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In this first-in-human phase 1 study (NCT02964013; MK-7684-001), we investigated the safety and efficacy of the anti-TIGIT (T cell immunoglobulin and ITIM domain) antibody vibostolimab as monotherapy or in combination with pembrolizumab.Part A enrolled patients with advanced solid tumors, and part B enrolled patients with non-small-cell lung cancer (NSCLC). Patients received vibostolimab 2.1-700 mg alone or with pembrolizumab 200 mg in part A and vibostolimab 200 mg alone or with pembrolizumab 200 mg in part B. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and objective response rate (ORR) per RECIST v1.1.Part A enrolled 76 patients (monotherapy, 34; combination therapy, 42). No dose-limiting toxicities were reported. Across doses, 56% of patients receiving monotherapy and 62% receiving combination therapy had treatment-related adverse events (TRAEs); grade 3-4 TRAEs occurred in 9% and 17% of patients, respectively. The most common TRAEs were fatigue (15%) and pruritus (15%) with monotherapy and pruritus (17%) and rash (14%) with combination therapy. Confirmed ORR was 0% with monotherapy and 7% with combination therapy. In part B, 39 patients had anti-PD-1 (programmed cell death protein 1)/PD-L1 (programmed death-ligand 1)-naive NSCLC (all received combination therapy), and 67 had anti-PD-1/PD-L1-refractory NSCLC (monotherapy, 34; combination therapy, 33). In patients with anti-PD-1/PD-L1-naive NSCLC: 85% had TRAEs-the most common were pruritus (38%) and hypoalbuminemia (31%); confirmed ORR was 26%, with responses occurring in both PD-L1-positive and PD-L1-negative tumors. In patients with anti-PD-1/PD-L1-refractory NSCLC: 56% receiving monotherapy and 70% receiving combination therapy had TRAEs-the most common were rash and fatigue (21% each) with monotherapy and pruritus (36%) and fatigue (24%) with combination therapy; confirmed ORR was 3% with monotherapy and 3% with combination therapy.Vibostolimab plus pembrolizumab was well tolerated and demonstrated antitumor activity in patients with advanced solid tumors, including patients with advanced NSCLC.

BACKGROUND: In the phase III KEYNOTE-061 trial (NCT02370498), pembrolizumab did not significantly improve overall survival versus paclitaxel as second-line therapy for gastric/gastroesophageal junction (GEJ) adenocarcinoma with programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥1 tumors. The association of tissue tumor mutational burden (tTMB) status and clinical outcomes was determined, including the relationship with CPS and microsatellite instability-high (MSI-H) status. PATIENTS AND METHODS: In patients with whole exome sequencing (WES) data [420/592 (71%); pembrolizumab, 218; paclitaxel, 202], the association of tTMB with objective response rate (ORR; logistic regression), progression-free survival (PFS; Cox proportional hazards regression), and overall survival (OS; Cox proportional hazards regression) were measured using one-sided (pembrolizumab) and two-sided [paclitaxel] P values. tTMB was also evaluated using FoundationOne®CDx [205/592 (35%)]. Prespecified equivalent cut-offs of 175 mut/exome for WES and 10 mut/Mb for FoundationOne®CDx were used. RESULTS: WES-tTMB was significantly associated with ORR, PFS, and OS in pembrolizumab-treated (all P < 0.001) but not paclitaxel-treated patients (all P > 0.6) in univariate analysis. The area under the receiver operating characteristics curve for WES-tTMB and response was 0.68 [95% confidence interval (CI) 0.56-0.81] for pembrolizumab and 0.51 (95% CI 0.39-0.63) for paclitaxel in univariate analysis. There was low correlation between WES-tTMB and CPS in both treatment groups (r ≤ 0.16). WES-tTMB remained significantly associated with all clinical endpoints with pembrolizumab after adjusting for CPS and with PFS and OS after excluding known MSI-H tumors (n = 26). FoundationOne®CDx-tTMB demonstrated a positive association with ORR, PFS, and OS in pembrolizumab-treated patients (all P ≤ 0.003) but not PFS or OS in paclitaxel-treated patients (P > 0.1). CONCLUSION: This exploratory analysis from KEYNOTE-061 is the first to demonstrate a strong association between tTMB and efficacy with pembrolizumab but not paclitaxel in patients with gastric/GEJ adenocarcinoma in a randomized setting. Data further suggest tTMB is a significant and independent predictor beyond PD-L1 status. ispartof: ANNALS OF ONCOLOGY vol:32 issue:9 pages:1127-1136 ispartof: location:England status: published

