Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Cumulative incidence rates for CNS and non-CNS progression in two phase II studies of alectinib in ALK-positive NSCLC

Cumulative incidence rates for CNS and non-CNS progression in two phase II studies of alectinib... SHORT COMMUNICATION British Journal of Cancer (2018) 118, 38–42 | doi: 10.1038/bjc.2017.395 Keywords: alectinib; ALK positive; central nervous system; cumulative incidence rates; disease progression; non-small-cell lung cancer; phase II Cumulative incidence rates for CNS and non-CNS progression in two phase II studies of alectinib in ALK-positive NSCLC ,1 2 3 4 5 Shirish Gadgeel , Alice T Shaw , Fabrice Barlesi , Lucio Crino` , James Chih-Hsin Yang , 6 7 8 9 9 Anne-Marie C Dingemans , Dong-Wan Kim , Filippo de Marinis , Mathias Schulz , Shiyao Liu , 9 10 11 Ravindra Gupta , Ahmed Kotb and Sai-Hong Ignatius Ou Department of Internal Medicine, Division of Hematology and Oncology, The University of Michigan, 1500 E. Medical Center Drive, 7217CC, Ann Arbor, MI 48109, USA; Department of Medicine, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA; Multidisciplinary Oncology and Therapeutic Innovations Department, Aix-Marseille University, Assistance Publique Ho ˆ pitaux de Marseille, 58 Boulevard Charles Livon, Marseille 13284, France; Department of Oncology, Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori IRCCS Meldola, Meldola Province of Forl´ı-Cesena 47014, Italy; Department of Oncology, National Taiwan University Hospital and National Taiwan University Cancer Center, No. 7, Zhongshan South Road, Zhongzheng District, Taipei City, Taiwan; Department of Pulmonology, Maastricht University Medical Center, PO Box 5800, Maastricht 6202 AZ, The Netherlands; Department of Internal Medicine, Seoul National University Hospital, 101, Daehak-ro Jongno-GU, Seoul 03080, South 8 9 Korea; Division of Thoracic Oncology, European Institute of Oncology, Via Ripamonti 435, Milan 20146, Italy; Genentech Inc., DNA Way, South San Francisco, CA 94080, USA; F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Basel 4070, Switzerland and Department of Medicine, University of California Irvine School of Medicine, 1001 Health Sciences Road, Irvine, CA 92617, USA Background: We evaluated the cumulative incidence rate (CIR) of central nervous system (CNS) and non-CNS progression in alectinib-treated patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) to determine the extent to which alectinib may treat or control CNS disease. Methods: Patients with crizotinib-pretreated locally advanced or metastatic disease received alectinib 600 mg orally twice daily in two phase II trials. All patients underwent baseline imaging and regular centrally reviewed scans. Results: At 24 months, the CIR for CNS progression was lower in patients without vs with baseline CNS metastases (8.0 vs 43.9%). Patients with baseline CNS disease and prior radiotherapy had a higher CIR of CNS progression than radiotherapy-naive patients (50.5 vs 27.4%) and a lower CIR of non-CNS progression (25.8 vs 42.5%). Adverse events leading to withdrawal occurred in 5.9% and 6.7% of patients with and without baseline CNS metastases, respectively. Conclusions: This analysis indicates a potential role for alectinib in controlling and preventing CNS metastases. Rearrangements of the anaplastic lymphoma kinase (ALK) gene are Alectinib is a highly specific ALK inhibitor with good efficacy indicative of a distinct subset of non-small-cell lung cancer and tolerability demonstrated in phase II studies in patients (NSCLC), characterised by excellent responses to ALK-targeted with NSCLC harbouring ALK rearrangements (NP28673 therapy. Crizotinib was the first ALK inhibitor to receive US Food [NCT01801111] and NP28761 [NCT01871805]) (Ou et al, 2016; and Drug Administration (FDA) approval for the treatment of Shaw et al, 2016). Based on these results, alectinib gained ALK-positive NSCLC (Food and Drug Administration press accelerated FDA approval for patients whose disease has release, 2011). progressed on, or who are intolerant to, crizotinib (Food and *Correspondence: Dr S Gadgeel; E-mail: sgadgeel@med.umich.edu Received 17 July 2017; revised 2 October 2017; accepted 11 October 2017; published online 16 November 2017 r The Author(s) named above 38 Published by Springer Nature on behalf of Cancer Research UK. CIRs for CNS progression with alectinib in ALKþ NSCLC BRITISH JOURNAL OF CANCER Table 1. Baseline characteristics of the overall pooled population and the subgroups for this analysis by baseline metastases and prior radiation Baseline CNS Baseline CNS metastases No baseline CNS metastases Baseline CNS metastases without prior CNS RT All patients Characteristic (n¼ 136) (n¼ 41) metastases (n¼ 89) with prior CNS RT (n¼ 95) (n¼ 225) Median age, years 54 (34–79) 51 (22–75) 50 (22–75) 54 (33–72) 53 (22–79) (range) Sex, n (%) Male 42 (47.2) 58 (42.6) 43 (45.3) 15 (36.6) 100 (44.4) Female 47 (52.8) 78 (57.4) 52 (54.7) 26 (63.4) 125 (55.6) ECOG PS, n (%) 0 28 (31.5) 46 (33.8) 30 (31.6) 16 (39.0) 74 (32.9) 1 55 (61.8) 74 (54.4) 54 (56.8) 20 (48.8) 129 (57.3) 2 6 (6.7) 16 (11.8) 11 (11.6) 5 (12.2) 22 (9.8) Histology, n (%) Adenocarcinoma 87 (97.8) 128 (94.1) 90 (94.7) 38 (92.7) 215 (95.6) Other 2 (2.2) 8 (5.9) 5 (5.3) 3 (7.3) 10 (4.4) Prior CTX, n (%) Yes 65 (73.0) 109 (80.1) 80 (84.2) 29 (70.7) 174 (77.3) No 24 (27.0) 27 (19.9) 15 (15.8) 12 (29.3) 51 (22.7) Abbreviations: CNS¼ central nervous system; CTX¼ chemotherapy; ECOG PS¼ Eastern Cooperative Oncology Group performance status; RT¼ radiotherapy. Drug Administration press release, 2015). Data from these and progression, non-CNS progression, and death were calculated for other studies suggest that alectinib is highly effective in treating patients with or without baseline CNS metastases using a central nervous system (CNS) metastases and in controlling the competing risks method. The CIR analysis considers the first spread of the disease in the