Trastuzumab deruxtecan (T-DXd; DS-8201) is an antibody-drug conjugate of an anti-HER2 antibody, a cleavable linker, and a topoisomerase I inhibitor. In primary analyses of DESTINY-Gastric01 (DG-01; NCT03329690), T-DXd showed clinically meaningful improvements in objective response rate (ORR) and overall survival (OS) vs chemotherapy in patients (pts) with HER2+ advanced gastric cancer (AGC; primary cohort [PrC], IHC3+ or IHC2+/ISH+), which led to the regulatory approvals in the US and Japan, and also showed preliminary efficacy in the exploratory cohort (EC) 1 (IHC2+/ISH−) and EC 2 (IHC1+) (Shitara NEJM 2020; Yamaguchi ESMO 2020). Here we examined biomarker (BM) data from DG-01 to identify factors associated with T-DXd treatment outcomes. We also explored clinical outcomes of pts enrolled based on tumor samples taken pre/post trastuzumab (Tmab). DG-01 enrolled pts who progressed on ≥2 prior lines with centrally confirmed (Ventana 4B5) HER2+ AGC in a randomized PrC, and HER2-low AGC pts in single-arm ECs. In both treatment arms of PrC, IHC/ISH (T-DXd n=125; Control n=55) was analyzed. In the T-DXd arm, RNAseq (PrC n=34) analyses of tumor biopsy samples, and ctDNA (GuardantOMNI; PrC n=114; ECs n=37) and HER2ECD (ELISA; PrC n=124; ECs n=42) analyses of liquid biopsy samples were conducted. Exploratory cutoff values used for plasma ERBB2 copy number in ctDNA and HER2ECD analyses were defined as those with the smallest p-value by log-rank test for OS. In tissue-based analysis in the T-DXd arm of PrC, 87 pts were identified as HER2+ based on tumor samples taken before Tmab therapy and 38 pts based on tissues post Tmab. In an exploratory analysis, both patient subgroups showed a response to T-DXd; ORRs were 48.8% and 56.8%, respectively. In those pts tested before Tmab, hazard ratio for OS was 0.76 (95%CI: 0.46-1.2, median OS (mOS): 12.1 months (mo) in T-DXd arm vs. 9.3mo in control arm), and in those tested after Tmab was 0.28 (95%CI: 0.13-0.63, mOS: 12.5mo vs. 8.1mo). In the liquid-based analysis of ctDNA among pts treated with T-DXd in PrC, antitumor activity of T-DXd was observed both in pts with baseline ERBB2 amplification (n=71, ORR 60.6%) and in pts without it (n=38, ORR 34.2%). Pts with baseline plasma ERBB2 copy number above 6.0 showed T-DXd activity (n=33, ORR 75.8%), and pts below 6.0 also showed activity (n=76, ORR 40.8%) in the T-DXd arm. In HER2ECD analysis, pts in PrC with baseline HER2ECD above 14.4ng/mL showed T-DXd activity (n=66, ORR 60.6%), while those below 14.4ng/mL (n=52) showed ORR 40.4%. In ECs, pts with baseline HER2ECD above 11.6ng/mL (n=30) showed ORR 36.7%, and in those below 11.6ng/mL (n=10) showed ORR 0%. In this post-hoc exploratory analysis, regardless of the timing of testing for HER2 status or level of plasma ERBB2 amplification in ctDNA, clinically meaningful efficacy of T-DXd was demonstrated in HER2+ AGC. Plasma ERBB2 copy number or HER2ECD warrants further investigation as a means to enrich a population of T-DXd treatment responders in HER2+ or HER2-low AGC.

