Geneva, Switzerland, 12 April 2018 - Alectinib provides longer symptom improvement than crizotinib in ALK-positive non-small-cell lung cancer (NSCLC), according to results from the ALEX trial (1) presented at the ELCC 2018 (European Lung Cancer Congress) in Geneva, Switzerland. (2)
The phase III ALEX trial was a head-to-head comparison of the next-generation tyrosine kinase inhibitor (TKI) alectinib versus the standard of care TKI crizotinib in patients with anaplastic lymphoma kinase (ALK)-positive NSCLC, dependent on a rearrangement of the ALK gene. Approximately 4% of NSCLC patients are ALK-positive and are at high risk of central nervous system (CNS) metastases. Alectinib improved progression-free survival and prolonged the time to CNS progression compared to crizotinib. Alectinib had a better toxicity profile than crizotinib despite a longer duration of treatment. (3)
Patient-reported outcomes in terms of health-related quality of life and lung cancer-related symptoms with alectinib and crizotinib are reported for the first time at ELCC. The EORTC QLQ-C30 questionnaire was used to evaluate health-related quality of life and the EORTC QLQ-LC13 questionnaire was used to assess lung cancer-related symptoms. Patients completed the questionnaires at baseline, every four weeks during treatment, within the four weeks after study withdrawal, and after disease progression. The reasons for withdrawal have been previously reported (3); very few were due to symptom deterioration in either group.
Around two-thirds of patients in both treatment groups completed the questionnaires (66% and 64% in the alectinib and crizotinib groups, respectively). Patients in both the alectinib and crizotinib treatment groups had clinically meaningful improvements in health-related quality of life. However, there was a longer duration of improvement in health-related quality of life for patients treated with alectinib (88 weeks) compared to crizotinib (68 weeks).
For the patients with CNS metastases at baseline, a lower proportion of patients in the alectinib arm had worsening in health-related quality of life compared with crizotinib starting at week four (10.8% vs. 20.6%) and persisting for most assessments through week 84 (0% vs. 16.7 %). In addition, a lower proportion of these patients reported worsening in cognitive function with alectinib compared to crizotinib (17.9% vs. 34.6% at week 32, respectively).
Regarding lung cancer symptoms, there was a clinically meaningful improvement in both treatment arms. But the duration of improvement was longer with alectinib compared to crizotinib (cough: 96 versus 84 weeks; chest pain: 96 versus 80 weeks; fatigue: 96 versus 68 weeks; pain in other parts: 96 versus 68 weeks, respectively).
Fewer patients in the alectinib group reported a clinically meaningful worsening in treatment-related symptoms such as diarrhoea, peripheral neuropathy, constipation, dysphagia, appetite loss, and nausea/vomiting.
Lead author Dr Maurice Pérol, medical oncologist, Centre Léon Bérard, Lyon, France, co-chair of ELCC 2018, said: "The patient-reported outcome data is consistent with the main results of the study. The primary analysis showed a similar response rate for crizotinib and alectinib, but a longer duration of response with alectinib. This is consistent with the improvements in health-related quality of life and lung cancer symptoms, which were of similar magnitude in both groups but lasted longer with alectinib."
"The high level of CNS activity shown with alectinib in the primary analysis is consistent with the fact that fewer patients treated with alectinib reported clinically meaningful worsening in health-related quality of life or cognitive function compared to crizotinib," he continued. "Finally, the superior tolerability profile of alectinib compared to crizotinib shown in this analysis is consistent with the adverse events profile recorded during the study."
Pérol said: "The patient-reported outcome data supports the use of alectinib as a new standard of care in the frontline treatment of patients with ALK-positive lung cancer."
Commenting on the study, Dr Fiona Blackhall, Honorary Consultant in Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK, said: "The ALEX trial was a practice-changing study that firmly placed alectinib as a first-line palliative treatment for ALK-positive non-small-cell lung cancer patients. This secondary analysis strengthens the rationale for alectinib as the standard of care in first-line treatment."
Blackhall said that increasingly, because of the cost of conducting clinical trials, patient-reported outcomes are not measured. But she said: "In this context of palliating advanced lung cancer, living better is as important, if arguably not more important, than living longer. And for this reason, patient-reported outcomes and health-related quality of life are crucial to assess and analyse."
She continued: "In patients with advanced lung cancer the symptom burden is high, particularly cough, breathlessness and chest pain. And so to have meaningful palliation and improvement in symptoms is of paramount importance. So alongside wishing to identify drugs that improve progression-free survival and overall survival ultimately, we need to ensure that those drugs also allow patients to live better. Goals of care are important in the everyday management of patients with lung cancer and alleviating the symptoms it causes is a key goal."
Regarding the impact of alectinib on symptoms in the ALEX trial, Blackhall said: "The time to deterioration in common and difficult to palliate lung cancer symptoms including cough, dyspnoea, and chest pain was comparable between alectinib and crizotinib. However, alectinib prolonged the improvement in those symptoms. That fits in with the previously reported improvement in progression-free survival and favourable tolerability with alectinib."
