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We characterized the SLC3A2-NRG1 fusion gene in non–small cell lung cancer (NSCLC) and established an effective therapy for patients with SLC3A2-NRG1 fusion–positive cancer. The SLC3A2-NRG1 fusion product was composed of the SLC3A2 transmembrane domain and the EGF-like domain of the neuregulin 1 (NRG1) protein. The NRG1 family is classified as a ligand of the ERBB family. We identified ERBB3 and ERBB4 in the ERBB family as binding partners of the SLC3A2-NRG1 fusion protein via ligand and receptor binding assays. We confirmed that SLC3A2-NRG1 increased formation of a heterocomplex of ERBB3 with ERBB2. Activation of the ERBB2–ERBB3 heterocomplex by SLC3A2-NRG1 increased colony formation and tumor growth through PI3K-AKT and MAP kinase. The specific siRNAs for ERBB2 and ERBB3, pertuzumab, lumretuzumab, and afatinib all decreased ERBB2–ERBB3 heterocomplex formation, phosphorylation of each protein, and their downstream signaling. In addition, single treatment with pertuzumab, lumretuzumab, or afatinib decreased tumor volume and weight, whereas combination treatment with these drugs and taxol enhanced generation of cleaved caspase 3, PARP, and TUNEL-positive cells compared with each single treatment. Thus, the SLC3A2-NRG1 fusion gene plays an important role in lung cancer cell proliferation and tumor growth by promoting generation of the ERBB2–ERBB3 heterocomplex, its phosphorylation, and activation of the PI3K/ERK/mTOR signaling pathway. Inhibition of either ERBB2 or ERBB3 alone did not completely shut down downstream signaling of ERBB2 and ERBB3; however, inhibition of both ERBB2 and ERBB3 blocked downstream signaling activated by SLC3A2-NRG1 fusion. ERBB2 and ERBB3 might be promising targets for treatment of SLC3A2-NRG1–positive tumors. Mol Cancer Ther; 17(9); 2024–33. ©2018 AACR.

Combination of targeted therapies is expected to provide superior efficacy in the treatment of cancer either by enhanced antitumor activity or by preventing or delaying the development of resistance. Common challenges in developing combination therapies include the potential of additive and aggravated toxicities associated with pharmacologically related adverse effects. We have recently reported that combination of anti-HER2 and anti-HER3 antibodies, pertuzumab and lumretuzumab, along with paclitaxel chemotherapy in metastatic breast cancer, resulted in a high incidence of diarrhea that ultimately limited further clinical development of this combination. Here, we further dissected the diarrhea profile of the various patient dose cohorts and carried out in vitro investigations in human colon cell lines and explants to decipher the contribution and the mechanism of anti-HER2/3 therapeutic antibodies to intestinal epithelium malfunction. Our clinical investigations in patients revealed that while dose reduction of lumretuzumab, omission of pertuzumab loading dose, and introduction of a prophylactic antidiarrheal treatment reduced most severe adverse events, patients still suffered from persistent diarrhea during the treatment. Our in vitro investigations showed that pertuzumab and lumretuzumab combination treatment resulted in upregulation of chloride channel activity without indication of intestinal barrier disruption. Overall, our findings provide a mechanistic rationale to explore alternative of conventional antigut motility using medication targeting chloride channel activity to mitigate diarrhea of HER combination therapies. Mol Cancer Ther; 17(7); 1464–74. ©2018 AACR.

This study aimed at evaluating if pharmacokinetic and pharmacodynamic data from the first few patients treated with an investigational monoclonal antibody in a dose-escalation study can be used to guide the early initiation of potentially more efficacious combination regimens. Emerging pharmacokinetic and pharmacodynamic data from the first nine patients treated with lumretuzumab (a glycoengineered anti-HER3 monoclonal antibody) monotherapy at doses from 100 to 400 mg q2w were used along with a pharmacokinetic model that incorporated target-mediated drug disposition to guide the selection of the starting dose for use in combination regimens. The dose-escalation study investigated lumretuzumab doses up to 2000 mg q2w and a maximum tolerated dose was not reached. However, the model described in this report predicted linear lumretuzumab pharmacokinetics and >95% target saturation at doses ≥400 mg q2w. These data, along with safety data, contributed to the decision to begin dose-escalation studies in combination with cetuximab and erlotinib using a starting dose of 400 mg lumretuzumab. Pharmacokinetic data from patients treated with lumretuzumab 400–2000 mg q2w in combination regimens were consistent with the model predictions. PK/PD modelling of emerging clinical data might accelerate development programs by enabling additional parts of a trial to commence before completion of the monotherapy part. The dose and schedule of lumretuzumab were optimised for concomitant therapy at doses substantially below the highest dose investigated.

