Concurrent osimertinib–gefitinib feasible in advanced EGFR-mutated NSCLC
medwireNews: Combining osimertinib with gefitinib has promising efficacy and tolerability in treatment-naïve patients with metastatic EGFR-mutated non-small-cell lung cancer (NSCLC), suggest early data presented at the virtual 2020 ASCO Annual Meeting.
Julia Rotow (Dana-Farber Cancer Institute, Boston, Massachusetts, USA) explained that “[t]he predominant second-site EGFR resistance mutations are distinct between osimertinib and gefitinib.”
She added that combination treatment has been shown to delay acquisition of these mutations in preclinical models and therefore may assist in “prolonging treatment response and improving patient outcomes to therapy” in the clinical setting.
The dose-escalation stage of the phase 1/2 study, which comprised individuals with stage IV NSCLC positive for the EGFR exon 19 deletion (59%) or exon 21 L858R (41%) mutation, established daily osimertinib 80 mg plus gefitinib 250 mg as the maximum tolerated dose subsequently used in the dose-expansion stage.
Rotow reported that treatment with the combination led to a best objective response rate of 88.9% among the 27 participants with evaluable data (median age 60 years, 63% female), which she said is “comparable to those reported for first-line use of osimertinib.”
All responses were partial and the remaining 11.1% of patients had stable disease, giving a disease control rate of 100%.
Rotow described the combination as “feasible” with 81.5% of participants receiving the EGFR–tyrosine kinase inhibitors (TKI) for at least 6 months, with one patient stopping osimertinib and eight discontinuing gefitinib due to toxicity.
The toxicity profile was “consistent” with that of EGFR–TKI monotherapy, said Rotow, with 29.6% experiencing a grade 3 treatment-related (TRAE), most frequently diarrhea (11.1%) and increased alanine aminotransferase levels (7.4%).
There were no grade 4 or 5 TRAEs and no cases of pneumonitis attributable to treatment.
Serial analysis of cell-free DNA showed plasma EGFR mutations in 65% of patients at baseline, but after 2 weeks of combination therapy, 88% of these patients had no detectable mutations.
And of note, nine patients had a progression event over a median 15.3 months of follow-up; none of the seven with next-generation sequencing data available had acquired second-site pathogenic EGFR mutations.
Therefore, Rotow concluded that “combination therapy resulted in rapid and near-universal clearance of the mutant EGFR allele from the plasma,” and was both “feasible and tolerable.”
But, she added that study enrollment was ongoing, and “analysis of progression-free and overall survival outcomes is pending full data maturity and will facilitate understanding of the clinical utility of first-line dual EGFR–TKI therapy.”
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