ESMO: Merck chalks one up for TIGIT with phase 1 Keytruda combo

Lung cancer
Like PD-L1, TIGIT is an immune checkpoint that acts as a “brake” to stop T cells from attacking tumors. Blocking them both could make checkpoint inhibitors work for more people. (Isabella Del Priore and Lindsay LaFave)

Companies are searching high and low for ways to make checkpoint inhibitors work for more people. One solution Merck is trying out is combining different checkpoint blockers—and early data from its TIGIT-blocking prospect and blockbuster PD-1 med Keytruda are promising.

The data, presented in posters Thursday at the virtual meeting of the European Society for Medical Oncology, come from two studies of patients with non-small cell lung cancer (NSCLC). The company tested the anti-TIGIT antibody vibostolimab alone and in tandem with Keytruda in 79 patients whose disease got worse despite trying a PD-1/PD-L1 inhibitor. It also tested the combo in 41 patients with advanced NSCLC, about three-quarters of whom had tried other treatments such as chemotherapy, but no checkpoint inhibitors.

The treatment showed “modest antitumor activity” in the first study, shrinking 7% of tumors in the 41 patients who received vibostolomab alone and 5% of the 38 patients who got the TIGIT med alongside Keytruda.

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In the second study, the combination shrank tumors in 29% of patients, but it did better—as expected—in a subset of patients whose tumors expressed PD-L1 at levels of 1% or higher.

“For people whose tumors had more than 1% PD-L1, the response rate was pretty nice at 46%. That’s in line with other TIGIT combinations,” said Xiuning Le, M.D., assistant professor of thoracic/head and neck medical oncology at MD Anderson Cancer Center, who wasn’t involved in either study. 

The combo kept cancer at bay for 5.4 months in all patients, doing better in the PD-L1 population, staving off progression for 8.4 months.

“The progression-free survival even in the best cohort is 8.4 months. For an immunotherapy, I’d like to see that be a little longer—but again, these data are from just 13 patients and you can see six patients responded,” Le said, adding that data from more patients are needed to understand what is going on.

“With an initial look, the data are consistent, not surprisingly good or surprisingly bad, but we need a little more to validate,” she added.

That said, Merck reckons the data are strong enough to start a phase 3 trial in 2021. Merck is also testing vibostolimab in other tumor types, including melanoma.

But the implications extend beyond Merck. Roche also has a TIGIT drug that's slightly ahead in development, and some industry watchers viewed Merck's data set as validating for the class.

Roche's data "for this treatment-naïve patient population is at the 55% mark—so, to me, they’re in the same ballpark,” Le said.

SVB Leerink analyst Daina Graybosch agreed, writing in an investor note on Monday that the data are enough to “confirm and extend … early signals” seen in a TIGIT/PD-L1 combination in the works at Roche’s Genentech unit.

“Both companies have now demonstrated that inhibiting TIGIT deepens benefit for patients who likely respond to anti-PD(L)1 alone,” Graybosch said. “Here, the combination has potential to meet a large unmet need, as less than half of patients respond to PD-(L)1 antagonism in treatment-naïve (1L), PD-L1 high NSCLC.”

Genentech reported data for tiragolumab in tandem with PD-L1 blocker Tecentriq at this year’s American Society of Clinical Oncology meeting, showing the combo shrank tumors in 31% of patients with metastatic NSCLC—twice as many patients as Tecentriq alone. Like the vibostolimab-Keytruda combo, it did better in patients expressing PD-L1, though its 55% figure comes from patients with PD-L1 levels of 50% or higher.

So, why are Merck and Genentech combining these drugs?

Checkpoint inhibitors like Keytruda, Tecentriq and Bristol Myers Squibb's Opdivo have transformed treatment in certain cancers, but they don’t work for everyone—hence the proliferation 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. They work in parallel, so, if you block one, the other will still work, Le said.

“One of the reasons that not all patients respond to an anti-PD-L1 is because these other pathways kick in,” Eric Rubin, senior vice president of global clinical oncology at Merck Research Laboratories, said. “It’s logical for one to combine these types of things with an anti PD-L1.”

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