HER3-targeted antibody–drug conjugate shows promise for TKI-resistant NSCLC
medwireNews: Early results suggest that a novel antibody–drug conjugate directed against HER3 has antitumor activity and manageable safety in patients with EGFR-mutated metastatic non-small-cell lung cancer (NSCLC) and acquired resistance to EGFR–tyrosine kinase inhibitors (TKIs).
Data from the dose-escalation part of the phase I trial of U3-1402 were presented at the 2019 ASCO Annual Meeting by Pasi Jänne, from Dana-Farber Cancer Institute in Boston, Massachusetts, USA.
He told the audience in Chicago, Illinois, USA, that multiple EGFR–TKI resistance mechanisms have been identified and “developing therapies to combat all individual resistance mechanisms is likely impractical, if not impossible.”
Jänne explained that HER3, an EGFR family member, is expressed in the majority of EGFR-mutated lung cancers, and therefore “we wished to explore whether targeting HER3 with an antibody–drug conjugate may be an alternative strategy to overcome resistance.”
Their phase I trial enrolled individuals who had developed resistance to erlotinib, gefitinib, or afatinib – but were negative for the EGFR T790M mutation – or had progressed on osimertinib. A total of 23 participants received the antibody–drug conjugate U3-1402 every 3 weeks at a dose of 3.2, 4.8, 5.6, or 6.4 mg/kg, and were followed up for a median of 4.2 months.
All but one patient experienced a drug-related treatment-emergent adverse event (TEAE), but just three participants had a serious TEAE related to the study drug. One person discontinued due to a TEAE, but there were no deaths attributed to a TEAE.
Dose-limiting toxicities occurred in three (grade 4 thrombocytopenia in each case) of the five patients who received the 6.4 mg/kg dose, and one patient given the 5.6 mg/kg dose experienced two dose-limiting toxicities (grade 3 febrile neutropenia and grade 4 thrombocytopenia).
Nausea was the most common TEAE of any grade, while thrombocytopenia was the most frequent TEAE of grade 3 or worse.
All 16 patients who were evaluated for response at data cutoff had “some degree of tumor shrinkage,” noted Jänne, with four having a confirmed partial response to date.
Of note, the antitumor activity of the agent was observed in patients with diverse mechanisms of EGFR–TKI resistance, such as the known osimertinib resistance EGFR C797S mutation and HER2 and CDK4 amplifications.
And at data cutoff, 16 of the 23 trial participants were continuing treatment.
In light of these results, Jänne concluded that “targeting HER3 with U3-1402 may be a practical approach to treat EGFR-mutant NSCLC with diverse mechanisms of resistance to EGFR TKIs.”
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