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NCI SEER Registry Data Analysis Suggests Precision Medicine's Role in Fewer NSCLC Deaths


NEW YORK – The availability of targeted treatments — namely EGFR- and ALK-directed tyrosine kinase inhibitors — likely played a significant role in lowering non-small cell lung cancer mortality rates from 2013 to 2016 compared to prior years, according to a recently published analysis.

The suggestion, published earlier this month in a New England Journal of Medicine paper, that biomarker-based treatments have been the primary force driving a significant decrease in NSCLC lung cancer deaths in recent years comes at a time when some oncologists are growing increasingly skeptical of precision oncology, characterizing it as driven more by hype and hope than evidence that such drugs are truly helping patients live longer and better. While individual studies have demonstrated the benefits of targeted agents among specific subpopulations of patients whose cancers harbor targetable mutations, it has been challenging to prove that precision oncology is benefitting patients with NSCLC on the whole.

The recent analysis in the NEJM certainly had its share of limitations. Mainly, the lack of biomarker-specific treatment data in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) cancer registry kept researchers from definitively concluding that precision oncology treatments were behind the observed accelerated rate of NSCLC mortality decline.

Still, the paper's authors, including Nadia Howlader of the NCI's Division of Cancer Control and Population Sciences, laid out the reasons why they believe that precision oncology drugs are playing a major role in improving NSCLC survival in recent years.

"When we looked at the data and saw this trend [of sharper mortality rate decreases] after 2013, we asked ourselves, 'Why is that?'" Howlader said. "And we approached the answer by going down a sort of decision tree." This decision tree, she explained, involved considering possible factors, such as smoking cessation, screening trends, and specific treatment advances, and asking whether each factor might have been the main force driving the decline. If the researchers identified reasons why a factor could not have been responsible for the steepened mortality decline, they would rule it out and move on to the next factor.

To conduct the study and work through this decision tree, the researchers used lung cancer incidence data from the SEER cancer registry program linked with de-identified death records. This allowed the researchers to separate population-level mortality rates by lung cancer subtype, focusing mainly on NSCLC, which accounts for 76 percent of lung cancer cases in the US, and small cell lung cancer, which accounts for 13 percent.

"This link was actually a very important piece of this paper," Howlader explained. "Because subtype information doesn't come from the death certificate alone. The death certificate just says [that] somebody died of lung cancer. But with this novel linkage, we were able to reconstruct the mortality curve using an incidence-based mortality technique and take the overall lung cancer trend and break it up by subtype."

Looking at the data by cancer subtype, researchers found that mortality rates in NSCLC had decreased more rapidly than rates of cancer incidence. In comparison, the same was not seen for SCLC, for which incidence and mortality rates declined at about the same rate. When considering the differences in data between NSCLC and SCLC, the researchers could not overlook the fact that there hadn't been many biomarker-directed treatment advances for SCLC, whereas such treatments had transformed the standard of care in NSCLC.

Furthermore, the NSCLC mortality rate declined more sharply after 2013, right around when the US Food and Drug Administration approved the EGFR inhibitor erlotinib (Genentech's Tarceva) as a first-line treatment for metastatic NSCLC patients with EGFR mutations and the ALK inhibitor crizotinib (Pfizer's Xalkori) for advanced NSCLC patients with ALK rearrangements. Specifically, in men with NSCLC, incidence-based mortality decreased at a rate of 3.2 percent per year from 2006 to 2013, then to an annual rate of 6.3 percent per year from 2013 to 2016. In women, the death rates went down by 2.3 percent per year from 2006 to 2014, to 5.9 percent per year from 2014 to 2016.

In SCLC, on the other hand, the researchers found that mortality rates declined at a steady clip from 2006 to 2016 — that is, without the same acceleration around 2013 that they saw for NSCLC.

"Our study shows that the decrease in SCLC mortality can be explained entirely by a decrease in incidence, since we observed no improvement in survival among patients with SCLC over time," the authors wrote, contrasting this finding with the improved two-year survival rates for NSCLC.

In SCLC, survival rates fluctuated minimally within the analysis' timeframe. In men with SCLC, the two-year survival rate dropped slightly from 12 percent in 2001 to 11 percent in 2014, and in women with SCLC, it increased from 14 percent in 2001 to 17 percent in 2014. In contrast, the two-year survival rates for men with NSCLC jumped from 26 percent in 2001 to 35 percent in 2014, and for women jumped from 35 percent in 2001 to 44 percent in 2014. "Substantial improvements in two-year survival are probably behind the faster decrease (double the rate) in mortality from NSCLC as compared with incidence," they wrote.

Accounting for smoking, screening

As part of the decision tree approach that Howlader described, the researchers assessed whether smoking cessation and lung cancer screening programs could have played a role in the declining incidence-based mortality rates. Smoking has declined in popularity in the US since the 1960s, and Howlader said that there is no doubt that this has played a major role in reducing both lung cancer incidence and death.

