Variant ALK-fusion positive anaplastic large cell lymphoma (ALCL): A population-based paediatric study of the NHL-BFM study group.

Frequency, distribution and prognostic meaning of ALK-partner genes other than NPM1 in ALK-positive anaplastic large-cell lymphoma (ALCL) are unknown. Forty-nine of 316 ALCL diagnosed in the NHL-BFM study group showed no nuclear ALK expression suggestive of a variant ALK-partner; 41 were analysed by genomic capture high-throughput sequencing or specific RT-PCRs. NPM1::ALK was detected in 13 cases. Among the 28 patients with a non-NPM1::ALK-fusion partner, ATIC (n = 8; 29%) and TPM3 (n = 9; 32%) were the most common. Five of eight patients with ATIC::ALK-positive ALCL relapsed, none of nine with TPM3::ALK. Variant ALK-partners are rare and potentially associated with different prognoses.

Inflammation-related molecular signatures involved in the anticancer activities of brigatinib as well as the prognosis of EML4-ALK lung adenocarcinoma patient.

Although ALK tyrosine kinase inhibitors (ALK-TKIs) have shown remarkable benefits in EML4-ALK positive NSCLC patients compared to conventional chemotherapy, the optimal sequence of ALK-TKIs treatment remains unclear due to the emergence of primary and acquired resistance and the lack of potential prognostic biomarkers. In this study, we systematically explored the validity of sequential ALK inhibitors (alectinib, lorlatinib, crizotinib, ceritinib and brigatinib) for a heavy-treated patient with EML4-ALK fusion via developing an in vitro and in vivo drug testing system based on patient-derived models. Based on the patient-derived models and clinical responses of the patient, we found that crizotinib might inhibit proliferation of EML4-ALK positive tumors resistant to alectinib and lorlatinib. In addition, NSCLC patients harboring the G1269A mutation, which was identified in alectinib, lorlatinib and crizotinib-resistant NSCLC, showed responsiveness to brigatinib and ceritinib. Transcriptomic analysis revealed that brigatinib suppressed the activation of multiple inflammatory signaling pathways, potentially contributing to its anti-tumor activity. Moreover, we constructed a prognostic model based on the expression of IL6, CXCL1, and CXCL5, providing novel perspectives for predicting prognosis in EML4-ALK positive NSCLC patients. In summary, our results delineate clinical responses of sequential ALK-TKIs treatments and provide insights into the mechanisms underlying the superior effects of brigatinib in patients harboring ALKG1269A mutation and resistant towards alectinib, lorlatinib and crizotinib. The molecular signatures model based on the combination of IL6, CXCL1 and CXCL5 has the potential to predict prognosis of EML4-ALK positive NSCLC patients.

ALK-positive histiocytosis: Report of a rare case with exclusive involvement of the central nervous system in an adult woman.

ALK-positive histiocytosis is a rare histiocytic disease characterized by ALK positivity. It was first described in 2008 as a systemic disease in infants. The disease often shows positivity for CD68 and CD163 on immunohistochemistry, and genomic analysis frequently reveals KIF5B::ALK fusions. ALK-positive histiocytosis typically follows an indolent course and has a promising prognosis, with conventional treatments usually being effective. Here, we report a rare case of ALK-positive histiocytosis with exclusive involvement of the central nervous system in a 33-year-old Asian adult woman. Although cranial MRI suggested a meningioma, immunohistochemical workup showed that the ALK-positive tumor cells expressed macrophage/histiocyte markers such as CD163 and CD68. Additionally, second-generation sequencing revealed a KIF5B::ALK fusion. Our case highlights the importance of the differential diagnosis in adult central nervous system tumors, emphasizing the combination of morphology, immunophenotype, and molecular approach with ALK status evaluation to confirm a diagnosis of ALK-positive histiocytosis. This case also expands the clinicopathologic spectrum of ALK-positive histiocytosis.