CNS (Seto et al, 2013; Gadgeel et al, event in the competing risks setting. For example, if a patient had 2016), a common site of progression with crizotinib (Gainor et al, CNS progression before non-CNS progression or death, then the 2013; Costa et al, 2015). Improving systemic and CNS efficacy, patient was considered as having a CNS progression event. while maintaining good tolerability, is a clear goal in developing Subgroup analysis of CIRs of CNS progression by prior radiation treatments for ALK-positive NSCLC. therapy status was undertaken in patients with baseline CNS This exploratory analysis evaluated cumulative incidence rates metastases. (CIRs) of CNS and non-CNS progression in alectinib-treated patients in the pivotal phase II studies (Ou et al, 2016; Shaw et al, 2016) to determine to what extent alectinib may treat and/or RESULTS control the spread of the disease in the CNS in ALK-positive NSCLC. Patients. Enrolment began in June 2013 for study NP28673 and in September 2013 for study NP28761; results are based on data cutoffs of 1 February 2016 and 22 January 2016, respectively. MATERIALS AND METHODS Baseline characteristics of the overall pooled population and the subgroups for this analysis were comparable and balanced between Study design. Methodology for both studies has been published patients with or without baseline CNS metastases or prior radiation (Ou et al, 2016; Shaw et al, 2016). Eligible patients were aged X18 (Table 1). years with locally advanced or metastatic ALK-positive NSCLC, confirmed by an FDA-approved test, and an Eastern Cooperative CIRs of progression. For patients with baseline CNS metastases, Oncology Group performance status p2. All patients had CIRs of CNS and non-CNS progression at 24 months were 43.9% progressed on crizotinib. Patients with treated CNS metastases and 31.0%, respectively (Figure 1 and Table 2). In patients without were eligible, provided any symptoms were stable for X2 weeks baseline CNS metastases, the CIR of CNS progression was 8.0% at before study entry; patients with untreated CNS metastases had to 24 months; these patients progressed at a higher rate in organs be asymptomatic. Patients received 600 mg oral alectinib twice other than the CNS, as suggested by a higher CIR of non-CNS daily until progression, death, or withdrawal. progression (50.9%). Assessments. Response was centrally evaluated using Response Patients with baseline CNS metastases who had received prior radiotherapy had a higher CIR of CNS progression at 24 months Evaluation Criteria in Solid Tumors v1.1. The study protocols stated that all patients, not only those with known CNS metastases, than radiotherapy-naive patients (50.5% vs 27.4%, respectively) (Table 2). Data on the use of radiosurgery vs whole-brain should undergo baseline brain imaging by magnetic resonance imaging, and have centrally reviewed CNS scans (every 8 weeks for radiotherapy were not collected. NP28673; every 6 weeks for NP28761). Computed tomography of the chest and abdomen was also required. Safety. Median treatment duration was similar in the overall The CNS progression events were analysed by cumulative pooled population (43.57 weeks, range 2.4–89.0) and in patients incidence functions. The CNS progression was any new CNS lesion with (44.79 weeks, range 3.0–85.7) or without (42.14 weeks, range or progression of pre-existing CNS lesions vs baseline, according to 2.4–89.0) baseline CNS metastases. an independent review committee (IRC). Non-CNS progression Grade 3–5 adverse events (AEs) were reported in 45.6% of was any new lesion or progression of pre-existing lesions in areas patients with baseline CNS metastases and in 32.6% of those outside the CNS, according to the same IRC. The CIRs for CNS without. Serious AEs occurred in 24.3% and 14.6% of patients, www.bjcancer.com | DOI:10.1038/bjc.2017.395 39 BRITISH JOURNAL OF CANCER CIRs for CNS progression with alectinib in ALKþ NSCLC respectively, and AEs leading to treatment withdrawal occurred in CNS PD 0.5 5.9% and 6.7% of patients, respectively. Non-CNS PD Death N =225 0.4 DISCUSSION 0.3 The management of CNS metastases is essential for long-term 0.2 outcome in ALK-positive NSCLC, with recent data identifying extended survival following radiotherapy and tyrosine kinase 0.1 inhibitor treatment (Johung et al, 2016). The ALK inhibitor, alectinib, is highly active, both systemically (Ou et al, 2016; Shaw et al, 2016) and in the CNS (Seto et al, 2013; Gadgeel et al, 2016). Results of this exploratory analysis confirm these findings across all 0 2468 10 12 14 16 18 20 22 24 26 28 patient subgroups examined, and suggest a preventative effect of Time (months) alectinib in the CNS. Cumulative no. of events These results must be considered in the context of the overall 0 15 28 38 47 49 52 57 59 59 60 60 62 62 62 CNS PD phase II study data. The curves of CIRs for CNS progression Non-CNS PD 020 33 49 56 62 65 71 74 80 83 83 84 84 85 Death represent progression in one organ, whereas those for non-CNS 0 810 12 15 18 18 18 18 20 20 21 21 21 21 progression represent progression at many possible sites. At 24 months, the CIR of CNS progression was only 43.9% in patients 0.5 CNS PD Non-CNS PD with baseline brain metastases, indicating that alectinib is active Death against CNS metastases. For patients without baseline CNS 0.4 N =136 metastases, CIRs were higher for non-CNS progression than for CNS progression/death, suggesting that alectinib may prevent the 0.3 spread of ALK-positive NSCLC to the brain, in addition to its activity against CNS metastases. If replicated in prospective analyses, these findings may provide an effective treatment strategy 0.2 for patients with ALK-positive NSCLC to achieve long-term control of their systemic disease, by treating existing CNS lesions 0.1 and protecting against new ones. These findings also support the hypothesised early administration of alectinib to maximise patient benefit. In patients with baseline CNS