Human epidermal growth factor receptor 2 (HER2)-positive metastatic gastric and gastroesophageal adenocarcinoma (GEA) is globally treated with chemotherapy plus trastuzumab. Novel therapeutic strategies strive to not only optimize efficacy, but also limit toxicities. In MAHOGANY cohort A, margetuximab, an Fc-engineered, anti-HER2 monoclonal antibody (mAb) was combined with retifanlimab, an anti-programmed cell death protein 1 mAb, in the first-line HER2-positive/programmed death-ligand 1 (PD-L1)-positive GEA.MAHOGANY cohort A part 1 is a single-arm trial to evaluate margetuximab plus retifanlimab in patients with HER2 immunohistochemistry 3+, PD-L1-positive (combined positive score ≥1%), and non-microsatellite instability-high tumors. Primary objectives for cohort A were safety/tolerability and the confirmed objective response rate (ORR).As of 3 August 2021, 43 patients were enrolled and received margetuximab/retifanlimab. Nine grade 3 treatment-related adverse events (TRAEs) were reported in eight (18.6%) patients and eight serious TRAEs in seven (16.3%) patients. There were no grade 4/5 TRAEs. Three patients discontinued margetuximab/retifanlimab because of immune-related adverse events. The ORR by independent assessment was 53% [21/40 (95% confidence interval (CI) 36.1-68.5)], with a median duration of response of 10.3 months (95% CI 4.6-not evaluable); disease control rate was 73% [29/40 (95% CI 56.1-85.4)]. The study sponsor discontinued the study in advance of the planned enrollment when it became apparent that the study design would no longer meet the requirements for drug approval because of recent advances in the treatment of GEA.The chemotherapy-free regimen of combined margetuximab/retifanlimab as first-line treatment in double biomarker-selected patients demonstrated a favorable toxicity profile compared with historical outcomes using chemotherapy plus trastuzumab. The ORR observed in this study compares favorably versus ORR observed with other chemotherapy-free approaches.

Introduction Lenvatinib, an antiangiogenic multiple receptor tyrosine kinase inhibitor, plus pembrolizumab, a programmed death-1 immune checkpoint inhibitor, demonstrated promising clinical benefit in a previous phase Ib/II trial across several cancer types (ClinicalTrials.gov, NCT02501096). We assessed clinical outcomes with lenvatinib plus pembrolizumab in patients with ovarian cancer in the ongoing, open-label, multicohort, phase 2 LEAP-005 study (ClinicalTrials.gov, NCT03797326). Methods Female patients aged ≥18 years with histologically/cytologically confirmed, metastatic/unresectable ovarian cancer, measurable disease per RECIST v1.1, ECOG performance status 0/1, and 3 prior lines of therapy were enrolled. Patients received lenvatinib 20 mg daily plus pembrolizumab 200 mg every 3 weeks for 35 cycles, or until confirmed disease progression or unacceptable toxicity. Primary endpoints were objective response rate (ORR; response assessed every 9 weeks for 54 weeks, then every 12 weeks, by blinded independent central review per RECIST v1.1) and safety. Secondary endpoints included disease control rate, duration of response, and progression-free survival. Results 31 patients with ovarian cancer received ≥1 dose of lenvatinib plus pembrolizumab in LEAP-005 (median age 62 years [range 40–76]); median study follow-up was 7.8 months (range, 4.6–12.4) as of April 10, 2020. ORR was 32% (95% CI, 17–51); other efficacy endpoints were also favorable (table 1). Treatment-related adverse events occurred in 29 (94%) patients (table 1). Conclusion Lenvatinib plus pembrolizumab demonstrated encouraging efficacy and manageable safety in patients with heavily pretreated ovarian cancer, including those with prior platinum failure and those with previous bevacizumab exposure.