HER2 levels that will meaningfully identify patients who benefit from the HER2 antibody drug conjugate T-DxD are under investigation. We developed a quantitative machine learning (ML) method to measure HER2 expression and evaluated our approach for predicting patient outcomes. T-DXd demonstrated clinical activity in advanced-stage breast cancer (BC) patients in the DS8201-A-J101 trial. Digitized pathology images stained for HER2 from 154 patients were added to the PathAI research platform (PathAI; Boston, MA). The ML model was trained on 91,413 annotations created by 87 pathologists to identify HER2 positivity in BC cells, immune cells (IC, macrophages and lymphocytes), and tissue compartments in the HER2 stained BC samples. ML derived patient-level features were clustered and selected, with false discovery rate control, for predicting patient outcomes and HER2 status. Thresholds for feature-based patient selection were identified using cross validation optimizing for hazard ratio (HR) between patients with feature values above and below the threshold. 149 patients with BC treated by T-DXd were included in this study. Patients selected by high manual HER2 ASCO/CAP achieved an ORR of 53% vs. 41% (p=0.29). AI feature measuring complete membranous HER2 positive BC cells with increased cytoplasmic HER2 staining identified more patients than manual HER2 (86% vs. 82%) and patients selected by this achieved an ORR of 55% vs. 24% (p<0.009). A novel biomarker measuring the ratio of IC density in the BC stroma vs. BC epithelium achieved an ORR of 57% vs. 38% (p<0.027). A composite biomarker using both features achieved an ORR of 59% vs. 37% (p<0.011). Similar results were found with PFS. ML models identified tissue compartments and HER2 positivity in BC cells. ML-based feature combining IC density with complete membranous/increased cytoplasmic HER2 staining in BC cells achieved a comparable ORR (59% vs. 53%) to manual HER2 scoring. These results show the potential of ML models to select patients for HER2 therapy beyond manual HER2 scoring.

T-DXd is an antibody-drug conjugate consisting of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a membrane-permeable topoisomerase I inhibitor payload. T-DXd is approved for the treatment of HER2-positive metastatic breast cancer in the US and Japan. T-DXd increased confirmed ORR (42.9% vs 12.5%) and OS (median, 12.5 vs 8.4 mo; HR, 0.59; P = .0097) vs chemotherapy in patients (pts) with HER2+ (IHC 3+; IHC 2+/ISH +) metastatic gastric or GEJ cancer in the primary cohort in the DESTINY-Gastric01 open-label, multicenter, phase II trial (NCT03329690).

Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate composed of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a topoisomerase I inhibitor. In a phase 1 trial of T-DXd (5.4 or 6.4 mg/kg), the objective response rate (ORR) was 43.2% (19/44) and median progression-free survival (mPFS) was 5.6 mo in patients with advanced HER2+ gastric cancer (GC). DESTINY-Gastric01 (DS8201-A-J202; NCT03329690) is an open-label, multicenter, randomized, phase 2 study of T-DXd in HER2-expressing advanced GC or gastroesophageal junction (GEJ) adenocarcinoma; results are from the primary analyses for ORR and interim overall survival (OS) in HER2+ patients. Patients with centrally confirmed HER2+ (IHC 3+ or IHC 2+/ISH+ on archival tissue) GC that progressed on ≥ 2 prior lines were randomized 2:1 (T-DXd 6.4 mg/kg q3w or physician’s choice [PC] irinotecan or paclitaxel). All patients received prior HER2 therapy. Stratification factors were region, ECOG PS (0;1), and HER2 status. The primary endpoint was unconfirmed ORR by independent central review. Secondary endpoints were OS (alpha controlled), PFS, disease control rate (DCR), duration of response (DOR), and safety. 187 patients received T-DXd (n = 125) or PC (n = 62 [55 irinotecan; 7 paclitaxel]); 79.7% Japan, 20.3% Korea. Patients had a median of 2 prior lines of therapy, and 44.4% had ≥ 3. At data cutoff (8 Nov 2019), 22.4% of T-DXd and 4.8% of PC patients remained on treatment. ORR was 51.3% (61/119; 11 CR and 50 PR) with T-DXd vs 14.3% (8/56; all PR) with PC (P = .0005); median DOR, 11.3 vs 3.9 months; median PFS, 5.6 vs 3.5 months (HR, 0.47 [95% CI, 0.31-0.71]; P = .0003). The estimated 6- and 12-month PFS rates for the T-DXd and PC arms were 42.8% vs 20.6% and 29.9% vs 0%, respectively. OS was significantly prolonged with T-DXd (median OS, 12.5 vs 8.4 months; HR, 0.59 [95% CI, 0.39-0.88]; P =.0097; prespecified O'Brien Fleming boundary, P = .0202); 12-month OS, 52.1% vs 28.9%. Grade ≥ 3 AEs occurred in 85.6% of patients with T-DXd vs 56.5% with PC; the most common were decreased neutrophil count (51.2%; 24.2%), anemia (37.6%; 22.6%), and decreased white blood cell count (20.8%; 11.3%). 12 patients (9.6%) had T-DXd–related interstitial lung disease (ILD; 2 grade 3, 1 grade 4, no grade 5) vs 0 with PC. 1 drug-related death (pneumonia [non-ILD] in the T-DXd arm) occurred. T-DXd demonstrated statistically significant and clinically meaningful improvements in ORR and OS compared with standard chemotherapy (paclitaxel or irinotecan) in patients with HER2+ advanced gastric or GEJ adenocarcinoma.