metastases, CIRs were higher 02 4 68 10 12 14 16 18 20 22 24 26 28 for CNS progression than for non-CNS progression/death, Time (months) reflecting the fact that these patients were at a higher risk of progressing in the brain, even if they received an active drug. It Cumulative no. of events may also suggest a biologic specificity of ALK-rearranged tumours CNS PD 013 25 33 41 43 46 50 52 52 53 53 55 55 55 Non-CNS PD 0 9 16 24 27 31 34 34 35 38 39 39 40 40 40 favouring the CNS as the elective site of progression. Death 0 4 5 77 88 88 8 88 88 8 Patients with baseline CNS metastases receiving radiotherapy had a higher CNS progression rate than untreated patients (data on CNS PD 0.7 the type of radiotherapy administered were not captured). This Non-CNS PD may be because patients who already received radiation carried the Death 0.6 greatest burden or had symptomatic CNS disease requiring N =89 therapy. 0.5 This analysis is limited by its retrospective, exploratory nature, although data pooling enabled assessment in a broader patient 0.4 population. The different CNS imaging schedules may have 0.3 affected the CIRs, but the consistent trends over time suggest that any difference in rate between the study populations was minimal. 0.2 Our results confirm the potent ALK inhibition and robust efficacy of alectinib systemically and in the CNS. These findings 0.1 may help to explain the longer progression-free survival observed with alectinib vs crizotinib in the global phase III ALEX study in 02 4 68 10 12 14 16 18 20 22 24 26 28 patients with previously untreated ALK-positive NSCLC (Peters Time (months) et al, 2017) and in the Japanese phase III J-ALEX study in the ALK inhibitor-naive setting (Hida et al, 2017). The ALEX study Cumulative no. of events 03 2 5 6 6 6 7 7 7 7 7 7 7 7 CNS PD provided further evidence of the systemic and CNS efficacy of 0 11 1725 29 31 31 37 39 42 44 44 4444 45 Non-CNS PD alectinib, with a complete CNS response rate of 38% in patients 0 45 5 8 10 10 10 10 12 12 13 13 13 13 Death with measurable CNS lesions at baseline (Peters et al, 2017). In the intent-to-treat population, the CIR of CNS progression in ALEX, Figure 1. Cumulative incidence rates for CNS progression, non-CNS taking into account the competing risks of non-CNS progression progression, and death in alectinib-treated patients in the pivotal and death, was 9.4 with alectinib vs 41.4% with crizotinib (Peters phase II studies. (A) The overall pooled population, (B) patients with et al, 2017). When analysed according to baseline CNS metastases baseline CNS metastases, and (C) patients without baseline CNS status, CIR trends observed for CNS PD vs non-CNS PD in ALEX metastases. CNS¼ central nervous system; PD¼ progressive disease. were similar to those in the pooled analysis described above, reinforcing the CNS effectiveness of alectinib in preventing or delaying CNS metastases in ALK-positive NSCLC (Gadgeel et al, 40 www.bjcancer.com | DOI:10.1038/bjc.2017.395 Cumulative incidence Cumulative incidence Cumulative incidence CIRs for CNS progression with alectinib in ALKþ NSCLC BRITISH JOURNAL OF CANCER Table 2. Cumulative incidence rates for CNS progression, non-CNS progression, and death Months CIR, % (95% CI) CNS PD CIR, % (95% CI) Non-CNS PD CIR, % (95% CI) Death All patients (n¼ 225) 6 17.1 (12.2–22.1) 22.1 (16.6–27.6) 5.4 (2.4–8.3) 12 23.6 (18.0–29.2) 29.5 (23.5–35.5) 8.1 (4.5–11.8) 18 26.9 (21.0–32.8) 36.6 (30.2–43.0) 9.1 (5.3–12.9) 24 30.1 (23.3–36.8) 39.1 (32.5–45.7) 9.7 (5.8–13.7) 28 30.1 (23.3–36.8) 46.1 (33.3–58.9) 9.7 (5.8–13.7) Patients with no baseline CNS metastases (n¼ 89) vs patients with baseline CNS metastases (n¼ 136) 6 5.7 (0.8–10.5) vs 24.8 (17.4–32.1) 28.2 (18.8–37.6) vs 18.1 (11.5–24.6) 5.6 (0.8–10.4) vs 5.2 (1.5–9.0) 12 6.8 (1.5–12.0) vs 34.9 (26.7–43.0) 35.1 (25.1–45.0) vs 25.8 (18.3–33.3) 11.3 (4.7–17.9) vs 6.0 (2.0–10.0) 18 8.0 (2.3–13.6) vs 39.5 (31.2–47.9) 48.0 (37.5–58.5) vs 29.0 (21.2–36.7) 13.7 (6.5–20.9) vs 6.0 (2.0–10.0) 24 8.0 (2.3–13.6) vs 43.9 (34.7–53.1) 50.9 (40.2–61.5) vs 31.0 (23.0–39.1) 15.4 (7.6–23.2) vs 6.0 (2.0–10.0) Patients with baseline CNS metastases with prior CNS RT (n¼ 95) vs patients with baseline CNS metastases without prior CNS RT (n¼ 41) 6 30.3 (20.9–39.6) vs 12.2 (2.2–22.2) 16.2 (8.7–23.8) vs 22.2 (9.4–35.0) 5.4 (0.8–10.0) vs 4.9 (0.0–11.5) 12 41.4 (31.3–51.6) vs 19.8 (7.5–32.1) 19.6 (11.5–27.7) vs 39.9 (24.8–55.1) 5.4 (0.8–10.0) vs 7.4 (0.0–15.5) 18 44.8 (34.6–55.0) vs 27.4 (13.6–41.2) 23.0 (14.4–31.7) vs 42.5 (27.1–57.8) 5.4 (0.8–10.0) vs 7.4 (0.0–15.5) 24 50.5 (39.4–61.6) vs 27.4 (13.6–41.2) 25.8 (16.6–35.0) vs 42.5 (27.1–57.8) 5.4 (0.8–10.0) vs 7.4 (0.0–15.5) Abbreviations: CI¼ confidence interval; CIR¼ cumulative incidence rate; CNS¼ central nervous system; PD¼ progressive disease; RT¼ radiotherapy. The CIR presents the first event in the competing risks setting, and thus patients who had first events of systemic PD or CNS PD would have death as a later event. 2017). However, a more pronounced CNS prevention/delay effect was and received honoraria for non-branded presentations from observed in ALK inhibitor-naive, front-line ALK-positive NSCLC Genentech/Roche, AstraZeneca, Bristol-Mayer Squibb, and Pfizer; patients as studied in ALEX; at 24 months, 16.0 and 4.6% of patients MS is an employee of Genentech and owns Roche stocks; SL and with or without CNS metastases at baseline, respectively, had CNS RG are employees of Genentech and own shares in the company; progression in ALEX, whereas 43.9 and 8% of patients had CNS PD AK is an employee of F. Hoffmann-La Roche Ltd and owns shares in the phase II studies. Given the totality of available data, we propose in the company; S-HIO has acted in a consulting or advisory role a potential front-line role for alectinib in preventing/delaying the to ARIAD, AstraZeneca, Boehringer Ingelheim, Novartis, and development of CNS metastases in ALK-positive NSCLC. Roche, and participated in Speaker Bureaus for AstraZeneca, Boehringer