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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. 2018 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 (710). 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 2018 American Association for Cancer Research. by IHC 2þ/3þ staining reported in 13% to 20%, IHC 3þ staining

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to increased HER2 transcription, independent of HER2 gene Translational Relevance amplification or mutation (710). 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 -amplified 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 therapy 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 defini- reverse transcriptase PCR (Roche Molecular Diagnostics) and tions, which impairs the interpretation of the predictive value of evaluated in subgroups defined using the median mRNA expres- specific HER2 alterations in NSCLC. sion distribution values (>median vs. median). Pending tissue Trastuzumab emtansine (T-DM1) is an antibody–drug con- availability, HER2 mutation status and amplification was also jugate composed of trastuzumab joined via a stable linker to assessed using next-generation sequencing (NGS; Foundation DM1, a cytotoxic microtubule-inhibitory agent (17). T-DM1 Medicine Inc.), where amplification was defined by copy number targets the delivery of DM1 to HER2-positive cancer cells, 5 in a diploid model. maximizing the therapeutic index of DM1 and minimizing Eligible patients also had an Eastern Cooperative Oncology off-target effects. T-DM1 has been approved for the treatment Group (ECOG) performance status of 0 or 1, measurable disease of previously treated HER2-positive metastatic breast cancer. (per RECIST v1.1), adequate organ function, and left ventricular In preclinical studies, T-DM1 demonstrated potent in vitro ejection fraction 50% (echocardiogram or multiple-gated growth inhibition of HER2 IHC 3þ (Calu-3, H2170) and IHC acquisition scan). Patients with untreated or symptomatic brain 1þ (H1781) NSCLC cells (18). T-DM1 also showed robust metastases (baseline brain imaging required but repeat imaging antitumor activity in Calu-3 HER2 IHC 3þ and H1781 HER2 was not required), or who had received anticancer or investi- IHC 1þ mouse xenograft tumor models. gational therapy within 21 days of the start of study treatment Altogether, this evidence provided rationale to conduct were excluded. this first phase II study of T-DM1 in patients with HER2-overexpressing advanced NSCLC prior to considering a more defin- Procedures itive trial and to investigate potential predictive biomarkers. Patients were able to enroll in the screening portion of the Given the T-DM1 mechanism of action, we selected patients trial and underwent IHC testing prior to disease progression on with moderate-to-high HER2 overexpression, defined as IHC current therapy to determine if they were potentially eligible 2þ or 3þ only. Specifically, HER2 overexpression can occur due for the trial. Eligible patients were subdivided according to

