User:Holawolga/Tiragolumab

Tiragolumab (MTIG7192A, RG6058) is a Fc-intact, fully-human, anti-TIGIT monoclonal antibody developed by Genentech/Chugai/Roche. Its efficacy and safety is being evaluated in multiple clinical trial program, across a broad range of malignancies.

Mechanism of action

Tiragolumab targets TIGIT (T cell Immunoglobulin and ITIM Domain), perturbing it from binding to CD155 and CD112, thus:

• Inhibits TIGIT inhibitory signaling, and
• Allows CD226 to bind to CD155.

By doing so, tiragolumab enhances effector function of CD8 T-cell, reduces immunosuppresive function of Treg, improves NK-cell mediated cytotoxicity and modulates antigen-presenting cells function. Fc-active antibodies like tiragolumab also modulate immune function through Fc receptor engagement.

History of clinical development

Tiragolumab's efficacy and tolerability were first evaluated in human in the phase Ia/Ib GO30103 trial. The study start dates were May 23, 2016, achieved first-patient-in (FPI) in May 2016 and was first refered to by Roche in an analyst event on ASCO 2016. Results was presented in AACR 2020 virtual meeting, showing limited activity in phase Ia when used alone with no objective response and stabilization of disease was the best result despite complete, sustained inhibition of TIGIT receptors that express on CD8+ T-cells and NK-cells present in blood at the 30mg dose and above (note that the patients population there were highly-pretreated with 42% of them received more than or equal to 4 previous lines of therapies). However, the combination of atezolizumab and tiragolumab showed better antitumor activity with 6% response rate. These findings led to the initiation of phase Ib dose-expansion, using the recommended 600mg dose every three weeks combined with 1200mg atezolizumab in patients whose tumors expressed PD-L1 and hadn't been treated with checkpoints inhibitor. In metastatic non-small cell lung cancer (mNSCLC) setting, tiragolumab yielded 77% disease control rate (10/13 patients), 46% objective response rate (6/13 patients), including two complete response and median duration of response (mDoR) was 24.2 months. In metastatic esophageal cancer (EC) cohort, 50% of the participants (9/18) achived disease control, 28% (5/18) responded, and median duration of response was 15.2 months.

Nearly two months prior to the presentation of GO30103 (May 29, 2020), the phase II CITYSCAPE trial was presented in ASCO 2020. The CITYSCAPE trial was a phase II, randomized, double-blinded, placebo-controlled study, comparing the combination of atezolizumab and tiragolumab against atezolizumab in NSCLC treatment.

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