How much has precision medicine helped? A new NCI study offers clues but provokes skeptics
Does precision medicine work?
The approach, based on finding a drug to target a patient’s specific genes, has undoubtedly saved individual lives, spurring Lazarus-like reversals in health in once-terminally ill patients. But critics have pointed out that its pursuit has meant drug companies spending hundreds of millions of dollars to target mutations that affect narrow slices of the populations, and that many of the gains researchers thought it would bring have eroded as cancers evolve resistance.
A new New England Journal of Medicine study from the National Cancer Institute, though, offers evidence — albeit far from proof — that these new medicines are having a noticeable impact on a population level, allowing patients with the most common form of lung cancer to live significantly longer.
“Twenty, thirty years ago, a diagnosis of lung cancer was nearly a death sentence, there were really not a lot of therapeutic options available,” lead author Nadia Howlader, who heads NCI’s Division of Cancer Control and Population Sciences, told Endpoints News. “Now we have therapeutic options, and for the first time we are seeing signals that it is bringing down death rate at a population level, beyond clinical trials.”
Still, while some oncologists said the study reflected what they saw in their practice, others argued that the statistical analysis was well short of ironclad.
Peter Bach, who directs Memorial Sloan Kettering’s Center for Health Policy and Outcomes, pointed out that the mutations these drugs target are relatively rare. He didn’t question the data that lung cancer mortality fell, but he said there was little evidence tying that trend to new treatments. He noted they didn’t even estimate how widely those new treatments were used.
“I find it a little confusing,” he said in an email to Endpoints. “I don’t see any place where they actually attempted to measure the impact of treatments on survival gains.”
Bach and University of California, San Francisco oncologist and health policy researcher Vinay Prasad questioned on Twitter whether the drugs mentioned in the study were used enough to cause such a large benefit in overall mortality, noting that up-take has been chronically low.
Second, even if you maxed out these drugs, they are not cures. Majority will still die in a couple years. (this diminutes the overall effect)
— Vinay Prasad (@VPrasadMDMPH) August 13, 2020
For the study, researchers at NCI looked at lung cancer incidence and mortality over the last 20 years. They found that after slow declines in the first decade of the millennium, the number of people who died from the most common form of lung cancer, non-small cell lung cancer, decreased significantly since 2013. The number of NSCLC deaths fell 3.1% per year from 2006 to 2013, but 6.2% per year from 2013 to 2016. By comparison, the number of diagnoses fell only 3.1% from 2008 to 2016.
Two-year survival rates for patients with NSCLC also jumped from 26% in 2001 to 35% in 2014. NSCLC accounts for about 76% of all lung cancers.
The study’s authors attributed that decline in mortality to the first targeted therapies for patients with EGFR and ALK mutations. The first EGFR-targeted therapy, erlotinib, was approved in 2004 and the first ALK-targeted therapy, crizotinib, was approved in 2011, but it wasn’t until 2013 that genetic screening was recommended for all non-squamous NSCLC patients.
Only 15% of NSCLC patients have EGFR mutations and only 5% have ALK mutations, but patients with these mutations who receive targeted therapies can live for years on what was once a death sentence.
Julia Rotow, a thoracic oncologist at Dana Farber who was not involved in the study, said those numbers didn’t prove the treatments caused the decline in mortality, but that it provided good evidence and matched what researchers have seen in clinical trials.
“This paper itself would only be able to imply correlation,” Rotow told Endpoints.
“But I think given what we know clinically about the benefit to patients of these new treatments,” she added, “I think it’s certainly reasonable to infer that the new therapeutic options are likely translating into the kind of survival benefit reported in this study.”
Although the researchers don’t have data for what drugs patients receive, they point out that the story for the other major type of lung cancer looks much different. Small cell lung cancer, which accounts for about 13% of all lung cancer diagnoses, has not seen the same wave of treatments. Accordingly, over the same time period, survival rates for SCLC patients remained flat. (The number of people who died of SCLC did still decline, because fewer people have been diagnosed).
The researchers checked but discarded the theory that increased lung cancer screening accounted for the decline in mortality. Screening rates had remained low and stable.
Roy Herbst, a lung cancer specialist at the Yale School of Medicine, said researchers still have a ways to go. Despite the guidelines, he said, a significant portion of NSCLC patients still don’t get genetic testing that allow them to receive these kinds of treatments. And researchers have to find new options and methods for overcoming resistance that many patients develop.
Still, he said, the paper offered proof that the approach oncologists have been taking over the last couple decades is working. And he said newer immunotherapies have likely improved survival even further.
“It’s what I’ve been seeing in my 25 years treating lung cancer,” Herbst told Endpoints. “There’s momentum and the momentum is real and it’s measurable.”
The authors didn’t look beyond 2016, when immunotherapies were first introduced for NSCLC. Beginning with Merck’s Keytruda and Bristol Myers Squibb’s Opdivo, these checkpoint inhibitors gave NSCLC patients without targetable mutations new options. In addition, new targeted therapies have been approved to treat patients with more mutations and who evolved developed resistance to the first wave of treatments.
Howlader, the lead author, said they’re now looking at data from that period, with high hopes.
“What we expect is that immunotherapy is going to have an even bigger impact on mortality,” she said. “So, I guess stay tuned.”
Social: National Cancer Institute via Unsplash