FDA Grants Breakthrough Therapy Designation to Tiragolumab Plus Atezolizumab for PD-L1–High NSCLC

January 5th, 2021 - The FDA has granted a breakthrough therapy designation to the anti-TIGIT therapy tiragolumab for use in combination with atezolizumab in the frontline treatment of patients with metastatic non–small cell lung cancer whose tumors are PD-L1 high and do not harbor any EGFR or ALK aberrations.

The FDA has granted a breakthrough therapy designation to the anti-TIGIT therapy tiragolumab for use in combination with atezolizumab (Tecentriq) in the frontline treatment of patients with metastatic non­–small cell lung cancer (NSCLC) whose tumors are PD-L1 high and do not harbor any EGFR or ALK aberrations.1

The decision was based on data from the phase 2 CITYSCAPE trial (NCT03563716), where the doublet was found to demonstrate better efficacy than checkpoint inhibitor monotherapy in patients with chemotherapy-naïve, locally advanced or metastatic NSCLC.2

Results from the primary analysis presented during the 2020 ASCO Virtual Scientific Program showed that tiragolumab/atezolizumab, when given every 3 weeks, led to a 43% reduction in the risk of disease progression or death versus atezolizumab/placebo in the intent-to-treat (ITT) population (n = 135; stratified HR, 0.57; 95% CI, 0.37-0.90). Moreover, the doublet elicited a confirmed overall response rate (ORR) of 31% versus 16% with placebo in the ITT population per investigator assessment.

With a median follow-up of 10.9 months, the improvement in progression-free survival was maintained with a median of 5.6 months in the investigative arm and 3.9 months in the control arm (stratified HR, 0.58; 95% CI, 0.38-0.89). The updated confirmed ORR in the investigative and control arms were 37% versus 21%, respectively.

“We have been researching TIGIT as a novel cancer immunotherapy target for almost 10 years and we are pleased that the FDA has acknowledged the potential of tiragolumab to substantially improve outcomes for people with certain types of lung cancer,” Levi Garraway, MD, PhD, chief medical officer and head of global product development at Roche, stated in a press release. “We look forward to advancing our tiragolumab development programme, which includes chemotherapy-free combinations and trials in early stages of disease across multiple cancer types with high unmet need.”

In the 2-arm, blinded trial, a total of 135 participants with a PD-L1 tumor proportion score (TPS) of 1% or greater by 22C3 immunohistochemistry via local or central assay were randomized 1:1 to receive intravenous (IV) tiragolumab or placebo at a dose of 600 mg every 3 weeks in combination with IV atezolizumab at a dose of 1200 mg every 3 weeks.

Patients were stratified based on PD-L1 TPS (1-49% vs greater than 50%), histology (nonsquamous vs squamous), and tobacco use (yes vs no). The co-primary end points of the trial were ORR and PFS. Key secondary end points comprised duration of response, overall survival, and patient-reported outcomes, while other exploratory end points included an efficacy assessment via PD-L1 status.

Additional results revealed that when broken down by PD-L1 TPS, the updated confirmed ORRs in those with a TPS of 50% or greater (n = 58) were 66% with tiragolumab/atezolizumab and 24% with placebo/atezolizumab; in those with a TPS between 1% and 49% (n = 77), these rates were 16% and 18%, respectively.

In the group of patients with a PD-L1 TPS of 50% or greater, the updated median investigator-assessed PFS was not estimable in the experimental arm versus 4.1 months in the control arm (unstratified HR, 0.30; 95% CI, 0.15-0.61). In the group who had a PD-L1 TPS between 1% and 49%, the investigator-assessed median PFS was 4.0 months with the doublet and 3.6 months with the monotherapy (unstratified HR, 0.89; 95% CI, 0.53-1.49).

Regarding safety, tiragolumab plus atezolizumab was found to be well tolerated, with a toxicity profile that was comparable to that of atezolizumab alone. Grade 3-5 adverse effects were reported in 48% of patients who received the doublet versus 44% of those given the monotherapy, with 5% versus 7%, respectively, of patients experiencing grade 5 toxicities.

More patients on the investigational arm experienced toxicities that resulted in a dose modification or interruption versus the control arm, at 40% versus 28%, respectively. Ten percent of patients who received the doublet experienced an effect that resulted in discontinuation versus 9% of those given the monotherapy.

Notably, immune-mediated toxicities were more commonly reported with tiragolumab plus atezolizumab versus atezolizumab alone, but these effects were mostly grade 1 or 2 in severity and were determined to be manageable.

The combination is also under evaluation in the first-in-human phase 1 Study GO30103 (NCT02794571). Results presented during the 2020 AACR Virtual Annual Meeting II showed that the doublet had early clinical activity with favorable tolerability when used in patients with advanced solid tumors, including those with metastatic NSCLC who had PD-L1 positivity and did not receive previous treatment with a checkpoint inhibitor.3

In the expansion subset of 13 patients who received the doublet, the ORR was 46% with an 85% disease control rate. No objective responses were reported with single-agent tiragolumab, but many participants experienced a reduction in their tumor size. Moreover, no dose-limiting toxicities were reported at the dose levels evaluated in the dose-escalation portion of the trial.

Tiragolumab is currently under investigation in several clinical trials. For example, the phase 3 SKYSCRAPER-01 trial (NCT04294810) is examining tiragolumab plus atezolizumab versus placebo/atezolizumab in treatment-naïve patients with locally advanced, unresectable or metastatic, PD-L1–selected NSCLC. In the phase 3 SKYSCRAPER-02 trial (NCT04256421), the agent is being examined in combination with atezolizumab plus carboplatin and etoposide in patients with untreated extensive-stage small cell lung cancer. In the phase 3 SKYSCRAPER-03 trial (NCT04513925), tiragolumab/atezolizumab is being compared with durvalumab (Imfinzi) in patients with locally advanced, unresectable stage III NSCLC.


  1. Roche’s novel anti-TIGIT tiragolumab granted FDA breakthrough therapy designation in combination with Tecentriq for PD-L1-high non-small cell lung cancer. News release. Roche. January 5, 2021. Accessed January 5, 2021. http://bit.ly/2LoNrj2.
  2. Rodriguez-Abreu D, Johnson ML, Hussein MA, et al. Primary analysis of a randomized, double-blind, phase II study of the anti-TIGIT antibody tiragolumab (tira) plus atezolizumab (atezo) versus placebo plus atezo as first-line (1L) treatment in patients with PD-L1-selected NSCLC (CITYSCAPE). J Clin Oncol. 2020;38(suppl 15):9503. doi:10.1200/JCO.2020.38.15_suppl.9503
  3. Bendell JC, Bedard P, Bang Y-J, et al. CT302 - Phase Ia/Ib dose-escalation study of the anti-TIGIT antibody tiragolumab as a single agent and in combination with atezolizumab in patients with advanced solid tumors. Presented at: 2020 AACR Virtual Annual Meeting; June 22-24, 2020; Virtual. Abstract CT302.