Since completion of the Trastuzumab for Gastric Cancer study, trastuzumab with doublet chemotherapy (a fluoropyrimidine and a platinum) has been the gold-standard first-line therapy for patients with locally advanced unresectable or metastatic human epidermal growth factor receptor 2-positive (HER2+) gastroesophageal adenocarcinoma (GEA). The safety and efficacy of 23 studies of first-line trastuzumab plus doublet chemotherapy, without checkpoint inhibitors (n = 19) or with checkpoint inhibitors (n = 4), conducted in patients with locally advanced unresectable or metastatic HER2+ GEA, including phase II/III, prospective, and retrospective observational studies, were summarized. In studies without checkpoint inhibitors, the median duration of trastuzumab treatment ranged from 19.5 to 39.0 weeks and from 15.3 to 30.0 weeks for chemotherapy. In studies with checkpoint inhibitors, the median duration of pembrolizumab/trastuzumab/chemotherapy was 30 weeks, and 18 weeks for chemotherapy. In studies without checkpoint inhibitors, treatment-emergent adverse events (TEAEs) of grade ≥3 ranged from 32% to 84%. Serious adverse events (SAEs) ranged from 15% to 39%. Adverse events resulting in discontinuation ranged from 0% to 30%. Treatment-related deaths occurred in 0%-9% of patients. In studies with checkpoint inhibitors, TEAEs of grade ≥3 were 57%. SAEs ranged from 31% to 38%. Adverse events resulting in discontinuation ranged from 5% to 24%. Treatment-related deaths occurred in 0%-3% of patients. In studies without checkpoint inhibitors, objective response rate (ORR) ranged from 39% to 82%, median progression-free survival (PFS) from 5.7 to 11.6 months, and median overall survival (OS) from 11.2 to 27.6 months. In studies with checkpoint inhibitors, ORR ranged from 39% to 86%, median PFS from 8.0 to 13.0 months, and median OS from 19.3 to 27.3 months. This review provides a historical benchmark on safety and efficacy of available first-line chemotherapy-based standard of care for patients with locally advanced unresectable or metastatic HER2+ GEA., Highlights • A benchmark study on safety and efficacy of first-line standard of care in metastatic HER2+ GEA was conducted. • The safety and efficacy in 23 first-line trastuzumab + doublet chemotherapy ± checkpoint inhibitor studies were summarized. • Minus checkpoint inhibitors, grade ≥3 TEAEs ranged from 32% to 84%; SAEs ranged from 15% to 39%; ORR ranged from 39% to 82%. • With checkpoint inhibitors, grade ≥3 TEAEs were 57%; SAEs ranged from 31% to 38%; ORR ranged from 39% to 86%.

Background Previous studies have identified several targetable oncogenic mutations in biliary tract cancer (BTC). However, reliable predictors of clinical response to therapeutic agents have not been established. This study aimed to identify predictors of clinical response to chemotherapy and immune checkpoint blockade in advanced BTC patients. Methods Genomic alterations in 54 patients with recurrent or metastatic BTC were investigated by targeted deep-sequencing for 524 key cancer genes using pre-treatment tumor tissues. The predictive value of genomic alterations, including mutational signatures, on response to chemotherapy and anti-PD-1/PD-L1 therapy, was assessed. Results Frequently altered genes included TP53 (50.0%), NOTCH1 (31.5%), KRAS (24.1%), KMT2C (22.2%), BAP1 (22.2%), and ERBB2 (22.2%). BAP1 deletion and NOTCH1 mutation were associated with a favorable response to chemotherapy. The homologous recombination deficiency (HRD)-associated signature (signature 3) was significantly higher in the responding patients to chemotherapy and a positive correlation between the HRD-signature and BAP1 deletion was observed, suggesting that HRD caused by BAP1 deletion may contribute to a favorable response to chemotherapy. A high proportion of signature 12 was associated with favorable overall and progression-free survival after chemotherapy. Among 19 patients treated with anti-PD-1/PDL1 therapy, the mismatch repair (MMR) deficiency–associated signatures (signatures 6, 15, 20, and 26) were significantly higher in the responding patients. Conclusions This study identified several predictors on therapeutic response of advanced BTC. BAP1 deletion and NOTCH1 mutation were predictors of a favorable response to chemotherapy. Furthermore, the mutational signatures associated with HRD and MMR significantly correlated with the response to chemotherapy and anti-PD-1/PD-L1 therapy, respectively. Legal entity responsible for the study The authors. Funding National R&D Program for Cancer Control, Republic of Korea. Disclosure All authors have declared no conflicts of interest.

