For the most common type of lung cancer in Americans, deaths are falling faster than new cases, a new study reports, suggesting  — but not proving — that new therapies targeting genetic mutations are having an outsize effect on survival.

Mortality rates for patients with non-small cell lung cancer, which accounts for three-quarters of cancers originating in the lung, declined for men by 3.2% per year from 2006 to 2013. The drop accelerated to 6.3% per year from 2013 to 2016, when targeted therapies were introduced. The declines in both periods outstripped the drop in new cases. Two-year survival jumped from 26% for men diagnosed in 2001 to 35% in 2014.

For women, the slope is not quite as steep, but it moved in the same direction. Incidence was flat from 2001 through 2006 and then dropped by 1.5% annually from 2006 to 2016. Deaths decreased by 2.3% a year from 2006 to 2014 but then more rapidly, falling 5.9% a year from 2014 through 2016. Two-year survival climbed from 35% to 44% over that decade.

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Notably, the improvement was consistent among all races and ethnic groups studied: non-Hispanic Asian or Pacific Islander, non-Hispanic white, Hispanic, and non-Hispanic Black. 

Small cell lung cancer, which makes up 13% of diagnoses, was a different story. Over the time period studied, deaths were down, but almost in lockstep with fewer diagnosed cases. There was no improvement in survival rates. The National Cancer Institute researchers drew their numbers from the NCI’s SEER registry and their report appeared Wednesday in the New England Journal of Medicine.

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Nadia Howlader, a study co-author and a mathematical statistician in surveillance research at NCI, said recent treatment advances for non-small cell lung cancer are likely primarily responsible for the sharp decline in deaths. “Declining smoking rates will have an influence on incidence rates and then subsequently death rates downstream, but the kind of abrupt and sharp fall we see for non-small cell lung cancer and the magnitude and the timing of that fall in death rates leads us to believe that it has something to do with approval of the new drugs in 2013.”

Those drugs include two targeted therapies: the tyrosine kinase inhibitor erlotinib that targets EGFR mutations and the ALK inhibitor crizotinib.

Lung cancer survival has been improving at a population level for about 40 years for men and 30 years for women. The study adds a new hypothesis based on SEER subtype data that targeted therapies are responsible for the uptick in non-small cell lung cancer survival. SEER data does not include information on the drugs that patients receive.

The authors contend that the impact of targeted drugs, specifically those tailored to attack mutations of the EGFR and ALK genes, are what sent death rates sloping downward. Although only 15% of non-small cell lung cancer patients have faulty EGFR genes and only 5% have ALK gene translocations, their survival is measured in years, not the months more typical for chemotherapy. That dramatic benefit accounts for the lower death rate, the researchers say. 

Immunotherapies known as checkpoint inhibitors —  drugs that take the brakes off the immune system after cancer hijacks it — were first approved in 2015, near the end of the study period. Howlader said future projects are monitoring these drugs as well as newer therapies targeting other genetic mutations in addition to EGFR and ALK.

Grace Dy, chief of thoracic medicine at Roswell Park Comprehensive Cancer Center, expects future reports to show continuing improvement, especially if genomic testing becomes more widely available as new drugs are developed and approved to attack mutations in ROS1, BRAF, MET exon 14, and others. She also thinks there may be more to the story. She was not involved in the study.

“It’s a convergence of many things. There have been more adjuvant chemotherapy improvements,” she said. “It’s essentially a new standard of care that has been introduced that incrementally improved survival.”

David Jones, chief of thoracic surgery at Memorial Sloan Kettering Cancer Center, also said other factors could contribute to the brighter picture for a disease that is the leading cause of cancer death in the U.S., citing better radiation oncology and greater use of minimally invasive surgery as care of lung cancer patients has become more multidisciplinary. Jones, who was not involved in the study, was encouraged that the survival gains extended to all races and ethnicities. 

“If it’s due to more widespread use of these targeted therapies, they must be getting to those that we’ve historically thought of as maybe suffering from some health care disparities,” he said. 

Jones pegged at 30% the proportion of patients who have a mutation or genomic alteration in their tumors that a drug can now treat. And it turns out that most patients who don’t have EGFR and ALK mutations are candidates for immunotherapies.

“As we learn more about immune checkpoint inhibitors and related compounds, we are beginning to see data emerging at first for non-small cell lung cancer and even for small cell lung cancer, a survival benefit that is very significant,” he said. “I anticipate when this paper or some version of it comes out again in five more years, we’ll see even further improvements in lung cancer mortality. And I do think a lot of that could be attributed to the immunotherapies.”

The SEER data do not say whether patients smoked, but 70% of lung cancer is still attributed to smoking, generations after the habit and the disease were first connected. As smoking rates fall, doctors have seen an increase in lung cancer cases among nonsmokers with possible risk factors such as exposure to radon, asbestos, secondhand smoke, or air pollution. While those non-small cell lung cancers have completely different biology and disease processes than smoking-related lung cancers, the tumors are more likely to contain EGFR mutations. That means nonsmokers may have more options in terms of genomically targeted treatment, Jones said.

When he began his career in thoracic oncology 40 years ago, there was a sense  of nihilism about lung cancer, he said. Considered a death sentence, it also carried the stigma of smoking being an avoidable choice (though cigarettes are highly addictive and difficult to quit). There’s been a sea change in the last 10 years.

“You see a paper come out now in the New England Journal of Medicine that is laudatory in terms of advances that are being made — it’s still a very tough disease, [but] I’m encouraged by the fact that it’s a positive report, emphasizing the benefits across all ethnicities and gender.”

  • I’m not in this data set but will be in next data set showing continued decreases in death rates for women with non-small cell lung cancer (with mutations; non-smoker). My amazing oncologists at Dana Farber took a chance on crizotinib to treat my late stage cancer after traditional chemo and radiation failed to work. Going on over three years of clear scans and four years since diagnosis. Lucky to be alive thanks to fantastic medical professionals at Dana Farber and Brigham & Women’s, cancer researchers and the orphan drug program.

  • The immune checkpoint inhibitors are a breakthrough for many non-small cell lung cancers. They are very well tolerated and can give lasting remissions, for those tumors that express PD-L1. Which is most lung cancers.

    • Amen! My 83 year old father is a grateful recipient of years of keytruda, and is alive today because of it. He was diagnosed with stage IV NSCLC, from aquired while serving in the US Navy, on the USS MANLEY. The ship was full of asbestos. He also smoked, and the Navy actually gave them cigarettes back in those days. Keytruda has given my father many years of life, after being on the brink of death, from years of ordinary chemotherapy such as carboplatin, Alimta, and taxotere. He only recently restarted keytruda treatments, after I one year break, as his last scan showed slight involvement with an adrenal.

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