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Purpose This study investigated the safety and clinical activity of lumretuzumab, a humanised antihuman epidermal growth factor receptor 3 (HER3) monoclonal antibody, in combination with carboplatin and paclitaxel in first-line treatment of patients with squamous non-small cell lung cancer (sqNSCLC). HER3 ligand heregulin and HER3 protein expression were evaluated as potential biomarkers of clinical activity. Patients and methods This open-label, phase Ib/II study enrolled patients receiving lumretuzumab at 800 mg (flat) in combination with carboplatin (area under the curve (AUC) 6 mg/mL×min) and paclitaxel (200 mg/m 2) administered intravenously on a every 3-week schedule. Adverse event (AE) rates and tumour responses were determined. Heregulin messenger RNA (mRNA) and HER3 protein expression were investigated in archival tumour biopsies. Results Altogether, 12 patients received lumretuzumab in combination with carboplatin and paclitaxel. The most frequent AEs were gastrointestinal, haematological and nervous system toxicities, which were generally mild and manageable. Partial responses were observed in 3 of 12 patients lasting 81, 177 and 207 days. All responses were achieved in tumours expressing higher heregulin mRNA levels. Conclusion Lumretuzumab in combination with carboplatin and paclitaxel was well tolerated. Objective responses were enriched in tumours expressing higher heregulin mRNA levels.

Introduction ERBB family of receptors tirosine kinases (RTK) are potent drivers of tumorogenesis and metastasis. In breast tumours, 70%–80% of patients, although clinically not classified as HER2 positive, show low or moderate expression of HER2 along with EGFR and ERBB3. Concomitant blockade with specific monoclonal antibodies based on proteomic profile determined by Reverse Phase Protein Array (RPPA), appears as a beneficial approach to improve treatment strategies. Material and methods Cancer cells lines from different breast cancer subtypes were selected based on their ERBB expression levels. Cell number was quantified upon exposure to different ligands (HRG1β, EGF, AREG, TGF) and to combinations of monoclonal antibodies targeting EGFR, ERBB2 and ERBB3 (cetuximab, trastuzumab/pertuzumab and lumretuzumab respectively). Using RPPA and over 100 specific antibodies, abundance and phosphorylation states of downstream signalling molecules in an extended MAPK/AKT network were quantified. Results and discussions Short time stimulation with ERBB ligands, allowed to determine phosphorylation state of the ERBB receptors and their immediate downstream signalling effectors in different cell lines, and thus, to elucidate which combination therapy would be more effective in reverting such activation. For luminal A cell lines T47D and MCF7, stimulation with HRG1β led to a high phosphorylation levels of ERBB3 in both cell lines, but not for ERBB2, with higher phosphorylation in the T47D cell line. Proteomic activation profiles correlated with efficacy of inhibition after combination treatment with pertuzumab/lumretuzumab. For the triple negative cell lines MDA-MB468 and MDA-MB231, response to ligands stimulation did not identify a common activation pattern and thus only blockade of EGFR receptor showed minimal effects in MDA-MB468. Phosphorylation status of downstream signalling effectors in the AKT/MAPK network may help to identify putative targets responsible for incomplete unresponsiveness to ERBB blockade. Conclusion Targeting ERBB members in a HER2 moderate/low scenario seems to be a promising approach when combining targeted therapies. Phenotypic characterisation together with mathematical modelling based on the proteomic activation profile, aroused as a way to better predict response to drug combinations. Better characterisation of ERBB network activation profile in different tumour cell lines and in further tumour tissues, should help to pave the way to improve personalization treatment in HER2 low breast cancers.