Ingelheim, and Roche/Genentech. ACKNOWLEDGEMENTS REFERENCES We thank the patients, their families, and the participating centres Costa DB, Shaw AT, Ou SH, Solomon BJ, Riely GJ, Ahn MJ, Zhou C, for both studies. Third-party medical writing assistance, under the Shreeve SM, Selaru P, Polli A, Schnell P, Wilner KD, Wiltshire R, direction of the authors, was provided by Fiona Fernando of Camidge DR, Crino` L (2015) Clinical experience with crizotinib in Gardiner-Caldwell Communications and funded by F. Hoffmann- patients with advanced ALK-rearranged non-small-cell lung cancer and La Roche Ltd. brain metastases. J Clin Oncol 33: 1881–1888. Food and Drug Administration press release, 26 August (2011). Available at: https://wayback.archive-it.org/7993/20170113081129/http://www.fda.gov/ AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ CONFLICT OF INTEREST ucm270058.htm. Last accessed 17 January 2017. Food and Drug Administration press release, 11 December (2015). Available SG has participated in advisory boards for Genentech/Roche, at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ Ariad, Pfizer, and Bristol-Myers Squibb, and received honoraria for ucm476926.htm. Last accessed 9 June 2017. non-branded presentations for Genentech/Roche; ATS has parti- Gadgeel SM, Peters S, Mok T, Shaw AT, Kim DW, Ou SI, Perol M, Dziadziuszko R, Ahn JS, Rosell R, Zeaiter A, Mitry E, Nueesch E, Balas B, cipated in advisory boards for Pfizer, Novartis, Roche/Genentech, Camidge DR (2017) Alectinib vs crizotinib in treatment-naı¨ve ALKþ Ariad, Blueprint Medicines, Loxo, and EMD Serono, and received NSCLC: CNS efficacy results from the ALEX study. ESMO Abstract 1298O. honoraria for non-branded presentations for Pfizer, Novartis, Ann Oncol 28(suppl_5): v605–v649. Genentech/Roche, Ignyta, Taiho and Foundation Medicine; FB has Gadgeel SM, Shaw AT, Govindan R, Gandhi L, Socinski MA, Camidge DR, participated in advisory boards for Genentech/Roche, Novartis, De Petris L, Kim DW, Chiappori A, Moro-Sibilot DL, Duruisseaux M, and Pfizer, and received honoraria for non-branded presentations Crino L, De Pas T, Dansin E, Tessmer A, Yang JC, Han JY, Bordogna W, for Genentech/Roche and Novartis; LC has received honoraria Golding S, Zeaiter A, Ou SI (2016) Pooled analysis of CNS response to from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, alectinib in two studies of pretreated patients with ALK-positive non- and Pfizer; JC-HY has participated in compensated advisory small-cell lung cancer. J Clin Oncol 34: 4079–4085. Gainor JF, Ou SH, Logan J, Borges LF, Shaw AT (2013) The central nervous boards for Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genen- system as a sanctuary site in ALK-positive non-small-cell lung cancer. tech/Chugai, Astellas, MSD, Merck Serono, Pfizer, Novartis, Clovis J Thorac Oncol 8: 1570–1573. Oncology, Celgene, Merrimack, Yuhan Pharmaceuticals, Bristol- Hida T, Nokihara H, Kondo M, Azuma K, Seto T, Takiguchi Y, Nishio M, Myers Squibb, and Ono Pharmaceutical, and in an uncompensated Yoshioka H, Imamura F, Hotta K, Watanabe S, Goto K, Satouchi M, advisory board for AstraZeneca; A-MCD has participated in Kozuki T, Shukuya T, Nakagawa K, Mitsudomi T, Yamamoto N, advisory boards for Genentech/Roche, Pfizer, Eli Lilly, Clovis, and Asakawa T, Asabe R, Tanaka T, Tamura T (2017) Alectinib versus MSD, and received honoraria for non-branded presentations for crizotinib in patients with ALK-positive non-small-cell lung cancer Genentech/Roche and AstraZeneca (paid to her institute); D-WK (J-ALEX): an open-label, randomised phase 3 trial. Lancet 390: 29–39. has no conflict of interest to disclose; FdM has participated in Johung KL, Yeh N, Desai NB, Williams TM, Lautenschlaeger T, Arvold ND, advisory boards for Genentech/Roche, Boehringer, and Novartis, Ning MS, Attia A, Lovly CM, Goldberg S, Beal K, Yu JB, Kavanagh BD, www.bjcancer.com | DOI:10.1038/bjc.2017.395 41 BRITISH JOURNAL OF CANCER CIRs for CNS progression with alectinib in ALKþ NSCLC Chiang VL, Camidge DR, Contessa JN (2016) Extended survival and (AF-001JP study): a single-arm, open-label, phase 1-2 study. Lancet Oncol prognostic factors for patients with ALK-rearranged non-small-cell lung 14: 590–598. cancer and brain metastasis. J Clin Oncol 34: 123–129. Shaw AT, Gandhi L, Gadgeel S, Riely GJ, Cetnar J, West H, Camidge DR, Ou SH, Ahn JS, De Petris L, Govindan R, Yang JC, Hughes B, Lena H, Socinski MA, Chiappori A, Mekhail T, Chao BH, Borghaei H, Gold KA, Moro-Sibilot D, Bearz A, Ramirez SV, Mekhail T, Spira A, Bordogna W, Zeaiter A, Bordogna W, Balas B, Puig O, Henschel V, Ou SH, study Balas B, Morcos PN, Monnet A, Zeaiter A, Kim DW (2016) Alectinib in investigators (2016) Alectinib in ALK-positive, crizotinib-resistant, non- crizotinib-refractory ALK-rearranged non-small-cell lung cancer: a phase small-cell lung cancer: a single-group, multicentre, phase 2 trial. Lancet II global study. J Clin Oncol 34: 661–668. Oncol 17: 234–242. Peters S, Camidge DR, Shaw AT, Gadgeel S, Ahn JS, Kim DW, Ou SI, Perol M, Dziadziuszko R, Rosell R, Zeaiter A, Mitry E, Golding S, Balas B, Noe J, Morcos PN, Mok T, ALEX Trial Investigators (2017) Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J This work is licensed under the Creative Commons Med 377: 829–838. Attribution 4.0 International License. To view a copy Seto T, Kiura K, Nishio M, Nakagawa K, Maemondo M, Inoue A, Hida T, of this license, visit http://creativecommons.org/licenses/by/4.0/ Yamamoto N, Yoshioka H, Harada M, Ohe Y, Nogami N, Takeuchi K, Shimada T, Tanaka T, Tamura T (2013) CH5424802 (RO5424802) for r The Author(s) named above 2018 patients with ALK-rearranged advanced non-small-cell lung cancer 42 www.bjcancer.com | DOI:10.1038/bjc.2017.395 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png British Journal of Cancer Springer Journals

Cumulative incidence rates for CNS and non-CNS progression in two phase II studies of alectinib in ALK-positive NSCLC

Loading next page...
