From the Journal Lung Cancer

What effect does delaying ALK+ treatment have on survival?

Several obstacles may result in delaying ALK+ treatment in patients with anaplastic lymphoma kinase positive (ALK+) non-small-cell lung cancer (NSCLC). This study examined the factors associated with delayed initiation of ALK inhibitor (ALKi) treatment and its impact on overall survival (OS) as well as the impact of initiating chemotherapy before biomarker test results.

Chemotherapy before ALK+ treatment

Using real-world data that reflects clinical practice, it was demonstrated that in patients with ALK+ aNSCLC, a delay in initiating ALKi treatment is associated with a higher risk of death. It was further demonstrated that receiving chemotherapy, whether before or after the availability of ALK+ test results, does not appear to affect survival outcomes.

When the early- and delayed-use cohorts were first compared, it was found that patients most likely to remain untreated with an ALKi by 3 weeks after the ALK+ test results were those who had ≥2 office visits, who were >65 years old, who were covered by commercial insurance, or who had received chemotherapy before initiation of ALKi treatment. The most reasonable explanation for this profile of characteristics is delays in the initiation of ALKi treatment related to the receipt of chemotherapy; chemotherapy was found by Illei et al. to be initiated before the receipt of biomarker test results in 20.4 % of patients being tested for ALK. The joint guideline issued by the College of American Pathologists, International Association for the Study of Lung Cancer, and the Association for Molecular Pathology (CAP/IASLC/AMP) and supported by the American Society of Clinical Oncology (ASCO) speaks directly to the critical issue of the timing of screening for ALK+ test results. They note that delays can occur if the clinical team does not support reflex testing and recommend that ALK+ testing be ordered at the time of a NSCLC diagnosis so that results can be received in time for the oncology consult. Previous studies also have found biomarker test results are available for only 21 % of patients at their initial oncology consultation, resulting in delays of up to 5 weeks in the initiation of ALKi treatment. Consequently, 19%–21% of patients may initiate chemotherapy before ALKi treatment.

The impact of a delay in initiation of ALKi therapy on survival was subsequently examined, and it was found that a ≥3-week delay in initiating ALKi treatment was associated with a >2-fold higher risk of death. While this profound difference in outcomes when ALKi treatment is delayed could not be directly attributed to the use of chemotherapy, which was adjusted for as a confounding factor from the analysis, given that targeted inhibition with ALK inhibitors can decrease tumor burden and increase PFS compared with chemotherapy, earlier utilization may have contributed to the survival benefit observed. Indeed, the reduction in PFS after delayed treatment with crizotinib was demonstrated in a head-to-head comparison of its use as first- and second-line therapy in ALK+ patients with aNSCLC, where PFS was 13.3 months vs. 9.9 months, respectively. In addition, our results are consistent with other studies that demonstrate the association between delays in the initiation of treatment and shortened survival times.

Since chemotherapy before ALKi treatment has been used as a stopgap measure when biomarker test results are delayed, the final analyses evaluated the impact of chemotherapy on survival, either when chemotherapy was received only before ALKi treatment or when it was continued after receipt of ALK+ test results. The National Comprehensive Cancer Network (NCCN) guideline is equivocal on how to address altering treatment in the event of delays in biomarker results, recommending either completing planned systemic therapy, including maintenance therapy, or interrupting it and treating with alectinib. This equivocation was first noted in the 2015 NCCN guideline, with reference to treatment of ALK+ NSCLC with crizotinib (alectinib was not approved until 2015), and before that crizotinib alone was recommended as first-line treatment for this subpopulation of patients once biomarker test results were received. This lack of clarity in the guideline may be a contributor to the variation in the practice patterns observed in this study, where 17 % (77/442) of patients received chemotherapy before their test results and among those, 45 % (35/77) continued to receive chemotherapy. Furthermore, neither of the chemotherapy utilization scenarios in our study appeared to significantly differ with respect to survival outcomes. While we appear to be the first to directly assess the impact on outcomes of chemotherapy prior to and after biomarker test results, the negative impact of chemotherapy on quality of life (QoL) has been well documented. Consequently, the balance between QoL and potential outcomes should be considered when determining whether to initiate or complete a patient’s chemotherapy regimen prior to switching to an ALKi.

Limitations of study

The present study has a few limitations. First, ALKi use is based on abstracted clinical notes from the EHR, which may be less precise than other data sources such as pharmacy claims. This may result in the misclassification of some patients who did not fill their prescription until a later time point. Nevertheless, this limitation may result in a more conservative estimate of the impact of a delay in therapy because more of the non-delayed patients would potentially be included in the delayed-use cohort. Second, as is the case with all retrospective studies, certain data may be missing, particularly data from clinics not participating in the EHR database. This is particularly relevant to the characteristics of ECOG performance status, geographic region, and payer; it is unclear in which direction the absence of these data may skew the results. Finally, since we only examined the ALK+ cohort, and the study was restricted to practices in the United States, the results may not be generalizable.

Increased Risk of Death

In summary, we demonstrated that a delay in initiating ALKi treatment in patients with ALK+ aNSCLC is associated with an increased risk of death. While this population may be started on chemotherapy before the results of ALK+ biomarker testing are available, we further demonstrated that there were no significant differences in survival outcomes regardless of whether patients received chemotherapy before or after the availability of ALK+ test results. Initiating ALKi treatment in patients with ALK+ aNSCLC in a timely manner may have a positive impact on survival outcomes. Given the variation in timing of targeted therapy initiation and the associated outcomes observed in this study and others, further research and development of quality measures or other initiatives that address the timing of testing and treatment initiation may be warranted to improve the quality of care for patients.