Published OnlineFirst September 11, 2018; DOI: 10.1158/1078-0432.CCR-18-1590 Research Article Clinical Cancer Research Trastuzumab Emtansine (T-DM1) in Patients with Previously Treated HER2-Overexpressing Metastatic Non–Small Cell Lung Cancer: Efficacy, Safety, and Biomarkers Solange Peters1, Rolf Stahel2, Lukas Bubendorf3, Philip Bonomi4, Augusto Villegas5, Dariusz M. Kowalski6, Christina S. Baik7, Dolores Isla8, Javier De Castro Carpeno9, Pilar Garrido10, Achim Rittmeyer11, Marcello Tiseo12, Christoph Meyenberg13, Sanne de Haas14, Lisa H. Lam15, Michael W. Lu15, and Thomas E. Stinchcombe16 Abstract Purpose: HER2-targeted therapy is not standard of care Results: Forty-nine patients received T-DM1 (29 IHC 2þ, for HER2-positive non–small cell lung cancer (NSCLC). This 20 IHC 3þ). No treatment responses were observed in the phase II study investigated efficacy and safety of the HER2- IHC 2þ cohort. Four partial responses were observed in the targeted antibody–drug conjugate trastuzumab emtansine IHC 3þ cohort (ORR, 20%; 95% confidence interval, 5.7%– (T-DM1) in patients with previously treated advanced 43.7%). Clinical benefit rates were 7% and 30% in the IHC HER2-overexpressing NSCLC. 2þ and 3þ cohorts, respectively. Response duration for the Patients and Methods: Eligible patients had HER2-over- responders was 2.9, 7.3, 8.3, and 10.8 months. Median expressing NSCLC (centrally tested IHC) and received progression-free survival and overall survival were similar previous platinum-based chemotherapy and targeted between cohorts. Three of 4 responders had HER2 gene therapy in the case of EGFR mutation or ALK gene amplification. No new safety signals were observed. rearrangement. Patients were divided into cohorts based Conclusions: T-DM1 showed a signal of activity in patients on HER2 IHC (2þ,3þ). All patients received T-DM1 3.6 with HER2-overexpressing (IHC 3þ) advanced NSCLC. Addi- mg/kg intravenously every 3 weeks until disease progres- tional investigation into HER2 pathway alterations is needed sion or unacceptable toxicity. The primary endpoint was to refine the target population for T-DM1 in NSCLC; however, investigator-determined overall response rate (ORR) HER2 IHC as a single parameter was an insufficient predictive using RECIST v1.1. biomarker. Clin Cancer Res; 1–9. Ó2018 AACR. 1Oncology Department, Lausanne University Hospital, Lausanne, Introduction Switzerland. 2Cancer Center Zurich,€ University Hospital of Zurich,€ Zurich,€ – 3 The development of targeted therapy for non small cell lung Switzerland. Institute of Pathology, University Hospital Basel, Basel, fi Switzerland. 4Section of Medical Oncology, Rush University Medical Center, cancer (NSCLC) with speci c molecular alterations such as anaplastic lymphoma kinase ALK EGFR Chicago, Illinois. 5Florida Cancer Specialists and Research Institute, Fleming ( ) rearrangements or muta- Island, Florida. 6Center of Oncology, Maria Skłodowska Curie Memorial tions represents a tremendous advance (1, 2). Current research Cancer Centre, Warsaw, Poland. 7SeattleCancerCenterAlliance,University is focused on the identification and development of targeted 8 of Washington, Seattle, Washington. Medical Oncology Section, Hospital therapy for additional molecular subtypes. HER2 is overexpress- Clinico Universitario Lozano Blesa, Zaragoza, Spain. 9Medical Oncology 10 ed on the surface of multiple tumor cell types, including NSCLC Section, Hospital Universitario La Paz, Madrid, Spain. Medical Oncology – Department, Hospital Universitario Ramon y Cajal, Madrid, Spain. (3 5). Survival data meta-analyses show HER2 overexpression is 11Department of Thoracic Oncology, Fachklinik fur€ Lungenerkrankungen, associated with poor prognosis in lung cancer (3, 6). There are Immenhausen, Germany. 12Medical Oncology Unit, Azienda Ospedaliero- currently no standard therapies targeting the HER2 pathway in Universitaria di Parma, Parma, Italy. 13Biostatistics, F. Hoffmann-La Roche, NSCLC, whereas HER2-targeted therapies are standard for breast 14 Basel, Switzerland. Oncology Biomarker Development, F. Hoffmann-La and gastric cancer. In breast and gastric cancer, HER2 overexpres- Roche, Basel, Switzerland. 