Optimal timing and clinical value of radiotherapy in advanced ALK-rearranged non-small cell lung cancer with or without baseline brain metastases: implications from pattern of failure analyses

Lung cancer is the leading cause of cancer-related deaths across the world [1]. Anaplastic lymphoma kinase (ALK) rearrangements lead to an in-frame fusion protein with oncogenic activity and are detected in approximately 5% of non-small cell lung cancer (NSCLC) cases [2, 3]. Crizotinib was the first tyrosine kinase inhibitor (TKI) targeting ALK and demonstrated remarkable efficacy against ALK-positive lung cancer [4, 5]. Generally, crizotinib treatment is associated with a median progression-free survival (PFS) of 7–11 months and an objective response rate of approximately 60%, which is significantly superior to chemotherapy in both treatment-naïve and pretreated patients [5, 6]. However, disease progression ultimately occurs, and the molecular mechanisms underlying crizotinib resistance are currently being investigated [7, 8]. However, elaborate analyses of patterns of crizotinib-treatment failure in these patients to examine the feasibility of radiotherapy has not been performed.

Brain metastases occur in up to 60% of ALK-positive NSCLC and lead to considerable morbidity and mortality [9, 10]. Compared with chemotherapy, crizotinib demonstrated a higher intracranial response rate and a longer intracranial PFS [5, 6]. However, the brain is the most common site of disease progression during crizotinib treatment, and up to 70% of patients with baseline brain metastases (BBM) develop treatment failure in the central nervous system [9, 10]. Among patients with advanced ALK-positive NSCLC, tumor characteristics in the central nervous system, patterns of disease evolution in the brain, and eligibilities for stereotactic radiotherapy, in the baseline or after certain treatment, have not been fully elucidated.

The clinical value of radiotherapy for patients with metastatic ALK-positive NSCLC remains controversial. Recently, synergistic effects between radiation and TKIs are demonstrated [11, 12] and under certain circumstance, radiotherapy may improve survival among advanced oncogene-driven NSCLC [13, 14]. In addition, despite development of several next-generation TKIs targeting ALK rearrangement with higher potency and greater blood-brain-barrier penetrating capacity, crizotinib remains one of the first-line treatment options for advanced ALK-positive NSCLC [15] and is widely used in situations where next-generation TKIs are not yet approved or economically inaccessible. Therefore, to investigate the real-world outcomes of radiotherapy in crizotinib-treated advanced ALK-positive NSCLC, are still having great significance.

Despite development of several next generation TKIs, crizotinib remain one of the first-line treatment options for advanced ALK-positive NSCLC and is widely used across the world. Hence, examining the feasibility and optimal timing of incorporating radiotherapy into crizotinib treatment, in order to improve patients’ quality of life as well as progression-free survival, is still of great significance. To the best of our knowledge, this is the first comprehensive analysis of patterns of crizotinib-treatment failure and the real-world use of radiotherapy in patients with metastatic ALK-positive NSCLC. Initial disease progression to crizotinib predominantly occurred in originally-existing lesions, which is consistent with previous studies done in unselected lung cancer populations and in EGFR-mutant patients [17, 18]. These findings provide a rationale for local therapies, especially radiations, directed at existing disease sites.

In this study, brain radiotherapy prior to crizotinib in patients with BBM improved PFS1 and decreased the risk of developing progressive disease in the brain. In a retrospective analysis of patients with asymptomatic BBM using combined data from PROFILE 1005 and PROFILE 1007, brain radiotherapy prior to crizotinib was shown to prolong the intracranial time to progression from 7.0 to 13.2 months, but not overall PFS (5.9 months vs 6.0 months) [10]. In our study, patients with both asymptomatic and symptomatic BBM were included, and more than half of the patients harbored multiple-metastatic disease; thus representing a cohort of patients with higher cranial tumor burden, which is more comparable to the unselected patient populations seen in routine clinical practice [9, 19]. An underlying reason for the clinical benefits of brain radiotherapy prior to crizotinib may be that uncontrolled brain metastases can serve as seeds for new brain metastases, and brain radiotherapy effectively controls cranial metastases. In fact, patients with BBM were found to have a higher risk of developing initial disease progression in the brain, as well as developing multiple-progressive lesions in the brain. Furthermore, 40% of the patients with baseline oligo-metastatic disease who were eligible for brain SRS but did not receive prior brain radiotherapy ultimately developed multiple-progressive disease in the brain. Therefore, deferring brain radiotherapy in patients with baseline oligo-metastatic disease may result in losing the opportunity for brain SRS. Among patients with ALK-rearranged NSCLC and brain metastases, initial treatment with SRS or WBRT was shown to induce a similar OS in a multi-institutional study [9]. However, compared with WBRT, brain SRS has been repeatedly demonstrated to show superior efficacies in preserving cognition and improving quality of life [20‐22].

Nevertheless, the clinical values of extracranial radiation prior to crizotinib remain controversial. In our study, extracranial radiotherapies were administered before crizotinib in 15 patients, including thoracic radiation, bone radiation, and adrenal gland radiation. They were efficient in mitigating patients’ symptoms, such metastatic bone pain, obstructive pneumonitis and superior vena cava syndrome, which not only improved patients’ quality of life but may also lengthen their ability to receive further therapy. However, extracranial radiation didn’t prolong PFS1 in our study, which is consistent with previous studies demonstrating that palliative radiotherapy can provide safe, effective, and durable symptom control, but generally could not prolong survival, especially in patients with multiple metastases and node-positive disease [23, 24]. In our study, OF was found to be the predominant pattern of crizotinib-treatment failures, but most OF occurred in original metastatic lesions with a diverse distribution of involved organs, making it difficult to select the appropriate organ to target before crizotinib. Moreover, salvage radiotherapies were feasible and beneficial in a considerable percentages of patients after RECIST-defined disease progression. In our study, approximately 66% of patients who progressed on crizotinib were eligible for salvage radiation and patients who indeed received salvage radiotherapies had a significantly longer PFS2. This is in agreement with previous studies that investigated the potential roles of SBRT for patients with limited cranial- and extracranial-progressive disease [13, 25].

There were some limitations to this retrospective study. Next-generation ALK inhibitors are not approved in China by the time of data cut-off of this study and only five patients have received second-generation ALK inhibitors in clinical trials. Hence, the conclusions derived from this study should be interpreted with caution. However, there are preliminary data supporting the administration of brain radiotherapy prior to next-generation TKIs. More than half of the patients with BBM who received first-line ceritinib developed initial progression in the brain [26]. In the ALEX study, patients with BBM receiving first-line alectinib had a 12-month cumulative incidence rate of central nervous system progression, of 8.6 and 20.5%, among those who had received prior brain radiotherapy and those who had not receive prior brain radiotherapy, respectively [27]. In addition, among patients with BBM who received alectinib [28] or brigatinib [29] after failing crizotinib, the cumulative rates of cranial disease progression were still higher than that of extra-cranial disease progression, commonly exceeding 40% at 24 months. On the other hand, accumulating evidence suggest that continuing crizotinib and subsequent administration of proper local therapy, mostly radiation, seem to be a cost-effective treatment strategy among patients with initial crizotinib-treatment failure [30, 31]. Patients who received salvage radiotherapy after crizotinib failure had a median PFS2 of 10 months in our study, which is comparable to the median PFS reported among patients who are subsequently treated with ceritinib [32] or alectinib [33] or brigatinib [34]. By incorporating proper radiotherapies, the duration of crizotinib treatment could be prolonged and next-generation TKIs may be used after the second disease progression, which may translate into overall survival benefit. However, this hypothesis need to be tested in randomized clinical trials.