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Targeting RET in Patients With RET-Rearranged Lung Cancers: Results From the Global, Multicenter RET Registry
Oliver Gautschi1, Julie Milia1, Thomas Filleron1
1Oliver Gautschi, Kristin Zeidler, and Joachim Diebold, Lucerne Cantonal Hospital, Luzern; Patrizia Froesch, Ente Ospedaliero Cantonale, Bellinzona; Martin Früh, Kantonsspital St Gallen, St Gallen; Sacha I. Rothschild, University Hospital Basel, Basel, Switzerland; Julie Milia and Julien Mazières, Hôpital Larrey; Thomas Filleron, Institut Universitaire du Cancer, Claudius Regaud, Toulouse; Benjamin Besse and Jordi Remon-Masip, Institute Gustave Roussy, Villejuif; Gérard Zalcman, University Hospital Bichat, Paris; Isabelle Monnet, Centre Hospitalier Intercommunal de Creteil, Creteil; Florian Cabillic, Université de Rennes 1, Rennes, France; Juergen Wolf and Sebastian Michels, Center for Integrated Oncology, Cologne; Georg Pall, Fachkliniken Wangen, Wangen Im Allgäu; Arne Warth, Heidelberg University Hospital; Thomas Muley, Thoraxklinik at University of Heidelberg and Translational Lung Research Center, Heidelberg, Germany; David P. Carbone and Dwight Owen, Ohio State University Comprehensive Cancer Center, Columbus; Vamsidhar Velcheti, Cleveland Clinic, Pepper Pike, OH; Ross Camidge and Vignhesh Narayanan, University of Colorado, Denver; Robert C. Doebele, University of Colorado, Aurora, CO; Pasi A. Janne and Mark M. Awad, Dana-Farber Cancer Institute, Boston, MA; Daniel D. Karp, The University of Texas MD Anderson Cancer Center, Houston, TX; Heather A. Wakelee and Joel W. Neal, Stanford University, Stanford; Sai-Hong Ignatius Ou, University of California, Irvine, Orange; David R. Gandara and Jonathan W. Riess, University of California, Davis Cancer Center, Sacramento, CA; Alexander Drilon, Memorial Sloan Kettering Cancer Center, New York, NY; Nir Peled, Davidoff Cancer Center, Petach Tiqwa, Israël; Chul-Cho Byoung, Yonseï Cancer Center, Seoul, Republic of Korea; Michael Van Den Heuvel, Netherlands Cancer Institute, Amsterdam, the Netherlands; Tony S.K. Mok, The Chinese University of Hong Kong, Hong Kong, Special Administrative Region, People's Republic of China; James C.H. Yang and Jin-Yuan Shih, National Taiwan University Hospital, Taipei, Republic of China; Sanjay Popat, Royal Marsden Hospital, London, United Kingdom; and Rafael Rosell and Niki Karachaliou, Catalan Institute of Oncology, Barcelona, Spain.
Abstract:
Purpose In addition to prospective trials for non-small-cell lung cancers (NSCLCs) that are driven by less common genomic alterations, registries provide complementary information on patient response to targeted therapies. Here, we present the results of an international registry of patients with RET-rearranged NSCLCs, providing the largest data set, to our knowledge, on outcomes of RET-directed therapy thus far. Methods A global, multicenter network of thoracic oncologists identified patients with pathologically confirmed NSCLC that harbored a RET rearrangement. Molecular profiling was performed locally by reverse transcriptase polymerase chain reaction, fluorescence in situ hybridization, or next-generation sequencing. Anonymized data-clinical, pathologic, and molecular features-were collected centrally and analyzed by an independent statistician. Best response to RET tyrosine kinase inhibition administered outside of a clinical trial was determined by RECIST v1.1. Results By April 2016, 165 patients with RET-rearranged NSCLC from 29 centers across Europe, Asia, and the United States were accrued. Median age was 61 years (range, 29 to 89 years). The majority of patients were never smokers (63%) with lung adenocarcinomas (98%) and advanced disease (91%). The most frequent rearrangement was KIF5B-RET (72%). Of those patients, 53 received one or more RET tyrosine kinase inhibitors in sequence: cabozantinib (21 patients), vandetanib (11 patients), sunitinib (10 patients), sorafenib (two patients), alectinib (two patients), lenvatinib (two patients), nintedanib (two patients), ponatinib (two patients), and regorafenib (one patient). The rate of any complete or partial response to cabozantinib, vandetanib, and sunitinib was 37%, 18%, and 22%, respectively. Further responses were observed with lenvantinib and nintedanib. Median progression-free survival was 2.3 months (95% CI, 1.6 to 5.0 months), and median overall survival was 6.8 months (95% CI, 3.9 to 14.3 months). Conclusion Available multikinase inhibitors had limited activity in patients with RET-rearranged NSCLC in this retrospective study. Further investigation of the biology of RET-rearranged lung cancers and identification of new targeted therapeutics will be required to improve outcomes for these patients.
Insights
This study found that available multikinase inhibitors showed limited effectiveness in treating non-small-cell lung cancer (NSCLC) with RET rearrangements. Further research is needed to develop new targeted therapies for this rare cancer subtype.
Area of Science:
- Oncology
- Genomics
- Pharmacology
Background:
- Non-small-cell lung cancer (NSCLC) registries offer valuable data on targeted therapy responses, especially for rare genomic alterations.
- RET rearrangements are uncommon drivers in NSCLC, necessitating specific research into treatment outcomes.
Purpose of the Study:
- To present outcomes from an international registry of patients with RET-rearranged NSCLC treated with RET-directed therapies.
- To provide the largest dataset to date on the efficacy of RET-targeted treatments in this patient population.
Main Methods:
- Global, multicenter retrospective study identifying 165 patients with pathologically confirmed RET-rearranged NSCLC.
- Molecular profiling via PCR, FISH, or NGS; data collected centrally and analyzed by an independent statistician.
- Best response assessed by RECIST v1.1 for patients receiving RET tyrosine kinase inhibitors outside clinical trials.
Main Results:
- The most common rearrangement was KIF5B-RET (72%).
- 53 patients received sequential RET tyrosine kinase inhibitors, including cabozantinib, vandetanib, and sunitinib.
- Response rates for cabozantinib, vandetanib, and sunitinib were 37%, 18%, and 22%, respectively. Median progression-free survival was 2.3 months, and median overall survival was 6.8 months.
Conclusions:
- Current multikinase inhibitors demonstrate limited clinical activity in patients with RET-rearranged NSCLC.
- Further investigation into RET-rearranged lung cancer biology and novel targeted therapeutics is crucial for improving patient outcomes.
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