[Successful bridging therapy with alectinib prior to allogeneic stem cell transplantation for refractory ALK-positive anaplastic large cell lymphoma].

Although alectinib is effective for relapsed or refractory ALK-positive anaplastic large cell lymphoma (ALCL) and has a favorable safety profile, its role as a bridging therapy for allogeneic hematopoietic stem cell transplantation (allo-HSCT) and the role of allo-HSCT itself in this setting are unknown. A 35-year-old man with ALK-positive ALCL experienced relapse after first-line therapy with CHOP. Brentuximab vedotin led to partial response and high-dose chemotherapy combined with autologous HSCT was performed. However, disease progressed 15 months after transplantation, and alectinib was initiated. Complete response (CR) was achieved after three months of treatment, and alectinib was continued for 5 months. After cessation of alectinib, allogeneic bone marrow transplantation from an HLA 1-locus mismatched unrelated donor was performed after conditioning with fludarabine, busulfan, and total body irradiation. GVHD prophylaxis consisted of tacrolimus and short-term methotrexate. The post-transplant course was unremarkable except for grade I acute GVHD. The lymphoma has not recurred for 2 years after allo-HSCT without resuming alectinib. The clinical course of our case suggests that alectinib bridging therapy and allo-HSCT are effective in relapsed/refractory ALK-positive ALCL.

[ALK-positive anaplastic large cell lymphoma of paranasal sinuses: two cases report and literature review]. / ALK-pozitivnaya anaplasticheskaya krupnokletochnaya limfoma s porazheniem pridatochnykh pazukh nosa: dva klinicheskikh nablyudeniya i obzor literatury.

ALK-positive anaplastic large cell lymphoma is a rare T-cell lymphoma with ALK gene rearrangement that develops in children and young adults. The disease almost always affects the lymph nodes, and extranodal areas are also frequently involved. This article describes two cases of atypical localization of ALK-positive anaplastic large cell lymphoma with involvement of the paranasal sinuses.

Matching-Adjusted Indirect Comparisons of Lorlatinib Versus Chemotherapy for Patients With Second-Line or Later Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer.

OBJECTIVES: This study aimed to compare the relative efficacy of lorlatinib, an anaplastic lymphoma kinase-tyrosine kinase inhibitor, with chemotherapy, for patients with second-line or later advanced anaplastic lymphoma kinase-positive non-small cell lung cancer. The endpoints of interest were overall survival (OS) and progression-free survival (PFS). METHODS: Evidence for lorlatinib was informed by the single-arm phase I/II trial B7461001. A systematic literature review (SLR) was performed to identify OS and PFS data for chemotherapy. Unanchored matching-adjusted indirect comparisons (MAICs) between lorlatinib and chemotherapy (pemetrexed/docetaxel, platinum-based, or systemic therapy) were performed. RESULTS: The SLR identified 3 relevant studies reporting PFS. Lorlatinib was associated with a significant decrease in the hazard of progression versus the 2 types of chemotherapy assessed. For PFS, the MAIC of lorlatinib versus the combined treatment arm of docetaxel or pemetrexed resulted in an adjusted hazard ratio (HR) of 0.22 (95% confidence interval [CI] 0.15-0.31). When lorlatinib was compared with platinum-based chemotherapy through an MAIC, the adjusted HR for PFS was 0.40 (95% CI 0.29-0.55). An exploratory comparison was performed for OS with evidence for systemic therapy (assumed equivalent to chemotherapy) not identified in the SLR. Lorlatinib provided a significant decrease in hazard of death (OS) versus systemic therapy, with HRs ranging from 0.12 (95% CI 0.05-0.27) to 0.43 (95% CI 0.27-0.60). CONCLUSIONS: Lorlatinib demonstrated a significant improvement in PFS compared with chemotherapy, although limitations in the analyses were identified. The evidence informing OS comparisons was highly limited but suggested benefit of lorlatinib compared with systemic therapy.

The changing landscape of pediatric histiocytoses: Birth, life, and transdifferentiation of pediatric histiocytes.

