HER3-Targeting Antibody Shrinks Tumors in EGFR-Mutated, TKI-Resistant NSCLC

By Jeff Craven /alert Contributor
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The anti-HER3 antibody drug conjugate U3-1402 appeared to decrease tumor size among patients with epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC), according to recent research from a phase 1 study presented at the ASCO 2019 Annual Meeting.

“These initial clinical data demonstrate activity with U3-1402, including early tumor shrinkage in patients who had developed resistance to approved EGFR [tyrosine kinase inhibitors (TKIs)],” Pasi A. Jänne, MD, PhD, director of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute, stated in a press release. “There is a need for new treatment approaches for EGFR mutated non-small cell lung cancer that develops resistance to TKIs, especially osimertinib, and preliminary results from this study indicate that targeting HER3 with U3-1402 is a strategy that may be effective across multiple different resistance mechanisms.”


Cancer cell. Source: Getty

Jänne and colleagues presented results of 15 patients (6 men, 9 women) who were median 63 years old with metastatic or unresectable EGFR-mutated NSCLC with T790M negative disease. Patients underwent treatment with U3-1402 over a 21-day cycle at doses of 3.2 mg/kg, 4.8 mg/kg or 6.4 mg/kg. The patients included if they were already receiving treatment with erlotinib, gefitinib, afatinib or osimertinib and experienced disease progression, with those receiving osimertinib being included regardless of the presence of T790M negative disease. There were 10 patients who had EGFR exon 19 deletion, and 5 patients with EGFR L858 mutation included in the study. Of those included, 6 patients had undergone chemotherapy prior to the trial, and 14 of 15 patients had received osimertinib as second-line therapy or later.

The researchers found 11 tumors with HER3 expression with a median membrane H-score of 188, while 5 patients discontinued treatment. At baseline, the median sum of longest diameters (SLD) was 69 mm (range 22–143 mm); 12 of 13 available patients had an SLD decrease with a median best change of −29% (range, 10% to −67%), while 2 patients had a partial response.

The most common treatment-emergent adverse events consisted of nausea (60%), vomiting (40%), fatigue (33%), reduction of appetite (27%) and alopecia (20%). One in 15 patients experienced adverse events involving nausea, hypoxia, while 2 patients experienced a decrease in platelet counts.

“U3-1402 was designed using Daiichi Sankyo’s proprietary DXd [antibody drug conjugate] technology to target and deliver chemotherapy inside cancer cells that express HER3 as a cell surface antigen,” Dalila Sellami, MD, vice president and U3-1402 Global Team Leader, Global Oncology Research and Development at Daiichi Sankyo, stated in a press release. “These findings provide evidence of promising activity of U3-1402 in non-small cell lung cancer…”