LUGANO, Switzerland – A subanalysis of the phase III ALEX study has shown that alectinib (1) 600 mg twice daily is more effective than standard of care crizotinib in Asian patients with anaplastic lymphoma kinase (ALK) positive non-small-cell lung cancer (NSCLC), researchers report at the ESMO Asia 2017 Congress. (2)
The J-ALEX study demonstrated that alectinib 300 mg twice daily improved progression-free survival compared to crizotinib in Japanese patients with ALK positive NSCLC. (3) The ALEX study subsequently showed improvement in progression-free survival with alectinib 600 mg twice daily compared to crizotinib in a global population of ALK positive NSCLC patients. (4)
This subanalysis of the ALEX study investigated the efficacy and safety of alectinib 600 mg twice daily compared to crizotinib in Asian versus non-Asian patients with ALK positive NSCLC. As previously reported, the ALEX study included 303 patients who were randomised in a 1:1 ratio to receive alectinib or standard of care crizotinib. There were 69 Asian patients in each treatment group. The primary endpoint was progression-free survival.
A distinguishing feature of the study was that all patients underwent magnetic resonance imaging (MRI) of the brain every six months, regardless of whether or not they had brain metastases at the start of the study. The time to progression in the brain was measured and compared between the two treatment groups.
“Around 50% of NSCLC patients with ALK mutations will develop brain metastases so it is very important to demonstrate the efficacy of alectinib in the brain,”said lead author Professor Tony S.K. Mok, Chairman, Department of Clinical Oncology, The Chinese University of Hong Kong.
The subanalysis showed similar efficacy and safety with alectinib in Asian and non-Asian patients. Progression-free survival was longer with alectinib compared to crizotinib in Asian and non-Asian populations, with hazard ratios (HRs) of 0.46 and 0.49, respectively. Alectinib reduced central nervous system (CNS) progression compared to crizotinib in the Asian and non-Asian groups, with cause-specific HRs of 0.21 and 0.16, respectively. Median overall survival was not reached in either subgroup.
Response rates to alectinib and crizotinib were 81.2% versus 76.8%, respectively, for the Asian subgroup and 84.3% versus 74.4%, respectively, for the non-Asian subgroup.
The rates of nausea, vomiting, and grade III toxicities overall were lower with alectinib compared to crizotinib, and similar between the Asian and non-Asian subgroups. Liver toxicity due to alectinib was slightly higher in the Asian compared to the non-Asian subgroup.
Mok said: “Alectinib 600 mg twice daily was similarly effective in Asian and non-Asian patients in the ALEX study in terms of progression-free survival, CNS progression, and response rate. The rates of toxicities were also comparable. The findings suggest that 600 mg should be the standard dose of alectinib across Asia.”
Commenting on the research, Dr Pilar Garrido, Head of the Thoracic Tumour Section, Medical Oncology Department, Ramón y Cajal University Hospital, Madrid, Spain, said: “ALK rearrangements emerged as important therapeutic targets in NSCLC in 2007, defining a distinct molecular subset of tumours. Around 5% of NSCLC patients harbour ALK mutations and are highly sensitive to ALK tyrosine kinase inhibitors, which efficiently induce apoptosis. Patients wih advanced ALK positive NSCLC have a high lifetime risk of CNS metastases and a high frequency of brain metastases at diagnosis, with the CNS being the most common site of disease progression.”
Garrido continued: “The first approved ALK inhibitor, crizotinib, significantly increased response rate and prolonged progression-free survival compared to first- and second-line chemotherapy. However, patients almost invariably relapse on crizotinib, commonly within one year. Alectinib is a highly selective and potent next-generation ALK inhibitor – with high CNS penetration – that has demonstrated significant anti-tumour activity against ALK-rearranged NSCLC in several trials. The phase III ALEX and J-ALEX trials showed the superiority of alectinib compared with crizotinib in progression-free survival and reducing the risk of progression in both non-CNS and CNS lesions. Alectinib also had a favourable adverse event profile compared to crizotinib in both studies although in the J-ALEX trial the dose of alectinib (300 mg twice daily) was lower than the approved dose in countries other than Japan.”
