Response to Cabozantinib in patients with RET fusion-positive lung adenocarcinomas

Abstract

The discovery of RET fusions in lung cancers has uncovered a new therapeutic target for patients whose tumors harbor these changes. In an unselected population of non-small cell lung carcinomas (NSCLCs), RET fusions are present in 1% to 2% of cases. This incidence increases substantially, however, in never-smokers with lung adenocarcinomas that lack other known driver oncogenes. Although preclinical data provide experimental support for the use of RET inhibitors in the treatment of RET fusion-positive tumors, clinical data on response are lacking. We report preliminary data for the first three patients treated with the RET inhibitor cabozantinib on a prospective phase II trial for patients with RET fusion-positive NSCLCs (NCT01639508). Confirmed partial responses were observed in 2 patients, including one harboring a novel TRIM33-RET fusion. A third patient with a KIF5B-RET fusion has had prolonged stable disease approaching 8 months (31 weeks). All three patients remain progression-free on treatment.

Figure 1

A, photomicrograph of a supraclavicular lymph node biopsy showing a lung adenocarcinoma with papillary morphology. B, a positive RET FISH break-apart test. Split green and red signals indicate the presence of a RET fusion. Probes were designed as previously published (13). C, the presumptive t(1;10)(p13;q11.2) translocation places TRIM33 exons 1 to 14 upstream of RET exons 12 to 18, generating an in-frame TRIM33–RET fusion gene.

Figure 2

A1, baseline chest CT of the first patient with TRIM33–RET showing paramediastinal and pleural-based nodularities in the left upper lobe. A2, repeat imaging after 4 weeks of therapy revealing the disappearance of paramediastinal disease and a significant reduction of pleural-based disease. B1, chest CT of the second RET fusion-positive patient showing 2 nodules in the right lower lobe. B2, decrease in both size and solid components of both lesions at 4 weeks. C1, baseline imaging of the third patient with KIF5B–RET showing small bilateral pulmonary nodules. C2, stable disease at 4 weeks. All responses have been confirmed at 12 weeks and have since been maintained clinically and radiographically. Baseline disease burden was relatively low for all 3 cases.

Figure 3

RET fusions reported in the literature are depicted including major recurrent KIF5B–RET fusions, CCDC6–RET, NCOA4–RET (–16, 20), and the novel TRIM33–RET. All fusions encode an intact RET kinase domain as shown in blue. Regions encoding coiled-coil domains that mediate dimerization are shown in red (the N-terminal NCOA4 coiled-coil domain is not well defined). Part of the RET transmembrane domain encoded by RET exon 11 is shown in purple.