A phase Ib study of lumretuzumab, a glycoengineered monoclonal antibody targeting HER3, in combination with carboplatin and paclitaxel as 1st-line treatment in patients with squamous non-small cell lung cancer

Preclinical data suggest that high mRNA expression levels of heregulin (HRG) could predict anti-tumor activity of lumretuzumab, an anti-HER3 antibody. HRG mRNA is more highly expressed in squamous (sq)NSCLC compared to non-sqNSCLC. This was an open-label, multicenter phase Ib study in patients (pts) with advanced or metastatic sqNSCLC who have not received prior chemotherapy or targeted therapy for NSCLC. Lumretuzumab (800 mg) was administered in combination with carboplatin (AUC 6 mg/mL x min) and paclitaxel (200 mg/m2) on a q3w schedule. The primary objectives were to evaluate safety and efficacy and an exploratory objective was to correlate tumor HRG mRNA expression to clinical activity. HRG mRNA expression levels were assessed by RT-PCR in archival formalin-fixed paraffin-embedded tumor samples. To distinguish high vs low HRG gene expression levels, the median gene expression level of sqNSCLC tumor samples from an internal tumor bank (n = 150) was used as an exploratory cut-off. Twelve pts were enrolled (median age 66.5 years, 10 pts male). The most frequently reported adverse events (AEs) (in >2 pts) were diarrhea (9 pts), asthenia (8 pts), neurotoxicity (5 pts), nausea and infusion-related reaction (4 pts each). Grade ≥3 AEs were only reported for single pts except for anemia which was reported for two pts. Overall, three pts achieved a partial response (25%) and 8 pts achieved stable disease (67%). High HRG mRNA expression levels were found in 7 pts (58%). All three responding pts showed high HRG mRNA expression levels. The duration of responses were 2.8, 6.0, and 6.2 months. Lumretuzumab in combination with carboplatin and paclitaxel was safe and well tolerated. While all 3 responding pts had tumors with high HRG mRNA expression levels, the addition of lumretuzumab to platinum-based therapy was not associated with a clear signal of higher clinical activity than what would have been expected with platinum-based therapy alone.