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HER2 IHC status (2þ or 3þ). Overenrollment was allowed elect for alternative treatment. Of the 49 enrolled patients, to the IHC 2þ cohort to accommodate patients who had HER2 status was based on archival samples for 41 patients initiated the screening process and met the eligibility criteria. and freshly obtained samples (collected within 8 weeks before All patients received T-DM1 (3.6 mg/kg intravenously every start of study treatment) for 6 patients; the sample collection 3 weeks) until investigator-assessed disease progression, date was unknown for 2 patients. Median age was 61 years unmanageable toxicity, or study termination. Survival status (range, 36–80), and the majority of patients were male, pre- was assessed every 3 months following discontinuation due to vious smokers, and had adenocarcinoma (Table 1). All but disease progression. Tumor assessments by radiographic eval- 1 patient previously received platinum-based chemotherapy uation were performed every 6 weeks. (98%; 48/49); information on prior and follow-up treatments The trial protocol was approved by the Institutional Review isshowninSupplementaryTableS1.TheIHC2þ cohort was Boards at each participating center. The study was conducted in overenrolled and included 29 patients, and the IHC 3þ cohort accordance with the Declaration of Helsinki, Good Clinical included 20 patients. Practice guidelines, and applicable local laws. All patients At the cutoff date (May 29, 2017), 15 of 49 (31%) patients provided written informed consent. remained on study for survival follow-up, and 1 in the IHC 3þ cohort remained on treatment; 3 were lost to follow-up, 30 died Outcomes (29 due to disease progression; 1 died of an unknown cause as The primary efficacy endpoint was confirmed investigator- reported in death registry records), and 1 discontinued the assessed objective response rate (ORR) using RECIST v1.1, defined study due to clinical progression. as a complete response (CR) or partial response (PR) determined on 2 consecutive assessments 4 weeks apart (19). Efficacy Secondary endpoints were investigator-assessed progression- Median follow-up was 23.1 months (range, 0.9–26.7) and free survival (PFS), duration of response (DoR; time from 18.4 months (1.0–25.1) in the IHC 2þ and 3þ cohorts, initial documented response to documented disease progres- respectively. In the IHC 2þ cohort, there were no treatment sion or death from any cause), clinical benefitrate[CBR; responses; 8 of 29 (28%) patients had SD, 16of 29 (55%) had proportion of patients with CR or PR or stable disease (SD) progressive disease (PD), and response was not evaluable for determined by the investigator at 6 months), overall survival 5of29(17%;Fig.1AandB).IntheIHC3þ cohort, ORR (OS), and safety. Patients were monitored continuously for was 20% (95% CI, 5.7%–43.7%); 4 of 20 (20%) patients had adverse events (AEs). aPR,4of20(20%)hadSD,11of20(55%)hadPD,and1 (5%) died prior to first scheduled tumor assessment (response Statistical analysis missing; Fig. 1C). CBR was 7% (2/29, 95% CI, 1%–23%) and The primary efficacy objective was investigator-assessed ORR. 30% (6/20; 95% CI, 12%–54%) in the IHC 2þ and 3þ cohorts, Given the exploratory nature of this study, a sample size of 20 respectively. DoR for the 4 IHC 3þ responders was 2.9, 7.3, 8.3, patients per cohort was selected to estimate 2-sided 95% and 10.8 months (censored for 1 patient still on treatment; Clopper–Pearson confidence intervals (CIs) for ORR in each Fig. 1D). cohort and overall. The data cutoff for the ORR analysis In the IHC 2þ and 3þ cohorts, median PFS was 2.6 months occurred when all enrolled patients were expected to have (95% CI, 1.4–2.8) and 2.7 months (95% CI, 1.4–8.3), respec- completed 4.5 months of follow-up (when 3 postbaseline tively; median OS was 12.2 months (95% CI, 3.8–23.3) and 15.3 tumor assessments were expected to be performed). Efficacy months (95% CI, 4.1–NE), respectively (Fig. 2). and safety were evaluated in patients who received 1doseof T-DM1. DoR and Kaplan–Meier estimates of PFS and OS are Safety reported for all evaluable patients and separately for the 2 IHC Median duration of T-DM1 treatment was 3.6 months (range, cohorts. For PFS and DoR, data for patients without disease 0–24.8 months; Supplementary Fig. S2). AEs, regardless of cau- progression or death were censored at the time of the last tumor sality or attribution, are reported (Table 2). Forty-five patients assessment. For OS, data from patients without a death event (92%) reported an AE (any grade). Ten patients reported grade 3 were censored on the date last known to be alive. Exploratory AEs (regardless of relationship to treatment), and fatigue (n ¼ 2) biomarker data were analyzed using descriptive statistics. was the only grade 3 AE reported in more than 1 patient. One Safety was assessed through summaries of AEs, deaths, and grade 4 seizure was reported in a patient with prior history of brain changes in laboratory results. All AEs occurring on or after first metastases receiving concurrent treatment for seizures. There were study treatment were summarized by mapped term, appropriate no deaths due to AEs. Two patients withdrew from study treat- thesaurus levels, and National Cancer Institute Common Termi- ment due to AEs (grade 2 infusion-related reaction and grade 3 nology Criteria for Adverse Events v4.0 toxicity grade. Serious AEs influenza). Of AEs of particular interest in T-DM1–treated were listed separately and summarized. patients, 1 event each of grade 3 thrombocytopenia and infusion-related reaction/hypersensitivity occurred.

Results Exploratory biomarker analysis Study population All responding patients were in the IHC 3þ cohort (Table 3). A Of 370 screened patients, 133 had IHC 2þ or 3þ tumors higher proportion of IHC 3þ patients had HER2-ampliﬁed (Supplementary Fig. S1). Of these, 49 patients from 5 centers in tumors, higher HER2 gene copy number, and HER2 mRNA the United States and 13 European centers were eligible and expression >median compared with the IHC 2þ cohort. enrolled between December 15, 2014, and June 21, 2016; the Biomarker characteristics of the responders and those with SD remaining 84 patients did not meet eligibility criteria or get >6 months are shown in Table 4. Of 4 responding patients, 3 had