Histiocytic neoplasms in the children are very rare, and histiocytoses can occur in the perinatal period. The presumed origins and presentation of specific histiocytoses in the pediatric age group are described. Common and newly described histiocytoses are presented including Langerhans cell histiocytosis, Rosai-Dorfman disease, histiocytic sarcoma, ALK positive histiocytosis, and hemophagocytic lymphohistiocytosis. Molecular findings common to pediatric histiocytoses are also discussed.

Nuclear NPM-ALK Protects Myc from Proteasomal Degradation and Contributes to Its High Expression in Cancer Stem-Like Cells in ALK-Positive Anaplastic Large Cell Lymphoma.

In ALK-positive anaplastic large cell lymphoma (ALK+ALCL), a small subset of cancer stem-like (or RR) cells characterized by high Myc expression have been identified. We hypothesize that NPM-ALK contributes to their high Myc expression. While transfection of NPM-ALK into HEK293 cells effectively increased Myc by inhibiting its proteosomal degradation (PD-Myc), this effect was dramatically attenuated when the full-length NPM1 (FL-NPM1) was downregulated using shRNA, highlighting the importance of the NPM-ALK:FL-ALK heterodimers in this context. Consistent with this concept, immunoprecipitation experiments showed that the heterodimers are abundant only in RR cells, in which the half-life of Myc is substantially longer than the bulk cells. Fbw7γ, a key player in PD-Myc, is sequestered by the heterodimers in RR cells, and this finding correlates with a Myc phosphorylation pattern indicative of ineffective PD-Myc. Using confocal microscopy and immunofluorescence staining, we found that the fusion signal between ALK and FL-NPM1, characteristic of the heterodimers, correlates with the Myc level in ALK+ALCL cells from cell lines and patient samples. To conclude, our findings have revealed a novel oncogenic function of NPM-ALK in the nucleus. Specifically, the NPM-ALK:FL-NPM1 heterodimers increase cancer stemness by blocking PD-Myc and promoting Myc accumulation in the cancer stem-like cell subset.

Leukaemic Presentation of Small-Cell Alk-Positive Anaplastic Large Cell Lymphoma in a Young Woman-Report of a Case with 9-Year Survival.

Anaplastic large cell lymphoma (ALCL) with leukaemic presentation (either ab initio or along the course of the disease) has been rarely reported. Irrespective of ALK expression in the neoplastic cells, it features a dismal prognosis. We report a rare case of leukaemic, small cell variant ALK-positive ALCL with 9-year survival in a young woman who was treated upfront with corticosteroids and standard chemotherapy, and review thoroughly the previously published cases. Such an unexpected, good outcome hints at the existence of different clinical subgroups in the leukaemic variant of ALK-positive ALCL.

Intracranial efficacy of alectinib in ALK-positive NSCLC patients with CNS metastases-a multicenter retrospective study.

