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Commentary: EML4-ALK fusion gene is a product of inversion within the short arm of chromosome 2, where the ALK (anaplastic lymphoma kinase) gene joins the EML4 (echinoderm microtubule-associated protein-like 4) gene.1 The product of EML4-ALK fusion gene is a chimeric protein with constitutive ALK kinase activity.2 ALK rearrangements are found in approximately 5% (3–7%) of NSCLC patients,3 the majority of whom are never-smokers or ex-light smokers, female, with adenocarcinoma histology without EGFR or KRAS mutations, although some rare exceptions exist.4 ALK-positive NSCLC represents a distinct molecular subtype of lung cancer that can be targeted with ALK-specific treatments.1,5

Crizotinib is an oral small-molecule tyrosine kinase inhibitor that targets ALK, MET, and ROS1 tyrosine kinases.6-9 Crizotinib received accelerated US Food and Drug Admin-istration (FDA) approval for treatment of ALK-positive NSCLC based on an objective response rate of 60% and median PFS between 8 and 10 months in single-arm studies.6,10

While initially the majority of patients with ALK-positive NSCLC will respond to crizotinib, secondary resistance inevitably develops in all patients after a median of 8 months’ treatment. The first report of acquired resistance to crizo-

tinib due to gatekeeper mutations (L1196M and C1156Y) within the ALK kinase domain actually accompanied the initial report describing clinical activity of crizotinib in ALK-positive NSCLC.11 Since then, multiple mutations in the ALK kinase domain conferring resistance to crizotinib have been identified (mainly due to their ability to prevent binding of crizotinib to the ATP-binding pocket within the kinase domain) and new mechanisms of resistance, such as increased copy numbers of the ALK gene or emergence of tumour clones with mutated KRAS, BRAF, MET, EGFR or KIT genes have been described.12,13 The CNS remains a common site of relapse in nearly 50% of ALK-positive NSCLC patients treated with crizotinib, and the drug concentrations within cerebrospinal fluids are less than 0.3% of its blood concen-tration, which reflects very poor CNS penetration of crizo-tinib.14-15 Treatment options for patients who developed brain metastases while treated with crizotinib are very limit-ed and usually consist of radiation therapy or surgery.

After clinical recognition of secondary resistance to crizotinib, multiple second-generation ALK inhibitors (LKD378, AP26113, TSR-011) entered early clinical trials for patients with ALK-positive solid tumours (including NSCLC).16,17

landmarks

Report from the World Conference on Lung Cancer

lung cancersecONd-geNeratiON aLk iNhibitOrs

Dr. Grzegorz Korpanty, mD, PhD, mrCP, department of medical Oncology, Princess margaret hospital

trial summary: new alK inhibitor for patients who fail crizotinibgadgeel s, Ou s-h, chiappori a, et al. a phase 1 dose escalation study of a new aLk inhibitor, ch5424802/rO5424802 (alectinib), in aLk+ non-small cell lung cancer (NscLc) patients who have failed crizotinib (aF-002Jg/NP28761, Nct01588028). J Thorac Oncol 2013; 8 (suppl 2):s199 abstract O16.6

Ou s-h, gadgeel s, chiappori a, et al. consistent therapeutic efficacy of ch5424802/rO5424802 in brain metastases among crizotinib-refractory aLk-positive non-small cell lung cancer (NscLc) patients in an ongoing phase i/ii study (aF-002Jg/NP28761, Nct015880288). J Thorac Oncol 2013;8(suppl 2):s200 abstract O16.7.

Anaplastic lymphoma kinase (ALK) is a tyrosine kinase constitu-tively activated following chromosomal fusion/translocation in 3 to 7% of NSCLC patients. This phase I dose escalation study assessed the activity of CH5424802 in patients with ALK-positive NSCLC who failed treatment with crizotinib.

The primary endpoint was dose-limiting toxicity, and the secondary endpoints were efficacy, safety and pharmacokinetic (PK) analyses. Patients with ALK-positive NSCLC with progression of disease after crizotinib treatment, with ECOG performance status 0–2, and adequate organ function were

eligible. Patients with symptomatic central nervous system (CNS) disease required treatment before participation in the study and stable CNS disease subsequently. Alectinib was administered orally at doses of 300, 460, 600, 760 and 900 mg BID until lack of clinical benefit, with intensive PK sampling performed. Efficacy was assessed by RECIST criteria v1.1. Toxicities were evaluated by CTCAE v4.0.