 
/lp/springer-journals/cumulative-incidence-rates-for-cns-and-non-cns-progression-in-two-leN6maOnWz

References (16)

Publisher
Springer Journals
Copyright
Copyright © 2018 by The Author(s)
Subject
Biomedicine; Biomedicine, general; Cancer Research; Epidemiology; Molecular Medicine; Oncology; Drug Resistance
ISSN
0007-0920
eISSN
1532-1827
DOI
10.1038/bjc.2017.395
Publisher site
See Article on Publisher Site

Abstract

SHORT COMMUNICATION British Journal of Cancer (2018) 118, 38–42 | doi: 10.1038/bjc.2017.395 Keywords: alectinib; ALK positive; central nervous system; cumulative incidence rates; disease progression; non-small-cell lung cancer; phase II Cumulative incidence rates for CNS and non-CNS progression in two phase II studies of alectinib in ALK-positive NSCLC ,1 2 3 4 5 Shirish Gadgeel , Alice T Shaw , Fabrice Barlesi , Lucio Crino` , James Chih-Hsin Yang , 6 7 8 9 9 Anne-Marie C Dingemans , Dong-Wan Kim , Filippo de Marinis , Mathias Schulz , Shiyao Liu , 9 10 11 Ravindra Gupta , Ahmed Kotb and Sai-Hong Ignatius Ou Department of Internal Medicine, Division of Hematology and Oncology, The University of Michigan, 1500 E. Medical Center Drive, 7217CC, Ann Arbor, MI 48109, USA; Department of Medicine, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA; Multidisciplinary Oncology and Therapeutic Innovations Department, Aix-Marseille University, Assistance Publique Ho ˆ pitaux de Marseille, 58 Boulevard Charles Livon, Marseille 13284, France; Department of Oncology, Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori IRCCS Meldola, Meldola Province of Forl´ı-Cesena 47014, Italy; Department of Oncology, National Taiwan University Hospital and National Taiwan University Cancer Center, No. 7, Zhongshan South Road, Zhongzheng District, Taipei City, Taiwan; Department of Pulmonology, Maastricht University Medical Center, PO Box 5800, Maastricht 6202 AZ, The Netherlands; Department of Internal Medicine, Seoul National University Hospital, 101, Daehak-ro Jongno-GU, Seoul 03080, South 8 9 Korea; Division of Thoracic Oncology, European Institute of Oncology, Via Ripamonti 435, Milan 20146, Italy; Genentech Inc., DNA Way, South San Francisco, CA 94080, USA; F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Basel 4070, Switzerland and Department of Medicine, University of California Irvine School of Medicine, 1001 Health Sciences Road, Irvine, CA 92617, USA Background: We evaluated the cumulative incidence rate (CIR) of central nervous system (CNS) and non-CNS progression in alectinib-treated patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) to determine the extent to which alectinib may treat or control CNS disease. Methods: Patients with crizotinib-pretreated locally advanced or metastatic disease received alectinib 600 mg orally twice daily in two phase II trials. All patients underwent baseline imaging and regular centrally reviewed scans. Results: At 24 months, the CIR for CNS progression was lower in patients without vs with baseline CNS metastases (8.0 vs 43.9%). Patients with baseline CNS disease and prior radiotherapy had a higher CIR of CNS progression than radiotherapy-naive patients (50.5 vs 27.4%) and a lower CIR of non-CNS progression (25.8 vs 42.5%). Adverse events leading to withdrawal occurred in 5.9% and 6.7% of patients with and without baseline CNS metastases, respectively. Conclusions: This analysis indicates a potential role for alectinib in controlling and preventing CNS metastases. Rearrangements of the anaplastic lymphoma kinase (ALK) gene are Alectinib is a highly specific ALK inhibitor with good efficacy indicative of a distinct subset of non-small-cell lung cancer and tolerability demonstrated in phase II studies in patients (NSCLC), characterised by excellent responses to ALK-targeted with NSCLC harbouring ALK rearrangements (NP28673 therapy. Crizotinib was the first ALK inhibitor to receive US Food [NCT01801111] and NP28761 [NCT01871805]) (Ou et al, 2016; and Drug Administration (FDA) approval for the treatment of Shaw et al, 2016). Based on these results, alectinib gained ALK-positive NSCLC (Food and Drug Administration press accelerated FDA approval for patients whose disease has release, 2011). progressed on, or who are intolerant to, crizotinib (Food and *Correspondence: Dr S Gadgeel; E-mail: sgadgeel@med.umich.edu Received 17 July 2017; revised 2 October 2017; accepted 11 October 2017; published online 16 November 2017 r The Author(s) named above 38 Published by Springer Nature on behalf of Cancer Research UK. CIRs for CNS progression with alectinib in ALKþ NSCLC BRITISH JOURNAL OF CANCER Table 1. Baseline characteristics of the overall pooled population and the subgroups for this analysis by baseline metastases and prior radiation Baseline CNS Baseline CNS metastases No baseline CNS metastases Baseline CNS metastases without prior CNS RT All patients Characteristic (n¼ 136) (n¼ 41) metastases (n¼ 89) with prior CNS RT (n¼ 95) (n¼ 225) Median age, years 54 (34–79) 51 (22–75) 50 (22–75) 54 (33–72) 53 (22–79) (range) Sex, n (%) Male 42 (47.2) 58 (42.6) 43 (45.3) 15 (36.6) 100 (44.4) Female 47 (52.8) 78 (57.4) 52 (54.7) 26 (63.4) 125 (55.6) ECOG PS, n (%) 0 28 (31.5) 46 (33.8) 30 (31.6) 16 (39.0) 74 (32.9) 1 55 (61.8) 74 (54.4) 54 (56.8) 20 (48.8) 129 (57.3) 2 6 (6.7) 16 (11.8) 11 (11.6) 5 (12.2) 22 (9.8) Histology, n (%) Adenocarcinoma 87 (97.8) 128 (94.1) 90 (94.7) 38 (92.7) 215 (95.6) Other 2 (2.2) 8 (5.9) 5 (5.3) 3 (7.3) 10 (4.4) Prior CTX, n (%) Yes 65 (73.0) 109 (80.1) 80 (84.2) 29 (70.7) 174 (77.3) No 24 (27.0) 27 (19.9) 15 (15.8) 12 (29.3) 51 (22.7) Abbreviations: CNS¼ central nervous system; CTX¼ chemotherapy; ECOG PS¼ Eastern Cooperative Oncology Group performance status; RT¼ radiotherapy. Drug Administration press release, 2015). Data from these and progression, non-CNS progression, and death were calculated for other studies suggest that alectinib is highly effective in treating patients with or without baseline CNS metastases using a central