BACKGROUND: Central nervous system (CNS) metastases in patients with ALK-positive non-small cell lung cancer (NSCLC) are a cause of substantial morbidity and mortality. Although alectinib had demonstrated promising intracranial efficacy in several clinical trials, data were limited on its CNS activity in real-world settings. METHODS: In this retrospective study, ALK-positive NSCLC patients with brain metastases (BM) or leptomeningeal metastases (LM) from six hospitals in China were divided into three cohorts based on the treatment history before the administration of alectinib. ALK-TKI-naive patients were enrolled in cohort 1, cohort 2 included patients who experienced intracranial progression with or without extracranial progression after treatment with crizotinib, and cohort 3 included patients who developed progression only in CNS following treatment with other second-generation ALK-TKIs. The definition and evaluation of intracranial and extracranial lesions were based on Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: Sixty-five patients were eligible and included in our study (cohort 1: 20, cohort 2: 32, cohort 3: 13). For the overall population and patients with uncontrolled CNS metastases, similar intracranial response in CNS target lesions was observed: cohort 1: 81.8% and 80%; cohort 2: 76.5% and 86.7%; cohort 3: 42.8% and 33.3%. For patients in these three cohorts, 75% (6/8), 78.6% (11/14), and 83.3% (5/6) were reported to have significant improvement in CNS-related symptoms respectively. The number of patients who were in need of mannitol or corticosteroids decreased remarkably after the treatment of alectinib (p < 0.001), and there was also a steep fall-over in the number of patients with ECOG ≥2 points before and after the administration of alectinib (p = 0.003). All patients (8/8) diagnosed with LM ± BM experienced substantial alleviation in CNS-related symptoms. In cohort 1 and cohort 2, no significant difference in CNS-time to progression was found between patients with symptomatic or asymptomatic BM when treated with alectinib alone. CONCLUSIONS: Our study substantiated the potent CNS activity of alectinib in real-world settings. Patients with symptomatic and asymptomatic BM could benefit from alectinib comparatively, which indicated that alectinib alone might defer the timing of local treatment. However, our results should be treated cautiously owing to limited sample size.

Cutaneous histiocytoses in children.

Cutaneous histiocytoses constitute a heterogeneous group of diseases characterised by the cutaneous accumulation of cells with the cytological and phenotypic features of macrophages or dendritic cells. The clinical spectrum ranges from self-resolving, skin-limited conditions to severe, multiorgan disease with a high morbidity rate. Until recently, cutaneous histiocytoses were classified according to the immunophenotype of the pathological cells, with differentiation between Langerhans cell histiocytosis (LCH) [CD1a+, CD207 (langerin)+] and non-Langerhans cell histiocytosis (CD68+, CD163+, CD1a-, CD207-). Over the last 12 years, a number of new pathophysiological findings (in particular, molecular pathology results) regarding histiocytoses have contributed to a new classification based on molecular alterations, as well as on clinical and imaging characteristics and the phenotype. The most frequent entities in children are juvenile xanthogranuloma and LCH.

Failure of crizotinib based systemic treatment in ALK positive histiocytosis involving the central nervous system: a case report and literature review.

BACKGROUND: Among the histiocytic disorders, anaplastic lymphoma kinase (ALK)-positive histiocytosis emerged in 2008. As more and more cases of the novel entity are reported, our understanding of it is deepened. However, only a few cases with central nervous system (CNS) involvement have been reported. Furthermore, the lesion in the suprasellar region has not been documented.  CASE PRESENTATION: We presented a case of ALK-positive histiocytosis involving the suprasellar region of a one-year-and-four-month-old boy. Through clinical, neuropathological, and genomic analyses, the patient was diagnosed with ALK-positive histiocytosis. After lesions were resected he started treatment with a combination of the three compounds vincristine, prednisolone, and crizotinib, but they did not work. Cytarabine was then added as an additional chemotherapy drug for him, and the lesions in the brain and lungs were shrunk by combining treatment of crizotinib, dexamethasone, vincristine, and cytarabine according to the RECIST (esponse Evaluation Criteria In Solid Tumours). CONCLUSIONS: Additional adjuvant chemotherapy drugs are needed when ALK-inhibitor treatment is ineffective.

[Successful alectinib monotherapy for residual disease after brentuximab vedotin combined chemotherapy in ALK-positive anaplastic large cell lymphoma].

A 28-year-old male patient presented with multiple lymphadenopathies and extranodal masses. He was diagnosed with stage IVB ALK-positive anaplastic large cell lymphoma after the right axillary lymph node biopsy. A partial metabolic response with fluorodeoxyglucose accumulation was observed in the residual disease of the upper left hilar lymph node after eight courses of brentuximab vedotin, cyclophosphamide, adriamycin, and prednisolone. We started alectinib at 600 mg daily, which achieved a complete metabolic response (CMR) after three months. The CMR was maintained and alectinib was continuously administered without adverse events at the last follow up. Alectinib showed high efficacy and tolerability, though the optimal period and long-term adverse effects of administration remain unclear. Therefore, further studies are necessary.