FinDinGsNo dose-limiting toxicities were observed up to the highest dose tested (900 mg BID) and only 1 patient required dose modification due to grade 2 fatigue. The most common adverse events (AEs) were fatigue, myalgia, cough, rash, peripheral edema, and creatinine phosphokinase and ala-nine aminotransferase increase. Grade 3/4 AEs included gamma-glutamyltransferase increase, neutropenia, hypo-phosphatemia, hyperglycemia, syncope, renal failure and pericardial effusion. An objective overall response was observed in 54.5% across all the studied cohorts. Median PFS has not yet been reached, with 27 patients (73%) remaining on the study as of June 2013 with median treat-ment duration of 85 days (range 39–347 days). Alectinib is also active against CNS disease, as was shown in a separate abstract presented.

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CH5424802/RO5424802 (alectinib) is a novel, small-molecule, highly-selective, second-generation oral ALK inhibitor developed based on the rational drug design con-cept.18 CH5424802 shows high antitumour activity both in vitro and in vivo, not only against ALK-rearranged tumour cell lines but also against a variety of crizotinib-resistant ALK mutations (e.g. L1196M).19 In the phase I/II study of ALK-positive NSCLC patients previously treated with more than 1 line of systemic chemotherapy and no prior exposure to ALK inhibitors, treatment with CH5424802 at 300 mg BID PO resulted in the highest-ever reported objective response rate for an ALK inhibitor (93.5%) and a favourable toxicity profile.20 Three patients with brain metastases who did not receive radiation therapy before starting CH5424802 showed response within CNS. Visual (blurred vision, increased sensitivity to light, “floaters”) and gastrointestinal (nausea, vomiting, diarrhea) side effects, which were frequently reported with crizotinib, occurred at a lower rate in this study, most likely due to high selectivity to ALK, which is expressed at very low levels in healthy tis-sues. Additional inhibitory activity of crizotinib against MET and ROS-1 may also explain the higher rate of those side effects in patients receiving crizotinib.

High response rate, limited side effects and activity against CNS disease make CH5424802 (alectinib) a promising ALK inhibitor. During the 15th World Congress on Lung Cancer, results of a phase I dose-escalation trial of CH5424802 in patients with ALK-positive NSCLC who failed crizotinib therapy were presented, showing an overall response rate (ORR) of 54.5% for all cohorts and 59.5% in the 600 mg twice-daily dose cohort. Treatment was well tolerated with mainly grade 1/2 toxicities.21

In a separate abstract, data were presented showing activity of CH5424802 in CNS metastatic disease.22 This is very encour-aging. Second-generation ALK inhibitors like CH5424802 may provide clinically meaningful therapy for CNS disease, delaying implementation of radiation therapy, and improv-ing quality of life and, hopefully, survival of these patients.

other next-Generation tKisEncouraging results from other trials of novel TKIs targeting ALK (including L1196M gatekeeper mutation), ROS1 and mutated EGFR in preclinical models were presented at the WCLC.

Results of the first-in-human dose-finding study of AP26113 [26] showed that among 24 evaluable ALK-positive patients, 15 responded to AP26113 and responses were observed in both crizotinib-naive (2/4; 50%) and crizotinib pretreated (13/17; 76%) patients. Among ALK-positive NSCLC patients with prior crizotinib-only treatment, 12/16 (75%) responded. Four out of 5 ALK-positive patients with untreated or progressing CNS lesions at baseline had evidence of radiographic improvement, including 1 patient resistant to crizotinib and LDK378.

LDK378 is another second-generation ALK inhibitor under clinical investigation in ALK-positive NSCLC. In a phase I study of 88 NSCLC patients who received LDK378 at 400–750 mg daily, the ORR was 70%, and in 64 crizotinib-

resistant patients, it was 73%.24 Updated results of the phase I dose-escalation study with LDK378 in ALK-positive NSCLC were also presented.25 Among 18 patients (all doses), the overall response rate was 50%. Partial response was observed in 7/9 crizotinib-resistant patients. In patients pretreated with other ALK inhibitors, 3/5 had a partial response (including 2 patients who received CH5424802). An ongoing phase II study in ALK-positive NSCLC is evaluating LDK378 at a 750 mg dose (www.clinicaltrials.gov; NCT01685138).

