Targeting RET in Patients With RET-Rearranged Lung Cancers: Results From the Global, Multicenter RET Registry

Abstract

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 RETrearranged NSCLCs, providing the largest data set, to our knowledge, on outcomes of RET-directed therapy thus far. MethodsA 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 nextgeneration 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. ResultsBy 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). ConclusionAvailable 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.

Novel targeted therapeutics for MEN2

“…However, numbers are too small to draw any conclusions. Cabozantinib, vandetanib and sunitinib, for which at least 10 patients were evaluable, achieved 37, 18 and 22% overall responses, respectively (Gautschi et al 2017), in line with observations in thyroid cancer. No data are available for the use of nintedanib in MEN2 or MTC, yet.…”

“…In a recent retrospective analysis, the drug was reported to have achieved one complete response (CR) and one SD in two RET-rearranged NSCLC patients (Gautschi et al 2017). Interestingly, according to the same study, ponatinib obtained only stabilization in two treated patients, while alectinib (n = 2) failed.…”

Molecular Pathology of Lung Cancer

“…Akciğer adenokarsinomlarının yaklaşık %1-2'sinde görülür ve yine sıklıkla sigara kullanmamış hastalarda saptanır (28,29,30). RET gen değişiklikleri FİSH yöntemiyle saptanabilir, ayrıca sekanslama veya PCR yöntemlerinin daha faydalı olacağı düşünülmektedir (31).…”

“…İmmünhistokimyasal yöntemlerin henüz RET rearranjmanı tespitinde net bir yeri yoktur. RET gen değişikliklerinin en sık rastlanan formunun KIF5B-RET füzyonu olduğu gösterilmiştir (30,32). Günümüze kadar yapılmış klinik çalışmalar, birden çok hedefli kinaz inhibitörlerine RET rearranjmanı izlenen hastalarda sınırlı yanıt alındığı ve bu konuda yeni hedefe yönelik etki gösteren ilaçların geliştirilmesi gerekliliğini göstermiştir (30).…”

Standardizing Biomarker Testing for Canadian Patients with Advanced Lung Cancer

“…Cabozantinib and vandetanib have demonstrated an overall response ranging from 18 to 53% but with relatively short progression-free survival (4.7 to 5.5 months), likely reflecting the aggressive nature of nsclc harbouring this oncogene, especially when compared with the response of other driver mutations to tkis 69,70 .…”