This subgroup analysis presented at the ESMO Asia 2017 Congress confirms that alectinib can be safely used at the standard dose of 600 mg twice daily in the Asian population, said Garrido. She continued: “We now have an extremely efficacious drug to be added to our first line armamentarium without differences in efficacy or safety based on ethnicity.”
Regarding the need for further research, Garrido said: “Although next generation ALK inhibitors are extremely potent, eventually all patients relapse. Our next step is to better identify the underlying mechanisms of resistance to provide the best sequence of available agents to our patients.”
Notes to Editors
Please make sure to use the official name of the meeting in your reports: ESMO Asia 2017 Congress
- The use of alectinib as first line therapy for ALK positive lung cancer patients has been approved by the FDA on 6 November 2017, based on the ALEX study.
- Abstract 410O_PR ‘Alectinib (ALC) vs crizotinib (CRZ) in treatment-naïve ALK+ non-small-cell lung cancer (NSCLC): Asian vs non-Asian subgroup analysis of the ALEX study’ will be presented by Tony S.K. Mok during Proffered paper session 1 on Saturday, 18 November 2017, 08:30 to 10:30 (SGT) in Hall 405. Annals of Oncology, Volume 28, 2017 Supplement 10.
- Hida T, Nokihara H, Kondo M, et al. Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial. Lancet. 2017;390(10089):29–39.Peters S, Camidge R, Shaw AT, et al. Alectinib versus crizotinib in untreated ALK-positive non–small-cell lung cancer. N Engl J Med. 2017;377:829–838.
- Peters S, Camidge R, Shaw AT, et al. Alectinib versus crizotinib in untreated ALK-positive non–small-cell lung cancer. N Engl J Med. 2017;377:829–838.
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Alectinib (ALC) vs crizotinib (CRZ) in treatment-naïve ALK+ non-small-cell lung cancer (NSCLC): Asian vs non-Asian subgroup analysis of the ALEX study
T.S.K. Mok1, S. Peters2, D.R. Camidge3, S-H.I. Ou4, J.S. Ahn5, E.H. Tan6, Z. Li7, J-S. Lee8, B.C. Cho9, S.L. Geater10, V. Sriuranpong11, J. Ho12, O.S-H. Chan13, A. Zeaiter14, B. Balas14, E. Nueesch14, E. Mitry14, P.N. Morcos15, D-W. Kim16 1Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong, Hong Kong PRC, 2Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland, 3Division of Medical Oncology, University of Colorado, Denver, USA, 4Medicine, Hematology Oncology, Chao Family Comprehensive Cancer Center, University of California, Irvine School of Medicine, Orange, CA, USA, 5Medicine, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea, 6Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore, 7Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China, 8Medical Oncology, Seoul National University Bundang Hospital, Seongnam-si, Republic of Korea, 9Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea, 10Internal Medicine, Prince of Songkla University, Songkhla, Thailand, 11Medical Oncology Unit, Department of Medicine, Chulalongkorn University, Bangkok, Thailand, 12Respiratory Medicine, The University of Hong Kong, Hong Kong, Hong Kong PRC, 13Department of Clinical Oncology, Pamela Youde Nethersole Eastern Hospital, Chai Wan, Hong Kong PRC, 14Medical Oncology, F. Hoffmann-La Roche Ltd., Basel, Switzerland, 15Clinical Pharmacology, Roche Innovation Center, New York, NY, USA, 16Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
Background: We present efficacy and safety data of Asian vs non-Asian patients (pts) in the global phase III ALEX study of ALC (600 mg BID) vs CRZ (250 mg BID) in treatment-naı¨ve advanced ALKþNSCLC.
