PMID- 30010763 OWN - NLM STAT- MEDLINE DCOM- 20191223 LR - 20200407 IS - 1569-8041 (Electronic) IS - 0923-7534 (Linking) VI - 29 IP - 9 DP - 2018 Sep 1 TI - Correlation of extent of ALK FISH positivity and crizotinib efficacy in three prospective studies of ALK-positive patients with non-small-cell lung cancer. PG - 1964-1971 LID - S0923-7534(19)34163-8 [pii] LID - 10.1093/annonc/mdy242 [doi] AB - BACKGROUND: In clinical trials of patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) treated with crizotinib, evaluation of the relationship between the percentage of ALK-positive cells by fluorescence in situ hybridization (FISH)-particularly near the cut-off defining positive status-and clinical outcomes have been limited by small sample sizes. PATIENTS AND METHODS: Data were pooled from three large prospective trials (one single-arm and two randomized versus chemotherapy) of crizotinib in patients with ALK-positive NSCLC determined by Vysis ALK Break Apart FISH using a cut-off of >/=15% ALK-positive cells. Logistic regression and proportional hazards regression analyses were used to explore the association of percent ALK-positive cells with objective response and progression-free survival (PFS), respectively. RESULTS: Of 11 081 screened patients, 1958 (18%) were ALK positive, 7512 (68%) were ALK negative, and 1540 (14%) were uninformative. Median percentage of ALK-positive cells was 58% in ALK-positive patients and 2% in ALK-negative patients. Of ALK-positive patients, 5% had 15%-19% ALK-positive cells; of ALK-negative patients, 2% had 10%-14% ALK-positive cells. Objective response rate for ALK-positive, crizotinib-treated patients with >/=20% ALK-positive cells was 56% (n = 700/1246), 55% (n = 725/1312) for those with >/=15% ALK-positive cells, and 38% for those with 15%-19% ALK-positive cells (n = 25/66). As a continuous variable, higher percentages of ALK-positive cells were estimated to be associated with larger differences in objective response and PFS between crizotinib and chemotherapy; however, tests for interaction between treatment and percentage of ALK-positive cells were not significant (objective response, P = 0.054; PFS, P = 0.17). CONCLUSIONS: Patients with ALK-positive NSCLC benefit from treatment with crizotinib across the full range of percentage of ALK-positive cells, supporting the clinical utility of the 15% cut-off. The small number of patients with scores near the cut-off warrant additional study given the potential for misclassification of ALK status due to technical or biologic reasons. FAU - Soria, J-C AU - Soria JC AD - Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif; Universite Paris-Sud, Orsay, France. Electronic address: jean-charles.soria@gustaveroussy.fr. FAU - Ho, S N AU - Ho SN AD - Global Product Development, Pfizer Oncology, La Jolla. FAU - Varella-Garcia, M AU - Varella-Garcia M AD - Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora. FAU - Iafrate, A J AU - Iafrate AJ AD - Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, USA. FAU - Solomon, B J AU - Solomon BJ AD - Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia. FAU - Shaw, A T AU - Shaw AT AD - Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, USA. FAU - Blackhall, F AU - Blackhall F AD - The Christie Hospital and Institute of Cancer Sciences, Manchester University, Manchester, UK. FAU - Mok, T S AU - Mok TS AD - Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong. FAU - Wu, Y-L AU - Wu YL AD - Guangdong General Hospital, Guangdong Lung Cancer Institute, Guangzhou, China. FAU - Pestova, K AU - Pestova K AD - Abbott Molecular, Des Plaines, USA. FAU - Wilner, K D AU - Wilner KD AD - Global Product Development, Pfizer Oncology, La Jolla. FAU - Polli, A AU - Polli A AD - Global Clinical Development and Operations, Pfizer Oncology, Milan, Italy. FAU - Paolini, J AU - Paolini J AD - Global Clinical Development and Operations, Pfizer Oncology, Milan, Italy. FAU - Lanzalone, S AU - Lanzalone S AD - Global Clinical Development and Operations, Pfizer Oncology, Milan, Italy. FAU - Green, S AU - Green S AD - Global Product Development, Pfizer Oncology, Groton, USA. FAU - Camidge, D R AU - Camidge DR AD - Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - England TA - Ann Oncol JT - Annals of oncology : official journal of the European Society for Medical Oncology JID - 9007735 RN - 0 (Protein Kinase Inhibitors) RN - 53AH36668S (Crizotinib) RN - EC 2.7.10.1 (Anaplastic Lymphoma Kinase) SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - Anaplastic Lymphoma Kinase/*analysis/metabolism MH - Carcinoma, Non-Small-Cell Lung/*drug therapy/mortality/pathology MH - Clinical Trials, Phase II as Topic MH - Clinical Trials, Phase III as Topic MH - Crizotinib/pharmacology/*therapeutic use MH - Drug Resistance, Neoplasm MH - Female MH - Humans MH - In Situ Hybridization, Fluorescence MH - Lung/pathology MH - Lung Neoplasms/*drug therapy/mortality/pathology MH - Male MH - Middle Aged MH - Progression-Free Survival MH - Prospective Studies MH - Protein Kinase Inhibitors/pharmacology/*therapeutic use MH - Randomized Controlled Trials as Topic MH - Young Adult EDAT- 2018/07/17 06:00 MHDA- 2019/12/24 06:00 CRDT- 2018/07/17 06:00 PHST- 2018/07/17 06:00 [pubmed] PHST- 2019/12/24 06:00 [medline] PHST- 2018/07/17 06:00 [entrez] AID - S0923-7534(19)34163-8 [pii] AID - 10.1093/annonc/mdy242 [doi] PST - ppublish SO - Ann Oncol. 2018 Sep 1;29(9):1964-1971. doi: 10.1093/annonc/mdy242.