Design, synthesis and application of near-infrared fluorescence probe IR-780-Crizotinib in detection of ALK positive tumors.

At present, the early diagnosis and treatment of NSCLC has become an international research hotspot. However, how to realize the organic combination of highly sensitive and high-resolution tumor imaging diagnosis and effective treatment, and to provide effective information for the diagnosis and treatment of cancer is still a major problem in the integration of cancer diagnosis and treatment. In this study, based on the Crizotinib has a good targeted inhibitory effect on ALK positive tumor cells, the near-infrared targeted fluorescent dye IR-780 was covalently bound with the drug molecule Crizotinib, thus the near-infrared fluorescent probe IR-780-Crizotinib targeting ALK positive tumor cells was synthesized. The probe structure is confirmed by NMR and MS. The optical properties of the fluorescent probe and the imaging process in ALK positive tumor-bearing mice were analyzed using ultraviolet spectrophotometer, near-infrared fluorescence spectrometer, and near-infrared fluorescence imaging system. The results show that the probe had better photoactivity. In vivo imaging shows that the probe maintained the biological activity of Crizotinib, effectively targeting the tumor site involved with clear imaging, and ultimately excreted from the body. It was confirmed that the probe could be used for the tracking, positioning and targeted therapy of nude mice with ALK positive tumors in vivo, thus exploring a new approach for the clinical application of near-infrared fluorescent probe to detect ALK positive tumors in the future.

A Bayesian network meta-analysis regarding the comparative efficacy of therapeutics for ALK-positive, brain metastatic non-small cell lung cancer.

More clinical evidence is needed regarding the ranking priority of interventions for ALK-positive, brain metastatic (BM) non-small cell lung cancer (NSCLC). Eligible randomized controlled trials (RCTs) were identified. Progression-free survival (PFS), objective response rate (ORR) and overall survival (OS) for the intended populations were analyzed with random effects, Bayesian network meta-analysis with the estimated hazard ratio (HR) and odds ratio (OR) with 95% credible interval (95% CrIs). We included 11 RCTs (2687 NSCLC and 991 BM patients) investigating 7 treatments and 5 medication classes. For PFS for BM patients, lorlatinib (hazard ratio (HR): 0.01, 95% CrI: 0.001-0.12), alectinib (HR: 0.05, 95% CrI: 0.01-0.21) and brigatinib (HR: 0.07, 95% CrI: 0.007-0.76) were top-ranking individual treatments; for ORR for BM patients, brigatinib, lorlatinib and alectinib were top-ranking treatments. For PFS for all NSCLC patients, the top-ranking individual treatments were lorlatinib (HR: 0.05, 95% CrI: 0.02-0.13), alectinib (HR: 0.09, 95% CrI: 0.05-0.18) and brigatinib (HR: 0.11, 95% CrI: 0.05-0.28). For OS for all NSCLC patients, we found that no individual treatments were superior to chemotherapy, whereas the following top-ranking interventions were alectinib (HR: 0.29, 95% CrI: 0.03-1.68), lorlatinib (HR: 0.41, 95% CrI: 0.04-4.13), and ceritinib (HR: 0.63, 95% CrI: 0.10-4.25). The results of individual treatments and medication classes were similar. Data were limited in regard to subgroup analyses and adverse events of BM patients. Lorlatinib has the most statistical superiority for BM patients, but ORR differences between third- and second-generation inhibitors are not obvious. All things considered, alectinib is recommended as first-line treatment, followed by lorlatinib, especially after developing drug resistance to alectinib.

Association between circulating tumor DNA burden and disease burden in patients with ALK-positive lung cancer.