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Table 1. Patient baseline and exploratory biomarker characteristics HER2-amplified tumors (ISH, HER2/CEP17 gene ratio 2). Three IHC 2þ IHC 3þ All patients responders had central NGS data; 2 of these patients had HER2 n ¼ n ¼ N ¼ ( 29) ( 20) ( 49) amplification (NGS, copy number 5; Tables 3 and 4). The other Baseline characteristics responder had locally-determined NGS results (same platform Median age, years (range) 61 (36–80) 61 (40–75) 61 (36–80) Sex, n used for central assessment) showing an equivocal test result for HER2 fi HER2 Male 16 13 29 ampli cation. Two responders had mutations Female 13 7 20 including 1 HER2 gene rearrangement (unknown functional Smoking status, n status). Current 6 4 10 A heatmap of the top 20 genetic alterations found across all Previous 16 13 29 patients was prepared for those with central NGS results (n ¼ 24, Never 7 3 10 HER2 ECOG performance status, n Supplementary Fig. S3). Of these 24 patients, mutations HER2 fi 07512were detected in 4 patients (no responders), and ampli - 1221537cation was detected in 5 patients (2 responders). Stage of disease, n Metastatic disease 29 19 48 Locally advanced 0 1 1 Discussion Histology, n Squamous 2 1 3 In NSCLC, activation of HER2 occurs through various mechan- fi Adenocarcinomaa 20 17 37 isms including protein overexpression, gene ampli cation, or Undifferentiated/poorly 32 5mutation, and is considered an oncogenic driver. In our study differentiated of T-DM1 in patients with HER2-overexpressing advanced Unknown 4 0 4 NSCLC, objective responses were observed in patients with IHC n Prior lines of therapy, 3þ tumors. No responses were observed in the IHC 2þ cohort, Any 29 20 49 HER2 fi 17613regardless of ampli cation status. However, 4 additional > 210717patients achieved SD 6 months, resulting in CBRs of 7% and 30% 311617in the IHC 2þ and 3þ cohorts, respectively. Neoadjuvant/adjuvant 1 1 2 Several small studies have also investigated the use of HER2- CNS metastases at baseline, n targeted therapies in lung cancer (Supplementary Table S2). A Yes 3 1 4 phase II trial investigated treatment with T-DM1 in NSCLC No 26 19 45 fi ALK rearrangement, nb characterized by overexpressed, ampli ed, or mutated HER2 and fi Present 0 1 1 was stopped early due to limited ef cacy (20). Among 15 patients Not present/not done/ 29 19 48 with HER2-positive NSCLC treated with T-DM1 (5 IHC 3þ, 3 IHC not evaluable 2þ/FISH-positive, 7 with HER2 mutations), there was only 1 PR b EGFR status, n in a patient with HER2 mutation (ORR, 6.7%; 90% CI, 0.2%– Exon 19 deletion 0 1 1 32.0%). The small number of patients enrolled in the trial, and in Exon 20 T790M mutation 1 0 1 Exon 20 insertion 3 1 4 the various molecular subsets limits the interpretation of these Other (including wild-type/ 25 18 43 results. Analyses from the NCT02675829 basket trial further not done/not evaluable) support the potential role of TDM-1 in advanced NSCLC char- HER2 mutation status, nb acterized by HER2 oncogenic alterations. This trial investigates A775_G776insYVMA 2 0 2 efficacy of T-DM1 in various HER2-amplified solid tumors and > G776_V777 VCV 0 1 1 HER2-mutant lung cancers (21, 22). In the cohort of patients Not done/not evaluable/ 27 19 46 HER2 not reported with advanced -mutant lung adenocarcinoma, ORR was 44% (8/18; 95% CI, 22%–69%), median PFS was 5 months Exploratory biomarker characteristics – ISH HER2 amplification status, n (95% CI, 3 9 months), and median DoR was 4 months (95% Nonamplified, gene ratio <2c 17 9 26 CI, 2–9 months). In the cohort of patients with HER2-amplified Amplified, gene ratio 2c 51116advanced lung cancer, ORR was 50% (3/6; ref. 22). Missingd 70 7Other limited datasets have reported activity of HER2-targeted HER2 gene copy number, n therapy in NSCLC. In a retrospective analysis of patients with a <412618 HER2 mutation who received 22 individual anti-HER2 treat- 4–<68513 62911ments, there were 11 PRs, leading to an ORR of 50% (11/22; Missingd 70 7ref. 13). The MyPathway basket trial (NCT02091141) is evaluat- HER2 mRNA expression, ne ing dual inhibition of the HER2 pathway with pertuzumab plus Median 14 8 22 trastuzumab in patients with HER2-overexpressing, -amplified, or >Median 9 12 21 -mutated tumors, including lung cancer (23). Based on interim Missingd 60 6 data for NSCLC, ORR was 13% (2/16; 95% CI, 2%–38%) in the a þ Includes 1 patient from the IHC 2 group with lepidic predominant HER2-amplified cohort and 21% (3/14; 95% CI, 5–51%) in the adenocarcinoma. HER2 bEGFR, ALK, and HER2 mutations are derived from local assessment. -mutated cohort. cHER2 gene ratio represents the HER2 gene/centromere 17 ratio. HER2 ampli- In a phase II study, patients with HER2-mutant or HER2- fication (ISH) defined as HER2/CEP17 gene ratio 2. amplified lung cancer received treatment with dacomitinib, dMissing values due to lack of sufficient sample, sample quality, and/or assay a pan-HER TKI, and the ORR was 12% (3/26; 95% CI, 2%– failure. 30%) for HER2-mutant disease and 0% (0/4; 95% CI, 0%–60%) e Median HER mRNA level was 7.26. for HER2-amplified disease (14). Neratinib, another pan-HER