Background: HER2-targeted therapies have improved survival for advanced HER2-positive breast cancers (BC), but none have been approved for tumors with low levels of HER2 expression (ie, HER2 IHC 1+ or 2+/ISH-negative). Trastuzumab deruxtecan (DS-8201a) is a novel HER2-targeted antibody-drug conjugate with a humanized HER2 antibody attached to a potent topoisomerase I inhibitor payload by a cleavable peptide-based linker, which is designed to have broad antitumor activity in HER2-expressing tumors. It has a drug-to-antibody ratio of 7 to 8, a novel linker that is stable in plasma and that is selectively cleaved by lysosomal cathepsins which are upregulated in cancer cells, and its payload has a short systemic half-life. In 2015, a phase 1 study (NCT02564900) was initiated to evaluate the safety and efficacy of DS-8201a in subjects with advanced HER2-expressing or HER2-mutated solid tumors, including HER2-low expressing BC. In this study, the overall confirmed response rate (ORR) in the evaluable subjects was 49.3% (103/209) (April 2018 data cutoff; Iwata H, et al. ASCO 2018). Expanded results from the HER2-low expressing BC subjects are presented here. Methods: This ongoing phase 1 trial included 2 parts. The dose escalation part served to determine the dose-limiting toxicities, the maximum tolerated dose, and to select the recommended dose for expansion (RDE). The dose expansion part further evaluated the safety, tolerability, and efficacy of the DS-8201a at the RDE (5.4 and 6.4 mg/kg; q3wks) in various advanced HER2-expressing or HER2-mutated solid tumors, including heavily pretreated HER2-low BC (IHC 1+ or 2+, ISH-negative). Enrollment of HER2-low subjects is ongoing. Results: At the cutoff date of 18 April 2018, data from 34 HER2-low BC subjects were collected. The median age was 55.8 (range; 33, 75) years, the median number of prior endocrine therapies was 2, and the median number of prior chemotherapies was 3. In this HER2-low BC population, most patients had hormone receptor (HR)-positive disease (85.3%; 29/34); of which 17.2% (5/29) received prior treatment with a CDK4/6 inhibitor. The confirmed ORR was 50.0% (17/34), the disease control rate was 85.3% (29/34), the median time to response was 2.8 (range; 1.2, 13.8) months, the median duration of response (DOR) was 11.0 months, and the median progression-free survival (PFS) was 12.9 months. In the subgroup with HR-positive disease, the ORR was 55.2% (16/29), the median DOR was 11.0 months, and the median PFS was 13.6 months. After exclusion of 8 HER2-low subjects who received prior HER2-targeted therapy, the ORR was 46.2% (12/26). In the overall study, among the 145 BC subjects who received ≥1 dose of DS-8201a (5.4 or 6.4 mg/kg), the most frequent grade ≥3 adverse events included anemia (14.5%), and decreased counts of neutrophils (13.8%) and white blood cells (10.3%). There were 4 fatal cases of interstitial lung disease/pneumonitis in BC subjects, including 2 fatal cases in HER2-low BC subjects. Conclusions: In this study, DS-8201a showed substantial antitumor activity and acceptable safety in heavily pretreated HER2-low BC. Citation Format: Modi S, Tsurutani J, Tamura K, Park H, Sagara Y, Murthy R, Iwata H, Krop IE, Doi T, Redfern C, Moreno-Aspitia A, Redman R, Lee C, Sugihara M, Fujisaki Y, Takahashi S. Trastuzumab deruxtecan (DS-8201a) in subjects with HER2-low expressing breast cancer: Updated results of a large phase 1 study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-02.