15Product Development Oncology, Genentech, fi 16 sion generally occurs in the context of gene ampli cation, whereas Inc., South San Francisco, California. Duke Cancer Institute, Duke University fi School of Medicine, Durham, North Carolina. discordance between IHC overexpression and gene ampli cation is observed in NSCLC (7À10). Instead, increased HER2 expres- Note: Supplementary data for this article are available at Clinical Cancer sion in NSCLC may result from upregulated transcriptional/ Research Online (http://clincancerres.aacrjournals.org/). posttranscriptional mechanisms (7, 9). Corresponding Author: Solange Peters, Lausanne University Hospital, Lausanne The reported prevalence of "HER2-positive" NSCLC varies 1011, Switzerland. Phone: 41795560192; E-mail: [email protected] because previous studies have used different definitions and doi: 10.1158/1078-0432.CCR-18-1590 testing methods (ISH and IHC), with HER2 positivity defined Ó2018 American Association for Cancer Research. by IHC 2þ/3þ staining reported in 13% to 20%, IHC 3þ staining www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst September 11, 2018; DOI: 10.1158/1078-0432.CCR-18-1590 Peters et al. to increased HER2 transcription, independent of HER2 gene Translational Relevance amplification or mutation (7À10). To date, there are no clinical There are no standard therapies targeting HER2 in non– data suggesting T-DM1, in contrast to trastuzumab or a HER2 small cell lung cancer (NSCLC); however, HER2-targeted tyrosine kinase inhibitor (TKI), would have a stronger effect in therapies are standard in breast and gastric cancer. Results HER2-mutated or HER2-ampli fied NSCLC. Although amplifi- from this phase II study indicate a signal of activity of the cation and mutations are considered potential driver onco- HER2-targeted antibody–drug conjugate trastuzumab genes, we hypothesize that targeting HER2 overexpression will emtansine (T-DM1) in patients with IHC 3þ HER2-positive address a potentially larger patient population that may be NSCLC. T-DM1 was tolerable in NSCLC, and safety was more relevant taking into account the mechanism of action of similar to findings from prior trials. An exploratory bio- T-DM1, targeting the HER2 extracellular component. marker analysis showed that, of the 4 responding patients, 3 had HER2-amplified tumors and 2 had HER2 mutations. Additional investigation into HER2 oncogenic modifica- Materials and Methods tions, including HER2 overexpression, amplification, or Study design and patients mutation may help refine a patient population likely to In this multicenter, single-arm, clinical trial (trial registration benefit from treatment with T-DM1. Of importance, HER2 NCT02289833), eligible patients were aged 18 years with IHC as a single parameter was an insufficient predictive HER2-positive (IHC 2þ or 3þ) locally advanced or metastatic biomarker to select patients with most benefitfromT-DM1. NSCLC previously treated with 1 prior platinum-based chemo- Further trials should refine the target population for HER2- therapeutic regimen. Patients with EGFR-mutated or ALK gene– targeted therapies in NSCLC. rearranged NSCLC were eligible if they had also experienced disease progression following treatment with prior targeted ther- apy or if they were intolerant to such treatment. Archived tumor specimens from previously collected tissue were centrally and prospectively tested for HER2 status (Ventana in 2% to 6%, and HER2 gene amplification by ISH in 2% to 4% Pathway HER2 (4B5) IHC assay; Ventana Medical Systems, Inc.). (8). HER2 gene mutation, another HER2 alteration in NSCLC, has HER2 overexpression was evaluated by IHC, the gold standard a frequency of 1% to 4% (8). HER2 gene mutations and ampli- for HER2 assessment in breast and gastric cancer. If archival tissue fications show limited co-occurrence in NSCLC (8, 10). The was unavailable for HER2 testing, patients could have a newly absence of correlation between HER2 overexpression, amplifica- collected biopsy specimen tested. Based on results from central tion, or mutation suggests 3 biologically distinct NSCLC subtypes, testing, patients with a HER2 status of IHC 2þ (defined as weak- leaving the question of which subtypes will be most effectively to-moderate complete, basolateral, or lateral membranous reac- treated with HER2-targeted therapy. tivity in 10% of tumor cells) or IHC 3þ (defined as strong Despite observation of these 3 alterations in NSCLC, the role of complete, basolateral, or lateral membranous reactivity in 10% these abnormalities as therapeutic biomarkers remains unde- of tumor cells) were eligible. fined. Few data sets report on the use of HER2-targeted therapies A retrospective exploratory biomarker analysis was conducted in patients with HER2-positive (11, 12) or -mutated (13–16) if sufficient tissue was available following IHC testing. In this NSCLC. These studies were small, and some included patients analysis, HER2 gene amplification (HER2/CEP17 gene ratio 2) treated concurrently with chemotherapy and a HER2-targeting was also assessed by ISH (similar to breast and gastric cancers). agent. Of note, most trials do not assess presence of all 3 types of HER2 mRNA expression levels were measured by quantitative HER2 alterations, and tend to use significantly divergent