PD-1 inhibitors work well in about one-fifth of patients with colorectal cancer, but the other 80% are not so lucky. Their tumors are immunologically “cold,” meaning they don’t respond to immunotherapies like Merck’s Keytruda.
Enter favezelimab, Merck’s LAG-3-targeting antibody, which helped Keytruda make a dent in metastatic colorectal cancer in very sick patients with microsatellite stable tumors. The phase 1 data will be presented virtually at the annual meeting of the American Society for Clinical Oncology next month. The combination is poised for a phase 3 study in the same type of colorectal cancer.
The combination, given to 80 patients whose cancer had worsened despite trying two other treatments, shrank tumors in five patients (6.3%), one of whom saw their tumors cleared completely. The treatment kept cancer progression at bay for a median of 2.1 months and helped patients live a median of 8.3 months—on par with the six- to nine-month range the investigators had cited in the study abstract.
However, the combination did better in a group of 36 patients whose tumors expressed high levels of PD-L1, as measured by the Combined Positive Score, or CPS. It shrank tumors in 11.1% of patients and helped patients live a median of 12.7 months. After one year of treatment, 51% of these patients were still alive, compared with 40.8% in the overall combo group.
That 11.1% may seem low, but it’s an improvement on the 0% Merck would expect had the patients taken Keytruda alone, said Eric Rubin, M.D., senior vice president of global clinical oncology at Merck Research Laboratories. Because immunotherapies don’t work in this patient group, they rely on chemotherapy and, later on, tyrosine kinase inhibitors. Cancers can develop resistance against the latter, underscoring the need for more treatment options.
“The data are limited, but it does look like PD-L1 staining is predictive for efficacy in this combination. Like any biomarker, it’s not perfect, but I think it identifies a patient population that is more likely to benefit from this treatment,” Rubin said. It will come in handy down the line when Merck starts designing registrational studies for the combination, he added.
Of the 20 patients who received favezelimab alone, none responded to treatment, which was “not terribly surprising” given what Merck has seen in its earlier research.
Side effects struck patients in the monotherapy and combination groups at similar rates: 65.0% and 65.2%, respectively. Slightly more patients who received the combination suffered severe side effects (20%) compared with those who received favezelimab alone (15%).
The most common side effect for the combination was fatigue, affecting 16.9% of patients, while the most common side effects for the LAG-3 drug alone were fatigue and nausea, hitting 20% and 15% of patients, respectively.
Merck and other companies are developing LAG-3 antibodies to make PD-1 blockers like Keytruda work in more people.
“When you look at preclinical models in patients exposed to anti-PD-1s, the LAG-3 pathway is upregulated, suggesting that it might be a compensatory pathway for tumors to evade anti-PD-1 treatments,” Rubin said.
Like PD-1, LAG-3 is an immune checkpoint receptor that acts as a “brake” to stop T cells from attacking tumors. In cancer, LAG-3 expression is linked to T-cell exhaustion, which helps tumors resist PD-1 blockade. Blocking LAG-3 as well as PD-1 could reinvigorate tired T cells, allow them to regain their cell-killing function and attack cancer.
Besides the phase 3 study in colorectal cancer that Merck plans to kick off later this year, the company is testing the combination in various other cancers including blood cancers, kidney cancer and non-small cell lung cancer.
Fevezelimab isn’t the only checkpoint inhibitor that Merck is combining with Keytruda. In September, the company presented data at the annual meeting of the European Society for Medical Oncology showing that Keytruda, along with its TIGIT-blocking antibody vibostolimab, shrank tumors in 29% of patients with non-small cell lung cancer. That combo did even better—as expected—in a subset of patients whose tumors expressed high levels of PD-L1, shrinking tumors in nearly half (46%) of them.