Background MET gene amplification/mutation is implicated in oncogenesis of many tumor types. Sym015 is a recombinant antibody (Ab) mixture containing 2 humanized Abs binding non-overlapping epitopes on MET which has superior preclinical activity compared to other MET Abs. Here we present interim results from the First in Human study of Sym015. Methods In part 1 dose escalation, Sym015 was evaluated on every 2-week (q2w) schedule at 6/12/18/24 mg/kg doses in late line advanced solid tumor patients (pts). Based on PK/PD assessment, 18 mg/kg loading dose followed by 12 mg/kg q2w was selected as RP2D. The on-going Part 2 Dose expansion enrolls pts with MET amplification (METAmp >5 MET copies by Next Generation Sequencing (NGS) or FISH MET/CEP7 ratio >2.2 updated to ≥ 3.0) and/or MET exon 14 deletion (METEx14Δ) positive tumors. Central FISH confirmation of tumor MET status and longitudinal circulating tumor (ct)DNA profiling is performed. Results By April 2019, 51 pts (median age 61 yrs) have been treated, 12 pts in Part 1 and 39 pts in Part 2, the majority are non small cell lung cancer (NSCLC; 14 pts; 6 METAmp,7 METEx14Δ, 1 both) and gastric cancer (GC; 12 METAmp pts). Treatment-related adverse events (TRAE) occurred overall in 41,2%; TRAE ≥ gr3 in 9,8% (edema, colitis, septic shock, hypoalbuminemia, hypophosphatemia, increased amylase). No pts discontinued or died due to TRAE. The most common TRAE of ≥ 5% were fatigue 15.7%, peripheral edema 7,8%, nausea, decreased appetite, pruritus and abdominal pain reported by 5.9% of pts each. The table shows preliminary efficacy in NSCLC patients. Sym015 PK was slightly non-linear, with a dose-dependent t½ of 7-10 days for the first dose. 83% METAmp concordance (10/12 samples) between tumor and blood was observed. Table . 1490PD NSCLC Pt MET Status (Local Assessment) Best Response (Best % Change From Baseline) Previous MET TKI therapy Duration of Response (weeks) 1 METAmp NGS 6.8 Copies PR (-53%) No 80 2 METAmp NGS >5 Copies SD (-29%) No 9, Ongoing 3 METAmp NGS >5 Copies SD (+3%) No 9, Ongoing 4 METEx14Δ SD (-28%) No 7, Ongoing 5 METAmp FISH MET/ CEP7:4.9 SD (+6%) No 11 6 METEx14Δ SD (-4%) Yes 8 7 METEx14Δ SD (-21%) Yes 15 8 METEx14Δ SD (-20%) Yes 8 9 METAmp SISH MET/ CEP7: 15.2 Pending No Ongoing 10 METEx14Δ Pending Yes Ongoing 11 METEx14Δ + METAmp Pending Pending Ongoing 12 METEx14Δ Pending No Ongoing 13 METEx14Δ Pending No Ongoing 14 METEx14Δ Not Evaluable Yes Not Evaluable Conclusions Sym015 was well tolerated with early evidence of antitumor activity. Predictive biomarker analysis is underway. The study continues to enroll NSCLC patients with METAmp and/or METEx14Δ. MET screening in blood seems feasible and may be included in future trials. Clinical trial identification NCT02648724. Legal entity responsible for the study Symphogen A/S. Funding Symphogen A/S. Disclosure D.R. Camidge: Advisory / Consultancy: 2019: Takeda, CBT Pharmaceuticals, Daiichi-Sankyo (ILD adjudication committee), G1 Therapeutics (DSMB), Bio-Thera (DSMB), Blueprint; Advisory / Consultancy: 2018: AstraZeneca, Takeda, Arrys/Kyn, Regeneron, Hengrui, G1 Therapeutics (DSMB), Daiichi Sankyo (ILD adjudication committee), Hansoh (SRC), Bio-Thera (DSMB), Ribon, BMS, Blueprint, Roche/Genentech, Inivata; Advisory / Consultancy: 2017: Genoptix, G1 Therapeutics (DSMB), Mersana Therapeutics, Roche/Genentech, Takeda, Ignyta, Daiichi Sankyo (ILD adjudication committee), Hansoh SRC, Bio-Thera DSMB, Lycera, Revolution Med; Research grant / Funding (self), Research grant / Funding (institution): 2017: Takeda Investigator-initiated Trial; Research grant / Funding (self), Research grant / Funding (institution), Company Sponsored Trials at Institution: 2018/9: AbbVie, AstraZeneca, BMS, Hansoh, Lycera, MedImmune, Merck, Pfizer, Phosplatin, Roche/Genentech, Seattle Genetics, Symphogen, Takeda. F. Janku: Research grant / Funding (self): Novartis, Genentech, BioMed Valley Discoveries, Astellas, Agios, Plexxikon, Deciphera, Piqur, Symphogen, Bristol-Myers Squibb, Asana, Upsher-Smith Laboratories; Advisory / Consultancy: Guardant Health, IFM Therapeutics, Synlogic, Deciphera; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Trovagene; Advisory / Consultancy: Immunomet. D.V. Catenacci: Honoraria (self), Advisory / Consultancy: Merck, BMS, Lilly, Astellas, Gritstone, Taiho, Five Prime, Genentech Roche, Foundation Medicine, Guardant Health, Tempus. H.C. Chung: Honoraria (self): Merck-Serono, Lilly, Foundation Medicine; Advisory / Consultancy: Taiho, Celltrion, MSD, Lilly,Quintiles, BMS, Merck-Serono; Research grant / Funding (institution): Lilly, GSK, MSD, Merck-Serono, BMS-ONO, Taiho. A. Dowlati: Advisory / Consultancy: Seattle genetics, Takeda, AbbVie; Research grant / Funding (institution): Takeda, Taiho, Roche, EMD Serono, Bayer, Tesaro, Regeneron, Amgen, Mirati, BMS. K.S. Rohrberg: Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Research grant / Funding (institution): Loxo Oncology, Orion Pharma, Pfizer, PUMA, Cantargia, Genmab, Novartis, Incyte, Bayer, AstraZeneca, Alligator, Merck, BMS; Travel / Accommodation / Expenses: Sanofi; Research grant / Funding (institution): Symphogen. T.T. Poulsen: Full / Part-time employment: Symphogen A/S. H. Rudbaek: Full / Part-time employment: Symphogen A/S. L. Alifrangis: Full / Part-time employment: Symphogen A/S. R.P. Dalal: Full / Part-time employment: Symphogen A/S. All other authors have declared no conflicts of interest.

