Co-Inhibition of TIGIT and PD-L1 Generates Promising Efficacy in NSCLC

Melissa L. Johnson, MD

Frontline tiragolumab, an inhibitor of the immunomodulatory receptor TIGIT, plus and anti–PD-L1 agent demonstrated greater efficacy versus single-agent checkpoint inhibitor therapy in locally advanced or metastatic non–small cell lung cancer (NSCLC). Results of the phase 2 CITYSCAPE trial (NCT03563716) were made available as part of the 2020 American Society of Clinical Oncology Virtual Scientific Program.

“Tiragolumab and atezolizumab showed clinically meaningful improvements in objective response rate [ORR] and PFS [progression-free survival] in the intention-to-treat [ITT] patient population compared with placebo plus atezolizumab,” Melissa Johnson, MD, associate director of Lung Cancer Research at Sarah Cannon Research Institute in Nashville, Tennessee, said in her presentation of the data. “With longer follow-up, the treatment benefit of tiragolumab and atezolizumab remained consistent with the primary analysis, with a greater magnitude of improvement seen in the [subgroup with] PD-L1 TPS [tumor proportion score] 50% and above.”

At the primary analysis, tiragolumab plus atezolizumab (Tecentriq) administered every 3 weeks resulted in a 43% reduction in the risk of disease progression or death compared with atezolizumab plus placebo in the ITT population (stratified HR, 0.57; 95% CI, 0.37-0.90). With an additional 6 months of follow-up, improvement in PFS was maintained with medians of 5.6 months versus 3.9 months, respectively (stratified HR, 0.58; 95% CI, 0.38-0.89).

At the primary analysis, ORR in the tiragolumab arm was almost double that of the placebo arm, at 31% versus 16%, respectively. Updated confirmed ORR in both groups was 37% and 21%, respectively.

In an exploratory analysis of patients with high PD-L1 expression, or those with TPS above 50% (n = 58), there was a 70% reduction in the risk of disease progression or death with tiragolumab versus placebo (stratified HR, 0.30; 95% CI, 0.15-0.61). Median PFS for patients with high PD-L1 expression was not evaluable with tiragolumab plus atezolizumab versus 4.1 months with atezolizumab alone. Corresponding ORRs were 66% and 24%.

Any-cause adverse effects (AEs) occurred in 99% of patients receiving tiragolumab and in 96% treated with placebo. AEs of grade 3 or higher occurred in 48% of patients in the tiragolumab arm versus 44% with placebo. Patients discontinuing therapy due to AEs occurred at a rate of 10% with tiragolumab therapy versus 9% in the placebo group. Dose modifications due to therapy happened in 40% versus 28% of patients, respectively.

Immune-mediated AEs were more frequent in the tiragolumab arm, with all-grade events occurring in 69% of patients versus 47% of those receiving atezolizumab alone. The most common immune-mediate toxicities in the tiragolumab arm were rash, infusion-related reaction, pancreatitis, hypothyroidism, hyperthyroidism, and colitis.

In the exploratory analysis of patients with PD-L1 expression of TPS 1% to 49% (n = 77), tiragolumab/atezolizumab resulted in a numerical but not statistically significant improvement in median PFS (4.0 vs 3.6 months; unstratified HR, 0.89; 95% CI, 0.53-1.49). The ORR was similar in both groups, at 16% for tiragolumab/atezolizumab and 18% for placebo/atezolizumab.

The 2-arm, blinded trial randomized patients 1:1 to received intravenous (IV) infusions of atezolizumab at 1200 mg plus either IV tiragolumab at 600 mg or matched placebo in 3-week cycles until progressive disease or loss of clinical benefit. Patients were stratified by PD-L1 status (TPS ≥50% or TPS 1%-49%), histology, and tobacco history. Coprimary end points of the study were investigator-assessed ORR and PFS, with secondary outcome measures including duration of response, overall survival, patient-reported outcomes, and safety.

Patients could be included on the trial if they had an ECOG performance status of 0 or 1, NSCLC with squamous or nonsquamous histology, no prior systemic therapy for locally advanced unresectable or metastatic disease, and PD-L1 expression as assessed by 22C3 IHC by local or central assay. Patients with ALK or EGFR mutations; symptomatic, untreated, or actively progressing central nervous system metastases; or other malignancies within 5 years were excluded from the trial.

Baseline characteristics of patients treated on the trial were balanced between the tiragolumab and placebo arms, with most patients being male (58% vs 71%, respectively) and white (63% vs 59%). More than half of patients in both arms had PD-L1 TPS 1% to 49% (57% each) and nonsquamous histology (60% vs 59%, respectively).

“The observed activity and safety of tiragolumab plus atezolizumab is to be confirmed in an ongoing phase 3 study called SKYSCRAPER-01 in first-line PD-L1 TPS 50% and above NSCLC,” Johnson said.

SKYSCRAPER-01 (NCT04294810) is currently enrolling and is examining the combination versus placebo/atezolizumab in patients with previously untreated locally advanced unresectable or metastatic PD-L1–selected NSCLC. SKYSCRAPER-02 (NCT04256421), another phase 3 trial, is currently ongoing and is exploring atezolizumab plus carboplatin or etoposide with or without tiragolumab in patients with untreated extensive-stage small cell lung cancer.

Tiragolumab is a novel, fully humanized monocloncal antibody that inhibits TIGIT—T-cell immunoglobin and ITIM domain protein—a novel inhibitory receptor that is expressed on multiple immune cells, including T cells and natural killer cells.

_References

^{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}