NSCLC A SUCCESS STORY

Mortality from non–small cell lung cancer (NSCLC) has fallen sharply in the United States over the past few years, and survival following its diagnosis has dramatically improved, the first analysis of its kind indicates.

"This analysis shows for the first time that nationwide mortality rates for the most common category of lung cancer, NSCLC, are declining faster than its incidence, an advance that correlates with the [FDA] approval of several targeted therapies for this cancer in recent years," coauthor Douglas Lowy, MD, deputy director, National Cancer Institute, Bethesda, Maryland, said in a statement.

The study was published online August 12 in The New England Journal of Medicine.

"Major improvements have been made in NSCLC treatment with the advent of targeted therapies and immunotherapies," lead author Nadia Howlander, PhD, National Cancer Institute, and colleagues observe.

"The survival benefit for patients with NSCLC treated with targeted therapy has been shown in clinical trials, but our study highlights their possible effect at the population level," they add.

However, the claim that the reduction in mortality is due to the impact of targeted drugs "may be an overly strong conclusion," counters Peter Bach, MD, MAPP, director, Center for Health Policy and Outcomes, Memorial Sloan Kettering Cancer Center, New York City.

In a Twitter thread, Bach writes: "To my read, the 'new Rx's reduced mortality' conclusion is built on on this (and only this) logic: 1) survival improved; 2) new Rx's were intro'd; 3) ergo new Rx's caused improved survival."

In contrast, mortality from small cell lung cancer (SCLC) has dropped only in tandem with a decline in the incidence of SCLC, and survival has remained largely unchanged, the same analysis shows.

NSCLC is by far the most common type of lung cancer, accounting for more than 75% of all lung cancer cases in the United States. SCLC accounts for about 13%.

Study Details

"Although overall mortality from lung cancer has been declining in the United States, little is known about mortality trends according to cancer subtype at the population level because death certificates do not record subtype information," the authors comment.

"To address this data limitation, the US Surveillance, Epidemiology and End Results (SEER) program has linked mortality records to incidence cancer cases," the authors explain. This allowed them to calculate incidence-based mortality among men and women in the United StatesThe incidence-based mortality method that the researchers used was applied to the SEER data to describe population-level mortality trends in the United States that were attributable to each subtype of lung cancer as well as gender from 2001 through 2016.

Among men, the incidence of NSCLC decreased gradually by 1.9% a year from 2001 through 2008, then more dramatically by 3.1% a year from 2008 through 2016.

Corresponding incidence-based mortality rates among men dropped by 3.2% a year from 2006 through 2013, then again more dramatically by 6.3% a year from 2013 through 2016.

"The 2-year relative survival among patients with lung cancer improved substantially from 26% among men with NSCLC diagnosed in 2001 to 35% among those with NSCLC diagnosed in 2014," the researchers add.

Among women, the incidence of NSCLC remained unchanged between 2001 and 2006, after which it began to drop by 1.5% a year from 2006 through 2016.

"In contrast, incidence-based mortality decreased slowly [among women] by 2.3% annually...from 2006 through 2014 and then at a faster rate of 5.9% annually...from 2014 through 2016," the authors note.

The 2-year relative survival rate for patients with NSCLC was higher among women than among men, improving from 35% in 2001 to 44% in 2014.

Improvements in survival were also observed for all races and ethnicities, despite concerns that new cancer treatments might increase treatment disparities between races, because they are all so expensive, the authors comment.

Mortality from SCLC declined by 4.3% a year among men, but that decline was entirely due to a similar decrease in the incidence of SCLC. Survival at 2 years for patients with this subtype of lung cancer remained largely unchanged over the same interval.

Genetic Testing 

The accelerating decline in NSCLC mortality starting in 2013 corresponds to the period in which clinicians began to routinely test for molecular alterations in epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), the authors point out.

In 2012, the National Comprehensive Cancer Network recommended that all patients with nonsquamous NSCLC undergo genetic testing for EGFR mutations and ALK rearrangements.