Cooperative learning has many pedagogical benefits. However, if the cooperative learning teams become ineffective, these benefits are lost. Accordingly, this study developed a computer-aided assessment method for identifying ineffective teams at their early stage of dysfunction by using the Mahalanobis distance metric to examine the difference between the sequential test scores of the unknown team and the test scores of a reference group of functioning teams. The effectiveness of the proposed method was verified by conducting field experiments over an 18-week engineering course in Taiwan. Forty-eight students were randomly assigned to cooperative learning teams. The students' learning performance was evaluated by means of unit tests and homework tests. The functioning of the cooperative teams was examined at seven different points during the course of the study. The ineffective teams were identified with quantified type I errors. It was found that some teams failed persistently. Such teams require some form of external intervention to remedy the group dynamics. The results also showed that teams can become ineffective at any stage of the cooperative learning process. Thus, continuous monitoring is required to ensure that appropriate remedial actions are taken in a timely manner.

Background KEYNOTE-061 (NCT02370498), an open-label, randomized, phase 3 trial of second-line chemotherapy for advanced gastric or GEJ cancer, evaluated IV pembro 200mg Q3W for up to 2 years vs standard-dose paclitaxel. In the primary analysis population (PD-L1 CPS>1), OS and PFS were not significantly different with pembro vs paclitaxel. We present results of prespecified HRQoL analyses in this population. Methods The EORTC QLQ-C30 and QLQ-STO22 were completed at baseline, various time points during treatment cycles up to 1 year or until end of treatment, and 30-day safety follow-up visit. Data were analyzed from patients receiving ≥1 dose of study treatment and completing ≥1 HRQoL assessment. Least-squares mean (LSM) change from baseline to prespecified week 12, 95% CIs, and nominal P values were calculated. Time to deterioration (TTD; ≥10-point decrease from baseline) was assessed by Kaplan-Meier method and Cox regression model. Multiplicity was not controlled for hypotheses testing. Results The HRQoL population included 371 subjects with PD-L1 CPS>1 (pembro, n=188; paclitaxel, n=183). Compliance for QLQ-C30 and QLQ-STO22 at week 12 was similar in both arms (86.6% and 82.1%, respectively). There was no significant difference in LSM between arms (–3.54; 95% CI, –8.92 to 1.84; P=0.196) in global health status (GHS)/QoL. At week 18, GHS/QoL scores showed consistent improvement in patients receiving pembro compared to those receiving paclitaxel. The LSM change from baseline to week 12 for most QLQ-C30 and QLQ-STO22 subscales/items showed some worsening of QoL and were similar between arms. TTD for GHS/QoL (HR, 1.06; 95% CI, 0.71-1.58; P=0.597), nausea/vomiting (HR, 0.81; 95% CI, 0.50-1.33; P=0.204), appetite loss (HR, 1.22; 95% CI 0.76-1.96; P=0.782) subscales in QLQ-C30, and pain (HR, 1.09; 95% CI, 0.65-1.83; P=0.619) subscales in QLQ-STO22 were similar between arms. Conclusions In this advanced gastric and GEJ cancer population receiving second-line treatment, HRQoL was similar in patients receiving pembro and those receiving paclitaxel. Clinical trial identification NCT02370498, February 25, 2015. Editorial acknowledgement Amy McQuay, PhD, of the ApotheCom pembrolizumab team (Yardley, PA, USA), funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Legal entity responsible for the study Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, U.S.A. (MSD). Funding Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Disclosure E. Van Cutsem: Advisory / Consultancy: Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Celgene, Incyte, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, Servier; Research grant / Funding (institution): Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Ipsen, Lilly, Roche, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, Servier. M. Amonkar: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. C.S. Fuchs: Advisory / Consultancy: Agios; Advisory / Consultancy: Bain Capital; Advisory / Consultancy: Bayer; Advisory / Consultancy: Celgene; Advisory / Consultancy, Shareholder / Stockholder / Stock options, Officer / Board of Directors, unexercised stock options: CytomX; Advisory / Consultancy: Dicerna; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy, Shareholder / Stockholder / Stock options, unexercised stock options: Entrinsic Health; Advisory / Consultancy: Five Prime