Long‐term response to crizotinib in a 17‐year‐old boy with treatment‐naïve ALK‐positive non‐small‐cell lung cancer

Abstract Background Lung cancer is the leading cause of cancer‐related death. NSCLC accounts for 80–90% of cases. In young patients, adenocarcinoma is the most frequent histotype and 3–7% expresses the rearrangement of ALK oncogene, sensitive to TKIs. Crizotinib is the first ALK inhibitor approved by the FDA. Case We present a case of a 17‐year‐old male with metastatic treatment‐naïve ALK‐positive adenocarcinoma. He was treated with crizotinib and obtained a prolonged response with PFS of 33 months. Conclusion Crizotinib can be extremely effective in adolescents with treatment‐naïve ALK‐positive NSCLC but fail to prevent a central nervous system relapse. Resistance mechanisms need to be investigated.


| INTRODUCTION
Lung cancer is the leading cause of cancer-related death representing the first cause in men and the third cause in women, while tobacco smoke is the main risk factor (85% of cases). [1][2][3] The incidence of primary lung cancer in children is rare, approximately 0.2% of all childhood malignancies. 4 In adulthood, over 95% of lung cancers are small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). 5,6 Adenocarcinoma is the most represented in young patients [7][8][9] with overlapping clinical presentation i with adults (cough, chest pain) but not smoking-related.
The diagnosis is often delayed with more than half of the cases with metastatic spread. 10,11 In the last 15 years, molecular studies have highlighted the role e of genes called "Oncodrivers" involved in tumor genesis, particularly Epidermal Growth Factor Receptor (EGFR) and Anaplastic Lymphoma Kinase (ALK), which have become the target of specific and selective drugs. 12 The 10-15% of the Caucasian population expresses activating mutations of EGFR and 3-7% expresses rearrangement of the ALK oncogene; the mutation expression predicts TKIs response.
Crizotinib is one of the first ALK inhibitors approved by the Food and Drug Administration (FDA). 13 Next-generation ALK inhibitors such as alectinib and ceritinib were approved for the treatment of ALK-positive NSCLC patients. [14][15][16][17][18][19] ALK mutations were reported 11% of adenocarcinoma in younger patients and in only 2-7% of adults. [20][21][22] There are no specific data about drugs management in pediatric population affected by lung adenocarcinoma and ALK mutation.
We present a case of a seventeen-year-old male with naïve ALKpositive NSCLC and treated with crizotinib. To our knowledge, this is the fifth report of a pediatric case treated with ALK-inhibitors, the first experiencing a prolonged response and progression-free survival (PFS).
We extensively reviewed the current literature about ALK positive NSCLC in childhood and the tailored management in pediatric age.

| CASE
A diabetic, non-smoker, 17-year-old boy was admitted in July 2015 for cough and dyspnea. A chest x-ray showed bilateral lung nodules confirmed at Computed Tomography (CT)-scan with lymphadenopathies ( Figure 1(A)). Liver, brain and bone metastases were also evident ( Figures 2 and 3(A)) .
By analyzing tissue using FISH probe "ON ALK (2q23) Break" (repeat-free POSEIDON ALK Break Probe, Kreatech, Amsterdam, the Netherlands), ALK rearrangement was detected while no ROS1 translocation was found with the FISH probe "ON ROS1 (6q22) Break" (Repeat-free POSEIDON ROS1 Dual Color Break Apart Probe, Kreatech, Amsterdam, the Netherlands).
After ALK rearrangement identification, the patient started therapy with crizotinib 500 mg/day with a partial response achieved after F I G U R E 1 CT scan of the lungs. Adenocarcinoma with consolidation, ground-glass opacity, centrilobular nodules, interlobular septal thickenin, before treatment (A) and after 2 months of Crizotinib (B) 2 months involving lungs (Figure 1(B)), nodes, liver and bone lesions,with a 33 month progression free survival (PFS). (Figure 3(B)).The  According to our knowledge, this is the fifth case reported of adolescent with diagnosis of pulmonary ALK-translocated adenocarcinoma [24][25][26] and the third treated with crizotinib as first-line treatment. 24,25 (Table 1).
At the time of diagnosis, the crizotinib represented the first-line treatment available.
At onset, he received crizotinib and obtained at least a partial response to all lesions after 3 months, demonstrating high sensitivity to tyrosine kinase inhibition and confirming the best response to crizotinib by 12 weeks as reported. 26 A 33 month PFS is impressive considering the PROFILE1014 trial results that showed a 10,9 months median PFS. 27 The treatment was well tolerated by our patient, experiencing only grade 1 neutropenia and grade 1/grade 2 hypertransaminasemia.
In our case, crizotinib demonstrated good control of extra-Central Nervous System (CNS) disease but limited control on brain progression, supporting the poor penetration of the blood-brain barrier (BBB). [28][29][30] Surgery was performed on our patient after CNS dissemination as well as radiotherapy and a second-line therapy with alectinib. As demonstrated by the ALEX trial, 31 alectinib was significantly superior to crizotinib in controlling brain progression.
The permeability of the BBB from alectinib and the results obtained on the control of brain metastases 31 limited the role of radiotherapy and surgery in this setting, particularly in untreated patients.
In our case, we decided to treat the frontal symptomatic brain lesion. and to add radiotherapy considering the post-surgical residual tumor and paraventricular lesion. We then started alectinib as secondline TKI.
Our report suggests that crizotinib can be extremely effective in ALK-positive lung adenocarcinoma without CNS involvement as a first line treatment in AYA patients. The occurrence of isolated CNS relapse, highlights the need for new TKI sequence studies to optimize the management of ALK-translocated lung cancer.
The optimal sequence of TKI in ALK-positive lung cancer and the role of surgery and radiotherapy at CNS dissemination remain critical.  Resistance mechanisms to TKIs need to be further investigated for a