Background DS-8201a is a HER2-targeting antibody-drug conjugate with a high drug-to-antibody ratio of 7 to 8. A novel cleavable peptide-based linker joins the humanized HER2 antibody to a topoisomerase I inhibitor payload. In an ongoing phase 1 study (J101), DS-8201a was tested at doses of 0.8 to 8.0 mg/kg and tolerated with no predefined dose-limiting toxicities; 5.4 and 6.4 mg/kg doses were recommended for expansion. Subjects with HER2-positive breast cancer (BC) treated at these 2 doses had an overall response rate (ORR) of 54.5% (54/99). The phase 2 DESTINY-BREAST01 trial began enrollment in August 2017 with a dose-finding stage, including 5.4, 6.4, and 7.4 mg/kg. To determine the recommended dose for continued development in HER2-positive BC, a comprehensive analysis of observed data and exposure-response (ER) from both trials was performed. Methods A population-PK (PPK) model was developed using data from all subjects with available concentration data. Individual exposure parameters (Cmin, Cmax, AUC) were estimated from the PPK model and used in the ER analyses. ER analyses were conducted using logistic regression or Cox proportional hazard modeling for efficacy (ORR, duration of response, and PFS) and safety (nausea, diarrhea, left ventricular ejection fraction, neutropenia, anemia, thrombocytopenia, dose reductions due to TEAE, discontinuations due to TEAE, and interstitial lung disease [ILD]). Results As of 18 Apr 2018, in J101, there are 111 HER2-positive BC subjects treated at 5.4- or 6.4-mg/kg doses. As of 25 Apr 2018, DESTINY-BREAST01 enrolled 65 HER2-positive BC subjects across 3 doses (5.4, 6.4, and 7.4 mg/kg). Confirmed ORRs in J101 for HER2-positive BC subjects at 5.4 and 6.4 mg/kg were 52.6% (20/38) and 55.7% (34/61), respectively. In J101, AEs Grade ≥3 were reported in 35.6% (16/45) at 5.4 mg/kg and 50% (33/66) at 6.4 mg/kg. The relationship between DS-8201a intact Cmin and ORR was statistically significant (P=0.035). There was a trend of improved PFS with higher intact exposures (P=0.238). Statistically significant relationships were observed between exposures and the following safety endpoints based on logistic regression: neutropenia (any grade, P=0.003; Grade ≥3, P=0.037), anemia (any grade, P=0.002; Grade ≥3, P Conclusions In J101, DS-8201a demonstrated an acceptable safety profile and high response rates in HER2-positive BC at both doses. The ER analyses showed a statistically significant relationship between exposures and ORR (with a trend for higher PFS at higher doses), as well as exposures and risk of key adverse events. Considering the predicted benefit/risk profile, 5.4 mg/kg is the recommended dose for continued development of DS-8201a in the DESTINY-BREAST01 trial and in phase 3 clinical trials in HER2-positive BC. Citation Format: Tamura K, Modi S, Tsurutani J, Takahashi S, Krop IE, Iwata H, Wada R, Yin O, Garimella T, Sugihara M, Zhang L, Lee C, Yver A, Baselga J. Dose justification for DS-8201a, a HER2-targeted antibody-drug conjugate, for HER2-positive breast cancer: Observed clinical data and exposure-response analyses [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-10.

