Taking Aim at TIGIT, a New Immunotherapy Approach to Non-Small Cell Lung Cancer

The 2020 annual meeting of the American Society of Clinical Oncology that launches today will feature the first results from CITYSCAPE, a trial involving a novel immunotherapy approach in non-small cell lung cancer (NSCLC). This phase 2 trial is the first to combine the immunotherapy tiragolumab with atelzolizumab (Tecentriq), the monoclonal antibody that targets the programmed cell death ligand-1 (PD-L1).

Tiragolumab offers a brand new way to fight cancer; it binds to TIGIT, a different immune checkpoint protein present on some T cells and also some natural killer (NK) cells. Like the better known PD-L1, TIGIT plays a role in immune suppression, and blocking both pathways at once could create a powerful tumor fighting regimen. Results being presented today show the combination met both co-primary endpoints among patients with high levels of PD-L1:

• Among 135 patients with TPS ≥50% randomized, those taking the combination (67 patients) compared with those taking atezolizumab alone showed clinically meaningful improvement in objective response rate (ORR), 55.2% vs 17.2, and a 67% reduction in the risk of disease worsening or death after 5.9 months;

• Median progression-free survival (PFS) for those taking the combination was not reached vs 3.9 months; HR = 0.33; 95% CI: 0.15-0.72, compared with patients taking atezolizumab alone.

• Grade 3 treatment related adverse events occurred in 14.9% of those taking the combination, compared with 19.1% of those taking atezolizumab alone.

• After an additional 6 months of follow-up (median of 10.9 months), improvement in ORR and median PFS was maintained in the intent-to-treat population taking the combination.

In a statement, a Genentech spokesperson said its scientists discovered TIGIT while researching innovative approaches to harnessing the person’s immune system fight cancer, and “tiragolumab is our novel cancer immunotherapy designed to bind to TIGIT. Although TIGIT is expressed on immune cells in multiple tumor types, it is highly expressed in lung cancer.”

CITYSCAPE co-author Melissa L. Johnson, MD, who is the associate director for Lung Cancer Research at the Sarah Cannon Research Institute a partner at Tennessee Oncology, explained that when TIGIT works similarly to PD-L1, in that it can blunt the immune response. “So, in a similar way that blocking PD-1 or PD-L1, when you block TIGIT with the anti-TIGIT antibody,” she said, “you can restore the anti-tumor response and activate the inflammatory cells to fight the cancer.”

The new combination “may be useful for patients and doctors who are looking for a chemotherapy-free option,” she said. There is work at viewing TIGIT as a second biomarker, but “right now, it appears to be expressed in many of the same cells PD-L1.”

The Genentech statement said that, “Both TIGIT and PD-L1 play an important role in immune suppression, and by blocking both pathways simultaneously we hope to deepen patient responses to immunotherapy and broaden the number of people who may benefit.” 

“Identifying the right treatment for the right patient is very important, especially as each person’s cancer is different. We’re investigating the predictive and prognostic value of PD-L1 as a biomarker for tiragolumab, as well the potential roles of TIGIT and poliovirus receptor (PVR), in clinical trials. We will look for further insights as part of our late-stage program.”

Johnson said her research basically involves the hunt for new compounds that can help patients who have developed resistance “to the standard FDA-approved agents.”

Johnson discussed the findings within the context of the advances in lung cancer since her arrival at Sarah Cannon in 2014. “Thinking back over the last 5 years, I think some of the biggest gains in lung cancer research include the recognition of the importance of our immune system for the care of patients with lung cancer. Now all patients with lung cancer will receive immunotherapy is part of their first line of treatment in the metastatic setting, and that wasn't happening 5 years ago.”

Physicians-and patients-now have multiple options for PD-1 and PD-L1 inhibitors, not just from a single company but several, she said. “We have learned so much because of the cumulative knowledge and wisdom gained across all those trials,” Johnson said.

The second major advance, she said, has been the recognition of the importance of  gain in the care of our lung cancer patients is a recognition of the importance of molecular profiling, in the form of next-generation sequencing (NGS. Ideally, she said, this occurs in the first-line setting before treatment is given. “In the past, we have done hotspot panels or isolated analyte testing for single mutations. We know that not only is NGS testing better, it's more effective, it's more likely to identify rare mutations and unique alterations. It's also more cost effective to do it in that way, as opposed to piecemeal testing, one mutation at a time. It has led to many, many different therapy options for our patients that we wouldn't otherwise know about.”

A third major advance is the way clinical trials are conducted. “Five years ago, we were still trying to compare each new therapy to Platinum based chemotherapy for lung cancer patients. We now know that if you can design trials with selection for particular mutations up front, and you can show a benefit north of 50% in terms of response rates, then you have you have an active drug.”

The ability to combine data sets from many small subsets of patients, across lung and other tumor types, has allowed not only for advances that lead to new drug approvals, but “in the way that we take care of patients.”

Reference

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). Presented at: The American Society of Clinical Oncology 2020 Annual Meeting. Alexandria, VA: May 29-31, 2020. Abstract 9503.