But the authors maintained that smoking reduction and cessation likely does not fully account for the difference between mortality and incidence rates in NSCLC, as compared with the steady rates of both in SCLC.

"We are not discounting the role of smoking in reducing lung cancer mortality death rates," Howlader said. "But if it was just smoking, then we would see this effect [of lower mortality rates] in all the cancer subtypes. We only saw it in non-small cell lung cancer." Due to this observation, Howlader and colleagues ruled out smoking reduction as the primary contributor to the NSCLC-specific mortality decline.

Additionally, the researchers asked whether lung cancer screening — which has been moving toward expanded eligibility guidelines and the use of better technology such as low-dose computed tomography instead of chest X-rays — might have played a role. But the data indicate that lung cancer screening did not begin to increase significantly until around 2016, leading the researchers to rule it out as a factor driving the sharper declines in NSCLC mortality rates from 2013 onwards.

Influence of treatment advances

Turning to treatment contributions, the researchers looked at the role of both targeted treatment and immune checkpoint inhibitors, including pembrolizumab (Merck's Keytruda), nivolumab (Bristol Meyers Squibb's Opdivo), and atezolizumab (Genentech's Tecentriq). The immune checkpoint inhibitors, the authors wrote, have no doubt contributed to the incidence-based mortality decline in NSCLC, but they are unlikely to account for the accelerated decline after 2013, given that their approvals and subsequent uptake all began around 2015.

Many oncologists began treating lung cancer patients with immune checkpoint inhibitors off-label and in clinical trials prior to official regulatory approvals, but the researchers argued that the percentage of patients benefitting from these drugs prior to their approvals would be too small to make a substantial difference in population-level mortality rates.

Having ruled out smoking, screening, and immunotherapy as primary drivers behind the mortality rate decrease that picked up speed in 2013, the researchers turned to targeted treatments, and deduced that drugs targeting EGFR mutations and ALK rearrangements, which occur in roughly 15 percent and 5 percent of NSCLC cases, respectively, were the likely answer.

The subsets of patients who would be eligible to receive drugs like erlotinib and crizotinib, however, comprise only around a quarter of all NSCLC cases. Moreover, surveys suggest that test access disparities mean that many eligible patients are missing out on the chance to receive such drugs. These caveats may raise questions as to whether these precision oncology drugs can really be responsible for the jump from 3.2 to 6.3 percent NSCLC annual mortality rates.

Howlader acknowledged that the percentages of patients harboring these mutations are small relative to the total population of patients with NSCLC, but at the same time, characterized small percentage decreases in mortality rates in a cancer with as great of a burden as NSCLC as still quite significant.

"Those fractions are small, but if you look at the overall number of lung cancer cases and deaths, it's going to be a large number," she said. "It could potentially have an impact."

According to the authors, this greater reduction in mortality than in incidence during the more recent period — after 2013 — "translates into an estimated 6,800 deaths from lung cancer among men and 3,200 deaths from lung cancer among women that may have been delayed in the United States from 2014 through 2016."

The conclusion that precision oncology agents have had such a considerable impact on NSCLC mortality could motivate oncologists and researchers working to further expand personalized treatment options for lung cancer patients. Indeed, the successes in targeting EGFR and ALK have given way to more recent advancements in treating patients with even less prevalent biomarkers, such as ROS1 and NTRK fusions.

That said, the NEJM paper has limitations, which kept the researchers from definitively concluding that targeted precision oncology drugs were responsible for the declining NSCLC mortality rates. Notably, the researchers relied on population-level datasets that did not contain information as to whether NSCLC patients were actually treated with erlotinib or crizotinib, or how many patients harbored EGFR and ALK alterations making them eligible for these treatments.

In light of these limitations, the authors wrote, "the attribution of the improved survival to these therapies must be done with caution." Howlader also acknowledged these missing data but said that the SEER program is actively working to incorporate patients' biomarker information into its datasets. If this occurs, future iterations of SEER's incidence-based mortality report will allow researchers to home in on biomarker-specific subgroups within NSCLC and SCLC.

For this reason, along with the fact that screening programs and immune checkpoint inhibitors have likely had a more significant impact on lung cancer treatment strategies following 2016 than they did from 2006 to 2016, Howlader anticipates that the next population-level analysis of lung cancer incidence and mortality could look quite different.

"Continued monitoring of trends in lung cancer incidence according to histologic type (and stage) will be important, particularly because the adoption of lung cancer screening is likely to lead to increased diagnosis of adenocarcinoma as a result of early detection and overdiagnosis," wrote Howlader and colleagues in the paper, adding as well that "…pilot projects linking registry data with oncology practice claims data might enable more specific treatment analyses in the future."