DS-8201a is a HER2-targeting antibody-drug conjugate with a novel peptide-based cleavable linker, a topoisomerase I inhibitor payload, and a high drug-to-antibody ratio (7 to 8). In preclinical studies, DS-8201a showed broad antitumor activity, in a wide range of tumors. The ongoing phase 1 trial has a dose-escalation (part 1) and -expansion (part 2) and includes subjects with advanced breast cancer, gastric cancer, and other HER2-expressing/-mutated solid tumors. Here, we present updated results for subjects with HER2-expressing or -mutated non-small cell lung cancer (NSCLC). Subjects with HER2-expressing (defined as IHC ≥1+ or amplified) or –mutated (detected by NGS or other platforms) NSCLC were eligible to enroll. HER2 expression and mutation were assessed using archival tissue. Adverse events (AEs), objective response rate (ORR), disease control rate (DCR: CR + PR + SD), and duration of response (DOR) were assessed. [Results will be updated for presentation at meeting] As of Apr 18, 2018, 12 subjects with HER2-expressing and/or -mutated NSCLC received ≥1 dose of DS-8201a at 6.4 mg/kg. Median age was 58.5 y with median of 3 prior regimens. At data cutoff, 8 of 12 (66.7%) subjects remain on treatment. HER2 IHC status was available for 7 subjects. Median duration of treatment was 3.66 months (range 0.69, 14.19). Eight of 10 (80.0%) subjects with ≥1 post-baseline scan (ps) experienced tumor shrinkage (100.0% of them at 1st ps at 6 weeks). Overall, confirmed ORR and DCR in the evaluable subjects was 5 of 8 (62.5%) and 6 of 8 (75.0%), respectively. Among subjects with HER2 IHC 2+ or IHC 3+ expression, 2 of 5 (40.0%) had a PR. Overall, median DOR was 11.5 months (range 0.03+, 11.53). Three of 12 (25.0%) subjects experienced a grade ≥3 AE. Common AEs included decreased appetite 66.7% (0.0% grade ≥3), nausea 58.3% (0.0% grade ≥3), alopecia 41.7% (0.0% grade ≥3), and fatigue 41.7% (0.0% grade ≥3). One fatal case of interstitial lung disease was reported in this subgroup. DS-8201a demonstrated promising antitumor activity in heavily pretreated NSCLC subjects.

Aim: : It is well known that percutaneous coronary intervention (PCI) in hemodialysis (HD) patients is associated with higher rates of in-stent restenosis (ISR) and major adverse cardiovascular events (MACEs) compared to those in non-HD patients, even if the cholesterol management target value is achieved.

Background: There is no HER2-targeted therapy for patients with HER2-positive gastric cancer who progressed on trastuzumab-based therapy. DS-8201a is a novel HER2-targeted antibody-drug conjugate with a humanized HER2 antibody attached to a topoisomerase I inhibitor payload by a cleavable peptide-based linker (deruxtecan), and with a high drug-to-antibody ratio of 7 to 8. In the ongoing phase 1 DS8201-A-J101 trial, DS-8201a showed a manageable safety profile and promising antitumor activity in salvage-line subjects with gastric cancer who previously received trastuzumab (confirmed objective response rate [ORR] of 45.5% at Oct 16, 2017 data cutoff) (Iwasa et al, ASCO-GI 2018). Trial design: The randomized, phase 2, multicenter, open-label, DESTINY-Gastric01 study will assess the efficacy and safety of DS-8201a in HER2-expressing gastric cancer subjects. The primary cohort, HER2-positive (IHC 3+ or IHC 2+/ISH+) subjects who progressed after ≥2 prior regimens and previously received trastuzumab, will be randomized (2:1) to DS-8201a (6.4 mg/kg dose; once every 3 weeks) or physician's choice (irinotecan or paclitaxel). Two nonrandomized exploratory cohorts will assess the efficacy and safety of DS-8201a in subjects with HER2-low gastric cancer (IHC 2+/ISH- and IHC 1+, respectively) who are treatment-naïve to HER2-targeted therapies. The primary endpoint is ORR assessed by an independent central review; secondary endpoints include overall survival (OS), progression-free survival, duration of response, disease control rate, pharmacokinetics, and safety (as shown in ClinicalTrials.gov). The primary analyses for ORR and interim OS analysis will occur after all subjects complete tumor assessments on week 18 and when approximately 108 OS events are observed, whichever comes later. The primary cohort will enroll 180 subjects; providing 92.9% power to detect a difference between the ORR of 40% for DS-8201a vs 15% for physician's choice. Each exploratory cohort will enroll a maximum of 20 subjects. Enrollment began in Oct 2017. Clinical trial: NCT03329690. ©2018 ASCO, Inc. Reused with permission. Accepted and presented at 2018 ASCO Annual Meeting. All rights reserved. Editorial acknowledgement: Stefan Kolata, PhD, of AlphaBioCom LLC, King of Prussia, PA, USA. Clinical trial identification: NCT03329690; Release November 6, 2017. Legal entity responsible for the study: Daiichi Sankyo Co., Ltd. Funding: Daiichi Sankyo Co., Ltd. Disclosure: K. Shitara: Personal fees: Astellas, Bristol-Myers Squibb, Lilly, Takeda, Ono Pharma, Pfizer, Novartis, Abbvie, Yakult; Grants: Dainippon Sumitomo Pharma, MSD, Daiichi Sankyo, Taiho Pharma, Ono Pharma, Lilly. D. Sakai: Grants: Ono Pharmaceutical and Yakult Honsha to Osaka University Hospital; Grants: Daiichi Sankyo, Lilly Japan; Personal fees, grants: Chugai Pharma. H. Yasui: Personal fees: Daiichi Sankyo. Y. Kawaguchi: Employee, holds stock: Daiichi Sankyo Co,. Ltd. M. Sugihara, K. Saito: Employee: Daiichi Sankyo Co,. Ltd. R. Dalal: Employee: Daiichi Sankyo, Inc.; Holds stock: Daiichi Sankyo, Inc., Eli Lilly. K. Yamaguchi: Personal fees: Bayer, Bristol-Myers Squibb, Merck, Sanofi, Takeda; Grants: Dainippon Sumitomo Pharma, Giriad, MSD; Personal fees, grants: Daiichi Sankyo, Lilly, Ono Pharmaceutical, Taiho Pharma, Yakult. All other authors have declared no conflicts of interest.