Background: Inhibition of HER2 and HER3 heterodimerisation is a novel treatment concept in HER2-”low” expressing breast cancer (BC). Lumretuzumab, a glycoengineered monoclonal anti-HER3 antibody, in combination with pertuzumab has demonstrated synergistic anti-tumor activity in preclinical HER2–low expressing preclinical BC models. Methods: This open-label, multicenter phase I study selectively enrolled metastatic BC patients (pts) expressing HER3 protein and low levels of HER2 (defined as IHC 1+ and 2+ and ISH-negative) in a formalin-fixed paraffin-embedded pretreatment tumor biopsy sample. Eligible pts were treated with a combination of paclitaxel (PA) qw plus lumretuzumab (L) and pertuzumab (P) q3w in three dose cohorts. The safety, antitumor activity and tumor biomarkers including protein expression (IHC, MS) and mutational data (NGS) in association with clinical activity were evaluated. Results: Overall, 35 pts were included in this study. The median age was 60 (range: 33 to 77) years. The median number of prior treatments for metastatic disease ranged from 0 to 5 with 23 pts (65.7%) without prior chemotherapy for metastatic disease. Cohort 1 was treated with PA at 80 mg/m2, L at 1000 mg and P at 840 mg for Cycle 1 followed by 420 mg for the following cycles. This cohort was stopped after two pts both experienced grade 3 diarrhea within the first treatment cycle which was considered a dose-limiting toxicity (DLT). For Cohort 2 the dose of L was reduced to 500 mg based on PK modelling and simulation data. No DLTs were seen for the first 6 pts. A total of 20 pts were recruited with an objective response rate (ORR) and disease control rate (DCR) of 30% and 75%, respectively, and 56% and 78%, respectively, for 1st-line pts (n=9) in this cohort. Diarrhea (≥G3) and hypokalemia (≥G3) occurred in 50% and 55% of pts, respectively, and all pts experienced chronic diarrhea throughout the course of treatment. For Cohort 3 the dose of L was maintained at 500 mg, PA at 80 mg/m2, and P was administered at 420 mg at all cycles. In addition, a prophylactic loperamide regimen was introduced. Altogether, 13 pts - all 1st-line for metastatic disease - were treated. No DLTs were seen for the first 6 pts. Diarrhea (≥G3) and hypokalemia (≥G3) were reduced to 31% and 15%, respectively, but chronic diarrhea was still observed throughout the treatment in all pts. The ORR and DCR were 31% and 77%, respectively. Preliminary mechanistic safety experiments revealed HER2/HER3-dependent chloride channels in the intestine as likely cause of diarrhea. Biomarker data will be presented along with updated clinical and safety data. Conclusions: The combination of L, P and PA was associated with high rates of persistent diarrhea. Dose modifications and prophylactic anti-diarrheal medication led to significantly reduced diarrhea intensity but did not change the incidence and persistence of diarrhea overall. Despite encouraging clinical activity especially in 1st line pts, the therapeutic window of this combination is too low to warrant further clinical development. Citation Format: Schneeweiss A, Park-Simon T-W, Albanell J, Lassen U, Cortes J, Dieras V, May M, Schindler C, Marmé F, Cejalvo JM, Martinez-Garcia M, Gonzalez I, Lopez-Martin J, Welt A, Joly F, Michielin F, Jacob W, Adessi C, Moisan A, Meneses-Lorente G, James I, Ceppi M, Hasmann M, Weisser M, Cervantes A. Phase Ib study evaluating the safety and clinical activity of lumretuzumab combined with pertuzumab and paclitaxel in HER2-low metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-11-13.

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.

Rearrangements of NRG1 have been identified in invasive mucinous adenocarcinoma of the lung (IMA), formerly referred to as mucinous bronchioloalveolar carcinoma. NRG1 ligand signals through induction of HER2-HER3 heterodimers, thus leading to PI3K-AKT pathway activation. Therefore, targeting HER2, HER3 and the downstream pathway may be a hypothesis-driven strategy for IMA with NRG1 fusion. Herein we reported two patients who benefited from lumretuzumab, a monoclonal anti-HER3 antibody, in combination of erlotinib during a clinical trial (NCT01482377). At least sixteen weeks of progression-free survival were achieved without any unacceptable toxicity.