Therapeutics; Advisory / Consultancy: Genentech; Advisory / Consultancy: Gilead Sciences; Advisory / Consultancy: KEW; Advisory / Consultancy: Merck; Advisory / Consultancy: Merrimack; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Roche; Advisory / Consultancy: Sanofi; Honoraria (institution): Taiho; Advisory / Consultancy: Unum. M. Alsina: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Servier; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Travel / Accommodation / Expenses: Roche; Honoraria (self), Travel / Accommodation / Expenses: Lilly; Honoraria (self), Travel / Accommodation / Expenses: Amgen; Research grant / Funding (institution): Merck. M. Ozguroglu: Honoraria (self): Novartis; Honoraria (self): Roche; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Astellas; Travel / Accommodation / Expenses: BMS; Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen. Y. Bang: Advisory / Consultancy: AstraZeneca, Novartis, Genentech/Roche, MSD, Merck Serano, Bayer, BMS, Eli Lilly, Taiho, Daiich-Sankyo, Astellas, BeiGene, GreenCross, Samyang Biopharm, Hanmi, Genexine; Research grant / Funding (institution): AstraZeneca, Novartis, Genentech/Roche, MSD, Merck Serano, Bayer, BMS, GSK, Pfizer, Eli Lilly, Boeringer-Ingelheim, MacroGenics, Boston Biomedical, FivePrime, Curis, Taiho, Takeda, Ono, Daiichi Sankyo, Astellas, BeiGene, Green Cross, CKD Pharma, Genexi. H.C. Chung: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck-Serono; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Lilly; Honoraria (self): Foundation Medicine; Advisory / Consultancy, Research grant / Funding (institution): Taiho; Advisory / Consultancy: Celltrion; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: Quintiles; Advisory / Consultancy: BMS; Research grant / Funding (institution): GSK; Research grant / Funding (institution): BMS-ONO. K. Muro: Honoraria (self): Takeda; Honoraria (self): Chugai Pharma; Honoraria (self): Yakult Honsha; Honoraria (self), Research grant / Funding (institution): Merck Serono; Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Lilly; Honoraria (self), Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self): Bayer; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Shionogi; Research grant / Funding (institution): Kyowa Hakko Kirin; Research grant / Funding (institution): Gilead Sciences; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Sanofi. E. Goekkurt: Advisory / Consultancy: MSD; Advisory / Consultancy: BMS; Advisory / Consultancy: Roche; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Merck; Travel / Accommodation / Expenses: Servier. A. Benson: Advisory / Consultancy: Bristol-Myers Squibb, Eli Lilly & Company, Guardant Health, Exelixis, Purdue Pharma, inVentive Health Inc., Axio, Genentech, Bayer, Merck, Rafael Pharmaceuticals, Astellas (Data Monitoring Committee member), Terumo, Taiho, Thera Bionic, LSK, Axio (Data Mo; Research grant / Funding (self): Acerta, Celgene, Advanced Accelerator Applications, Novartis, Infinity Pharmaceuticals (Data Monitoring Committee), Merck Sharp and Dohme, Taiho, Bristol-Myers Squibb, Medimmune/AstraZeneca, Xencor, Bristol-Myers Squibb (Data Monitoring Committee), PreECO. W. Sun: Advisory / Consultancy: Bayer; Speaker Bureau / Expert testimony: Taiho; Research grant / Funding (self): Merck. Z.A. Wainberg: Advisory / Consultancy: Sirtex Medical; Advisory / Consultancy: Array BioPharma; Advisory / Consultancy, Research grant / Funding (institution): Five Prime Therapeutics; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Lilly; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy: Merck KGaA; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Aduro Biotech; Advisory / Consultancy, Travel / Accommodation / Expenses: Genentech; Research grant / Funding (institution): Plexxikon; Research grant / Funding (institution): Pfizer. J. Norquist: Full / Part-time employment: Merck & Co., Inc. X. Chen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. C. Shih: Full / Part-time employment: Merck & Co., Inc. K. Shitara: Honoraria (self): Novartis; Honoraria (self): AbbVie; Honoraria (self): Yakult; Advisory / Consultancy, Research grant / Funding (institution): Astellas Pharma; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Takeda; Advisory / Consultancy: Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Ono Pharmaceutical; Advisory / Consultancy, Research grant / Funding (institution): MSD; Research grant / Funding (institution): Dainippon Sumitomo Pharma; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Taiho Pharmaceutical; Research grant / Funding (institution): Chugai Pharma; Research grant / Funding (institution): Medi Science.

