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The addition of tiragolumab to atezolizumab produced a clinically meaningful improvement in progression-free survival, overall survival, and objective response rate compared with atezolizumab alone in the first-line treatment of patients with PD-L1–positive non–small cell lung cancer.
The addition of tiragolumab to atezolizumab (Tecentriq) produced a clinically meaningful improvement in progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) compared with atezolizumab alone in the first-line treatment of patients with PD-L1–positive non–small cell lung cancer (NSCLC), according to data from an updated analysis of the phase 2 CITYSCAPE trial (NCT03563716).1
Results from the trial, which were presented during the 2021 ESMO Immuno-Oncology Congress, showed that at a median follow-up of 30.4 months, treatment with the combination yielded an investigator-assessed median PFS of 5.6 months (95% CI, 4.2-10.4) vs 3.9 months (95% CI, 2.7-4.5) with atezolizumab alone in the intention-to-treat (ITT) population. The median OS with the combination was 23.2 months (95% CI, 14.1-31.5) vs 14.5 months (95% CI, 9.6-20.4) with atezolizumab monotherapy.
“Durable responses and encouraging OS [data] continue to support evaluating tiragolumab plus atezolizumab as a chemotherapy-free regimen in metastatic PD-L1–high NSCLC,” lead study author Byoung Chul Cho, MD, PhD, of Yonsei University, said during a presentation on the findings. “The observed activity and safety are to be confirmed in the ongoing phase 3 SKYSCRAPER-01 trial [NCT04294810] in [the] first-line [treatment] of [patients with NSCLC and a] PD-L1 tumor proportion score [TPS] of 50% or less.”
TIGIT is a novel inhibitory immune checkpoint that is present on activated T cells and natural killer cells in multiple cancers. TIGIT expression has been linked with PD-1, particularly in tumor-infiltrating T cells.
Tiragolumab is a fully human IgG1/kappa anti-TIGIT monoclonal antibody with an intact Fc region that blocks the binding of TIGIT to its receptor PVR. Investigators hypothesized that anti-TIGIT antibodies, such as tiragolumab, can restore antitumor response and potentially strengthen the activity of anti–PD-L1/PD-1 antibodies.
CITYSCAPE is the first randomized, phase 2 study of an anti-TIGIT antibody. The trial enrolled treatment-naïve patients with stage IV NSCLC who had EGFR or ALK wild-type disease. Patients also needed to have a PD-L1 TPS of 1% or higher per 22C3 immunohistochemistry by local or central assay.
A total of 135 patients were randomized 1:1 to receive either intravenous (IV) tiragolumab at 600 mg every 3 weeks plus IV atezolizumab at 1200 mg every 3 weeks (n = 67), or IV placebo at 600 mg every 3 weeks plus IV atezolizumab at 1200 mg every 3 weeks (n = 68).
Treatment continued until disease progression or loss of clinical benefit. Patients were stratified based on PD-L1 TPS (1% to 49 vs more than 50%), histology (nonsquamous vs squamous), and tobacco use (yes vs no).
The co-primary end points of the study were ORR and PFS, and key secondary end points included safety, duration of response, and OS.
Among patients in the ITT population, baseline characteristics were well balanced, with 41.8% of those in the combination arm younger than 65 years vs 41.2% in the placebo arm. Additionally, most patients in the combination and placebo arms were male (58.2% vs 70.6%, respectively), White (62.7% vs 58.8%), had a nonsquamous histology (59.7% vs 58.8%), and had a PD-L1 TPS ranging from 1% to 49% (56.7% vs 57.4%).
At the time of the primary analysis, which had a cutoff date of June 30, 2019, and a median follow-up of 5.9 months, the doublet resulted in a clinically meaningful improvement in ORR and PFS in the ITT population compared with single-agent atezolizumab. This benefit was also maintained after 5 months of follow-up, with a greater magnitude of improvement observed in the subset of patients with a PD-L1 TPS of 50% or less.