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A IHC 2+ C IHC 3+ 100 ORR = 0% (95% CI, 0.0–11.9) 100 ORR = 20% (95% CI, 5.7–43.7) 75 75 * 50 U 50

25 * 25 * * * U UU* U 0 0 * * * U * * U * * –25 –25 * PR PR –50 –50 SD SD * * Change in diameter from baseline (%) –75 PD –75 PD Change in diameter from baseline (%) NE NE –100 –100 * 97531 29272323211917151311 1 2 3 4 5 6 789 10 11 12 13 14 15 16 17 18 19 Patient Patient

B IHC 2+ PR D IHC 3+ PR 150 SD 150 SD PD PD 100 100 NE NE 50 50 0 0 tumor size (%) –50 tumor size (%) –50 Change from baseline Change from baseline –100 –100 9630 12 2724211815 0153 6 9 12 18 Study month of tumor measurement Study month of tumor measurement

Figure 1. Investigator-assessed treatment response and change from baseline tumor size over time. Best treatment response and change from baseline in tumor size for the IHC 2þ cohort (A and B); best treatment response and change from baseline in tumor size for the IHC 3þ cohort (C and D). NE, not evaluable/missing; U, unknown HER2 ampliﬁcation. Indicates positive HER2 ampliﬁcation. The ISH status of all other patients is negative.

TKI, has been investigated in HER2-mutated lung cancer. In a example, in our study, all responders had IHC 3þ tumors, 3 had cohort of 26 lung cancer patients with HER2 or HER3 mutations HER2 amplification (by ISH and NGS), and 2 had HER2 gene from the phase II SUMMIT basket trial, only 1 patient with a HER2 mutations. By contrast, none of the 8 responders to T-DM1 in the exon 20 mutation (L755S) achieved a response (ORR 3.8% at 8 HER2-mutant cohort of the NCT02675829 basket trial had HER2 weeks; ref. 24). Median PFS was 5.5 months. A phase I study of levels beyond IHC 2þ, but 1 patient had HER2 amplification (21). neratinib plus temsirolimus, an mTOR inhibitor, observed Activity of T-DM1 in the context of HER2 mutations remains to be responses in 2 of 7 patients with HER2-mutated NSCLC; however, biologically elucidated (21), and, given co-occurring HER2 ampli- this was at the cost of significant treatment-related toxicity (25). fication and mutation in the majority of responders and the small Pyrotinib, a TKI targeting HER1 and HER2 receptors, has also been number of responders in our trial, we do not have sufficient studied, and preliminary results from a phase II study found an sample size to assess for a potential interaction between the ORR of 55% (6/11) among patients with previously treated molecular alterations. We used IHC to identify patients with HER2-mutant advanced NSCLC (26). Studies of afatinib, an ErbB intermediate-to-high HER2 protein levels, as IHC is the standard family blocker, have showed varied results. In a phase II study of assay used in indications where HER2-targeted therapy is estab- patients with heavily pretreated lung adenocarcinoma, a cohort of lished. HER2 mRNA levels were assessed as part of the exploratory 7 patients with HER2 mutation received afatinib monotherapy, biomarker evaluation; however, this did not identify a cutoff to and none experienced an objective response (27). Another phase identify patients who responded to T-DM1. Of the 4 responders, II study of afatinib demonstrated an ORR of 7.7% (1/13) among only 1 patient had HER2 mRNA levels above the median HER2 pretreated patients with NSCLC harboring HER2 exon 20 muta- mRNA level (Table 3). HER2 IHC alone is insufficient as a tions (28). Finally, a retrospective review of patients with meta- predictive biomarker, and identification of additional biomarkers static HER2-mutant lung cancer treated with afatinib from 7 is required. institutions found an ORR of 11% (3/27; ref. 29). Of note, a Our study has a few limitations. We did not test a predeter- study investigating response to immune checkpoint blockade mined response rate because this was an exploratory study to in HER2-mutated advanced lung cancer found an ORR of 12% obtain preliminary efficacy data and investigate potential bio- (3/26) and a median PFS of 1.9 months (95% CI, 1.5-4.0; ref. 30). markers for further rationale for development in this rare subset of Whereas data suggest a potential role for HER2-targeted therapy NSCLC. Higher patient numbers might be needed to provide in NSCLC, further investigation of HER2 as a biological target in clarity on potential relationships between different HER2 bio- NSCLC is needed. The relationship between the distinct, and markers and response. In addition, only 49 of 133 prescreened probably independent, features of HER2 activation, related bio- patients with IHC 2þ3 or þ tumors were enrolled and started markers, and response to treatment needs further elucidation. For treatment with T-DM. Prescreening was allowed while patients

