Tiragolumab Impresses in Multiple Trials

The TIGIT inhibitor tiragolumab (Genentech), alone or in combination with the PD-L1 inhibitor atezolizumab (Tecentriq; Genentech), may be effective against solid cancers. In phase I and II trials reported at two recent medical meetings, the agent achieved statistically significant results in multiple solid malignancies—most notably non–small cell lung cancer (NSCLC).

TIGIT is a receptor expressed on natural killer cells and T cells. It inhibits immune-cell activity by binding to the PVR ligand on tumor and antigen-presenting cells, and its expression strongly correlates with that of PD-1.

Thus, researchers hypothesized “that anti-TIGIT antibodies, which prevent TIGIT from binding to its ligand, could restore the antitumor response and could complement the activity of anti–PD-L1/PD-1 antibodies,” said Melissa Johnson, MD, of the Sarah Cannon Cancer Institute in Nashville, TN. This hypothesis, she added, is supported by preclinical data suggesting that anti-TIGIT plus anti–PD-L1 agents synergistically improve tumor control and prolong survival compared with either antibody alone.

A phase Ia/Ib trial tested tiragolumab in solid cancers. Alone, the drug led to stable disease in four of 24 patients; together, tiragolumab plus atezolizumab elicited responses in three of 49 patients—including a partial response in head and neck squamous cellcarcinoma and partial and complete responses in NSCLC. In an expansion cohort, seven of 14 patients with metastatic PD-L1–positive NSCLC responded to the combination. Results were reported by Johanna Bendell, MD, also of Sarah Cannon, at the American Association for Cancer Research Virtual Annual Meeting II: June 22–24, 2020.

Building on those results, Johnson and her colleagues launched the phase II CITYSCAPE trial, which enrolled patients with newly diagnosed locally advanced or metastatic NSCLC who expressed PD-L1 in at least 1% of tumor cells and did not have EGFR or ALK alterations. Patients were randomly assigned to receive tiragolumab plus atezolizumab or atezolizumab alone. Johnson reported on 135 patients at the 2020 American Society of Clinical Oncology Annual Meeting, May 29–31.

The combination arm had an overall response rate (ORR) of 37% and a median progression-free survival (PFS) of 5.6 months, compared with 21% and 3.9 months in the atezolizumab arm. This difference was linked to PD-L1 expression: Patients in the combination group with PD-L1 expression of at least 50% had an ORR of 66% and did not reach median PFS, compared with 24% and 4.1 months in the atezolizumab group. In contrast, patients in the combination group with lower PD-L1 expression had anORR of 16% and a median PFS of 4 months, compared with 18% and 3.6 months in the atezolizumab group.

More than 96% of patients in both groups experienced side effects. In addition, 69% of patients treated with the combination experienced immune-related adverse events—most commonly rash and infusion-related reactions—compared with 47% of patients receiving atezolizumab.

The phase III SKYSCRAPER-01 trial is currently investigating tiragolumab plus atezolizumab in patients with newly diagnosed NSCLC and PD-L1 expression of at least 50%. Early-phase trials are also exploring tiragolumab in cervical cancer and small cell lung cancer, as well as blood cancers.

“What has generated a lot of buzz is the objective response rate seen, which is mainly driven by the PD-L1–high group,” said Grace Dy, MD, of Roswell Park Cancer Institute in Buffalo, NY, who provided commentary on the phase II trial. Median PFS also favored the combination, she added, also due to PD-L1–high patients. She cautioned, however, that “while we are all excited by the data and want to see a winner, we should be careful.”

Cross-trial comparisons are difficult, Dy said, yet it is worth noting that the atezolizumab control group fared significantly worse than the control groups of other phase III trials in NSCLC, which could have magnified the benefit. She also said she wants to know whether favorable or unfavorable mutations were distributed evenly between groups. For example, preclinical data suggest that DNM1 expression maximizes the effect of TIGIT blockade and may correlate with MHC class I expression.

“Nonetheless,” she concluded, “we are cautiously optimistic that the combination is a promising advancement.” –Catherine Caruso

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