Here, investigators presented an updated analysis with 30 months of follow-up, including OS, updated PFS, and safety.
Additional results showed that the 12-month PFS rate in the ITT population with the combination was 36.2% vs 21.1% with atezolizumab alone.
Moreover, the median PFS among those with a PD-L1 TPS of more than 50% was 16.6 months (95% CI, 5.5-22.3) with the combination vs 4.1 months (95% CI, 2.1-6.8) with atezolizumab alone; the 12-month PFS rates were 51.0% and 21.8%, respectively. The median PFS among those with a PD-L1 TPS ranging from 1% to 49% was 4.0 months (95% CI, 1.6-5.6) with the doublet vs 3.6 months (95% CI, 1.4-5.5) with atezolizumab alone; the 12-month PFS rates in this subset were 24.9% and 20.5%, respectively.
In the ITT population, the OS rates at 12 months were 66.1% with the doublet vs 58.0% with single-agent atezolizumab; the 24-month OS rates were 47.2% and 34.3%, respectively.
The median OS in the subset of patients with a PD-L1 TPS of more than 50% was not evaluable (NE; 95% CI, 30.3–NE) with the combination vs 12.8 months (95% CI, 4.7-24.2) with atezolizumab alone; the 12- and 24-month OS rates were 81.9% and 56.1%, respectively, and 78.2% and 33.7%, respectively. Among the subset of patients with a PD-L1 TPS ranging from 1% to 49%, the median OS was 13.3 months (95% CI, 8.0-20.7) with the doublet vs 14.5 months (95% CI, 8.3-25.6) with atezolizumab alone; the OS rates at 12 months were 54.4% and 59.5%, respectively, and the 24-month OS rates were 24.5% and 35.0%, respectively.
Findings from the EORTC QLQ-C30 assessment showed that patients generally reported moderate global health status and moderately high functioning at baseline in both treatment arms. Changes from baseline scores of physical and role functioning were found to be maintained and comparable between the arms. Moreover, similar patterns were reported for global health status and other functioning scales.
Additionally, patients generally reported minimal to moderate symptom burden at baseline, and this was comparable between the 2 treatment arms. Symptom burden associated with lung cancer continued to be minimal to moderate over time in patients who received the doublet. Other symptoms included in the assessment demonstrated similar patterns at most of these visits.
Adverse effects of any grade occurred in 98.5% of patients who received the doublet vs 97.1% of those who received the monotherapy. Grade 3 or 4 AEs occurred in 52.2% vs 39.7% of patients, respectively; grade 5 AEs occurred in 4.5% vs 10.3% of patients, respectively. Moreover, serious AEs were experienced by 52.2% of those in the investigative arm and 41.2% of those on the control arm.
Treatment-related AEs (TRAEs) of any grade were reported in 82.1% of those in the combination arm vs 70.6% of those in the monotherapy arm, and grade 3 or 4 AEs occurred in 22.4% vs 25.0% of patients, respectively. Grade 5 TRAEs were experienced by 3.0% of those in the investigative arm vs no patients in the control arm, and serious TRAEs were reported in 20.9% vs 17.6% of patients, respectively.
Immune-mediated AEs of any grade were experienced by 76.1% of patients in the doublet arm vs 47.1% in the monotherapy arm; these effects were grade 3 or 4 in 19.4% vs 16.2% of patients, respectively.
AEs that resulted in the need for dose modification or interruption were experienced by 49.3% of patients in the combination arm vs 35.3% of those in the monotherapy arm. AEs leading to treatment withdrawal were experienced by 14.9% and 13.2% of patients, respectively.
All-cause AEs included infusion-related reaction, arthralgia, pruritus, fatigue, rash, anemia, lipase increased, amylase increased, hypokalemia, rash maculopapular, dyspnea, alanine aminotransferase increased, and nausea. Immune-mediated AEs included rash, infusion-related reaction, hepatitis, hypothyroidism, pancreatitis, hyperthyroidism, diabetes mellitus, adrenal insufficiency, and hepatitis.