Background Previous studies reveal that key oncogenic pathways are shared across various human cancer types, and molecularly targeted therapies show clinical efficacy, influenced by predictive biomarkers rather than by tumor histologic types. These results raised the concept of biomarker-driven therapy that enables personalized cancer treatment regardless of tumor location and origin. We hereby introduce the designs and goals of the K-BASKET trial (Korea-biomarker-driven multi-arm drug-screening, knowledge and evidence-generating targeted trial), enabling to match the right drug to right target like NCI-MATCH trial. Trial design This is a proof-of-concept phase II multiple basket trial to test the clinical significance of matched targeted therapies with comprehensive biomarker profiling. The patients with refractory metastatic or unresectable cancer of various origins will be screened for molecular biomarkers by next-generation sequencing, immunohistochemical staining, and in situ hybridization. Those who have cancer with druggable biomarkers will be treated with matched targeted agents. Three treatment arms for the second step are the followings; 1) Patients with MET amplification or exon 14 skipping MET mutation will be assigned to the TAS-115 arm, a novel multikinase inhibitor. 2) Patients with activating PIK3CA or AKT mutations will be assigned to the TAS-117 arm, a novel selective AKT inhibitor. 3) The remaining patients will be screened for PD-L1/MSI/EBV status and those with positive PD-L1/MSI/EBV results or PolD/PolE mutations will be treated with PD-L1 monoclonal antibody. The clinical efficacy and safety of the targeted therapy, as well as the feasibility of molecular profiling and drug matching, will be tested. This study is particularly relevant because: 1) it will identify new indications and predictive biomarkers of targeted therapies in common cancer types in Asian; 2) it is one of the earliest basket trials in tumor immunotherapy and molecular profiling. We anticipate that this trial will provide valuable information on biomarker-driven therapy in clinical practices of personalized treatment. Legal entity responsible for the study Yonsei University. Funding National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (HA16C0018). Disclosure All authors have declared no conflicts of interest.

Knowledge of the electro-active properties of piezoelectric materials is essential for the modeling and design of novel MEMS devices employing the piezoelectric effect. Cantilevers of piezoelectric thin film on Si were fabricated by using sol–gel and photolithograph wafer processing techniques. A scanning laser vibrometer was used to measure the displacement at the contact pad, the first resonant frequency and the tip deflection of the cantilever. The longitudinal (d33,f), transverse (d31,f) piezoelectric coefficients, and the Young's modulus for the piezoelectric thin films were then determined from these results. Finite element analysis (FEA) modeling was carried out to understand the device behaviors and a good agreement has been found between the measurement and the FEA simulated results.

PKB/Akt activation is a common step in tumour growth, proliferation and survival. Akt activation is understood to occur at the plasma membrane of cells in response to growth factor stimulation and local production of the phosphoinositide lipid phosphatidylinositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P3] following phosphoinositide 3-kinase (PI3K) activation. The metabolism and turnover of phosphoinositides is complex--they act as signalling molecules as well as structural components of biological membranes. The localisation and significance of internal pools of PtdIns(3,4,5)P3 has long been speculated upon. By using transfected and recombinant protein probes for PtdIns(3,4,5)P3, we show that PtdIns(3,4,5)P3 is enriched in the nuclear envelope and early endosomes. By exploiting an inducible dimerisation device to recruit Akt to these compartments, we demonstrate that Akt can be locally activated in a PtdIns(3,4,5)P3-dependent manner and has the potential to phosphorylate compartmentally localised downstream substrates. This could be an important mechanism to regulate Akt isoform substrate specificity or influence the timing and duration of PI3K pathway signalling. Defects in phosphoinositide metabolism and localisation are known to contribute to cancer, suggesting that interactions at subcellular compartments might be worthwhile targets for therapeutic intervention.

