The third factor that stood out was the 2013 introduction of targeted therapies including first-generation ALK inhibitors and EGFR tyrosine kinase inhibitors as first-line therapies for stage 4 mutation-positive NSCLC, which have shown benefits in clinical studies.3,4

“We saw this sharp drop in death rates from [NSCLC] around the time when FDA approved some of these targeted therapies,” Dr Howlader said. “Practicing oncologists already know that these new therapies are effective based on clinical trials and approval of these therapies, but our study for the first time demonstrated the impact at the population level.”

Peter B. Bach, MD, MAPP, director of the Center for Health Policy and Outcomes at the Memorial Sloan Kettering Cancer Center in New York City, who wasn’t involved in the study, said that more evidence is needed to draw the conclusion that the introduction of these targeted therapies caused improved survival.  

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“My concern here is not that the authors are right or wrong [about whether] new therapies explain the increase in survival in lung cancer . . . It is that they provided no evidence linking the shift in survival to the introduction of new therapies except basically that the calendar says they happened at the same time,” he wrote in an email to Cancer Therapy Advisor. In his view, the evidence is too weak to claim that this survival shift was attributable to targeted therapies.

Nailing down causation is impossible without individual drug use data, but the authors could have sought more evidence for their hypothesis in several ways, Dr Bach explained. For instance, they could have done a back-of-the-envelope calculation to gauge whether EGFR- and ALK-targeting agents plausibly boost 2-year survival to the extent observed. Dr Bach said that based on the known prevalence of those mutations, and assuming 100% optimal efficacy and utilization of treatments, his impression is that “it would be a stretch to get to ‘yes’ on that kind of calculation.”

The authors could have also investigated whether the observed real-world survival improvements varied in predictable ways given the known disparities in the uptake of new treatments, such as across age, insurance status, and race — an approach that may produce more convincing evidence, according to Dr Bach. “In fact, to my read, the authors found that there was homogeneity across the groups in survival improvement, which would not be the prediction,” he added.

Dr Le, on the other hand, said she thinks the study authors “are on the right track with the explanation . . . Although it’s an association, the time fits.” The subset of SCLC provides further evidence as an internal control, because no mutation-targeting therapies exist yet for the disease, and incidence and mortality are falling at the same speed, she reasoned.  In addition, even though between 15% and 20% of patients with NSCLC carry EGFR mutations, and only around 5% have ALK mutations, the magnitude of benefit from targeted therapies is large, which could account for the decline in incidence-based mortality, she noted, and added: “I do think this research is reflecting real-world experience.”

Dr Howlader, meanwhile, is also monitoring the real-world outcomes of the later-introduced immunotherapies both for NSCLC as well as SCLC, such as programmed cell death-1 (PD-1) pathway inhibitors, which were first approved in 2015 in the second line for patients with metastatic, PD-L1–positive NSCLC who had progressed on platinum-based chemotherapy. Such therapies have since been approved as monotherapies or combination treatments for a number of specific NSCLC patient groups with advanced or metastatic disease, and as of 2019, also for patients with metastatic SCLC who have progressed on or after platinum-based chemotherapy and at least 1 other line of therapy.5,6

“We may see even a bigger decline in death rates in the next couple of years,” Dr Howlader said.

Disclosure: Some of the authors of the original study disclosed financial ties to the pharmaceutical industry. For a full list of disclosures, please refer to the online version of the article at


  1. Siegel RL, Miller KD, Jemal A, et al. Cancer statistics, 2020. ACS Journals. 2020;70(1):7-20. doi:10.3322/caac.21590
  2. Howlader N, Forjaz G, Mooradian M, et al. The effect of advances in lung-cancer treatment on population mortality. N Engl J Med. 2020;383:640-649. doi:10.1056/NEJMoa1916623
  3. Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31:3327-3334. doi:10.1200/JCO.2012.44.2806
  4. Shaw AT, Kim D, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med.2013;368:2385-2394. doi:10.1056/NEJMoa1214886
  5. ASCO Post Staff. FDA grants accelerated approval to pembrolizumab for advanced NSCLC. The ASCO Post. Published online October 25, 2015. Accessed September 16, 2020.
  6. US Food and Drug Administration. FDA approves pembrolizumab for metastatic small cell lung cancer [press release]. Published online June 18, 2019. Accessed September 16, 2020.