Background: DS-8201a is a HER2-targeting antibody-drug conjugate with a novel peptide-based cleavable linker, a topoisomerase I inhibitor payload, and a high drug-to-antibody ratio (7 to 8). In preclinical studies, DS-8201a showed a broad antitumor activity in a wide range of tumors, including colorectal cancer (CRC) regardless of KRAS status. The ongoing phase 1 trial has a dose-escalation (part 1) and -expansion (part 2) and includes subjects (sbj) with advanced breast cancer, gastric cancer, and other HER2-expressing/mutated solid tumors. Here, we present updated results for HER2-expressing CRC. Methods: Sbj with advanced HER2-expressing (defined as IHC ≥1+) CRC were eligible to enroll. HER2 expression was assessed using archival tissue. Objective response rate (ORR), disease control rate (DCR; CR + PR + SD), duration of response (DOR), and adverse events (AEs) were assessed. Results: As of Apr 18, 2018, 19 HER2-expressing CRC sbj received ≥1 dose of DS-8201a at 6.4 mg/kg. Median age was 59 y with median of 4 prior regimens (range: 1 to 8). Sixteen of 19 sbj had prior treatment (tx) with irinotecan, another topoisomerase -I inhibitor. At the data cutoff, 7 of 19 (36.8%) sbj remain on treatment. Median duration of tx was 2.76 months (range 0.69, 15.44). Two sbj were known to have KRAS mutations. Overall, confirmed ORR and DCR in the efficacy evaluable sbj was 3 of 12 (25.0%) and 10 of 12 (83.3%), respectively. All responses were observed in KRAS wildtype sbj. One sbj with a KRAS mutation had SD with reduction in tumor markers. Median DOR has not been reached (NR, range 2.76, 5.52+ mo). Nine of 15 (60.0%) sbj with ≥1 post baseline scan experienced tumor shrinkage. Major reason for tx discontinuation was progressive disease (9/12; 75.0%). As for the safety outcomes, 12/19 (63.2%) experienced a grade ≥3 AE. Common AEs included nausea 57.9% (0.0% grade ≥3), platelet count decreased 52.6% (26.3% grade ≥3), anemia 47.4% (26.3% grade ≥3), vomiting 42.1% (0% grade ≥3), and diarrhea 42.1% (0% grade ≥3). Conclusions: DS-8201a demonstrated antitumor activity with manageable safety profile in heavily pretreated subjects with HER2-expressing CRC and warrants further investigation in a phase 2 trial. Clinical trial identification: NCT02564900. Editorial acknowledgement: Editorial and submission support was provided by Stefan Kolata, PhD of AlphaBioCom, LLC (King of Prussia, PA USA). Legal entity responsible for the study: Daiichi Sankyo Co,. Ltd. Funding: Daiichi Sankyo Co,. Ltd. Disclosure: T. Yoshino: Grants: MSD K.K., Sumitomo Dainippon Pharma Co., Ltd., GlaxoSmithKline K.K., Nippon Boehringer Ingelheim Co., Ltd; Grants and personal fees: Sanofi K.K., Chugai Pharmaceutical Co., Ltd.; Personal fees: Eli Lilly Japan K.K, Merck Serono Co., Ltd. H. Iwata: Dr. Iwata Grants and personal fees: Daiichi Sankyo, during the conduct of the study; Grants and personal fees: Chugai, AstraZeneca, Pfizer; Personal fees: Eisai; Grants from MSD, Kyowahakou Kirin, GSK, Lilly, Novartis, Bayer. S. Takahashi: Grants and personal fees: Daichi-Sankyo, during the conduct of the study; Grants and personal fees: Daiichi-Sankyo, outside the submitted work. T. Doi: Grants: Daiichi Sankyo during the conduct of the study; Grants and