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A 100 Median time to Patients with PFS event, IHC status PFS event, n (%) months (95% CI) 80 IHC 2+ 29 (100) 2.6 (1.4–2.8) IHC 3+ 19 (95) 2.7 (1.4–8.3) 60 All patients 48 (98) 2.6 (1.4–2.8)

n PFS (%) 40 IHC 2+ ( = 29) IHC 3+ (n = 20) All patients (N = 49) 20 Censored

0 Figure 2. 9630 2421181512 27 Kaplan–Meier analysis of investigator-assessed PFS (A) Time (months) and OS (B). A, Final descriptive Kaplan–Meier Number of patients at risk estimates of PFS in all patients as well as stratified by IHC 2+ 29 27 16 6 6 6 4 3 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 IHC 2þ and IHC 3þ. All patients were treated with IHC 3+ 20 19 12 8 8 8 6 6 6 4 3 3 2 1 1 1 1 1 1 T-DM1. PFS was defined as the time from first study All patients 49 46 28 14 14 14 10 9 8 6 4 4 3 2 2 2 2 2 2 1 1 1 1 1 1 1 1 1 treatment to first documented disease progression or death from any cause. PFS data for patients without disease progression or death was censored at the time B 100 Median time to of last tumor assessment. B, Descriptive Kaplan–Meier Patients with OS event, IHC status OS event, n (%) months (95% CI) estimates of OS by all patients as well as categorized by IHC 2þ and IHC 3þ.OSwasdefined 80 IHC 2+ 20 (69) 12.2 (3.8–23.3) IHC 3+ 10 (50) 15.3 (4.1–NE) asthetimefromfirst study treatment to death from any cause. Patients without a death event were 60 All patients 30 (61) 12.2 (4.7–23.6) censoredonthedatethepatientwaslastknowntobe alive. NE, not estimable. OS (%) 40 IHC 2+ (n = 29) IHC 3+ (n = 20) All patients (N = 49) 20 Censored

0 9630 2421181512 27 Time (months) Number of patients at risk IHC 2+ 29 28 25 21 19 17 16 16 15 15 15 14 14 12 12 12 12 11 10 8 8 6 6 6 3 1 1 1 IHC 3+ 20 19 17 16 15 14 14 14 13 12 11 10 10 8 8 8 7 7 6 4 4 3 2 2 2 1 All patients 49 47 42 37 34 31 30 30 28 27 26 24 24 20 20 20 19 18 16 12 12 9 8 8 5 2 1 1

