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TIGIT ( ; also called T cell immunoreceptor with Ig and ITIM domains) is an immune receptor present on some T cells and natural killer cells (NK). It is also identified as WUCAM and Vstm3. TIGIT could bind to CD155 (PVR) on dendritic cells (DCs), macrophages, etc. with high affinity, and also to CD112 (PVRL2) with lower affinity.
Numerous clinical trials on TIGIT-blockade in cancer have recently been initiated, predominantly combination treatments. The first interim results show promise for combined TIGIT and PD-L1 co-blockade in solid cancer patients. Mechanistically, research has shown that TIGIT-Fc fusion protein could interact with PVR on dendritic cells and increase its IL-10 secretion level/decrease its IL-12 secretion level under LPS stimulation, and also inhibit T cell activation in vivo. TIGIT's inhibition of NK cytotoxicity can be blocked by antibodies against its interaction with PVR and the activity is directed through its ITIM domain.
The phase III, randomized, double-blinded SKYSCRAPER-01 trial, which evaluates the efficacy of the combination of tiragolumab and atezolizumab in NSCLC patients whose tumors have high PD-L1 expression, failed to show a significant PFS improvement in the combination arm compared with placebo + atezolizumab, although it showed "a numerical improvement" in both endpoints of PFS and overall survival (OS). In August 2023, an internal PowerPoint presentation detailing OS data of the second analysis was mistakenly made public on the Internet and showed a numerical improvement in terms of OS estimated. No new safety signals were identified and the trial remains blinded to investigators and patients.
Tiragolumab also shows encouraging efficacy in hepatocellular carcinoma setting. In the MORPHEUS-liver trial, tiragolumab + atezolizumab + bevacizumab significantly improved response rate and PFS in both patients with positive PD-L1 expression and with negative PD-L1 expression.
In small-cell lung cancer, tiragolumab didn't show any OS and PFS benefit in the SKYSCRAPER-02 trial, but its development in SCLC setting is being continued as consolidation therapy for patients with limited-stage SCLC who have not progressed during/after chemotherapy and radiotherapy ( NCT04308785).
In the Skyscraper-04 trial assessing the efficacy and safety of tiragolumab in patients who have recurrent, PD-L1 positive cervical cancer, the combination of tiragolumab and atezolizumab, although improved response rate in both PD-L1 low and PD-L1 high subgroups, only did so marginally and non-significantly.
The combination of tiragolumab, atezolizumab, and platinum-containing chemotherapy improved PFS and OS compared with comparator arms in esophageal cancer patients in the phase II MORPHEUS-EC trial and the phase III SKYSCRAPER-08 trial.
The Skyscraper-06 trial was ended in July 2024 in metastatic non-squamous non-small cell lung cancer as tiragolumab plus Tecentriq and chemotherapy did not meet the primary endpoints of progression-free survival (PFS) at primary analysis and overall survival (OS) at the first interim analysis. The OS hazard ratio was 1.33 at the first interim analysis, indicating that patients are living longer on Pembrolizumab than tiragolumab.
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