personal fees: Lilly, Chugai Pharma, Kyowa Hakko Kirin, MSD, Daiichi Sankyo; Personal fees: Amgen; Grants from Taiho, Novartis, Merck Serono, Astellas Pharma, Janssen, Boehringer Ingelheim, Takeda, Pfizer, Sumitomo Group, Celegene, Bristol Myers Squibb, Abbvie, Quintiles. H. Kawakami: Grants: Diaiichi Sankyo; Personal fees: Eli Lilly, Ono Pharmaceutical, Co., Ltd., Chugai Pharmaceutical, Co., Ltd., Taiho Pharmaceutical, Co., Ltd., MSD Pharmaceutical, Co., Ltd., Merck Serono, Takeda Pharmaceutical, Co., Ltd., Astra Zeneca K.K., Yakult Pharmaceutical industry, Co., Ltd. H. Taniguchi: Grants and personal fees: Takeda; Personal fees: Taiho, Chugai. K. Yamaguchi: Research grants: MSD, Ono Pharmaceuticals, Dainppon-Sumitomo, Taiho Pharmaceuticals, Daiichi-Sankyo, Eli Lilly, Giriad, Yakurt Honsha; Consultation fees: Daiichi Sankyo Bristol-Myers Squibb; Speakers' bureau: Taiho Chugai, Merck, Tkeda, Yakurt Honsha, Bayer, Ono Pharmaceuticals, Sanofi, Eli Lilly. B. Li: Grants: Daiichi Sankyo, during the conduct of the study; Personal fees: Genentech. K. Saito, Y. Fujisaki, M. Sugihara: Full-time employee: Daiichi Sankyo Co., Ltd. J. Tsurutani: Grants: Daiichi-Sankyo, during the conduct of the study; Personal fees: Daiichi-Sankyo, outside the submitted work. All other authors have declared no conflicts of interest.

BACKGROUND:Since single lipid parameters are too weak to predict the risk of coronary artery disease, we examined whether the allocation of patients into four groups based on achievement of the target levels set by the Japan Atherosclerosis Guidelines at the time of percutaneous coronary intervention (PCI) would reveal different long-term (5 years) clinical outcomes in males and females. METHODS:The results of a 5-year follow-up study are summarized as FU-Registry, Long-Term Clinical Outcome Results. The subjects consisted of 1158 patients who underwent elective PCI. The male and female patients were separately allocated into four groups: (1) high-density lipoprotein cholesterol (HDL-C≥40mg/dl as well as low-density lipoprotein-cholesterol (LDL-C)≥100mg/dl); (2) HDL-C≥40mg/dl as well as LDL-C<100mg/dl; (3) HDL-C<40mg/dl as well as LDL-C≥100mg/dl; (4) HDL-C<40mg/dl as well as LDL-C<100mg/dl, for a comparison of both patient as well as lesion characteristics and the endpoint of major adverse cardiac events (MACEs). RESULTS:Regarding lesion characteristics, significant differences (p<0.05) were detected in the usage rate of a drug-eluting stent (DES) as well as the bend, stent reference diameter, and stent minimum lumen diameter in females by ANOVA, and in severe calcification, the bend, and usage rate of DES (p<0.001) in males. In females, significant differences (p<0.05) were observed in MACEs and target lesion revascularization-PCI. In contrast, among males, the four groups had nearly equivalent outcomes. Uni- and multivariate analyses revealed that HDL-C as well as LDL-C in females were associated with MACEs [OR 3.29 (95% CI 1.05-8.57, p=0.04)], while no association was observed in male multivariate analysis. CONCLUSION:In female patients, HDL-C<40mg/dl and LDL-C≥100mg/dl were even more strongly related to MACEs, whereas the combination of LDL-C and HDL-C was not related to MACEs in male patients.