Table 2. Safety summary Summary of AEs Na Any grade AE 45 Grade 3b 10 Grade 4c 1 Grade 5 0 Table 3. Responders categorized by HER2 ISH, NGS, and HER2 mRNA results d AEs leading to withdrawal 2 IHC 2þ IHC 3þ All patients Selected AEs in patients Grades Grades responder/total responder/total responder/total with at least 1 AEe 1–2, Na 3–5, Na (n/N) (n/N) (n/N) Hemorrhage 7 0 Responders 0/29 4/20 4/49 Infusion-related reaction/ 61ISH result, na 0/22 4/20 4/42 hypersensitivity HER2 not amplified 0/17 1/9 1/26 Peripheral neuropathy 7 0 HER2 amplified 0/5 3/11 3/16 Thrombocytopenia 4 1 Missingb 707 Hepatotoxicity 5 0 NGS resultc 0/12 3/12 3/24 Cardiac dysfunction 2 0 HER2 not amplified 0/12 1/7 1/19 Pulmonary toxicity 0 0 HER2 amplified 0/0 2/5 2/5 aN represents the number of patients with an AE, and patients may have Missing 17 8 25 experienced more than 1 AE. HER2 mRNAd 0/23 4/20 4/43 bThe only grade 3 AEs occurring in more than 1 patient was fatigue (n ¼ 2). The other Median 0/14 3/8 3/22 grade 3 AEs observed were abdominal pain, anemia, bronchitis, confusional state, >Median 0/9 1/12 1/21 decreased appetite, diarrhea, dyspnea, hyperglycemia, hypertension, infusion- Missing 6 0 6 related reaction, lung infection, nausea, platelet count decreased, pneumonia, aHER2 gene amplification was defined as HER2/CEP17 gene ratio 2. pulmonary embolism, and tumor pain (each grade 3 AEs reported in 1 patient). bMissing data due to lack of sufficient sample, sample quality, and/or unreadable c Grade 4 AE was a seizure. assay. d Withdrawal due to AEs was due to a grade 2 infusion-related reaction and grade cOnly 24 samples available for Foundation Medicine analysis due to insufficient 3influenza. sample and/or sample quality. HER2 amplification was defined by copy number e Events for selected AEs are consistent with the U.S. Prescribing Information for 5 in a diploid model. trastuzumab emtansine. AEs classified by National Cancer Institute Common dHER2 mRNA values are missing for 6 patients, due to insufficient sample or Terminology Criteria for Adverse Events grade for safety-evaluable patients (all assay failure. HER2 mRNA expression levels were evaluated in subgroups patients who received 1 dose of T-DM1). Multiple occurrences of the same AE in defined using the median distribution values for mRNA expression (>median 1 individual are counted once at the highest grade for this patient. vs. median). Median HER2 mRNA level was 7.26.

OF6 Clin Cancer Res; 2018 Clinical Cancer Research

Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2018 American Association for Cancer Research. www.aacrjournals.org Table 4. Exploratory biomarker characteristics for patients with a clinical benefit: clinical response (CR or PR) or prolonged SD (>6 months) Patients with clinical response (CR or PR) Patients with SD >6 months 36 years, male, Downloaded from 67 years, male, 56 years, female, 66 years, female, 60 years, male, 74 years, female, Black or African 52 years, male, 56 years, female, white, 87 kg, white, 79.5 kg, white, 60 kg, white, 71 kg, white, 65 kg, American, 122 kg, white, 99 kg, white, 65 kg, Demography ECOG 1 ECOG 1 ECOG 0 ECOG 0 ECOG 0 ECOG 1 ECOG 1 ECOG 1 NSCLC histology Adenocarcinoma Adenocarcinoma Adenocarcinoma Adenocarcinoma Adenocarcinoma Adenocarcinoma Adenocarcinoma Adenocarcinoma Sample source Archival Fresha Archival Archival Archival Archival Archival Archival Biomarkers HER2 Published OnlineFirstSeptember11,2018;DOI:10.1158/1078-0432.CCR-18-1590 IHC 3þ 3þ 3þ 3þ 2þ 2þ 3þ 3þ (15% staining) (75% staining) (100% staining) (60% staining) (30% staining) (40% staining) (90% staining) (35% staining) clincancerres.aacrjournals.org ISH status (ratio)b Negative Positive Positive Positive Unknown Unknown Positive Negative (<2) (2 and <4) (4) (2and<4) (4) (<2) ISH gene copy 3.55 4.45 20.0 6.53 Unknown Unknown 20.50 4.95 number NGS (HER2) HER2 amplification Nonamplified ND Amplified (145) Amplified (8) ND ND Amplified (59) ND by central FMIc (copy number) HER2 mutation by None ND HER2 gene None ND ND None ND central FMI rearrangement (unknown functional status) Cancer Research. HER2 mutation by ND G776_V777>VC ND ND ND A775_G776insYVMA ND ND local NGS on September 23, 2021. © 2018American Association for ALK No RA No RA No RA No RA No RA No RA No RA ND EGFR ND Negative ND Exon 19 deletion ND Negative Negative Exon 20 insertion DoR (months) 2.9 7.3 10.8d 8.3 NA NA NA NA PFS (months) 8.3 8.5 12.2d 9.6 27.5 9.5 11.2 18.7 OS (months) 18.4d 20.2d 12.9d 21.6d 27.5d 18.4 17.1d 25.1d Date of confirmed C11 C5 C5 C5 N/A N/A N/A N/A response e Prior cancer Carboplatin þ * Cisplatin þ * Carboplatin þ Erlotinib * Cisplatin/vinorelbine * Bevacizumab þ * Carboplatin þ * Carboplatin þ treatments pemetrexed þ pemetrexed vinorelbine * Bevacizumab þ carboplatin þ pemetrexed vinorelbine vinorelbine * Bevacizumab þ * Carboplatin carboplatin þ pemetrexed * AMP-514 þ * Docetaxel