BACKGROUND: Plasma genotyping is an emerging approach for the identification of genetic alterations mediating resistance to anaplastic lymphoma kinase (ALK)-targeted therapy. The authors reviewed plasma genotyping and imaging findings to assess the correlation between circulating tumor DNA (ctDNA) burden and disease burden in patients with ALK-positive lung cancer. METHODS: The authors analyzed 97 plasma specimens from 75 patients with ALK-positive lung cancer to identify ALK and non-ALK alterations. Disease burden was estimated by tabulating lesions per organ and calculating lesion diameters, areas, and volumes. Disease burden was correlated with the allelic frequency (AF) of plasma alterations. RESULTS: The mean interval between plasma collection and imaging was 8 days. ctDNA was detected in approximately 85% of plasma specimens. An ALK fusion and ALK mutation were detected in 79% and 76%, respectively, of plasma specimens. Using the maximum plasma alteration AF and maximum ALK alteration AF as independent surrogates of ctDNA burden, a higher disease burden measurement on imaging was found to be associated with higher ctDNA burden. Total body and extrathoracic tumor volume but not intrathoracic tumor volume correlated with ctDNA burden. Of all the disease sites assessed, the ctDNA burden correlated most with involvement of the liver, bones, and adrenal glands. Despite being the defining alteration in ALK-positive lung cancer, isolated plasma ALK fusion AF did not perform as well as the maximum plasma alteration AF or maximum ALK alteration AF for correlating tumor burden. CONCLUSIONS: In patients with ALK-positive lung cancer, the maximum plasma alteration AF and maximum ALK alteration AF correlate with the extrathoracic burden of disease and are more predictive of tumor burden compared with the ALK fusion AF alone. LAY SUMMARY: Analysis of genetic material shed from cancer cells into the circulation offers insights into the molecular composition of tumors. The circulating tumor DNA (ctDNA) varies over time and across individuals and is impacted by the distribution of disease. Herein, the authors estimated tumor burden on imaging and correlated it with ctDNA by calculating the maximum allelic frequency. The current study findings demonstrated that the greatest correlation exists between extrathoracic, extracranial tumor burden (particularly involvement of the liver, adrenal glands, or bones) and ctDNA burden, suggesting a biological basis for the interpatient and temporal intrapatient differences in ctDNA yield that have been described in previous studies.

Updated overall survival and final progression-free survival data for patients with treatment-naive advanced ALK-positive non-small-cell lung cancer in the ALEX study.

BACKGROUND: The ALEX study demonstrated significantly improved progression-free survival (PFS) with alectinib versus crizotinib in treatment-naive ALK-positive non-small-cell lung cancer (NSCLC) at the primary data cut-off (9 February 2017). We report mature PFS (cut-off: 30 November 2018) and overall survival (OS) data up to 5 years (cut-off: 29 November 2019). PATIENTS AND METHODS: Patients with stage III/IV ALK-positive NSCLC were randomized to receive twice-daily alectinib 600 mg (n = 152) or crizotinib 250 mg (n = 151) until disease progression, toxicity, withdrawal or death. Primary end point: investigator-assessed PFS. Secondary end points included objective response rate, OS and safety. RESULTS: Mature PFS data showed significantly prolonged investigator-assessed PFS with alectinib [hazard ratio (HR) 0.43, 95% confidence interval (CI) 0.32-0.58; median PFS 34.8 versus 10.9 months crizotinib]. Median duration of OS follow-up: 48.2 months alectinib, 23.3 months crizotinib. OS data remain immature (37% of events). Median OS was not reached with alectinib versus 57.4 months with crizotinib (stratified HR 0.67, 95% CI 0.46-0.98). The 5-year OS rate was 62.5% (95% CI 54.3-70.8) with alectinib and 45.5% (95% CI 33.6-57.4) with crizotinib, with 34.9% and 8.6% of patients still on study treatment, respectively. The OS benefit of alectinib was seen in patients with central nervous system metastases at baseline [HR 0.58 (95% CI 0.34-1.00)] and those without [HR 0.76 (95% CI 0.45-1.26)]. Median treatment duration was longer with alectinib (28.1 versus 10.8 months), and no new safety signals were observed. CONCLUSIONS: Mature PFS data from ALEX confirmed significant improvement in PFS for alectinib over crizotinib in ALK-positive NSCLC. OS data remain immature, with a higher 5-year OS rate with alectinib versus crizotinib. This is the first global randomized study to show clinically meaningful improvement in OS for a next-generation tyrosine kinase inhibitor versus crizotinib in treatment-naive ALK-positive NSCLC. CLINICAL TRIALS NUMBER: NCT02075840.

