medwireNews: Second-line dacomitinib treatment is associated with a low objective response rate (ORR) among patients with EGFR-mutated non-small-cell lung cancer (NSCLC) who progress on first-line osimertinib, report US researchers.
“Given the low ORR observed among the first 12 patients in this study, the study was terminated early,” they write in JCO Precision Oncology.
The investigators explain that although the third-generation EGFR–tyrosine kinase inhibitor (TKI) osimertinib elicits robust responses on initial use, “the development of resistance is ultimately universal,” adding that in vitro research suggests “dacomitinib may be effective after disease progression on osimertinib in patients with acquired second-site EGFR mutations or human [EGFR] family–mediated resistance.”
Their single-center, phase 2 study included 12 patients who experienced disease progression after first-line treatment with osimertinib for stage IV or recurrent, EGFR mutation-positive NSCLC.
Over a median follow-up of 13.0 months, treatment with the second-generation EGFR–TKI dacomitinib at a daily dose of 45 mg achieved a partial response in two patients, equating to an ORR of 17%. The median progression-free survival duration was 1.8 months and median overall survival was not reached.
“In summary, dacomitinib had limited benefit after disease progression after initial treatment on osimertinib,” write the study authors.
Sequencing of pretreatment biopsy or plasma samples showed that one of the responding patients carried an EGFR exon 18 G719A mutation, but molecular testing was not feasible for the other responder.
None of the three patients with second-site acquired EGFR resistance mutations – C797S in two patients and G724S in one – had a response to dacomitinib.
Nine of the 11 patients with assessable pretreatment samples harbored TP53 mutations, “which are associated with shortened response to EGFR TKIs and worse prognosis in lung cancer with EGFR alterations,” say Helena Yu and colleagues from Memorial Sloan Kettering Cancer Center in New York.
Noting that the participant with the EGFR G719A mutation had an ongoing response to dacomitinib at 17 months, which exceeded the response duration of 11 months with osimertinib, the team writes: “Further investigation is needed to determine whether upfront treatment with a second-generation TKI such as dacomitinib or afatinib may be superior to osimertinib for patients with atypical EGFR alterations.”
Yu and colleagues also suggest that combination treatment with dacomitinib and osimertinib “may be a more promising strategy” in light of the heterogeneity of tumors with EGFR second-site alterations.
“A follow-up trial of dacomitinib plus osimertinib solely in patients with acquired EGFR second-site mutations after osimertinib is ongoing,” they conclude.
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JCO Precis Oncol 2021; 5: 695–700