* carboplatin þ onartuzumab/ Docetaxel durvalumab NSCLC Metastatic HER2-Overexpressing in T-DM1 paclitaxel placebo (blinded) þ * Paclitaxel * Bevacizumab paclitaxel * Afatinib * Bevacizumab þ onartuzumab/ placebo (blinded) * Docetaxel þ selumetinib/placebo (blinded) * Erlotinib Follow-up Nivolumab Nivolumab Still on treatment Unknown Unknown Afatinib, ipilimumab, Cyclophosphamide, Cisplatin þ vinorelbine

lnCne e;2018 Res; Cancer Clin treatments (finished C19 in nivolumab, vinorelbine fludarabine, May 2017) investigational CAR-T cell therapy Abbreviations: C, treatment cycle; FMI, Foundation Medicine, Inc.; N/A, not applicable; ND, not done; RA, rearrangement. aSample was considered fresh if obtained within 8 weeks before start of study treatment. bHER2 gene amplification was defined as positive based on HER2/CEP17 gene ratio 2. cHER2 amplification defined as positive based on a copy number 5 in a diploid model by NGS. dDenoted a censored observation. ePatient was not treated with prior platinum therapy (protocol violation). OF7 Published OnlineFirst September 11, 2018; DOI: 10.1158/1078-0432.CCR-18-1590

Peters et al.

