compared to the control arm.
KEYVIBE 試驗因 SCLC 無效而停止；免疫相關不良事件（irAE）發生率高於對照組。
AdvanTIG-302 Phase III in NSCLC terminated. BeiGene exits the TIGIT space entirely.
AdvanTIG-302 三期 NSCLC 試驗終止，百濟神州完全退出 TIGIT 領域。
GALAXIES Lung-201 misses PFS; H&N-202 misses ORR. Full program halt including Phase III. iTeos seeks strategic alternatives.
GALAXIES Lung-201 未達 PFS；H&N-202 未達 ORR。包含三期在內全面停止，iTeos 尋求戰略替代方案。
Phase III gastric cancer trial fails. Arcus pivots to HIF2α inhibitor casdatifan as the new lead asset.
三期胃癌試驗失敗。Arcus 轉向 HIF2α 抑制劑 casdatifan 作為新核心資產。
9 Phase III trials ongoing. Bispecific design (anti-TIGIT × PD-1) with reduced Fc effector function. Phase III data readouts expected 2026+.
9 項三期試驗持續進行中。雙特異性設計（anti-TIGIT × PD-1）並具有降低的 Fc 效應功能，預計 2026 年後公布三期數據。
Leading mechanistic and trial-design hypotheses behind the systematic collapse of the anti-TIGIT class.
Anti-TIGIT 類藥物系統性失敗背後的主要機制與試驗設計假說。
All four major failed anti-TIGIT antibodies are unmutated IgG1 with fully active Fc effector functions (ADCC, CDC). A JCO hypothesis suggests the Fc effector function simultaneously depletes TIGIT-expressing Tregs and effector T cells, neutralizing therapeutic benefit.
四種主要失敗的 anti-TIGIT 抗體均為具有完整 Fc 效應功能（ADCC、CDC）的未突變 IgG1。《臨床腫瘤學雜誌》假說認為 Fc 效應功能同時耗盡 TIGIT 表達的 Treg 和效應 T 細胞，抵消了治療益處。
A striking pattern: ORR improves (tumors shrink initially), but PFS and OS do not improve meaningfully. TIGIT blockade may promote transient tumor regression without durable immune memory — possibly due to compensatory checkpoint upregulation (LAG-3, TIM-3).
明顯規律：ORR 改善（腫瘤初期縮小），但 PFS 和 OS 無顯著改善。TIGIT 阻斷可能促進短暫腫瘤消退而無持久免疫記憶——可能源於代償性檢查點上調（LAG-3、TIM-3）。
Most trials selected patients based on PD-L1 expression, not TIGIT-specific biomarkers. The absence of a validated companion diagnostic for TIGIT on tumor-infiltrating lymphocytes may have led to underpowered efficacy in the truly responsive subpopulation.
大多數試驗根據 PD-L1 表達而非 TIGIT 特異性生物標誌物篩選患者。缺乏驗證的腫瘤浸潤淋巴細胞 TIGIT 伴隨診斷，可能導致真正有反應亞群的療效評估能力不足。
TIGIT is one of many co-inhibitory receptors on T cells. Blocking TIGIT alone may be insufficient if other suppressive checkpoints (CD47/SIRPα, LAG-3, TIM-3, VISTA) remain active — particularly in PD-1/PD-L1 pre-treated patients where resistance mechanisms are already diverse.
TIGIT 是 T 細胞上眾多共抑制受體之一。若其他抑制性檢查點（CD47/SIRPα、LAG-3、TIM-3、VISTA）仍保持活性，單獨阻斷 TIGIT 可能不足——特別是在 PD-1/PD-L1 預處理患者中，耐藥機制已相當多樣。
Merck's vibostolimab trials showed elevated immune-related adverse events (irAEs) versus PD-1 monotherapy, including rash and systemic immune activation — adding toxicity burden without a corresponding survival benefit.
Merck 的 vibostolimab 試驗顯示免疫相關不良事件（irAE）較 PD-1 單藥治療更高，包括皮疹和全身免疫激活——在無生存獲益的情況下增加毒性負擔。
Several trials used ORR as the primary endpoint, which may be insufficient to predict OS benefit. Some trials were launched based on Phase I/II signals before confirming whether the mechanism was truly additive with anti-PD-1 for long-term survival.
部分試驗以 ORR 為主要終點，這可能不足以預測 OS 獲益。某些試驗在確認機制是否真正有助於長期生存前，便基於一/二期信號啟動。
AstraZeneca's rilvegostomig — a bispecific antibody simultaneously targeting TIGIT and PD-1 with reduced Fc effector function — is the field's last significant program. AZ argues that reduced Fc avoids depleting TIGIT+ effector T cells while still blocking the checkpoint. However, Gilead/Arcus's domvanalimab was also Fc-silent and still failed in STAR-221, which weakens this claim. Phase III data readouts expected 2026+.
阿斯利康的 rilvegostomig 是同時靶向 TIGIT 和 PD-1 且具有降低 Fc 效應功能的雙特異性抗體，是該領域最後的重大計畫。阿斯利康認為降低的 Fc 可避免耗盡 TIGIT+ 效應 T 細胞。然而 Gilead/Arcus 的 Fc 靜默型 domvanalimab 在 STAR-221 中仍告失敗，削弱了這一論點。三期數據預計 2026 年後公布。
If rilvegostomig fails, the TIGIT target will likely be abandoned industry-wide. If it succeeds, the class will be reborn under a bispecific/Fc-engineered paradigm. For TIGIT-adjacent biology, the emerging pivot is toward CD47/SIRPα combination approaches or myeloid cell engineering rather than T cell checkpoint blockade alone.
若 rilvegostomig 失敗，業界可能全面放棄 TIGIT 靶點。若成功，該類藥物將以雙特異性/Fc 工程化範式重生。對於 TIGIT 相鄰生物學，新興轉型方向是 CD47/SIRPα 組合方法或骨髓細胞工程，而非單純的 T 細胞檢查點阻斷。
TMS Laboratory Perspective: The systematic failure of anti-TIGIT antibodies underscores a core insight from our research — effective tumor microenvironment targeting requires a multi-dimensional strategy. Our work on CD24/macrophage-mediated immunity and the "don't eat me" signal axis (CD47/SIRPα) represents a complementary approach that may address the fundamental limitations revealed by these TIGIT trial failures, particularly the need to engage myeloid cells alongside T cell checkpoints.
TMS 實驗室觀點：Anti-TIGIT 抗體的系統性失敗印證了我們研究的核心見解——有效靶向腫瘤微環境需要多維度策略。我們在 CD24/巨噬細胞介導免疫及「別吃我」信號軸（CD47/SIRPα）方面的研究代表了一種互補方法，可能解決這些 TIGIT 試驗失敗所揭示的根本局限性，尤其是需要在 T 細胞檢查點之外同時調動骨髓細胞的問題。
Sources: Applied Clinical Trials Online · OncLive · BioSpace · Nasdaq GlobeNewswire · ApexOnco · Journal of Clinical Oncology · Report compiled: May 2025
資料來源：Applied Clinical Trials Online · OncLive · BioSpace · Nasdaq GlobeNewswire · ApexOnco · Journal of Clinical Oncology · 報告整理日期：2025 年 5 月