At about the same time, the FDA approved a number of targeted therapies for tumors that are sensitive to targeted tyrosine kinase inhibition.

More recently, immunotherapies that act as programmed cell death inhibitors have substantially improved NSCLC outcomes, the authors note.

The first of these was approved for NSCLC in 2015 (pembrolizumab). It was followed by a number of similar agents. It is unlikely that their approval contributed to the observed decline in NSCLC mortality, which started to accelerate in 2013 in the United States, the authors comment..

Nevertheless, the effect that the immune checkpoint inhibitors has had on the survival of patients with NSCLC can be expected to continue and to extend improvement in survival beyond the current study endpoint in 2016, they suggest.

Another contributing factor is the decline in smoking that has occurred in the United States since the 1960s. This has led to the decrease in the incidence of lung cancer. The faster decrease in the incidence of SCLC compared to NSCLC can be explained by the higher relative risk of smoking with regard to SCLC compared to NSCLC, they comment.

Criticism of Study on Twtter

However, the researchers' conclusions were questioned and criticized in two series of comments posted on Twitter after the NEJM study was published.

"As much as everyone wants to be a cheerleader for EGFR and ALK drugs, which do have a role in lung cancer, the authors are trying to tell a story that is threadbare," commented Vinay Prasad, MD, MPH, associate professor of medicine, University of California, San FranciscoDespite the authors' argument that the use of EGFR and ALK inhibitors improved lung cancer survival over the study interval, "it is not even possible that EGFR and ALK [therapies] are doing the heavy-lifting," Prasad continued.

First, these drugs are underused, and testing for these mutations is poor, he points out.

"Secondly, even if you maxed out the [use of] these drugs, they are not cures," Prasad continues, "and the majority [of patients] will still die in a couple of years," which would dilute the overall benefit of these drugs.

Prasad cites his own article, in which he and colleagues conclude that although the number of patients eligible for genome-driven treatment has increased over time, these drugs have only helped a minority of patients with advanced cancer ― it is estimated that 4.90% patients with cancer benefited from genome-targeted therapy in 2018.

"I think it is much more likely that [programmed cell death inhibitors] will bend mortality further down in lung cancer, but they were approved in 2014 and widespread use lagged," Prasad observed. (The study authors agree with these observations, but they point out that their study period ended in 2016, which was too early to see an effect from the immune checkpoint inhibitors on NSCLC survival).

On his own Twitter thread, Bach asked whether EGFR and ALK agents plausibly improved 2-year survival by over 3% a year starting in 2013. He notes that the prevalence of EGFR mutation is low in NSCLC, ranging between 15% to 20% for all NSCLC tumors.

In one study, investigators found that the prevalence of EGFR mutations in a retrospective cohort of 206 cases of advanced NSCLC from three hospitals within a health network was 7.8% lower than rates reported in the literature. For ALK rearrangements, it was 2% lower.

Moreover, despite physician assertions that mutation testing was essential, fewer than half of patients in these three hospitals had undergone mutation testing, at least from 2011 to 2013, when the analysis was conducted.

Bach also pointed out that investigators might simply have asked whether sales equated to widespread use of a drug such as erlotinib (Tarceva), an EGFR tyrosine kinase inhibitor used to treat lung cancer and other cancers. In 2013, treatment rates had to have been extremely limited, inasmuch as Roche reported $650 million in sales of erolitinib for that year for the whole country.

"My math, using price and treatment duration data, comes out with a ceiling treatment number of 10,000 lung cancer patients [treated] in 2013," Bach observed.

"That is about 15% of all stage IV NSCLC patients," he added.

"The study's claims that the observed impact [on survival was the result of] improved treatments may be an overly strong conclusion," Bach concluded.

The authors have disclosed no relevant financial relationships. Prasad has received royalties from sales of the book Ending Medical Reversal (Johns Hopkins University Press, 2015) as well as occasional honoraria for speaking for nonprofit groups. Bach has received grants from the Laura and John Arnold Foundation and Kaiser and honorarium from Yale University.

N Engl J Med. Published online August 12, 2020. Abstract

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