Methods: Pts aged _18 years were randomised 1:1 to receive ALC or CRZ until progression, toxicity, withdrawal or death. Race was a randomisation stratification factor. The primary endpoint was investigator (INV)-assessed progression-free survival (PFS). Secondary endpoints were: Independent Review Committee (IRC)-assessed PFS, time to central nervous system(CNS) progression, objective response rate (ORR) by INV, overall survival (OS) and safety.
Results: In total, 303 pts were randomised (ALC N=152 [N=69 Asian, N=83 non-Asian]; CRZ N=151 [N=69 Asian, N=82 non-Asian]). Baseline characteristics were consistent between Asian and non-Asian subgroups, except median weight. Efficacy and safety data were similar between subgroups (Table). PFS by INV was longer with ALC in Asian (HR 0.46) and non-Asian (HR 0.49) pts. Median OS has not yet been reached in either subgroup but data are immature: Asian HR 0.68, non-Asian HR 0.82. Rate of treatment discontinuation due to adverse events (AE): Asian 13.0% ALC, 11.6% CRZ; non-Asian 9.6% ALC, 13.4% CRZ. AE profiles of Asian and non-Asian subgroups were consistent with the ITT population. Diarrhoea was more common with CRZ in both subgroups vs ALC (Asian 15.0% ALC, 39.1% CRZ; non-Asian 10.0% ALC, 50.0% CRZ). Nausea was more common with CRZ in both subgroups vs ALC (Asian 10.1% ALC, 42.0% CRZ; non-Asian 17.0% ALC, 52.4% CRZ) and was more common in non-Asian vs Asian pts. Pharmacokinetics data of the subgroups will be presented.
Conclusions: Efficacy and safety data were similar between Asian and non-Asian pts for ALC or CRZ. The results confirm ALC 600 mg BID dosage is more effective than CRZ in Asian and non-Asian pts, and has an acceptable safety profile in Asian pts.
Table: Efficacy and safety data by subgroups
Clinical trial indentification: NCT02075840.
Legal entity responsible for the study: F. Hoffmann-La Roche
Funding: F. Hoffmann-La Roche Ltd.
Disclosure: T.S.K. Mok: Consultant (Participated in Advisory Boards for the last two years): AstraZeneca, BI, Pfizer, Novartis, SFJ, Roche, MSD, Clovis Oncology, BMS, Eisai and Taiho.
S. Peters: I have received education grants, provided consultation, attended advisory boards and/or provided lectures for the following organizations: Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Clovis, Eli Lilly, F. Hoffmann-La Roche, Janssen, Merck Sharp and Dohme and Merck Serono, Pfizer, Regeneron and Takeda.
D.R. Camidge: Roche Genetech, Genoptix, G1 Therapeutics, Orion, Clovis, Ariad, Novartis, Celgene, Array, Abbvie, Eli Lilly.
S-H.I. Ou: Corporate-sponsored research to institutions: Pfizer, Roche, Astra Zeneca, ARIAD, Ignyta and other substantive relationships including: Pfizer, Roche, Astra Zeneca, ARIAD, Ignyta and Foundation Medicine.
J.S. Ahn: Dr. Ahn reports personal fees from BMS, Eisai, Janssen, Roche, Menarini and Boehringer Ingelheim
B.C. Cho: Research funding: Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST; Consulting role: Novartis, AstraZeneca, Boehringer-Ingelheim, Roche, BMS, Yuhan, Pfizer, Eli Lilly.
S.L. Geater: Funding to institute for clinical research: Astra Zaneca, Boehringer Ingelheim, Novartis, Samsung, Roche
J. Ho: Has received speaker’s honorarium and research funding from Roche.
A. Zeaiter: Employment at F. Hoffmann-La Roche.
B. Balas: Employee and stockholder at F. Hoffmann-La Roche Ltd.
E. Nueesch: Employee at F. Hoffmann-La Roche
E. Mitry: Employee at F. Hoffmann-La Roche
P.N. Morcos: Employment and stock ownership at F. Hoffmann-La Roche.
All other authors have declared no conflicts of interest.
Keywords: ALK+, Asian, alectinib, NSCLC