By Enriqueta Felip, MD, PhD
ALK-directed TKIs are effective first- and second-line therapies in patients with ALK rearrangements. Testing of all patients with stage IV adenocarcinomas of the lung for ALK aberrations is supported by international guidelines.1,2 In Europe, there are also a number of published national guidelines supporting ALK testing in stage IV lung adenocarcinoma.3-5 Although the break-apart fluorescence in situ hybridization (FISH) test remains a core approach to detect ALK rearrangements, immunohistochemistry is widely used and is rapidly being adopted as the primary test for prescribing ALK TKIs. Overall, the current consensus is that reflex testing for ALK gene rearrangement should become routine and that ALK testing should be carried out in parallel with EGFR mutation assessment for all patients with stage IV adenocarcinomas; this is more efficient in terms of tissue usage and testing turnaround time for both EGFR and ALK gene aberrations.6
Worldwide, there is no clear information regarding the penetrance of biomarker testing, including ALK, in patients with NSCLC. The French National Cancer Institute reported the results of the BIOMARKERS-France study, which assessed the characteristics, molecular profiles, and clinical outcomes of 17,664 consecutive patients with NSCLC who were screened during a 1-year period by this program. The investigators showed that routine nationwide molecular profiling of patients with advanced NSCLC was feasible.7 In the discussion section, the authors mentioned that—considering that 39,000 new lung cancer cases (any stage and histology) are reported each year in France—18,000 patients with advanced non-squamous NSCLC represent the number of patients likely to be screened for EGFR mutations and ALK rearrangements according to current guidelines.
Recent preliminary results of the National Cancer Institute (NCI) Molecular Analysis for Therapy Choice (MATCH), a precision-medicine cancer treatment clinical trial, were presented in 2017.8 In this trial, patients whose tumors, regardless of site of origin, have genetic changes that match one of the treatments in the study may receive that treatment if they meet other eligibility criteria. By July 16, 2017, 5,963 tumor samples from patients with a wide range of cancer types had been screened using next-generation sequencing (NGS). Although the study was not designed to determine biomarker penetrance in different tumor types, the number of included patients with lung cancer was relatively small (7.4%), compared with those with cancers of the colon and rectum (15.4%), breast (12.8%), prostate (2.6%), and other rarer cancer types (61.8%).
In a similar ongoing program in Europe, the EORTC SPECTAlung (NCT02214134) study aims to screen 3,500 participants with thoracic tumors— including lung cancer, malignant pleural mesothelioma, thymoma, or thymic carcinoma—at any stage during a 5-year period (2015-2019) to identify the molecular characteristics of their disease. If a particular molecular alteration is detected, these patients are then considered for linked targeted clinical trials. ALK rearrangement determination, among other biomarkers, is a standard approach in stage IV lung adenocarcinoma. Biomarker testing in lung cancer is still a challenge due to the small tumor sample available in the majority of cases, as well as organizational and economic limitations in some cases. Furthermore, there is no common methodology for ALK testing, which may include immunohistochemistry, FISH, and NGS technologies. We must work to ensure the availability of biomarker testing in all patients with stage IV lung adenocarcinoma, and we must standardize the implementation of NGS technologies. ✦
About the Author: Dr. Felip is Head of the Thoracic Tumors Group, Specialist Physician in Medical Oncology, and Head of the Medical Oncology Service of the Thoracic Tumors Committee at Vall d’Hebron Hospital, Barcelona, Spain.
1. Novello: S, Barlesi F, Califano R, et al. Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016;27(suppl 5):v1-v27.
2. Leighl NB, Rekhtman N, Biermann WA, et al. Molecular testing for selection of patients with lung cancer for epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors: American Society of Clinical Oncology endorsement of the College of American Pathologists/International Association for the study of lung cancer/association for molecular pathology guideline. J Clin Oncol. 2014;32(32):3673-3679.
3. von Laffert M, Schirmacher P, Warth A, et al. ALK-Testing in non-small cell lung cancer (NSCLC): Immunohistochemistry (IHC) and/ or fluorescence in-situ Hybridisation (FISH)?: Statement of the Germany Society for Pathology (DGP) and the Working Group Thoracic Oncology (AIO) of the German Cancer Society e.V. (Stellungnahme der Deutschen Gesellschaft für Pathologie und der AG Thorakale Onkologie der Arbeitsgemeinschaft Onkologie/Deutsche Krebsgesellschaft e.V.). Lung Cancer. 2017;103:1-5
4. Felip E, Concha Á, de Castro J, et al. Biomarker testing in advanced non-small-cell lung cancer: a National Consensus of the Spanish Society of Pathology and the Spanish Society of Medical Oncology. Clin Transl Oncol. 2015;17(2):103-112.
5. Marchetti A, Ardizzoni A, Papotti M, et al. Recommendations for the analysis of ALK gene rearrangements in non-small-cell lung cancer: a consensus of the Italian Association of Medical Oncology and the Italian Society of Pathology and Cytopathology. J Thorac Oncol. 2013;8(3):352-358.
6. Kerr KM and López-Ríos F. Precision medicine in NSCLC and pathology: how does ALK fit in the pathway? Ann Oncol. 2016;27 Suppl 3:iii16-iii24.
7. Barlesi F, Mazieres J, Merlio JP, et al. Routine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT). Lancet. 2016;387(10026):1415-1426.
8. Harris L, Chen A, O’Dwyer P, et al. Update on the NCI-Molecular Analysis for Therapy Choice (NCI-MATCH/EAY131) precision medicine trial. 2017 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. Abstract B080. Presented October 29, 2017.