nervous system (CNS) metastases and in controlling the competing risks method. The CIR analysis considers the first spread of the disease in the CNS (Seto et al, 2013; Gadgeel et al, event in the competing risks setting. For example, if a patient had 2016), a common site of progression with crizotinib (Gainor et al, CNS progression before non-CNS progression or death, then the 2013; Costa et al, 2015). Improving systemic and CNS efficacy, patient was considered as having a CNS progression event. while maintaining good tolerability, is a clear goal in developing Subgroup analysis of CIRs of CNS progression by prior radiation treatments for ALK-positive NSCLC. therapy status was undertaken in patients with baseline CNS This exploratory analysis evaluated cumulative incidence rates metastases. (CIRs) of CNS and non-CNS progression in alectinib-treated patients in the pivotal phase II studies (Ou et al, 2016; Shaw et al, 2016) to determine to what extent alectinib may treat and/or RESULTS control the spread of the disease in the CNS in ALK-positive NSCLC. Patients. Enrolment began in June 2013 for study NP28673 and in September 2013 for study NP28761; results are based on data cutoffs of 1 February 2016 and 22 January 2016, respectively. MATERIALS AND METHODS Baseline characteristics of the overall pooled population and the subgroups for this analysis were comparable and balanced between Study design. Methodology for both studies has been published patients with or without baseline CNS metastases or prior radiation (Ou et al, 2016; Shaw et al, 2016). Eligible patients were aged X18 (Table 1). years with locally advanced or metastatic ALK-positive NSCLC, confirmed by an FDA-approved test, and an Eastern Cooperative CIRs of progression. For patients with baseline CNS metastases, Oncology Group performance status p2. All patients had CIRs of CNS and non-CNS progression at 24 months were 43.9% progressed on crizotinib. Patients with treated CNS metastases and 31.0%, respectively (Figure 1 and Table 2). In patients without were eligible, provided any symptoms were stable for X2 weeks baseline CNS metastases, the CIR of CNS progression was 8.0% at before study entry; patients with untreated CNS metastases had to 24 months; these patients progressed at a higher rate in organs be asymptomatic. Patients received 600 mg oral alectinib twice other than the CNS, as suggested by a higher CIR of non-CNS daily until progression, death, or withdrawal. progression (50.9%). Assessments. Response was centrally evaluated using Response Patients with baseline CNS metastases who had received prior radiotherapy had a higher CIR of CNS progression at 24 months Evaluation Criteria in Solid Tumors v1.1. The study protocols stated that all patients, not only those with known CNS metastases, than radiotherapy-naive patients (50.5% vs 27.4%, respectively) (Table 2). Data on the use of radiosurgery vs whole-brain should undergo baseline brain imaging by magnetic resonance imaging, and have centrally reviewed CNS scans (every 8 weeks for radiotherapy were not collected. NP28673; every 6 weeks for NP28761). Computed tomography of the chest and abdomen was also required. Safety. Median treatment duration was similar in the overall The CNS progression events were analysed by cumulative pooled population (43.57 weeks, range 2.4–89.0) and in patients incidence functions. The CNS progression was any new CNS lesion with (44.79 weeks, range 3.0–85.7) or without (42.14 weeks, range or progression of pre-existing CNS lesions vs baseline, according to 2.4–89.0) baseline CNS metastases. an independent review committee (IRC). Non-CNS progression Grade 3–5 adverse events (AEs) were reported in 45.6% of was any new lesion or progression of pre-existing lesions in areas patients with baseline CNS metastases and in 32.6% of those outside the CNS, according to the same IRC. The CIRs for CNS without. Serious AEs occurred in 24.3% and 14.6% of patients, www.bjcancer.com | DOI:10.1038/bjc.2017.395 39 BRITISH JOURNAL OF CANCER CIRs for CNS progression with alectinib in ALKþ NSCLC respectively, and AEs leading to treatment withdrawal occurred in CNS PD 0.5 5.9% and 6.7% of patients, respectively. Non-CNS PD Death N =225 0.4 DISCUSSION 0.3 The management of CNS metastases is essential for long-term 0.2 outcome in ALK-positive NSCLC, with recent data identifying extended survival following radiotherapy and tyrosine kinase 0.1 inhibitor treatment (Johung et al, 2016). The ALK inhibitor, alectinib, is highly active, both systemically (Ou et al, 2016; Shaw et al, 2016) and in the CNS (Seto et al, 2013; Gadgeel et al, 2016). Results of this exploratory analysis confirm these findings across all 0 2468 10 12 14 16 18 20 22 24 26 28 patient subgroups examined, and suggest a preventative effect of Time (months) alectinib in the CNS. Cumulative no. of events These results must be considered in the context of the overall 0 15 28 38 47 49 52 57 59 59 60 60 62 62 62 CNS PD phase II study data. The curves of CIRs for CNS progression Non-CNS PD 020 33 49 56 62 65 71 74 80 83 83 84 84 85 Death represent progression in one organ, whereas those for non-CNS 0 810 12 15 18 18 18 18 20 20 21 21 21 21 progression represent progression at many possible sites. At 24 months, the CIR of CNS progression was only 43.9% in patients 0.5 CNS PD Non-CNS PD with baseline brain metastases, indicating that alectinib is active Death against CNS metastases. For patients without baseline CNS 0.4 N =136 metastases, CIRs were higher for non-CNS progression than for CNS progression/death, suggesting that alectinib may prevent the 0.3 spread of ALK-positive NSCLC to the brain, in addition to its activity against CNS metastases. If replicated in prospective analyses, these findings may provide an effective treatment strategy 0.2 for patients with ALK-positive NSCLC to achieve long-term control of their systemic disease, by treating existing CNS lesions 0.1 and protecting against new ones. These