ConClusionALK rearrangements, although present on average in 5% of NSCLC cases, translate into approximately 60,000 new patients with ALK-positive disease annually. With the approval of crizotinib, ALK-positive NSCLC is now recognized as a separate molecular and clinical subtype of NSCLC. Treatment with crizotinib showed improved clinical benefit when compared with the 60% ORR in this selected patient popu-lation. Unfortunately, as with all other targeted treatments, secondary resistance develops, usually within the first 12 to 24 months of treatment. New ALK inhibitors like LDK378, AP26113 or CH5424802 show not only better response rates in ALK-positive NSCLC when compared with crizotinib, but notably, activity against crizotinib-resistant disease, including CNS metastases.

Many questions remain, including the optimal sequence of treatment for ALK-positive disease and an effective strat-egy for treatment of resistant disease. However, emergence of these new, generally well-tolerated second-generation ALK inhibitors in clinical practice is anxiously awaited by patients and lung cancer oncologists.

In BrIEFalready known• The first-generation ALK-inhibitor crizotinib achieves

a response rate of 60% in aLk-positive NscLc but resistance develops after a median of 8 months

• The second-generation ALK-inhibitor alectinib (ch5424802) 300 mg bid achieved an objective response rate of 93.5% in aLk-positive NscLc without prior exposure to aLk inhibitors, and had a favourable toxicity profile

What these studies showed• Alectinib achieved a response rate of 59.5% at

600 mg bid in aLk-positive NscLc patients who failed crizotinib therapy, and treatment was well tolerated

• Alectinib showed activity in CNS metastatic disease

next steps• Continue investigating these and other ALK inhibitors• Determine optimal sequence of treatment for ALK

positive disease

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9. Shaw AT, Yeap BY, Solomon BJ, et al. Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rear-rangement: a retrospective analysis. Lancet Oncol 2011;12:1004-12.

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12. Kim HR, Lim SM, Kim HJ, et al. The frequency and impact of ROS1 rearrange-ment on clinical outcomes in never smokers with lung adenocarcinoma. Ann Oncol 2013;24:2364-70.

13. Camidge DR, Kono SA, Lu X, et al. Anaplastic lymphoma kinase gene rear-rangements in non-small cell lung cancer are associated with prolonged pro-gression-free survival on pemetrexed. J Thorac Oncol 201;6:774-80.

14. Choi YL, Soda M, Yamashita Y, et al. EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N Engl J Med 2010. 363(18): p. 1734-9.

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17. Costa DB, Kobayashi S, Pandya SS, et al. CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib. J Clin Oncol 2011;29:e443-5.

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23. Seto T, Kiura K, Nishio M, et al. CH5424802(RO5424802) for patients with ALK¬-rearranged advanced non-small cell lung cancer (AF-001JP study): a sin-gle-arm, open-label, phase 1-2 study. Lancet Oncol 2013;14:590-98.

24. Gadgeel S, Ou S-H, Chiappori A, et al. A phase 1 dose escalation study of a new ALK inhibitor, CH5424802/RO5424802 (alectinib), in ALK+ Non-Small Cell Lung Cancer (NSCLC) patients who have failed crizotinib (AF-002JG/NP28761, NCT01588028). J Thorac Oncol 2013;8(suppl 2):S199 abstract O16.6.

25. Ou S-H, Gadgeel S, Chiappori A, et al. Consistent therapeutic efficacy of

CH5424802/RO5424802 in brain metastases among crizotinib-refractory ALK-positive non-small cell lung cancer (NSCLC) patients in an ongoing phase I/II study (AF-002JG/NP28761, NCT015880288). J Thorac Oncol 2013;8(suppl 2):S200 abstract O16.7.

26. Camidge DR, Bazhenova L, Salgia R, et al. Updated results of first-in-human dose-finding study of the ALK/EGFR inhibitor AP26113 in patients with advanced malignancies. J Thorac Oncol 2013;8(suppl 2):S296 abstract MO07.6.

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