Osimertinib and RET inhibitor BLU-667 in an EGFR-mutant patient with acquired RET rearrangement

The spectrum of acquired resistance to osimertinib is not yet fully characterised. Piotrowska et al. investigated RET-specific TKI BLU-667 and osimertinib in a cohort of acquired resistance biopsies and one patient with RET-mediated acquired resistance [1]. Osimertinib is a selective, CNS-penetrant, third generation EGFR TKI approved by the FDA and EMA for front-line use [2].

BLU-667 is an investigational selective RET inhibitor with clinical activity in NSCLCs and other cancers with RET alterations [3]. The patient in this single-centre study was treated with osimertinib/BLU-667 using an IRB- and FDA-approved compassionate use protocol. Forty-one EGFR-mutant patients with acquired resistance to osimertinib were histologically assessed and screened by tissue (n=22) or plasma next-generation sequencing (n=9), or both (n=10). Fusions in plasma and/or tissue were found in 4 patients treated with osimertinib.

Tissue from one patient had co-occurrent CCDC-RET and TPM3-NTRK1 fusions in circulating tumour DNA. Tissue from the other patients showed fusions in CCDC-RET, PCB2-BRAF, and AGK-BRAF. CCDC6-RET was expressed in EGRFm NSCLC cell lines PC9 (Ex19del) and MGH 134 (L858R/T790M). These maintained MAPK signalling and conferred resistance to osimertinib and afatinib. Inhibition of RET by BLU-667 or cabozantinib resensitised cells expressing CCDC6-RET to EGFR inhibition.

A 60-year-old woman with Ex19del progressed on afatinib (T790M+), then osimertinib. Tissue biopsy at osimertinib acquired resistance found acquired CCDC6-RET (T790-wt). She started osimertinib at 80 mg/BLU-667 200 mg daily for 2 weeks, then BLU-667 at 300 mg daily. Dyspnoea improved within days of starting treatment. Scans after 8 weeks showed a marked response, with RECIST tumour shrinkage of 78% (see Figure).

Figure: Scans after 8 weeks of treatment with osimertinib/BLU-667 showed tumour shrinkage of 78%



Study outcomes indicate that RET and other oncogene fusions are a recurrent finding in EGFRm NSCLC with acquired resistance to osimertinib and other EGFR TKIs. In vitro models suggest that CCDC6-RET mediates EGFR resistance and can be inhibited by combined EGFR + RET inhibition. This is the first report of a clinical response to combined EGFR + RET inhibition in EGFRm NSCLC and acquired CCDC-RET fusion after osimertinib. At the time of presentation, osimertinib/BLU-667 appeared to be well tolerated, with only grade 1 AEs. Treatment is ongoing.