[Editor’s note: Ben Fidler co-authored this report.] A decade from now, it’s possible that immunotherapy will have made a big dent in lung cancer, which is by far the deadliest type of the disease.
Drugs from several companies have worked their way forward, initially for patients who have failed chemotherapy, and now, in some cases, for patients newly diagnosed with advanced cancer.
They’re not miracle drugs. Only a minority of patients have positive benefits. But those benefits tend to be long-lasting—often better than the results from chemotherapy and targeted therapies such as Pfizer’s crizotinib (Xalkori) or Roche’s erlotinib (Tarceva). Will immunotherapies combined with each other, or with chemotherapy and other drugs, help more patients? That’s what some of the latest clinical studies aim to find out.
The latest results for lung cancer are out today at the American Association for Cancer Research meeting in Chicago. Last week we asked lung cancer specialists what they would be looking for, and today we’ll break the studies down here. (Note: All of the trials were for patients with advanced, previously untreated or first-line lung cancer.)
Keynote-189
Pembrolizumab (Keytruda), made by Merck (NYSE: [[ticker:MRK]]), was approved nearly a year ago, when combined with chemotherapy, for this patient group.
But that FDA approval was based on limited evidence. The new, much larger study, dubbed Keynote-189 and including 616 patients, is meant to reinforce the previous study. Funded by Merck, it showed that patients taking pembrolizumab and chemotherapy (let’s call it pembro-chemo) fared better in several ways than patients just taking chemo. The study is not finished, but it has reached its first planned milestone. The results, published in the New England Journal of Medicine this morning, are very good. The risk of death or worsening disease for the pembro-chemo patients was half that of the chemo-only patients. “We’ve never seen this magnitude of benefit over chemotherapy with any other regimen,” said study leader Leena Gandhi, director of thoracic medical oncology at NYU Langone’s Perlmutter Cancer Center in New York City.
The data reinforce pembrolizumab’s advantage over rival nivolumab in first-line lung cancer, ISI Evercore analyst Umer Raffat wrote in a research note Monday. But he cautioned that the advantage does not apply to other cancers or even to second-line lung cancer, and it’s not clear why. “I still scratch my head,” wrote Raffat.
In a measure of how long the drugs halted the march of a patient’s cancer, median progression-free survival was 8.8 months for the pembro-chemo patients and 4.9 months for the chemo-only patients. Overall survival one year after starting treatment was 69 percent for the pembro-chemo patients and 49 percent for the chemo patients.
Safety is always a big deal in Phase 3. Problems often do not emerge until larger groups of patients are tested in randomized settings. In Keynote-189, in which two-thirds received pembrolizumab and chemo, the rate of serious side effects was nearly equal (67.2 percent versus 65.8 percent). However, the pembrolizumab arm had twice the rate of serious side effects (8.9 percent versus 4.5 percent) with an immune-related cause. Gandhi says that was expected with the addition of immunotherapy. The worry with immunotherapy is that it will work too well and kick the patient’s immune system into dangerous overdrive. But the only side effects standing out for Gandhi were higher liver problems, which are associated with the chemotherapies used in Keynote-189. Patients with pre-existing kidney problems would not be put on this particular regimen, she says.
Another important data point was that the pembro-chemo combination was an improvement no matter how much of the protein PD-L1 was on the patient’s tumor. Pembrolizumab and other drugs like it are designed to block PD-L1, which some tumors use to evade the immune system. Measuring a tumor’s PD-L1 abundance has been the only way to predict which patients might respond better to these new drugs. It is an imperfect measurement and open to interpretation, but “it is the best we have,” says Gandhi. (Pembrolizumab was approved in 2016 without chemo to treat patients with 50 percent or more PD-L1 on their tumors.)
Keynote-189 showed that the survival benefit of pembro-chemo accrued to all PD-L1 categories—even patients who might not have any (less than 1 percent) on their tumor. Their reduction of risk of death was about 40 percent, and those with abundant PD-L1 saw their risk reduced nearly 60 percent.
Merck threw a layer of intrigue over Keynote-189 and other lung cancer results from AACR when, one week ago, it announced that similar patients in a different trial, Keynote-042, survived “significantly longer” after taking pembrolizumab only—no chemo—than patients taking chemo only. Merck did not divulge details, and the study did not include patients with less than 1 percent PD-L1 on their tumors.
So talk of pembrolizumab alone knocking aside chemo not just for high-PD-L1 tumors but for most first-line lung cancer patients is a bit premature, says Gandhi. “We know from the Keynote-042 release there was a survival benefit, but the magnitude is unknown. Was it driven by high PD-L1 expressors? We can’t interpret it yet or compare.”
Even with more details, however, she emphasizes that treatment decisions won’t be based just on
