Conference Coverage

Tiragolumab plus atezolizumab active in PD-L1+ NSCLC



Targeting TIGIT, an inhibitory receptor expressed on immune cells, could complement activity of anti–programmed death–ligand 1/PD-1 antibodies in patients with solid tumors, results of a phase 1 study suggest.

The combination of the anti-TIGIT antibody tiragolumab with the PD-L1 inhibitor atezolizumab was well tolerated and showed preliminary activity in the phase 1b portion of the study, according to investigator Johanna C. Bendell, MD, of Sarah Cannon Research Institute/Tennessee Oncology in Nashville, Tenn.

Objective responses occurred mainly in chemoimmunotherapy-naive, PD-L1-positive tumors. In an expansion cohort of 13 patients with PD-L1-positive non–small cell lung cancer (NSCLC), the confirmed overall response rate was 46%, with several responses demonstrating durability.

Dr. Bendell reported these results at the AACR virtual meeting II.

While several important research questions remain, the results in the lung cancer expansion cohort were encouraging, particularly in patients who were smokers and previous smokers, said invited discussant Michele Teng, PhD, of QIMR Berghofer Medical Research Institute in Brisbane, Australia.

“Although it was [a] small cohort, the data suggest promising duration of response in some of the patients [n = 4] who have been under study for more than 700 days,” Dr. Teng said.

Based on the preliminary safety and activity seen in this study, the combination of tiragolumab and atezolizumab is being evaluated in a randomized, placebo-controlled phase 2 study, and a phase 3 study is recruiting.

Rationale, design, and safety

TIGIT is a novel inhibitory receptor expressed on multiple immune cells, especially CD8-positive T cells and natural killer cells, Dr. Bendell explained. She added that TIGIT is coexpressed with PD-1 on immune cells.

“Using anti-TIGIT antibodies to prevent TIGIT from binding, and cotargeting TIGIT and PD-L1, may restore antitumor response and enhance anti-PD-L1 effect,” Dr. Bendell said.

The phase 1 study Dr. Bendell presented, known as GO30103, was designed to evaluate tiragolumab as a single agent and in combination with atezolizumab in advanced solid tumors.

There were 24 patients in the phase 1a portion of GO30103, which was intended to determine the preliminary safety, tolerability, and recommended phase 2 dose of tiragolumab. There were 49 patients treated with tiragolumab plus atezolizumab in the phase 1b portion, which was intended to provide data on pharmacokinetics as well as preliminary antitumor activity of the combination.

No dose-limiting toxicities were seen in either cohort. The recommended phase 2 dose of tiragolumab was 600 mg every 3 weeks.

Tiragolumab was well tolerated in the phase 1a and 1b portions of the trial, according to Dr. Bendell.

“Immune-related adverse events were seen, but their incidence was not out of proportion to events seen with atezolizumab alone,” she said.

Treatment-related grade 3-4 adverse events occurred in one patient (4%) in the phase 1a portion of the trial and two patients (4%) in the phase 1b portion. There were no grade 5 adverse events related to treatment.

Efficacy and next steps

No objective responses were seen with tiragolumab monotherapy, although several patients did exhibit tumor reduction.

“We were not really expecting much single-agent activity of the anti-TIGIT drug,” Dr. Bendell said. “There’s some preclinical data that suggests that TIGIT may be more important as a single agent in earlier stages of cancer.”

In contrast, the combination of tiragolumab and atezolizumab resulted in several responses, including one in a patient with PD-L1-positive NSCLC who was previously treated with immunotherapy, according to Dr. Bendell.

The 13-patient expansion cohort of patients with PD-L1-positive NSCLC were treated at the recommended phase 2 dose of tiragolumab and atezolizumab. In these chemoimmunotherapy-naive patients, the overall response rate was 46%. Responses occurred in 6 of 13 patients and included 2 complete responses. Four patients had stable disease, so the disease control rate was 85% (11/13).

Based on that expansion cohort, a randomized, phase 2 study called CITYSCAPE was initiated. Results of CITYSCAPE were recently presented as part of the American Society of Clinical Oncology virtual scientific program.

In that study, tiragolumab plus atezolizumab improved the overall response rate and progression-free survival when compared with placebo plus atezolizumab. More substantial improvement was seen in the subgroup of patients with PD-L1 tumor proportion scores of 50% or greater.

The activity and safety of tiragolumab plus atezolizumab will be confirmed in the ongoing SKYSCRAPER-01 trial (NCT04294810), a phase 3 study of first-line treatment in patients with NSCLC and a PD-L1 tumor proportion score of 50% or greater, according to investigators.

The phase 1 study presented by Dr. Bendell was sponsored by Genentech. Dr. Bendell disclosed relationships with Genentech/Roche, Gilead, Five Prime, Lilly, and other companies.

SOURCE: Bendell JC et al. AACR 2020, Abstract CT302.

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