were still on other therapy, and, at the time of disease progression, advisory board member for AstraZeneca, Biodesix, Merck, Helsinn, Pfizer, and patients may have no longer met all eligibility criteria or may have Roche Genentech. P. Garrido reports receiving speakers bureau honoraria from fi elected for alternative treatment. As some sites screened patients Roche, P zer, and MSD, and is a consultant/advisory board member for Roche, AstraZeneca, Abbvie, Pfizer, Bristol-Myers Squibb, MSD, and Lilly. A. Rittmeyer for HER2 status prior to the central laboratory assessment, the reports receiving speakers bureau honoraria from Roche Genentech, Bristol- prevalence of IHC 2þ and IHC 3þ NSCLC is likely higher than an Myers Squibb, and MSD, and is a consultant/advisory board member for actual population-based prevalence of HER2 IHC overexpression. Abbvie, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, MSD, Pfizer, Boehringer In our study, most tissue came from the archival specimen (41/49; Ingelheim, and Roche. L.H. Lam holds ownership interest (including patents) 84%). The absence of mandatory rebiopsy at study entry is a in Roche. M.W. Lu holds ownership interest (including patents) in Roche. weakness—adopted for practical reasons—given that HER2 status T.E. Stinchcombe is a consultant/advisory board member for Roche Genentech. No potential conflicts of interest were disclosed by the other authors. at diagnosis and study entry may theoretically vary under selective pressure of treatments and tumor evolution, whereas the majority of patient tumor samples came from primary tumors. HER2 Authors' Contributions amplification has been hypothesized as a resistance mechanism Conception and design: S. Peters, R. Stahel, L. Bubendorf, P. Bonomi, with EGFR TKIs (31, 32), indicating potential changes in HER2 J. De Castro Carpeno, S. de Haas, L.H. Lam, T.E. Stinchcombe status following treatment with EGFR TKIs. Although data from Development of methodology: S. Peters, L. Bubendorf, J. De Castro Carpeno, S. de Haas, L.H. Lam, M.W. Lu, T.E. Stinchcombe NSCLC showing loss of HER2 overexpression are not available, Acquisition of data (provided animals, acquired and managed patients, fi this cannot be excluded. Suf cient tissue was available for eval- provided facilities, etc.): S. Peters, R. Stahel, A. Villegas, D.M. Kowalski, uation of all mandatory biomarkers; however, our biomarker C.S. Baik, D. Isla, J. De Castro Carpeno, P. Garrido, A. Rittmeyer, M. Tiseo, analyses were limited by sample availability. Where possible, we L.H. Lam, M.W. Lu, T.E. Stinchcombe collected data on EGFR and ALK based on local testing, whereas Analysis and interpretation of data (e.g., statistical analysis, biostatistics, broader NGS testing for other molecular alterations is not rou- computational analysis): S. Peters, R. Stahel, L. Bubendorf, P. Bonomi, D.M.Kowalski,C.S.Baik,J.DeCastroCarpeno, A. Rittmeyer, C. Meyenberg, tinely performed and was available for selected patients (Supple- S.deHaas,L.H.Lam,M.W.Lu,T.E.Stinchcombe mentary Fig. S3). Finally, further dedicated studies would be Writing, review, and/or revision of the manuscript: S.Peters,R.Stahel, strengthened by independent radiologic review. L.Bubendorf,P.Bonomi,A.Villegas,D.M.Kowalski,C.S.Baik,D.Isla, In summary, our study indicates activity of T-DM1 in selected J. De Castro Carpeno, P. Garrido, A. Rittmeyer, M. Tiseo, C. Meyenberg, patients with IHC 3þ HER2-positive metastatic NSCLC. S.deHaas,L.H.Lam,M.W.Lu,T.E.Stinchcombe The safety profile of T-DM1 was similar to findings from prior Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): S. Peters, L.H. Lam T-DM1 clinical trials and showed that T-DM1 was also tolerable Study supervision: S. Peters, R. Stahel, D. Isla, J. De Castro Carpeno, S. de Haas, in NSCLC. Additional investigation into HER2 signaling path- L.H. Lam, M.W. Lu, T.E. Stinchcombe way oncogenic modifications, including HER2 overexpression, Other (Please enter any additional contributions here: I was member of the amplification, or mutation, may help to refine a patient pop- steering committee and directly involved in the trial, development manage- ulation more likely to benefit from treatment with T-DM1. Of ment, oral presentation, and manuscript development, editing and writing): importance, HER2 IHC—used as a single parameter—was an T.E. Stinchcombe insufficient predictive biomarker for T-DM1 activity. Further trialsareneededtorefine the target population for T-DM1 as Acknowledgments well as for other HER2-directed therapies in NSCLC. The authors would like to thank all the patients who participated in the trial and their families, as well as the participating study sites. Disclosure of Potential Conflicts of Interest The authors are grateful for the assistance of Sven Stanzel of F. Hoffmann- S. Peters is a consultant/advisory board member for Roche, has received La Roche, Ltd., and Yvonne G. Lin, Alan Sandler, and David Chen of honoraria or consultation fees from Abbvie, Amgen, AstraZeneca, Boehringer- Genentech, Inc. Ingelheim, Bristol-Myers Squibb, Clovis, Eli Lilly, F. Hoffmann-La Roche, This study was funded by F. Hoffmann La-Roche, Ltd. Support for third- Illumina, Janssen, Merck Sharp and Dohme, Merck Serono, Novartis, Pfizer, party writing assistance was provided by Meredith Kalish, MD, of Codon- fi Regeneron, Seattle Genetics and Takeda, given a talk in a company's organized Medical, an Ash eld Company, part of UDG Healthcare plc, and was funded public event for AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb,, Eli by F. Hoffmann-La Roche. Lilly, F. Hoffmann-La Roche, Merck Sharp and Dohme, Novartis, Pfizer, and received grants/research support as a (sub)investigator in trials sponsored by The costs of publication of this article were defrayed in part by the payment of Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Clovis, page charges. This article must therefore be hereby marked advertisement in F. Hoffmann-La Roche, Illumina, Merck Sharp and Dohme, Merck Serono, accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Novartis, and Pfizer. L. Bubendorf reports receiving commercial research grants from, holds ownership interest (including patents) in, and is a Received May 21, 2018; revised July 30, 2018; accepted September 7, 2018; consultant/advisory board member for Roche. P. Bonomi is a consultant/ published first September 11, 2018.

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www.aacrjournals.org Clin Cancer Res; 2018 OF9

Trastuzumab Emtansine (T-DM1) in Patients with Previously Treated HER2-Overexpressing Metastatic Non−Small Cell Lung Cancer: Efficacy, Safety, and Biomarkers

Solange Peters, Rolf Stahel, Lukas Bubendorf, et al.

Clin Cancer Res Published OnlineFirst September 11, 2018.

Updated version Access the most recent version of this article at: doi:10.1158/1078-0432.CCR-18-1590

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