An immunotherapy from Merck & Co. is the latest drug of its kind to slow the return of lung cancer in clinical testing, though mixed results in the large study supporting its benefit add to questions about the best way to use it.
The findings, revealed at a medical meeting Thursday, build on evidence that immunotherapies like Merck's Keytruda, already go-to treatments for metastatic disease, could soon become standard for use earlier, either before or after surgery to remove a tumor. The emerging results are from studies meant to show the drugs can delay the return of cancer, when it's more lethal and harder to eliminate.
"When a patient relapses, life is never the same and life is short," said study investigator Mary O'Brien, head of the Lung Unit at The Royal Marsden NHS Foundation Trust and a professor of medicine at Imperial College London. "The word 'cure' is never used again."
Since January, drug combinations involving Bristol Myers Squibb's immunotherapy Opdivo and Roche's similar drug Tecentriq have won Food and Drug Administration approvals for patients with early-stage lung cancer. Merck intends to follow with approval applications in the U.S. and elsewhere "as quickly as possible," according to a company spokesperson.
Yet Merck's new data might not set Keytruda apart. Results detailed Thursday show that patients who would have been expected to respond best to treatment surprisingly didn't do as well. The study also raises questions as to whether immunotherapy might be more effective before surgery, when more of a tumor is still present, than afterwards. If that proves true, Keytruda, which is currently the most widely used immunotherapy for advanced lung cancer, could be relegated to a more niche role in earlier settings.
"Overall it's a mixed result," said John Heymach, chair of thoracic/head and neck medical oncology at the University of Texas MD Anderson Cancer Center. Given the data supporting the two other drugs, "it's unclear whether [Keytruda] has in any way differentiated itself," said Heymach, who wasn't involved with the trial.
While immunotherapy has transformed treatment of many tumor types in the last decade, lung cancer remains the leading cause of cancer death. Over 350 people die from the disease each day, more than breast, pancreas and prostate cancers combined, according to the American Cancer Society.
The risk of death is particularly high if tumors return after they're surgically removed. About half do, according to O'Brien. Drugmakers and doctors hope that immunotherapies like Keytruda, Opdivo and Tecentriq can reduce that risk and, in turn, the number of people who die or need additional treatment.
When they work, these drugs can keep people with advanced disease alive much longer than can older treatment options. Encouraged by that progress, Merck, Bristol Myers and Roche in recent years launched large studies to see whether their drugs can do the same earlier on.
Each chose slightly different strategies. Bristol Myers tested a short, nine-week course of Opdivo and chemotherapy before surgery. Roche and Merck opted to evaluate longer regimens of their drugs — about a year — after surgery. Roche excluded patients with the earliest-stage disease from its study, while Merck and Bristol Myers didn't.
Though comparing one trial to another can be misleading, the results of those decisions appear to have left Merck with some ground to make up. Roche's study showed an average 21% reduction in the risk of relapse or death in all patients and a better result — 34% reduction — among those study participants whose tumors express at least some amount of a protein, PD-L1, that's associated with better treatment response. In Bristol Myers' trial, Opdivo led to an average 37% risk reduction in all patients, regardless of PD-L1 levels.
By comparison, giving chemotherapy alone after surgery reduces the risk of disease recurrence or death by about 15%, Heymach said.
Merck, with its new data, is reporting a 24% risk reduction overall, but a lower 18% average reduction in people with high PD-L1 levels, a finding that wasn't statistically significant. The latter result is "somewhat disappointing and puzzling," Heymach said, in the context of the other studies.
O'Brien noted there were far fewer patients with high PD-L1 levels in Merck's trial — only 333 of the 1,177 enrolled. That group's control arm might have outperformed expectations as well.
"Maybe there [wasn't] enough patients" in that group, she said, "to really make definitive answers." (An analysis on participants with very little or no PD-L1 hasn't been done.)
"It wasn't a negative effect and, overall, all-comers have a very positive benefit," she added.
However, to Heymach, the results leave Keytruda behind its rivals. Combined, the results from the three trials also raise the question of whether treating a tumor with immunotherapy before it's removed has more of an impact. Before surgery, a tumor is "present" and the body can be trained to recognize and attack it. Afterwards, "you're asking the immune system to target microscopic disease that you can't even see," he said.
Heymach pointed to the fact that a shorter course of Opdivo in Bristol Myers' trial led to a seemingly larger relative benefit. At this point, "my preference would be for neoadjuvant therapy," Heymach said, referring to treatment before surgery.
Still, the trials' results may not have an immediate impact on clinical care. None have gone on long enough to know how much Keytruda, Tecentriq or Opdivo might extend lives. Key details in Bristol Myers' study haven't been disclosed yet. All three drugs are expensive and have side effects that can be significant. For example, nearly 20% of the patients who received Keytruda in Merck's trial stopped treatment, compared to about 6% of the control group.
Additionally, some oncologists have criticized using so-called disease-free survival as a study goal, as Merck, Bristol Myers and Roche did in their trials. Doctors don't yet know whether using an immunotherapy early might make it less powerful if tried again later on, either.
Some of those answers might come with time. Several additional studies of immunotherapies before or after surgery are underway, including a trial with the AstraZeneca drug Imfinzi for which Heymach is an investigator. But both O'Brien and Heymach say they won't wait to use the drugs.
"The goal is to increase cure rates, and your best chance to cure people is up front," Heymach said. "You don't want to be saving your bullets for a later day."