Tiragolumab, an anti-TIGIT antibody, plus the PD-L1 inhibitor atezolizumab exhibited early clinical activity and was tolerated in patients with advanced solid tumors, including those with metastatic non–small cell lung cancer (NSCLC) that was PD-L1–positive and untreated with prior checkpoint inhibitor therapy. These results of the first-in-human phase I study of the combination were presented during the 2020 American Association for Cancer Research (AACR) Virtual Annual Meeting II.¹

In 13 patients with non–small cell lung cancer in the expansion phase of the trial treated with tiragolumab plus atezolizumab, the objective response rate was 46%, and the disease control rate was 85% (ie, response rates plus stable disease). No dose-limiting toxicities were reported at the dose levels studied in the dose-expansion phase of the trial.

When tiragolumab was given as monotherapy, no objective responses were observed, but some patients had tumor shrinkage. Most of the patients included in the trial had tumor types that typically do not respond well to PD-1 or PD-L1.

“Tiragolumab was well tolerated both as a single agent and in combination with atezolizumab. No dose-limiting toxicities were seen, and the safety profile with atezolizumab appears to be similar to that of other checkpoint inhibitors,” said lead author ­Johanna C. Bendell, MD, a medical oncologist and Chief Development Officer at Sarah Cannon Research Institute, Nashville.

­Johanna C. Bendell, MD

Background

TIGIT, a member of the immunoglobulin super family and an immune-inhibitory receptor, plays a key role in the suppression of T-cell proliferation and activation; it is involved in tumor cell immune evasion and the inhibition of antiviral immune responses. TIGIT binds to the poliovirus receptor, which can be expressed on antigen-presenting cells and tumors. Preclinical data suggested that using two different types of immune checkpoint inhibitor in combination—anti-TIGIT and anti–PD-L1—might enhance anticancer control and improve outcomes. A number of anti-TIGIT antibodies are in various stages of development.

Study Details

The study included two phases: phase Ia is evaluating tiragolumab as a single agent in 24 patients, and phase Ib is evaluating the combination of tiragolumab plus atezolizumab in 49 patients with advanced solid tumors. The dose-escalation phase evaluated the safety and tolerability of tiragolumab, and the dose-expansion phase evaluated the safety and tolerability of the combination. Tiragolumab at 600 mg every 3 weeks was selected in the dose-expansion phase as the recommended dose moving forward.

Patients enrolled in the trial had to have tried standard treatment for their advanced solid tumors. In the expansion cohorts, patients had to have PD-L1–positive tumors and be checkpoint inhibitor–naive. Study exclusions included prior anti-TIGIT therapy, anticancer therapy with 3 weeks of study treatment or palliative radiation with 2 weeks, discontinuation of prior immunotherapy due to adverse events, active or untreated central nervous system metastases, and a history of autoimmune disorder.

The dose-expansion phase evaluated 400 mg, 600 mg, and 1,200 mg of tiragolumab every 3 weeks with atezolizumab at 1,200 mg intravenously. The median age of study patients was 59.5 years. Almost 40% of patients had previously received four lines of therapy.

Key Findings

All patients who received single-agent tiragolumab discontinued treatment: 42% did so for disease progression, 8% withdrew, and 50% crossed over to the combination therapy in phase Ib. Among patients treated with the combination, 76% discontinued treatment (all with disease progression), 12% withdrew, and 12% were lost to follow-up.

No dose-limiting toxicities were observed across all dose levels in both phases of the trial. In the single-arm phase, 100% of patients reported any adverse event compared with 94% of those treated with the combination. Grades 3 to 5 adverse events were reported in 25% and 57%, respectively. Serious adverse events were reported in 25% and 53%, respectively. Adverse events leading to interruption of the study drug were reported in 17% and 25% of patients, respectively.

“Exposure increased with the dose of tiragolumab, and its pharmacokinetics are not altered when combined with atezolizumab. No objective responses were seen in phase Ia, but most of the patients included had tumor types not typically responsive to checkpoint inhibitor therapy,” Dr. Bendell stated.

Ongoing Clinical Trials

The combination of tiragolumab plus atezolizumab is being compared with placebo plus atezolizumab in NSCLC in the phase II CITYSCAPE trial. Dr. Bendell said results thus far seem to favor the combination, especially in patients with high PD-L1 expression. A phase III trial called SKYSCRAPER-01 is evaluating the combination versus placebo plus atezolizumab in previously untreated, locally advanced unresectable or metastatic, PD-L1–­selected NSCLC. Another phase III trial, SKYSCRAPER-2, is exploring atezolizumab plus carboplatin or etoposide with or without tiragolumab in patients with untreated extensive-stage small cell lung cancer. 

DISCLOSURE: The studies were sponsored by Genentech. Dr. Bendell reported financial relationships with Gilead, Genentech/Roche, BMS, Five Prime, Lilly, Merck, MedImmune, Celgene, EMD Serono, Taiho, MacroGenics, GSK, Novartis, OncoMed, Leap, TG Therapeutics, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, and Bayer.

REFERENCE

1. Bendell JC, Bedard P, Bang YJ, et al: 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. 2020 AACR Virtual Annual Meeting II. Abstract CT302.