To inform lumretuzumab and pertuzumab dose modifications in order to decrease the incidence, severity, and duration of the diarrhea events in metastatic breast cancer patients treated with a combination therapy of lumretuzumab (anti-HER3) in combination with pertuzumab (anti-HER2) and paclitaxel using quantitative clinical pharmacology modeling approaches. The safety and pharmacokinetic (PK) data from three clinical trials (lumretuzumab monotherapy n = 47, pertuzumab monotherapy n = 78, and the combination therapy of lumretuzumab, pertuzumab and paclitaxel n = 35) were pooled together to develop a continuous-time discrete states Markov model describing the dynamics of the diarrhea events. The model was able to capture the time course of different severities of diarrhea reasonably well. The effect of lumretuzumab and pertuzumab was well described by an Emax function indicating an increased rate of transition from moderate to mild or more severe diarrhea with higher doses. The concentration needed to trigger or worsen diarrhea episodes was estimated to be 120-fold lower in combination therapy compared to monotherapy, suggesting strong synergy between the two monoclonal antibodies. The prophylactic effect of loperamide in a subset of patients was also well captured by the model with a clear tendency to reduce the occurrence of diarrhea events. This work shows that PK-toxicity modeling provides insight into how the severity of key adverse events evolves over time and highlights the potential use to support decision making in drug development.

Summary Purpose To investigate the safety and clinical activity of comprehensive human epidermal growth factor receptor (HER) family receptor inhibition using lumretuzumab (anti-HER3) and pertuzumab (anti-HER2) in combination with paclitaxel in patients with metastatic breast cancer (MBC). Methods This phase Ib study enrolled 35 MBC patients (first line or higher) with HER3-positive and HER2-low (immunohistochemistry 1+ to 2+ and in-situ hybridization negative) tumors. Patients received lumretuzumab (1000 mg in Cohort 1; 500 mg in Cohorts 2 and 3) plus pertuzumab (840 mg loading dose [LD] followed by 420 mg in Cohorts 1 and 2; 420 mg without LD in Cohort 3) every 3 weeks, plus paclitaxel (80 mg/m2 weekly in all cohorts). Patients in Cohort 3 received prophylactic loperamide treatment. Results Diarrhea grade 3 was a dose-limiting toxicity of Cohort 1 defining the maximum tolerated dose of lumretuzumab when given in combination with pertuzumab and paclitaxel at 500 mg every three weeks. Grade 3 diarrhea decreased from 50% (Cohort 2) to 30.8% (Cohort 3) with prophylactic loperamide administration and omission of the pertuzumab LD, nonetheless, all patients still experienced diarrhea. In first-line MBC patients, the objective response rate in Cohorts 2 and 3 was 55% and 38.5%, respectively. No relationship between HER2 and HER3 expression or somatic mutations and clinical response was observed. Conclusions Combination treatment with lumretuzumab, pertuzumab and paclitaxel was associated with a high incidence of diarrhea. Despite the efforts to alter dosing, the therapeutic window remained too narrow to warrant further clinical development. Trial registration: on ClinicalTrials.gov with the identifier NCT01918254 first registered on 3rd July 2013.

Purpose: This study investigated the safety, clinical activity, and target-associated biomarkers of lumretuzumab, a humanized, glycoengineered, anti-HER3 monoclonal antibody (mAb), in combination with the EGFR-blocking agents erlotinib or cetuximab in patients with advanced HER3-positive carcinomas.Experimental Design: The study included two parts: dose escalation and dose extension phases with lumretuzumab in combination with either cetuximab or erlotinib, respectively. In both parts, patients received lumretuzumab doses from 400 to 2,000 mg plus cetuximab or erlotinib according to standard posology, respectively. The effect of HRG mRNA and HER3 mRNA and protein expression were investigated in a dedicated extension cohort of squamous non–small cell lung cancer (sqNSCLC) patients treated with lumretuzumab and erlotinib.Results: Altogether, 120 patients were treated. One dose-limiting toxicity (DLT) in the cetuximab part and two DLTs in the erlotinib part were reported. The most frequent adverse events were gastrointestinal and skin toxicities, which were manageable. The objective response rate (ORR) was 6.1% in the cetuximab part and 4.2% in the erlotinib part. In the sqNSCLC extension cohort of the erlotinib part, higher tumor HRG and HER3 mRNA levels were associated with a numerically higher disease control rate but not ORR.Conclusions: The toxicity profile of lumretuzumab in combination with cetuximab and erlotinib was manageable, but only modest clinical activity was observed across tumor types. In the sqNSCLC cohort, there was no evidence of meaningful clinical benefit despite enriching for tumors with higher HRG mRNA expression levels. Clin Cancer Res; 23(18); 5406–15. ©2017 AACR.