One of the standard treatments for aCRC is IRI-based regimens, which are commonly used as second line treatment in Japan. We conducted a prospective observational study to examine the correlation between UGT1A1 genotypes and the clinical outcome of IRI-based regimens in Japanese pts with aCRC (NCT 01039506). We presented previously the results of OS, the secondary endpoint (ASCO 2015, Abst No. 3525). Furthermore, We are going to present update results of OS (ASCO 2016, Abst No. 3571). We developed a nomogram for predicting survival of pts treated with second-line IRI-based regimens after first-line oxialiplatin-based treatment. From Oct 2009 to Mar 2012, 1,376 pts with histologically confirmed aCRC treated with IRI-based regimens were enrolled into the study. Among all enrolled pts, 747 pts were treated with the second-line IRI-based regimens after first-line oxialiplatin-based treatment. A nomogram for predicting OS was developed using multivariable Cox proportional hazards model. The discriminative ability and predictive accuracy of the nomogram were determined by concordance index (c-index) and calibration plot. The nomogram was internally validated using bootstrap resampling. The median OS was 18.5 months (95% CI, 16.8 – 20.7). The multivariable Cox proportional hazards model included age, performance status, resection of primary tumor, location of primary tumor (right vs left), tumor burden based on longitudinal diameters of target lesions according to the RECIST criteria, diabetes and white blood cell count as predictors of OS. The resulting nomogram demonstrated good discrimination and calibration in predicting OS, with a bootstrap-corrected c-index of 0.68. The nomogram showed good separation between risk groups stratified by tertile of the total score, with median OS of 10.1, 18.6, and 29.4 months for low, middle, and high risk groups, respectively. This proposed nomogram is well calibrated and internally validated. External validation is essential before implementing this nomogram in clinical practice.

Background: In Asians, the risk of irinotecan-induced severe toxicities is related in part to UGT1A1*6 (UGT, UDP glucuronosyltransferase) and UGT1A1*28 , variant alleles that reduce the elimination of SN-38, the active metabolite of irinotecan. We prospectively studied the relation between the UGT1A1 genotype and the safety of irinotecan-based regimens in Japanese patients with advanced colorectal cancer, and then constructed a nomogram for predicting the risk of severe neutropenia in the first treatment cycle. Methods: Safety data were obtained from 1312 patients monitored during the first 3 cycles of irinotecan-based regimen in a prospective observational study. In development of the nomogram, multivariable logistic regression analysis was used to test the associations of candidate factors to severe neutropenia in the first cycle. The final nomogram based on the results of multivariable analysis was constructed and validated internally using a bootstrapping technique and externally in an independent data set ( n =350). Results: The UGT1A1 genotype was confirmed to be associated with increased risks of irinotecan-induced grade 3 or 4 neutropenia and diarrhoea. The final nomogram included type of regimen, administered dose of irinotecan, gender, age, UGT1A1 genotype, Eastern Cooperative Oncology Group performance status, pre-treatment absolute neutrophil count, and total bilirubin level. The model was validated both internally (bootstrap-adjusted concordance index, 0.69) and externally (concordance index, 0.70). Conclusions: Our nomogram can be used before treatment to accurately predict the probability of irinotecan-induced severe neutropenia in the first cycle of therapy. Additional studies should evaluate the effect of nomogram-guided dosing on efficacy in patients receiving irinotecan.

Objectives: It is well known that percutaneous coronary intervention (PCI) in hemodialysis (HD) patients is associated with higher rates of in-stent restenosis (ISR) and major adverse cardiovascular events (MACEs) compared to those in non-HD patients, even if the cholesterol management target value is achieved.

Randomized controlled trials are the most scientifically informative studies for evaluating treatment effects.However, we need to conduct observational studies to evaluate unallocatable factors such as genotype, preference, or lifestyle.In observational studies, subject characteristics among the comparison groups might be imbalanced due to non-random allocation.We proposed a dynamic registration method to improve comparability among comparison groups with no allocation.The dynamic registration method is a registration method based on the minimization method, which decides whether or not to register a subject based on the background information of subjects already recruited and the new subject.Simulation studies were conducted to examine the performance of this method in improving comparability among comparison groups.Simulation studies showed that the dynamic registration method improves the comparability among comparison groups.The dynamic registration method can be used to enhance the quality of observational studies for unallocatable factors.