findings also support the hypothesised early administration of alectinib to maximise patient benefit. In patients with baseline CNS metastases, CIRs were higher 02 4 68 10 12 14 16 18 20 22 24 26 28 for CNS progression than for non-CNS progression/death, Time (months) reflecting the fact that these patients were at a higher risk of progressing in the brain, even if they received an active drug. It Cumulative no. of events may also suggest a biologic specificity of ALK-rearranged tumours CNS PD 013 25 33 41 43 46 50 52 52 53 53 55 55 55 Non-CNS PD 0 9 16 24 27 31 34 34 35 38 39 39 40 40 40 favouring the CNS as the elective site of progression. Death 0 4 5 77 88 88 8 88 88 8 Patients with baseline CNS metastases receiving radiotherapy had a higher CNS progression rate than untreated patients (data on CNS PD 0.7 the type of radiotherapy administered were not captured). This Non-CNS PD may be because patients who already received radiation carried the Death 0.6 greatest burden or had symptomatic CNS disease requiring N =89 therapy. 0.5 This analysis is limited by its retrospective, exploratory nature, although data pooling enabled assessment in a broader patient 0.4 population. The different CNS imaging schedules may have 0.3 affected the CIRs, but the consistent trends over time suggest that any difference in rate between the study populations was minimal. 0.2 Our results confirm the potent ALK inhibition and robust efficacy of alectinib systemically and in the CNS. These findings 0.1 may help to explain the longer progression-free survival observed with alectinib vs crizotinib in the global phase III ALEX study in 02 4 68 10 12 14 16 18 20 22 24 26 28 patients with previously untreated ALK-positive NSCLC (Peters Time (months) et al, 2017) and in the Japanese phase III J-ALEX study in the ALK inhibitor-naive setting (Hida et al, 2017). The ALEX study Cumulative no. of events 03 2 5 6 6 6 7 7 7 7 7 7 7 7 CNS PD provided further evidence of the systemic and CNS efficacy of 0 11 1725 29 31 31 37 39 42 44 44 4444 45 Non-CNS PD alectinib, with a complete CNS response rate of 38% in patients 0 45 5 8 10 10 10 10 12 12 13 13 13 13 Death with measurable CNS lesions at baseline (Peters et al, 2017). In the intent-to-treat population, the CIR of CNS progression in ALEX, Figure 1. Cumulative incidence rates for CNS progression, non-CNS taking into account the competing risks of non-CNS progression progression, and death in alectinib-treated patients in the pivotal and death, was 9.4 with alectinib vs 41.4% with crizotinib (Peters phase II studies. (A) The overall pooled population, (B) patients with et al, 2017). When analysed according to baseline CNS metastases baseline CNS metastases, and (C) patients without baseline CNS status, CIR trends observed for CNS PD vs non-CNS PD in ALEX metastases. CNS¼ central nervous system; PD¼ progressive disease. were similar to those in the pooled analysis described above, reinforcing the CNS effectiveness of alectinib in preventing or delaying CNS metastases in ALK-positive NSCLC (Gadgeel et al, 40 www.bjcancer.com | DOI:10.1038/bjc.2017.395 Cumulative incidence Cumulative incidence Cumulative incidence CIRs for CNS progression with alectinib in ALKþ NSCLC BRITISH JOURNAL OF CANCER Table 2. Cumulative incidence rates for CNS progression, non-CNS progression, and death Months CIR, % (95% CI) CNS PD CIR, % (95% CI) Non-CNS PD CIR, % (95% CI) Death All patients (n¼ 225) 6 17.1 (12.2–22.1) 22.1 (16.6–27.6) 5.4 (2.4–8.3) 12 23.6 (18.0–29.2) 29.5 (23.5–35.5) 8.1 (4.5–11.8) 18 26.9 (21.0–32.8) 36.6 (30.2–43.0) 9.1 (5.3–12.9) 24 30.1 (23.3–36.8) 39.1 (32.5–45.7) 9.7 (5.8–13.7) 28 30.1 (23.3–36.8) 46.1 (33.3–58.9) 9.7 (5.8–13.7) Patients with no baseline CNS metastases (n¼ 89) vs patients with baseline CNS metastases (n¼ 136) 6 5.7 (0.8–10.5) vs 24.8 (17.4–32.1) 28.2 (18.8–37.6) vs 18.1 (11.5–24.6) 5.6 (0.8–10.4) vs 5.2 (1.5–9.0) 12 6.8 (1.5–12.0) vs 34.9 (26.7–43.0) 35.1 (25.1–45.0) vs 25.8 (18.3–33.3) 11.3 (4.7–17.9) vs 6.0 (2.0–10.0) 18 8.0 (2.3–13.6) vs 39.5 (31.2–47.9) 48.0 (37.5–58.5) vs 29.0 (21.2–36.7) 13.7 (6.5–20.9) vs 6.0 (2.0–10.0) 24 8.0 (2.3–13.6) vs 43.9 (34.7–53.1) 50.9 (40.2–61.5) vs 31.0 (23.0–39.1) 15.4 (7.6–23.2) vs 6.0 (2.0–10.0) Patients with baseline CNS metastases with prior CNS RT (n¼ 95) vs patients with baseline CNS metastases without prior CNS RT (n¼ 41) 6 30.3 (20.9–39.6) vs 12.2 (2.2–22.2) 16.2 (8.7–23.8) vs 22.2 (9.4–35.0) 5.4 (0.8–10.0) vs 4.9 (0.0–11.5) 12 41.4 (31.3–51.6) vs 19.8 (7.5–32.1) 19.6 (11.5–27.7) vs 39.9 (24.8–55.1) 5.4 (0.8–10.0) vs 7.4 (0.0–15.5) 18 44.8 (34.6–55.0) vs 27.4 (13.6–41.2) 23.0 (14.4–31.7) vs 42.5 (27.1–57.8) 5.4 (0.8–10.0) vs 7.4 (0.0–15.5) 24 50.5 (39.4–61.6) vs 27.4 (13.6–41.2) 25.8 (16.6–35.0) vs 42.5 (27.1–57.8) 5.4 (0.8–10.0) vs 7.4 (0.0–15.5) Abbreviations: CI¼ confidence interval; CIR¼ cumulative incidence rate; CNS¼ central nervous system; PD¼ progressive disease; RT¼ radiotherapy. The CIR presents the first event in the competing risks setting, and thus patients who had first events of systemic PD or CNS PD would have death as a later event. 