Bidirectional cross talk between members of the human epidermal growth factor family of receptors (HER) and the estrogen receptor (ER) is believed to underlie resistance mechanisms that develop in response to treatment with anti-HER agents and endocrine therapy. We investigated the interaction between HER2, HER3 and the ER in vitro using human embryonic kidney cells transfected with human HER2, HER3, and ERα. We also investigated the additive efficacy of combination regimens consisting of anti-HER3 (lumretuzumab), anti-HER2 (pertuzumab), and endocrine (fulvestrant) therapy in vivo. Our data show that both HER2 and HER3 can directly complex with the ER and can mediate phosphorylation of the ER. Phosphorylation of the ER was only observed in cells that expressed both HER2 and ERα or in heregulin-stimulated cells that expressed both HER3 and ERα. Using a mouse xenograft model of ER+/HER2-low (HER2 immunohistochemistry 1+ or 2+ without gene amplification) human breast cancer we show that the combination of lumretuzumab and pertuzumab is highly efficacious and induces long-lasting tumor regression in vivo and adding endocrine therapy (fulvestrant) to this combination further improved efficacy. In addition, a prolonged clinical response was observed with the combination of lumretuzumab and pertuzumab in a patient with ER+/HER2-low breast cancer who had failed endocrine therapy. These preclinical data confirm that direct cross talk exists between HER2/HER3 and ER which may explain the resistance mechanisms to endocrine therapy and monoclonal antibodies that target HER2 and HER3. Our data also indicate that the triplet of anti-HER2, anti-HER3, and endocrine therapy might be an efficacious combination for treating patients with ER+/HER2-low breast cancer, which is an area of significant unmet medical need.

UNLABELLED Emerging evidence suggests that human epidermal growth factor receptor 3 plays a critical role in cell-survival and drug-resistance in cancer cells. Several kinds of agents targeting this receptor are currently progressing through preclinical or clinical investigations. These agents are usually monoclonal antibodies with unique characteristics, and some have shown efficacy and been welltolerated in clinical trials. For example, patritumab and seribantumab are thought to compete with ligand binding and have proven efficacy for some malignancies in Phase II clinical trials. LJM716 locks the human epidermal growth factor receptor 3 in the inactive conformation in both ligand-dependent and - independent cancers. Lumretuzumab is a glycoengineered antibody, which enhances antibody-dependent cell-mediated cytotoxicity. Duligotumab is an antibody that targets both the human epidermal growth factor receptors 1 and 3. Heregulin is a human epidermal growth factor receptor 3 ligand that represents an encouraging candidate biomarker for the prediction of the efficacy of agents targeting this receptor. CONCLUSION A number of antibodies that interact with human epidermal growth factor receptors have been evaluated for clinical use. Ongoing clinical trials will address the remaining issues related to optimization of drug combination therapy and improving the targeting of each agent to the most appropriate individuals.

Purpose: A first-in-human phase I study was conducted to characterize safety, efficacy, and pharmacokinetic (PK) and pharmacodynamic (PD) properties of lumretuzumab, a humanized and glycoengineered anti-HER3 monoclonal antibody, in patients with advanced cancer. Experimental Design: Twenty-five patients with histologically confirmed HER3-expressing tumors received lumretuzumab (100, 200, 400, 800, 1,600, and 2,000 mg) every two weeks (q2w) in 3+3 dose-escalation phase. In addition, 22 patients were enrolled into an extension cohort at 2,000 mg q2w. Results: There were no dose-limiting toxicities. Common adverse events (any grade) included diarrhea (22 patients, 46.8%), fatigue (21 patients, 44.7%), decreased appetite (15 patients, 31.9%), infusion-related reactions (13 patients, 27.7%), and constipation (10 patients, 21.3%). The peak concentration (Cmax) and area under the concentration–time curve up to the last measurable concentration (AUClast) of lumretuzumab increased more than dose proportionally from 100 mg up to 400 mg. Linear PK was observed with doses ≥400 mg q2w indicating target-mediated drug disposition saturation. Downregulation of HER3 membranous protein was observed in on-treatment tumor biopsies from 200 mg, and was maximal at and above 400 mg. An ex vivo assay demonstrated increased activation potential of peripheral NK lymphocytes with lumretuzumab compared with a non-glycoengineered anti-HER3 antibody. Ten patients (21.3%) had stable disease and remained on study at a median of 111 days (range, 80–225 days). Conclusions: Lumretuzumab was well tolerated and showed evidence of clinical activity. Linear serum PK properties and plateauing of PD effects in serial tumor biopsies indicate optimal biologically active doses of lumretuzumab from 400 mg onwards. Clin Cancer Res; 22(4); 877–85. ©2015 AACR.

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.

11555Background: Lumretuzumab is a humanized, glycoengineered, monoclonal antibody targeting human epidermal growth factor receptor 3 (HER3), in phase Ib clinical development in patients with HER3-...