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A Phase Ib/II Study of HER3-Targeting Lumretuzumab in Combination

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A Phase Ib/II Study of HER3-Targeting Lumretuzumab in Combination A phase Ib/II study of HER3-targeting lumretuzumab in combination with carboplatin and paclitaxel as first-line treatment in patients with advanced or metastatic squamous non-small cell lung cancer Cejalvo, Juan Miguel; Jacob, Wolfgang; Fleitas Kanonnikoff, Tania; Felip, Enriqueta; Navarro Mendivil, Alejandro; Martinez Garcia, Maria; Taus Garcia, Alvaro; Leighl, Natasha; Lassen, Ulrik; Mau-Soerensen, Morten; Adessi, Celine; Michielin, Francesca; James, Ian; Ceppi, Maurizio; Hasmann, Max; Weisser, Martin; Cervantes, Andrés Published in: ESMO Open DOI: 10.1136/esmoopen-2019-000532 Publication date: 2019 Document version Publisher's PDF, also known as Version of record Document license: CC BY-NC Citation for published version (APA): Cejalvo, J. M., Jacob, W., Fleitas Kanonnikoff, T., Felip, E., Navarro Mendivil, A., Martinez Garcia, M., Taus Garcia, A., Leighl, N., Lassen, U., Mau-Soerensen, M., Adessi, C., Michielin, F., James, I., Ceppi, M., Hasmann, M., Weisser, M., & Cervantes, A. (2019). A phase Ib/II study of HER3-targeting lumretuzumab in combination with carboplatin and paclitaxel as first-line treatment in patients with advanced or metastatic squamous non- small cell lung cancer. ESMO Open, 4(4), [e000532]. https://doi.org/10.1136/esmoopen-2019-000532 Download date: 30. sep.. 2021 Open access Original research ESMO Open: first published as 10.1136/esmoopen-2019-000532 on 22 July 2019. Downloaded from A phase Ib/II study of HER3-targeting lumretuzumab in combination with carboplatin and paclitaxel as first-line treatment in patients with advanced or metastatic squamous non-small cell lung cancer Juan-Miguel Cejalvo,1 Wolfgang Jacob, 2 Tania Fleitas Kanonnikoff,1 Enriqueta Felip,3 Alejandro Navarro Mendivil,3 Maria Martinez Garcia, 4 Alvaro Taus Garcia,4 Natasha Leighl,5 Ulrik Lassen,6 Morten Mau-Soerensen,6 Celine Adessi,7 Francesca Michielin,7 Ian James,8 Maurizio Ceppi,7 Max Hasmann,2 Martin Weisser,2 Andrés Cervantes 1 To cite: Cejalvo J-M, Jacob W, ABSTRACT Key questions Fleitas Kanonnikoff T, et al. Purpose This study investigated the safety and clinical A phase Ib/II study of HER3- activity of lumretuzumab, a humanised antihuman targeting lumretuzumab in What is already known about this subject? Protected by copyright. epidermal growth factor receptor 3 (HER3) monoclonal combination with carboplatin Human epidermal growth factor receptor 3 (HER3) is antibody, in combination with carboplatin and paclitaxel ► and paclitaxel as first-line associated with tumour development and poor clini- in first-line treatment of patients with squamous non- treatment in patients with cal prognosis in different cancers. advanced or metastatic small cell lung cancer (sqNSCLC). HER3 ligand heregulin ► HER3 ligand heregulin may serve as a response pre- squamous non-small cell and HER3 protein expression were evaluated as potential diction marker for HER3-targeting therapy. lung cancer. ESMO Open biomarkers of clinical activity. Heregulin expression levels are higher and more 2019;4:e000532. doi:10.1136/ Patients and methods This open-label, phase Ib/II study ► esmoopen-2019-000532 frequent in squamous non-small cell lung cancer enrolled patients receiving lumretuzumab at 800 mg (sqNSCLC). http://esmoopen.bmj.com/ (flat) in combination with carboplatin (area under the curve (AUC) 6 mg/mL×min) and paclitaxel (200 mg/m2) J-MC and WJ contributed What does this study add? equally. administered intravenously on a every 3-week schedule. ► HER3-targeting lumretuzumab in combination with Adverse event (AE) rates and tumour responses were carboplatin and paclitaxel was well tolerated. Annals of Oncology, Volume 27, determined. Heregulin messenger RNA (mRNA) and HER3 ► High heregulin expression levels enriched for pa- Issue suppl_6, 1 October 2016, protein expression were investigated in archival tumour tients more likely to show a clinical response. 372P. biopsies. ► Clinically meaningful contribution to efficacy by lum- Results Altogether, 12 patients received lumretuzumab retuzumab could not be demonstrated as compared Received 25 April 2019 in combination with carboplatin and paclitaxel. The most with chemotherapy and immunotherapy. Revised 27 May 2019 frequent AEs were gastrointestinal, haematological and on May 7, 2020 at Kobenhavns Universitets Bibliotek. Accepted 29 May 2019 nervous system toxicities, which were generally mild and How might this impact on clinical practice? manageable. Partial responses were observed in 3 of 12 ► HER3-targeting therapy may not add meaningful patients lasting 81, 177 and 207 days. All responses were clinical benefit as to what has been shown for plati- © Author (s) (or their achieved in tumours expressing