100 Background: Inhibiting the transforming growth factor β (TGF-β) pathway, which plays a key role in tumor immunosuppression, may enhance the response to programmed death 1/programmed death ligand 1 (PD-1/PD-L1) monoclonal antibodies (mAbs). M7824 (MSB0011359C) is an innovative first-in-class bifunctional fusion protein composed of a mAb against PD-L1 fused with the extracellular domain of TGF-β receptor II, which serves as a TGF-β “trap.” We report preliminary results in Asian patients with heavily pretreated gastric cancer. Methods: In this expansion cohort of the ongoing, phase 1, open-label trial NCT02699515, patients with recurrent or refractory unresectable stage IV gastric or gastroesophageal junction adenocarcinoma for which no standard therapy exists or standard therapy has failed receive M7824 1200 mg q2w until confirmed progressive disease, unacceptable toxicity or trial withdrawal. The primary objective is safety; secondary objectives include best overall response (BOR) per RECIST v1.1. Results: As of 6 September 2017, 31 heavily pretreated patients with advanced gastric cancer (67.7% received ≥3 prior anticancer therapies) received M7824 for a median duration of 6.1 (range: 2-30) weeks (median number of M7824 infusions: 3 [range: 1-13]); 8 patients remained on treatment. Four patients (12.9%) experienced grade 3 treatment-related adverse events (anemia and diarrhea 1 each and 2 rash). No treatment-related grade 4 AEs occurred. One grade 5 event (total 5 doses received) was considered possibly treatment related, but suspected rupture of preexisting thoracic aortic aneurysm was cited as other probable cause by the investigator. There were 5 confirmed partial responses (4 ongoing after 4-6 months of follow-up) based on investigator assessment of BOR (overall response rate: 16.1%). This is an ongoing study; updated data will be presented. Conclusions: These preliminary data show that M7824 resulted in a manageable safety profile in heavily pretreated Asian patients with gastric cancer. Early signs of clinical efficacy are encouraging. Clinical trial information: NCT02699515.

TPS195 Background: Outcomes with first-line (1L) chemotherapy for GC/GEJC are limited and new strategies to increase efficacy without added toxicity are needed. Avelumab, a human anti-PD-L1 IgG1 monoclonal antibody, is approved for metastatic Merkel cell carcinoma (US and EU) and advanced urothelial carcinoma after progression on platinum therapy (US). In phase 1 studies in advanced GC/GEJC, avelumab showed antitumor activity and a manageable safety profile, including in a subgroup of patients (pts) without progression on 1L chemotherapy who received avelumab as maintenance therapy. JAVELIN Gastric 100 (NCT02625610) is a global, randomized, open-label, phase 3 trial comparing maintenance therapy with avelumab vs continuation of 1L chemotherapy in pts with advanced GC/GEJC who have not progressed after 12 weeks of 1L oxaliplatin/fluoropyrimidine chemotherapy. Methods: Eligible pts have histologically confirmed, unresectable, measurable, locally advanced or metastatic GC/GEJC adenocarcinoma, no prior chemotherapy for advanced disease, no prior therapy targeting T-cell coregulatory proteins, and ECOG PS of 0–1. Pts are not preselected based on PD-L1 expression and pts with HER2+ tumors are excluded. Approximately 466 pts who achieve at least stable disease following 12 weeks of 1L oxaliplatin/fluoropyrimidine chemotherapy will be randomized 1:1 to receive maintenance therapy with either avelumab 10 mg/kg by IV infusion Q2W or continuation of 1L chemotherapy. Maintenance therapy is given until disease progression, unacceptable toxicity, or withdrawal. Primary endpoints are overall survival and progression-free survival. Secondary endpoints include best overall response, quality of life measures, safety (NCI-CTCAE v4.03), and tumor biomarkers. Responses are evaluated per RECIST 1.1 and adjudicated by independent review committee. Enrollment is ongoing at sites in North/South America, Asia-Pacific, and Europe. Clinical trial information: NCT02625610.

To investigate the molecular basis of reduced GLUT-1 concentration of the blood-brain barrier in patients with Alzheimer's disease (AD), the GLUT-1 mass, mRNA content, and structure were studied in eight patients with AD and seven age-matched controls. The results indicate that the 55-kDa GLUT-1 is significantly reduced in AD without a significant change in GLUT-1 mRNA concentrations. Because in some animal models changes in GLUT-1 expression is associated with changes in GLUT-1 mRNA structure, the length of the poly(A) tail of the GLUT-1 mRNA was estimated with a reverse transcription-polymerase chain reaction technique. The length of poly(A) tail of GLUT-1 mRNA in AD subjects was not significantly different from the controls. It is concluded that the AD-related change in GLUT-1 expression is not the result of altered poly(A) length of GLUT-1 mRNA.