Clinical Variables Affecting Outcomes

One of the major findings of Pacheco and colleagues is that brain metastasis at the time of stage IV disease diagnosis was not associated with worse median OS. Previous research has suggested that patients with ALK-positive NSCLC who had brain metastases could have a good prognosis, but it has not been demonstrated in the current era of treatments whether brain metastasis influences survival, Dr Pacheco said.6 The protracted median OS among these patients is likely due to the fact that most (78.4%) patients in the study received secondary ALK inhibitors that have good central nervous system efficacy, even though crizotinib does not have high central nervous system penetrance, he added.

It was “reassuring” to see that brain metastasis did not seem to impact OS in this study, said Alice T Shaw, MD, PhD, director of thoracic oncology at Massachusetts General Hospital Cancer Center in Boston. “We have so many brain penetrable ALK inhibitors for our patients that even those with brain metastases can do very very well,” she said. Dr Shaw, led the 2015 research that reported a 49.4-month median OS, but was not involved in the current study.

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Pacheco and colleagues did find that there was a 49% relative increase in the risk of death for each additional organ affected by the disease, such as brain, bone, lung, and other sites, at the time of stage IV disease diagnosis. “It is pretty well established that the more widespread the disease at diagnosis, the worse the outcomes,” probably because it reflects more aggressive disease or higher propensity for metastatic spread, Dr. Shaw said.

Additionally, male patients had 2.4 times higher relative risk of death compared with women in the cohort. The reasons for this difference are not clear, but these findings are consistent with what other studies and is likely generalizable to all types of NSCLC, not just ALK-positive types, Dr Shaw noted.

Pemetrexed-based chemotherapy was administered to 46 patients in the study either before or after starting crizotinib. Each additional month that patients received this therapy was associated with 7% relative decrease in the risk of death. However, as Dr Shaw explained, pemetrexed-based chemotherapy was likely a surrogate in this study for getting any kind of treatment.

“We’re always going to use an ALK inhibitor first and most patients will go through sequential ALK inhibitors, usually 2 or 3 and sometimes 4 or 5, and then failing those, will move onto pemetrexed-based therapy,” Dr Shaw said.

Dr Shaw and her colleagues published an article in 2018 recommending alectinib as a first-line ALK inhibitor for patients with newly diagnosed ALK-positive NSCLC, although off-label brigatinib and ceritinib would also be acceptable therapeutic choices.7 The recommendation was based in part on results of a phase 3 clinical trial called ALEX ( Identifier: NCT02075840), in which Dr Shaw was an investigator, that demonstrated longer progression-free survival in patients with untreated advanced ALK-positive NSCLC who were randomly assigned to receive alectinib compared with the group that received crizotinib.

Building on Success

Compared with the survival outcomes of patients with ALK-positive NSCLC before ALK inhibitors were available, it is “phenomenal” to see overall survival around 7 years, Dr Shaw said. “We can actually continue to build on that, with better therapies and better understanding of resistance mutations,” she added.

In December 2018, the FDA approved lorlatinib as a third-generation ALK inhibitor for patients with metastatic ALK-positive NSCLC who have disease progression on alectinib or ceritinib as their first-line ALK inhibitor or after crizotinib and a secondary ALK inhibitor.8 Lorlatinib can overcome all known ALK inhibitor resistance mutations that confer resistance to alectinib, ceritinib, and brigatinib.


  1. Cetin K, Ettinger DS, Hei Y, O’Malley CD. Survival by histologic subtype in stage IV nonsmall cell lung cancer based on data from the Surveillance, Epidemiology and End Results Program. Clin Epidemiol. 2011;3:139-148.
  2. Pacheco JM, Gao D, Smith D, et al. Natural history and factors associated with overall survival in stage IV ALK rearranged non-small-cell lung cancer [published online December 30, 2018]. J Thorac Oncol. doi: 10.1016/j.jtho.2018.12.014
  3. Anaplastic Lymphoma Kinase (ALK) Fusion Oncogene Positive Non-Small Cell Lung Cancer. UpToDate website. Updated December 12, 2018. Accessed February 28, 2019.
  4. Duruisseaux M, Besse B, Cadranel J, et al. Overall survival with crizotinib and next-generation ALK inhibitors in ALK-positive non-small-cell lung cancer (IFCT-1302 CLINALK): a French nationwide cohort retrospective study. Oncotarget. 2017;8:21903-21917.
  5. Gainor JF, Tan DS, De Pas T, et al. Progression-free and overall survival in ALK-positive NSCLC patients treated with sequential crizotinib and ceritinib. Clin Cancer Res. 2015;21:2745-2752.
  6. Johung KL, Yeh N, Desai NB, et al. Extended survival and prognostic factors for patients with ALK-rearranged non-small-cell lung cancer and brain metastasis. J Clin Oncol. 2016;34:123-129. 
  7. Peters S, Camidge DR, Shaw AT, et al. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med. 2017;377:829-838. 
  8. FDA approves lorlatinib for second- or third-line treatment of ALK-positive metastatic NSCLC. U.S. Food & Drug Administration website. Updated December 17, 2018. Accessed February 28, 2019.