Successful long-term treatment of non-small cell lung cancer positive for RET rearrangement with pemetrexed.

The discovery of RET rearrangement in non-small cell lung cancer (NSCLC) has prompted development of molecularly targeted therapy for such tumors, with several clinical trials being under way to evaluate the therapeutic effects of multitargeted tyrosine kinase inhibitors. The sensitivity of RET fusion-positive NSCLC to cytotoxic chemotherapy has remained unclear, however. We here report a case of NSCLC positive for the CCDC6-RET fusion gene that benefited from treatment with pemetrexed over a period of 30 months, suggesting that thymidylate synthase-targeted drugs such as pemetrexed may show efficacy for NSCLC harboring RET fusions.

Introduction

RET fusion genes such as KIF5B-RET and CCDC6-RET have recently been identified in non–small cell lung cancer (NSCLC).1,2 Several clinical trials are already under way to evaluate the therapeutic effects of tyrosine kinase inhibitors whose targets include RET—such as vandetanib, cabozantinib, and alectinib—in individuals with RET fusion–positive NSCLC, with some patients having shown marked treatment responses.3,4 However, no selective RET inhibitor has yet been approved specifically for RET-driven lung cancer, and it has remained unclear whether such patients manifest a sensitivity to cytotoxic chemotherapy similar to that of other NSCLC patients. We here report a case of RET fusion–positive NSCLC that showed long-term benefit from treatment with pemetrexed.

Case report

A 63-year-old female never-smoker with stage IV lung adenocarcinoma was enrolled in an ongoing observational study to evaluate the feasibility of the application of next-generation sequencing to mutation analysis of lung cancer specimens at Kindai University.5 The multiplex genetic testing identified a CCDC6-RET fusion gene in tissue specimens obtained from the patient for lung cancer diagnosis (Figure 1A). We verified this chromosomal inversion by fluorescence in situ hybridization with probes that flank the RET translocation site identified in tumors positive for the CCDC6-RET fusion (Figure 1B). The patient was treated with several lines of therapy, including platinum-based chemotherapy, docetaxel plus an experimental multikinase inhibitor, erlotinib plus an investigational drug, and an investigational antiangiogenic agent. Pemetrexed at a dose of 500 mg/m2 every 3 weeks was then initiated as a fifth-line therapy. After 7 weeks of pemetrexed administration, computed tomography revealed shrinkage of the primary lung lesion (Figure 1C), which was ultimately categorized as a partial response. The serum carcinoembryonic antigen (CEA) level had decreased markedly by this time and remained low thereafter throughout the period of tumor regression (Figure 2). Anemia of grade 3 and an aspartate aminotransferase elevation of grade 3 occurred during the first treatment cycle, but no severe adverse events were subsequently noted after the pemetrexed dose was reduced to 400 mg/m2. A total of 40 treatment cycles for pemetrexed was administered over 30 months until disease progression.

Figure 1

(A) Junction reads for CCDC6-RET fusion transcripts as determined by next-generation sequencing of tumor cDNA from the patient. (B) Fluorescence in situ hybridization analysis of tumor tissue from the patient with break-apart probes for RET (5′ probe, green; 3′ probe, red). The RET rearrangement is indicated by the presence of a single isolated red signal (arrowhead). (C) Chest computed tomography scans of the patient before, 7 weeks after, and 23 months after initiation of treatment with pemetrexed and carboplatin.

Figure 2

Time course of serum CEA level for the patient after initiation of pemetrexed treatment at time zero.

Abbreviations: CEA, carcinoembryonic antigen; PD, progressive disease.

Discussion

RET fusion genes have recently been identified in a subset of NSCLC tumors, being detected most often in patients who are never-smokers, are of a younger age, and have tumors with an adenocarcinoma histology. Multikinase inhibitors with activity against RET have shown marked clinical efficacy in NSCLC patients harboring RET fusions,3,4 but it has remained unclear whether such patients might receive benefit from cytotoxic chemotherapy. The present case shows long-term efficacy of pemetrexed for >2 years in the fifth-line setting. Preliminary data from a phase III study (PROFILE 1007) comparing crizotinib with pemetrexed or docetaxel chemotherapy after failure of one prior platinum-based chemotherapy regimen have shown that pemetrexed treatment produced a better outcome compared with docetaxel in patients with ALK fusion–positive NSCLC.6 Moreover, two retrospective studies have suggested that EML4-ALK–positive patients may have a superior progression-free survival when treated with pemetrexed-based therapies compared with patients with other molecularly defined subtypes of NSCLC.7,8 Given the importance of a low level of thymidylate synthase (TS) expression for sensitivity to pemetrexed-based regimens,9 a low TS expression level of the proband may have contributed to the long-term efficacy of pemetrexed.10 Similar to lung tumors positive for ALK rearrangement, a recent study also showed that RET fusion–positive lung cancers were sensitive to pemetrexed-based therapies, although data for TS expression were not available.11 TS-targeting agents such as pemetrexed and S-1 may thus offer promising treatment options for patients with RET fusion–positive NSCLC.

In conclusion, we report the successful long-term treatment of a RET fusion–positive NSCLC patient with pemetrexed. Given the insufficient data regarding pemetrexed sensitivity and RET fusion, further investigations are warranted to investigate these biological mechanisms.