2017). However, a more pronounced CNS prevention/delay effect was and received honoraria for non-branded presentations from observed in ALK inhibitor-naive, front-line ALK-positive NSCLC Genentech/Roche, AstraZeneca, Bristol-Mayer Squibb, and Pfizer; patients as studied in ALEX; at 24 months, 16.0 and 4.6% of patients MS is an employee of Genentech and owns Roche stocks; SL and with or without CNS metastases at baseline, respectively, had CNS RG are employees of Genentech and own shares in the company; progression in ALEX, whereas 43.9 and 8% of patients had CNS PD AK is an employee of F. Hoffmann-La Roche Ltd and owns shares in the phase II studies. Given the totality of available data, we propose in the company; S-HIO has acted in a consulting or advisory role a potential front-line role for alectinib in preventing/delaying the to ARIAD, AstraZeneca, Boehringer Ingelheim, Novartis, and development of CNS metastases in ALK-positive NSCLC. Roche, and participated in Speaker Bureaus for AstraZeneca, Boehringer Ingelheim, and Roche/Genentech. ACKNOWLEDGEMENTS REFERENCES We thank the patients, their families, and the participating centres Costa DB, Shaw AT, Ou SH, Solomon BJ, Riely GJ, Ahn MJ, Zhou C, for both studies. Third-party medical writing assistance, under the Shreeve SM, Selaru P, Polli A, Schnell P, Wilner KD, Wiltshire R, direction of the authors, was provided by Fiona Fernando of Camidge DR, Crino` L (2015) Clinical experience with crizotinib in Gardiner-Caldwell Communications and funded by F. Hoffmann- patients with advanced ALK-rearranged non-small-cell lung cancer and La Roche Ltd. brain metastases. J Clin Oncol 33: 1881–1888. Food and Drug Administration press release, 26 August (2011). Available at: https://wayback.archive-it.org/7993/20170113081129/http://www.fda.gov/ AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ CONFLICT OF INTEREST ucm270058.htm. Last accessed 17 January 2017. Food and Drug Administration press release, 11 December (2015). Available SG has participated in advisory boards for Genentech/Roche, at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ Ariad, Pfizer, and Bristol-Myers Squibb, and received honoraria for ucm476926.htm. Last accessed 9 June 2017. non-branded presentations for Genentech/Roche; ATS has parti- Gadgeel SM, Peters S, Mok T, Shaw AT, Kim DW, Ou SI, Perol M, Dziadziuszko R, Ahn JS, Rosell R, Zeaiter A, Mitry E, Nueesch E, Balas B, cipated in advisory boards for Pfizer, Novartis, Roche/Genentech, Camidge DR (2017) Alectinib vs crizotinib in treatment-naı¨ve ALKþ Ariad, Blueprint Medicines, Loxo, and EMD Serono, and received NSCLC: CNS efficacy results from the ALEX study. ESMO Abstract 1298O. honoraria for non-branded presentations for Pfizer, Novartis, Ann Oncol 28(suppl_5): v605–v649. Genentech/Roche, Ignyta, Taiho and Foundation Medicine; FB has Gadgeel SM, Shaw AT, Govindan R, Gandhi L, Socinski MA, Camidge DR, participated in advisory boards for Genentech/Roche, Novartis, De Petris L, Kim DW, Chiappori A, Moro-Sibilot DL, Duruisseaux M, and Pfizer, and received honoraria for non-branded presentations Crino L, De Pas T, Dansin E, Tessmer A, Yang JC, Han JY, Bordogna W, for Genentech/Roche and Novartis; LC has received honoraria Golding S, Zeaiter A, Ou SI (2016) Pooled analysis of CNS response to from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, alectinib in two studies of pretreated patients with ALK-positive non- and Pfizer; JC-HY has participated in compensated advisory small-cell lung cancer. J Clin Oncol 34: 4079–4085. Gainor JF, Ou SH, Logan J, Borges LF, Shaw AT (2013) The central nervous boards for Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genen- system as a sanctuary site in ALK-positive non-small-cell lung cancer. tech/Chugai, Astellas, MSD, Merck Serono, Pfizer, Novartis, Clovis J Thorac Oncol 8: 1570–1573. Oncology, Celgene, Merrimack, Yuhan Pharmaceuticals, Bristol- Hida T, Nokihara H, Kondo M, Azuma K, Seto T, Takiguchi Y, Nishio M, Myers Squibb, and Ono Pharmaceutical, and in an uncompensated Yoshioka H, Imamura F, Hotta K, Watanabe S, Goto K, Satouchi M, advisory board for AstraZeneca; A-MCD has participated in Kozuki T, Shukuya T, Nakagawa K, Mitsudomi T, Yamamoto N, advisory boards for Genentech/Roche, Pfizer, Eli Lilly, Clovis, and Asakawa T, Asabe R, Tanaka T, Tamura T (2017) Alectinib versus MSD, and received honoraria for non-branded presentations for crizotinib in patients with ALK-positive non-small-cell lung cancer Genentech/Roche and AstraZeneca (paid to her institute); D-WK (J-ALEX): an open-label, randomised phase 3 trial. Lancet 390: 29–39. has no conflict of interest to disclose; FdM has participated in Johung KL, Yeh N, Desai NB, Williams TM, Lautenschlaeger T, Arvold ND, advisory boards for Genentech/Roche, Boehringer, and Novartis, Ning MS, Attia A, Lovly CM, Goldberg S, Beal K, Yu JB, Kavanagh BD, www.bjcancer.com | DOI:10.1038/bjc.2017.395 41 BRITISH JOURNAL OF CANCER CIRs for CNS progression with alectinib in ALKþ NSCLC Chiang VL, Camidge DR, Contessa JN (2016) Extended survival and (AF-001JP study): a single-arm, open-label, phase 1-2 study. Lancet Oncol prognostic factors for patients with ALK-rearranged non-small-cell lung 14: 590–598. cancer and brain metastasis. J Clin Oncol 34: 123–129. Shaw AT, Gandhi L, Gadgeel S, Riely GJ, Cetnar J, West H, Camidge DR, Ou SH, Ahn JS, De Petris L, Govindan R, Yang JC, Hughes B, Lena H, Socinski MA, Chiappori A, Mekhail T, Chao BH, Borghaei H, Gold KA, Moro-Sibilot D, Bearz A, Ramirez SV, Mekhail T, Spira A, Bordogna W, Zeaiter A, Bordogna W, Balas B, Puig O, Henschel V, Ou SH, study Balas B, Morcos PN, Monnet A, Zeaiter A, Kim DW (2016) Alectinib in investigators (2016) Alectinib in ALK-positive, crizotinib-resistant, non- crizotinib-refractory ALK-rearranged non-small-cell lung cancer: a phase small-cell lung cancer: a single-group, multicentre, phase 2 trial. Lancet II global study. J Clin Oncol 34: 661–668. Oncol 17: 234–242. Peters S, Camidge DR, Shaw AT, Gadgeel S, Ahn JS, Kim DW, Ou SI, Perol M, Dziadziuszko R, Rosell R, Zeaiter A, Mitry E, Golding S, Balas B, Noe J, Morcos PN, Mok T, ALEX Trial Investigators (2017) Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J This work is licensed under the Creative Commons Med 377: 829–838. Attribution 4.0 International License. To view a copy Seto T, Kiura K, Nishio M, Nakagawa K, Maemondo M, Inoue A, Hida T, of this license, visit http://creativecommons.org/licenses/by/4.0/ Yamamoto N, Yoshioka H, Harada M, Ohe Y, Nogami N, Takeuchi K, Shimada T, Tanaka T, Tamura T (2013) CH5424802 (RO5424802) for r The Author(s) named above 2018 patients with ALK-rearranged advanced non-small-cell lung cancer 42 www.bjcancer.com | DOI:10.1038/bjc.2017.395

Journal

British Journal of CancerSpringer Journals

Published: Nov 16, 2017

There are no references for this article.