higher heregulin mRNA num-containing treatment regimens in the first-line employer(s)) 2019. Re-use levels. treatment setting of sqNSCLC. permitted under CC BY-NC. No Conclusion Lumretuzumab in combination with commercial re-use. Published carboplatin and paclitaxel was well tolerated. Objective by BMJ on behalf of the responses were enriched in tumours expressing higher 30% of NSCLC are squamous (sqNSCLC) European Society for Medical Oncology. heregulin mRNA levels. cell carcinomas. Approximately 80% of lung cancer cases are diagnosed at stages III and For numbered affiliations see 2 end of article. INTRODUCTION IV. Lung cancer is one of the most frequent types Until the advent of cancer immuno- Correspondence to of cancer worldwide both in terms of cases therapy, that is, checkpoint inhibition, plat- Dr Wolfgang Jacob, Roche (2.1 million cases, 11.6% of total) and deaths inum-based combination chemotherapy was Innovation Center Munich, 1 Roche Diagnostics GmbH, (1.8 million deaths, 18.4%). Among lung the standard of care in patients with newly 3 Penzberg, Germany; wolfgang. cancer subtypes, non-small cell lung cancer diagnosed advanced/metastatic sqNSCLC. jacob@ roche. com (NSCLC) is the most prevalent and about Targeted agents such as epidermal growth Cejalvo J-M, et al. ESMO Open 2019;4:e000532. doi:10.1136/esmoopen-2019-000532 1 Open access ESMO Open: first published as 10.1136/esmoopen-2019-000532 on 22 July 2019. Downloaded from factor receptor (EGFR) inhibitors and anaplastic METHODS lymphoma kinase (ALK) inhibitors have shown clin- Study design ical efficacy in molecular subgroups such as EGFR-mu- The study reported here was a phase Ib/II, open-label, tant and ALK-rearranged NSCLC particularly of the non-randomised, multicentre study ( ClinicalTrials. gov non-squamous subtype4–6 but less so for all-comers Identifier: NCT02204345) of lumretuzumab in combina- treated with cetuximab, cisplatin and vinorelbine7 or tion with paclitaxel and carboplatin in patients with meta- for patients with sqNSCLC treated with necitumumab, static or advanced sqNSCLC. The primary objectives of gemcitabine and cisplatin.8 In the meantime, phase the study were to evaluate the safety and tolerability of III studies have established antiprogrammed cell- lumretuzumab in combination with carboplatin and pacl- itaxel and to estimate the efficacy of the combination, as death protein 1 (ligand) (PD-(L)1) compounds as the measured by the objective response rate (ORR, defined as new standard of care in both sqNSCLC and non-squa- complete response (CR) rate+partial response (PR) rate). mous NSCLC. Pembrolizumab monotherapy has been As previously shown, pharmacokinetics of lumretu- approved as first-line therapy for patients with high 9 zumab was linear from ≥400 mg per patient, indica- PD-L1 expression (≥50%) and for non-squamous tive of saturated target-mediated drug disposition, and histology in combination with platinum and peme- maximum pharmacodynamic activity was reached in 10 trexed and also for squamous histology in combination monotherapy ≥400 mg 14. Therefore, a dose of 800 mg with carboplatin together with paclitaxel or nab-pacli- was defined as a fixed dose of lumretuzumab in this study. taxel11 independently of PD-L1 expression. Ethics HER3 is a key dimerisation partner of HER family All patients provided written informed consent. The study members which activates several signal transduction path- was conducted in accordance with Good Clinical Practice ways, particularly the phosphoinositide-3-kinase (PI3K)/ guidelines and the Declaration of Helsinki in five centres Akt pathway and is associated with tumour develop- in Spain, Canada and Denmark. ment and poor clinical prognosis in different cancers.12 Patients Lumretuzumab is a humanised, glycoengineered immu- Protected by copyright. Patients had a histologically confirmed diagnosis of noglobulin G1 antibody which binds with high affinity 22 and specificity to the extracellular domain of HER3. advanced or metastatic (stage IIIb or IV ) sqNSCLC. Prevention of the ligand heregulin binding to HER3 by Patients had not received prior chemotherapy or targeted therapy for NSCLC. Eligible patients were ≥18 years lumretuzumab resulted in almost complete inhibition of of age, had an Eastern Cooperative Oncology Group HER3 heterodimerisation and phosphorylation as well (ECOG) performance status of 0–1 and had adequate as inhibition of tumour growth in cell-line-based mouse haematology, blood chemistry and renal and liver func- models.13 In a phase I study, the safety of lumretuzumab tion. Prior radiotherapy to control local symptoms was http://esmoopen.bmj.com/ in patients with advanced solid tumours was evaluated; no allowed if target lesions outside the radiotherapy field dose-limiting toxicity was observed at doses up to 2000 existed. Patients eligible for enrolment
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