In a large number of samples of lung adenocarcinoma the incidence of RET fusion, as detected by routine diagnostics, was higher than expected, according to a report by Dr Oliver Gautschi of the Clinic for Oncology, Kantonsspital, Luzern, Switzerland presented during a proffered papers session at the 4th European Lung Cancer Conference (26-29 March 2014, Geneva, Switzerland). Together with colleagues from Austria and Germany, he observed preliminary activity of targeted agent cabozantinib in pretreated patients whose tumours show primary and secondary resistance to vandetanib.
Experience with diagnosis of lung adenocarcinoma with RET fusion and targeted therapy application in this setting is limited. RET fusion is an oncogenic driver in a subset of lung adenocarcinomas. Several RET inhibitors were active in preclinical models and the activity was reported for cabozantinib in several clinical cases.
In the study background, the investigators explained that in November 2012 they integrated RET and KIF5B commercial fluorescence in-situ hybridization (FISH) probes into diagnostic test algorithms for primary lung adenocarcinoma. Positive cases were recorded from the databases, and clinical outcomes were collected from patients who received RET inhibitors on an individual compassionate use or off-label use basis.
RET fusion identification and potentials from targeting treatments
The researchers performed next generation sequencing on selected diagnostic and repeat biopsy samples, to identify RET kinase mutations and fusion partners. All patients with targeted therapy consented to treatment, translational research and publication.
Until November 2013, they analysed by RET-FISH 529 tumour samples. In total, 12 (2.3%) samples were positive by FISH, and none carried a secondary mutation in EGFR, HER2, KRAS, BRAF, ALK, or ROS1.
Four patients with RET fusion and previous chemotherapy received one or more lines of targeted therapy with RET inhibitors after standard treatment. From those, one patient received sunitinib and achieved prolonged disease stabilisation being alive after follow-up of 56 months, while three patients received vandetanib as first targeted therapy and two of them had benefit in term of response. Those three patients received cabozantinib as a second targeted treatment after progression on vandetanib. Two of them achieved partial response to cabozantinib with death recorded at 36 and 34 months after diagnosis. One patient started with ponatinib recently and this patient is alive upon 50 months from diagnosis.
Tumour rebiopsy was performed in three patients after targeted therapy. No secondary RET mutations have been identified so far.
The authors concluded that the incidence of RET fusion was higher than expected in their patient dataset. RET fusion was detectable by routine diagnostics. Chemotherapy is currently standard of care in these patients. Preliminary activity of targeted therapy was observed with activity of cabozantinib in pretreated patients whose tumours showed primary and secondary resistance to vandetanib.
The study researchers warn clinicians that an activation of a global phase II trial with cabozantinib in RET fusion positive lung cancer is ongoing and asked them to refer patients to centres participating in the study.
Dr Mark Kris, who discussed the findings, congratulated the authors for joining forces between institutions. Regarding RET diagnostic screening strategies, he said that immunohistochemistry is ineffective, RT-PCR detects specific fusions, while FISH detects fusion variants. Next generation sequencing is useful for upstream partner identification and concurrent oncogene/tumour suppressor gene aberration identification.
From the authors list, Johannes Heuckmann reported that he is a co-founder, shareholder and full time employee of Blackfield AG, Cologne, Germany. All other authors declared no conflicts of interest.
Abstract 94O: Lung Adenocarcinoma with RET Fusion: Early Experience with Diagnosis and Targeted Therapy
The European Lung Cancer Conference (ELCC) is organised by the European Society for Medical Oncology (ESMO) and the International Association for the Study of Lung Cancer (IASLC). During the four-day programme, attendees benefit from educational and scientific updates provided by thoracic oncology specialists on different multidisciplinary topics important for research and clinical practice in the field of lung cancer.