Successful alectinib desensitization in a patient with anaplastic lymphoma kinase-positive adenocarcinoma of the lung and alectinib-induced drug rash.

INTRODUCTION: Alectinib is an oral tyrosine kinase inhibitor currently recommended by the National Comprehensive Cancer Network (NCCN) as the preferred first-line treatment option for the treatment of metastatic anaplastic lymphoma kinase (ALK) gene rearrangement-positive non-small cell lung cancer (NSCLC). Skin toxicity is a known adverse effect of this medication, yet current recommendations are unclear regarding how to best manage patients who develop severe skin toxicity while taking alectinib. CASE REPORT: Here, we describe a case of successful rechallenge with alectinib by utilizing a desensitization procedure in a patient who had developed severe alectinib-induced skin toxicity about two weeks into treatment.Management and outcome: Upon resolution of the initial skin toxicity symptoms, the patient was rechallenged with alectinib using a modified version of a previously published desensitization procedure. The patient tolerated the rechallenge with no recurrence of skin toxicity or other adverse effects and was able to continue treatment with alectinib. DISCUSSION: Alectinib is currently recommended as the preferred first-line treatment option for the treatment of metastatic anaplastic lymphoma kinase gene rearrangement-positive NSCLC due to improved progression-free survival when compared to crizotinib. The development of skin toxicity can lead to early discontinuation of alectinib treatment, forcing providers and patients to select alternative, potentially less effective options. This case report provides evidence that patients who have experienced severe skin toxicity due to alectinib may be able to continue this first-line treatment option by rechallenging them using a desensitization procedure.

Safety and effectiveness of alectinib in a real-world surveillance study in patients with ALK-positive non-small-cell lung cancer in Japan.

We conducted a large-scale surveillance study as a post-marketing commitment to investigate the safety and effectiveness of alectinib in patients with ALK-positive non-small-cell lung cancer (NSCLC) in Japan. Patients receiving 300 mg twice-daily alectinib (September 2014 to June 2015) were monitored until termination of alectinib or completion of 18 months of treatment at 519 Japanese study sites. The primary endpoint was the incidence of adverse drug reactions (ADR), which are important identified risks for alectinib in Japanese patients. Overall survival (OS), a key secondary endpoint, was assessed according to information on outcome. Overall, 1251 patients were enrolled. The median patient age was 62.0 years; 12.9% of patients were aged ≥75 years. At baseline, 63.0% of patients had received crizotinib and 40.6% had brain metastases. Altogether, 1512 ADR occurred in 654 patients (53.6%), with 164 grade ≥3 ADR in 123 patients (10.1%). Commonly occurring ADR were hepatic disorders (all grades, 19.8%; grade ≥3, 2.0%), decreased neutrophil and/or white blood cell count (all grades, 7.6%; grade ≥3, 1.1%), and interstitial lung disease (all grades, 3.8%; grade ≥3, .7%). Median OS was not estimable. The 18-month cumulative OS rate was longer in patients with ECOG performance status ≤1 (vs 2 or ≥3; 83.7% vs 44.5% or 27.2%), without prior crizotinib (vs with; 81.1% vs 73.4%), receiving first-line alectinib (vs second and third or later line; 83.0% vs 79.2% or 71.9%), without brain metastases (vs with; 79.5% vs 71.5%). These data confirm the favorable safety and effectiveness of alectinib in patients with ALK-positive NSCLC in Japan.