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

WCLC 2018

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-RETPCB2-BRAF, and AGK-BRAFCCDC6-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%

WCLC 2018: Figure 12 Scans after 8 weeks of treatment

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.

  1. Piotrowska Z et al. Cancer Discov 2018 Sep 2 [Epub ahead of print]

  2. Soria JC, Ohe Y, Vansteenkiste J, et al. N Engl J Med 2018;378:113-125.

  3. Subbiah V, Gainor JF, Rahal R, et al. Cancer Discov 2018;8:836-849.

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