Response to Pralsetinib Observed in Meningeal-Metastatic EGFR-Mutant NSCLC With Acquired RET Fusion: A Brief Report

Moving the Needle Cautiously in Targeting One of the Most Often Acquired Receptor Tyrosine Fusion (RET Fusion) Resistance Mechanisms to EGFR Tyrosine Kinase Inhibitors

“…Another patient (our patient) who was eventually dose escalated to osimertinib (80 mg daily) plus pralsetinib (400 mg daily at 100 mg increment starting at 200 mg once daily) had to be dose reduced back to pralsetinib 200 mg once daily and osimertinib (80 mg once daily) due to leukopenia and grade 1 pneumonitis but who enjoyed a durable response of more than 2 years. Thus, we do not recommend immediately starting both osimertinib and pralsetinib at a full dose as Zhao et al 10 have done.…”

“…In fact, as proof of principle, the combination of pralsetinib with osimertinib has been reported in two patients with EGFRþ NSCLC to overcome acquired RET fusion (CCDC6-RET and NCOA4-RET, respectively) as resistance to EGFR TKIs. 9 In the June, 2022 issue of JTO Clinical and Research Reports, Zhao et al 10 reported a similar case report of CCDC6-RET fusion arising as an acquired resistance to dacomitinib as the most immediate EGFR TKI in an EGFRþ L858R/ V834L. Missing in their report is the allele frequency of the EGFR L858R and V834L mutations to let the readers know whether V834L is in the same tumor clone as L858R or is a minor separate clone.…”

“…From the package insert, the unbound plasma fraction of pralsetinib is 2.9% (97.1% protein binding), 11 and the calculated unbound CSF-to-plasma ratio of the patient is 0.27. Although the CSF and plasma pharmacokinetic levels drawn were in combination with osimertinib, important missing information is whether osimertinib had any effect on the pralsetinib dose level and vice versa as Zhao et al 10…”

“… 9 In the June, 2022 issue of JTO Clinical and Research Reports, Zhao et al. 10 reported a similar case report of CCDC6-RET fusion arising as an acquired resistance to dacomitinib as the most immediate EGFR TKI in an EGFR+ L858R/V834L. Missing in their report is the allele frequency of the EGFR L858R and V834L mutations to let the readers know whether V834L is in the same tumor clone as L858R or is a minor separate clone.…”

“…Nevertheless, Zhao et al. 10 reported that this combination was able to symptomatically treat leptomeningeal carcinomatosis. Without cytology from lumbar puncture to evaluate the molecular profile of the tumor cells in the cerebrospinal fluid (CSF), however, it is impossible to pinpoint whether switching to osimertinib alone or the combination with pralsetinib led to the symptomatic improvement from the leptomeningeal carcinomatosis.…”