Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis.

By A. Shaw, B. Yeap, B. Solomon, Gregory Riely, J. Gainor, J. Engelman, G. Shapiro, D. Costa, S. Ou, M. Butaney and 13 more. The Lancet Oncology, 2011

898 citations recorded by the source corpus.

BACKGROUND ALK gene rearrangement defines a new molecular subtype of non-small-cell lung cancer (NSCLC). In a recent phase 1 clinical trial, the ALK tyrosine-kinase inhibitor (TKI) crizotinib showed marked antitumour activity in patients with advanced, ALK-positive NSCLC. To assess whether crizotinib affects overall survival in these patients, we did a retrospective study comparing survival outcomes in crizotinib-treated patients in the trial and crizotinib-naive controls screened during the same time period. METHODS We examined overall survival in patients with advanced, ALK-positive NSCLC who enrolled in the phase 1 clinical trial of crizotinib, focusing on the cohort of 82 patients who had enrolled through Feb 10, 2010. For comparators, we identified 36 ALK-positive patients from trial sites who were not given crizotinib (ALK-positive controls), 67 patients without ALK rearrangement but positive for EGFR mutation, and 253 wild-type patients lacking either ALK rearrangement or EGFR mutation. To assess differences in overall survival, we assessed subsets of clinically comparable ALK-positive and ALK-negative patients. FINDINGS Among 82 ALK-positive patients who were given crizotinib, median overall survival from initiation of crizotinib has not been reached (95% CI 17 months to not reached); 1-year overall survival was 74% (95% CI 63-82), and 2-year overall survival was 54% (40-66). Overall survival did not differ based on age, sex, smoking history, or ethnic origin. Survival in 30 ALK-positive patients who were given crizotinib in the second-line or third-line setting was significantly longer than in 23 ALK-positive controls given any second-line therapy (median overall survival not reached [95% CI 14 months to not reached] vs 6 months [4-17], 1-year overall survival 70% [95% CI 50-83] vs 44% [23-64], and 2-year overall survival 55% [33-72] vs 12% [2-30]; hazard ratio 0·36, 95% CI 0·17-0·75; p=0·004). Survival in 56 crizotinib-treated, ALK-positive patients was similar to that in 63 ALK-negative, EGFR-positive patients given EGFR TKI therapy (median overall survival not reached [95% CI 17 months to not reached] vs 24 months [15-34], 1-year overall survival 71% [95% CI 58-81] vs 74% [61-83], and 2-year overall survival 57% [40-71] vs 52% [38-65]; p=0·786), whereas survival in 36 crizotinib-naive, ALK-positive controls was similar to that in 253 wild-type controls (median overall survival 20 months [95% CI 13-26] vs 15 months [13-17]; p=0·244). INTERPRETATION In patients with advanced, ALK-positive NSCLC, crizotinib therapy is associated with improved survival compared with that of crizotinib-naive controls. ALK rearrangement is not a favourable prognostic factor in advanced NSCLC. FUNDING Pfizer Inc, V Foundation for Cancer Research.

Subfields: Oncology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/3349167ce28a24bb1ef78062af66011fe05ff080

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In Oncology

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Citations in the corpus

• Alectinib in Crizotinib-Refractory ALK-Rearranged Non-Small-Cell Lung Cancer: A Phase II Global Study. (2016, neutral): “Any cause, in $ 10% Patients Constipation 39 (28) 6 (4) 0 0 45 (33) Fatigue 26 (19) 8 (6) 2 (1) 0 36 (26) Peripheral edema 27 (20) 6 (4) 1 (1) 0 34 (25) Myalgia 25 (18) 5 (4) 1 (1) 0 31 (23) Asthenia 16 (12) 8 (6) 1 (1) 0 25 (18) Headache 16 (12) 4 (3) 2 (1) 0 22 (16) Cough 15 (11) 4 (3) 0 0 19 (14)”
• Targeted therapy for non-small cell lung cancer: current standards and the promise of the future. (2015, background): “Importantly, ALK-positivity itself is not a favourable prognostic factor as those without treatment have similar poor outcomes to the general population of NSCLC (106).”
• Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors (2013, neutral): “In contrast to EGFR-mutated lung cancer, ALK gene fusions do not show sharp differences in prevalence according to sex and ethnic origin, but do show a similar strong association with patients who have never smoked tobacco and younger age.(11,18,30,31) However, while these clinical characteristics m”
• Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. (2018, positive): “The anti-tumour activity of crizotinib was initially demonstrated in two multicentre single-arm studies, with significant ORR and PFS advantages, as well as a survival advantage, compared with other treatment options [197, 198].”