The more checkpoint inhibitors the merrier—at least, that’s what Genentech is hoping to prove. Its PD-L1 blocker, Tecentriq, combined with its experimental anti-TIGIT antibody shrank tumors in 31% of patients with metastatic lung cancer—twice as many patients as Tecentriq alone. The findings could pave the way for an approach that makes checkpoint inhibitors work for more people.
The phase 2 results, to be presented at the virtual annual meeting of the American Society for Clinical Oncology, are the first clinical data for the TIGIT-targeting med tiragolumab. Dubbed Cityscape, the trial enrolled 135 patients with non-small cell lung cancer (NSCLC) that had spread locally or elsewhere in the body and whose tumors expressed PD-L1.
At the first data analysis in June 2019, the Tecentriq-tiragolumab combo beat Tecentriq and placebo at shrinking tumors: 31.3% of patients versus 16.2%. It also kept cancer at bay for 5.4 months, compared with 3.6 months, slashing patients’ risk of cancer worsening or death by 43%.
Checkpoint inhibitors like Tecentriq, Merck & Co.’s Keytruda and Bristol Myers Squibb’s Opdivo have transformed treatment in certain cancers, but they don’t work for everyone—hence the glut of clinical trials testing combination approaches to see which drugs might boost their efficacy.
Like PD-L1, TIGIT is an immune checkpoint that acts as a “brake” to stop T cells from attacking tumors. Preclinical studies suggest that blocking both PD-L1 and TIGIT could work even better than targeting just one of them, Alan Sandler, Genentech’s global head of oncology product development, told FierceBiotech.
“The responses might be deeper and there might be more of them—there is more patient potential to benefit than either agent alone,” he said.
The combo worked best in a group of 58 patients with high PD-L1 levels in their tumors—the tiragolumab combination shrank cancers in more than half of them, while Tecentriq alone did so in only 17.2%. The response rates in patients with low PD-L1 levels were similar: 13.2% for the combo and 15.4% for the monotherapy.
When the data were checked again in December 2019, the combination had held its ground, nudging its response rate up to 37.3% compared to 20.6% for Tecentriq alone.
Genentech tested the tiragolumab combo in patients whose cancer couldn’t be treated surgically or had spread to other areas in the body. The standard of care for these patients typically involves chemotherapy, a treatment that “served its role for a number of years” but comes with well-known side effects, Sandler said.
“Anytime you can allow patients to not receive chemotherapy and suffer from side effects … you’re doing patients a service, particularly if you’re getting the same or better results without the addition of chemotherapy,” Sandler said.
Moving forward, Genentech already has two phase 3 studies of tiragolumab under way. The first pits the tiragolumab-Tecentriq combo against Tecentriq monotherapy in patients with PD-L1-positive NSCLC who have not received any cancer treatment. The second adds tiragolumab to Tecentriq and a pair of chemo drugs to see whether the cocktail can beat a Tecentriq-chemo combo in small cell lung cancer that has grown or spread.
Analysts clashed on what the data meant. For SVB Leerink analyst Daina Graybosch, the 38% response rate was a "home run," and an "indirect comparison" to Bristol Myers Squibb's Opdivo-Yervoy combo "looks promising." But "the restriction of benefit to PD-L1 high patients and poor performance of the atezolizumab arm raise some doubts on the market potential and strength of the signal, respectively," she wrote in an investor note Wednesday evening.
Evercore ISI's Umer Raffat, for his part, was "puzzled by the initial underwhelming feedback" for the combo, noting that high PD-L1 levels being the "primary driver of efficacy shouldn't be a surprise." That is, after all, the patient group Genentech is studying in one of its phase 3 studies, Raffat wrote in an investor note on Wednesday.
"And btw, cross-trial comparisons are irrelevant—this is a randomized trial! We just got a new SAFE IO target to add to lung armamentarium—now it’s about selecting the right pts," he wrote.
Editor's note: This story has been updated to include analyst comments.