Notes to Editors
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This press release contains information provided by the authors of the highlighted abstracts and reflects the content of those abstracts. It does not necessarily reflect the views or opinions of ESMO or IASLC who cannot be held responsible for the accuracy of the data. Commentators quoted in the press release are required to comply with the ESMO Declaration of Interests policy and the ESMO Code of Conduct.
1 Abstract 138PD_PR 'Patient-reported outcomes (PROs) in ALEX: A phase III study of alectinib (ALEC) vs crizotinib (CRIZ) in non-small-cell lung cancer (NSCLC)': presented by Maurice Pérol during the Poster Discussion session 'Immunotherapy and next-generation TKIs: from second to frontline treatment' on Thursday, 12 April, 07:45 to 09:00 (CEST) in Room A. Journal of Thoracic Oncology, Volume 13, Issue 4, Supplement, April 2018.
3 Peters S, Camidge DR, Shaw AT, et al. Alectinib versus Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2017;377(9):829-838. doi: 10.1056/NEJMoa1704795.
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138PD_PR - Patient-reported outcomes (PROs) in ALEX: A phase III study of alectinib (ALEC) vs crizotinib (CRIZ) in non-small-cell lung cancer (NSCLC)
M. Perol1, S. Peters2, N. Pavlakis3, E. Levchenko4, M. Platania5, J. Oliveira6, S. Novello7, T. Karagiannis8, A. Zeaiter9, R. Dziadziuszko10
1Medical Oncology, Centre Léon Bérard, Lyon, France, 2Centre Hospitalier Universitaire Vaudois - CHUV, Lausanne, Switzerland, 3Royal North Shore Hospital, St Leonards, Australia, 4Petrov Scientific Research Oncology Institute, St-Petersburg, Russian Federation, 5IRCCS MultiMedica Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy, 6Medical Oncology, Portuguese Oncology Institute of Porto - IPO Porto, Porto, Portugal, 7University of Turin, Orbassano, Italy, 8Genentech, San Francisco, CA, USA, 9F.Hoffman-La Roche Ltd, Basel, Switzerland, 10Medical University of Gdansk, Gdansk, Poland *
* on behalf of the ALEX author group
Background: ALEC showed superior efficacy versus CRIZ in patients (pts) with treatment-naïve ALK+ NSCLC in the phase III ALEX trial (NCT02075840). PRO data (disease burden, symptom tolerability and health-related quality of life [HRQoL]) are reported here.
Methods: Pts (n=303) were randomised 1:1 to receive ALEC (600mg BID) or CRIZ (250mg BID). Primary endpoint: investigator-assessed PFS. PROs were collected using EORTC QLQ-C30/QLQ-LC13 questionnaires. Pre-specified endpoints: time-to-deterioration (TTD) in lung cancer symptoms and HRQoL, longitudinal analyses of mean score changes from baseline, and proportion of pts with clinically meaningful change (?10-point change from baseline) during treatment in the ITT population and patients with baseline CNS metastases.
Results: Baseline completion rates and characteristics were balanced between arms in the PRO-evaluable population (ALEC n=100, 65.8%; CRIZ n=97, 64.2%). Median TTD in composite symptom endpoint (cough, dyspnoea, chest pain) was similar between arms (HR 1.10 [95% CI 0.72-1.68]). On average, ALEC pts reported a clinically meaningful improvement in baseline lung cancer symptoms for a longer duration of time versus CRIZ (cough, week 96 vs week 84; chest pain, week 96 vs week 80; fatigue, week 96 vs 68; pain in other parts, week 96 vs 68, respectively). Differences in lung symptoms between treatment arms tended to favour ALEC from 11.1 months (45 weeks), which was around the time of median PFS with CRIZ. ALEC pts reported a clinically meaningful improvement from baseline in HRQoL for a longer duration of time than CRIZ pts (week 88 vs 68, respectively). Fewer ALEC pts experienced a clinically meaningful worsening in treatment-related symptoms (nausea/vomiting, diarrhoea, appetite loss, dysphagia, peripheral neuropathy) than CRIZ pts.
Conclusions: TTD for lung cancer symptoms was comparable between arms. Clinically meaningful improvement in lung cancer symptoms was maintained for longer with ALEC versus CRIZ, consistent with the improved PFS with ALEC versus CRIZ. HRQoL was improved with ALEC versus CRIZ. PRO data are consistent with ALEX safety data and confirm greater tolerability with ALEC versus CRIZ.
Clinical trial identification: BO28984; 15 April 2016
Legal entity responsible for the study: F. Hoffmann-La Roche Ltd
Funding: F. Hoffmann-La Roche Ltd
Disclosures: M. Perol: Advisory role for Roche and Pfizer. S. Peters: Education grants, provided consultation, attended advisory boards and/or provided lectures for the following organisations: 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. N. Pavlakis: Advisory role for Novartis, Takeda, Roche and Pfizer. S. Novello: Speakers Bureau for: Eli Lilly, BMS, MSD, F. Hoffmann-La Roche Ltd and Astra Zeneca. T. Karagiannis: Employee of, owns stocks in and has taken part in company-sponsored research for Genentech. A. Zeaiter: Employee of F.Hoffman-La Roche Ltd. R. Dziadziuszko: Substantive relationships with Novartis, Pfizer and BMS. All other authors have declared no conflicts of interest.