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Background Expression of hyaluronidase from the selective oncolytic adenovirus VCN-01 modifies tumor matrix in pancreatic tumours. Such effect enhances gemcitabine uptake and induces potent immunomodulatory signals that could help recruit CD8+-T cells. Methods VCN-01 was administered as a single IV injection to 40 patients with ECOG 0-1 at doses ranging from 1E11 to 1E13 viral particles per patient (vp) as a single agent in patients with advanced solid tumors or in combination with gemcitabine/nab-paclitaxel in patients with advanced pancreatic adenocarcinoma using two independent administration regimens (concomitant or sequential). Blood levels of VCN-01 DNA and hyaluronidase together with several immunological markers and VCN-01 presence in paired tumor biopsies were measured. Response was assessed using RECIST v1.1 criteria. Results The most commonly reported VCN-01-associated adverse events of grade 3 or higher included transaminase increase, thrombocytopenia and neutropenia, accounting for 27% and 10% of patients respectively for the combination of VCN-01 with gemcitabine/nab-paclitaxel in the concomitant and the sequential regimen. Recommended Phase 2 Dose (RP2D) was 1E+13vp/patient both in monotherapy and in combination with chemotherapy in a sequential regimen whereas 3.3E+12vp was the RP2D for the concomitant regimen. VCN-01 reached and replicated in tumors when administered systemically. VCN-01 dose correlated with hyaluronidase positivity in sera and sustained viremia for over 3 weeks indicating replication. VCN-01 administration changed tumour environment into a more pro-inflammatory state, inducing CD8 T-cells infiltration and upregulation of IDO in 64% patients. RECIST evaluation resulted in a response rate between 40-45% ORR depending on regimen including a complete response and several partial responses. Conclusions VCN-01 shows a good safety profile when administered systemically in combination with the standard of care for pancreatic cancer. Its ability to reach systemically the tumours and modify tumour matrix to favour immune infiltration results in evidences of clinical activity. Clinical trial identification 2012-005555-16. Legal entity responsible for the study VCN Biosciences. Funding VCN Biosciences. Disclosure R. Garcia-Carbonero: Advisory / Consultancy: AAA; Advisory / Consultancy, Research grant / Funding (institution): Amgen; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Ipsen; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Pharma Mar; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Advisory / Consultancy, Research grant / Funding (institution): Servier; Research grant / Funding (institution): ARMO Biosciences; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Pharmacyclics; Research grant / Funding (institution): Boston Medicals; Research grant / Funding (institution): Boehringer; Research grant / Funding (institution): VCN Biosciences. M. Gil Martin: Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: PharmaMar; Speaker Bureau / Expert testimony: AstraZeneca. R. Alvarez Gallego: Advisory / Consultancy: Celgene; Advisory / Consultancy, Research grant / Funding (institution): Shire. T. Macarulla Mercade: Advisory / Consultancy: Servier; Advisory / Consultancy: Shire; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Baxter; Advisory / Consultancy, Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Agios; Research grant / Funding (institution): Aslan; Advisory / Consultancy: AstraZeneca; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Halozyme; Research grant / Funding (institution): Immunomedics; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Merimarck; Research grant / Funding (institution): Millenium; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Pharmacyclics. M.C. Riesco Martinez: Speaker Bureau / Expert testimony: Merck. C. Guillen-Ponce: Research grant / Funding (institution): BeiGene; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): PH Research; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Erytech Pharma; Research grant / Funding (institution): VCN Biosciences; Research grant / Funding (institution): Halozyme. N. Vidal: Research grant / Funding (institution): VCN Biosciences. F.X. Real: Speaker Bureau / Expert testimony: Roche; Research grant / Funding (institution): VCN Biosciences. V. Maliandi: Full / Part-time employment: VCN Biosciences. A. Mato-Berciano: Full / Part-time employment: VCN Biosciences. M. Bazan-Peregrino: Full / Part-time employment: VCN Biosciences. G. Capella: Advisory / Consultancy, Research grant / Funding (institution), Shareholder / Stockholder / Stock options: VCN Biosciences. R. Alemany: Advisory / Consultancy, Research grant / Funding (institution), Shareholder / Stockholder / Stock options: VCN Biosciences; Research grant / Funding (institution): Lokon Pharma; Research grant / Funding (institution): Mologen. E. Blasi: Full / Part-time employment: VCN Biosciences. C. Blasco: Full / Part-time employment: VCN Biosciences. M. Cascallo: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: VCN Biosciences. R. Salazar: Advisory / Consultancy, Research grant / Funding (institution): VCN Biosciences; Advisory / Consultancy: Agendia; Advisory / Consultancy: Guardiant Health; Advisory / Consultancy, Research grant / Funding (institution): Roche Diagnostics; Advisory / Consultancy: Ferrer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Ipsen; Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Roche Pharma; Advisory / Consultancy: Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: AZD; Speaker Bureau / Expert testimony: Celgene; Leadership role, Shareholder / Stockholder / Stock options: Sace MedHealth; Research grant / Funding (institution): PsiOxus; Research grant / Funding (institution): Mologen. All other authors have declared no conflicts of interest.

Background ABBV-621, a tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor agonist, induces cell death in tumor cells by activation of death receptor 4 and 5. Maximum tolerated dose was not reached in dose escalation (Ratain et al. ASCO 2019; NCT03082209). Herein is reported the analysis of safety and antitumor activity in additional pts enrolled in the dose-optimization cohorts with the goal of identifying the recommended phase 2 dose. Methods Eligible pts (≥18 years, relapsed/refractory [R/R] KRAS-mutant colorectal [CRC] or pancreatic cancer, ECOG 0–2, measurable disease, willingness to undergo mandatory biopsies) received ABBV-621 intravenously (1.25–7.5mg/kg) on day (D) 1, D8, and D15 of a 21-D cycle. Analyzed tumor types were evenly distributed across dose levels (DL). Results As of 16 Apr 2019, 48 pts received ≥1 dose of ABBV-621 (CRC, n=24/pancreatic, n=24; 1.25mg/kg, n=8/8; 3.75mg/kg, n=8/8; 7.5mg/kg, n=8/8). Median age: 63 years (range, 43–76); 65% male, 73% ≥3 prior treatment (Tx) regimens. Median duration of ABBV-621 exposure was 36 days (range, 1–251) with a median 2 Tx cycles (range, 1–12). Tx-emergent and Tx-related AEs are summarized in the table. Ten pts (20.8%) experienced AEs leading to discontinuation; 4 (9.3%) pts had dose-limiting toxicities possibly associated with ABBV-621 administration: respiratory failure (7.5mg/kg; Grade 5, the only Tx-related death), increased ALT and AST (1.25, 3.75mg/kg), toxic hepatitis (1.25mg/kg), non-cardiac chest pain (1.25mg/kg), and pleuritic pain (1.25mg/kg). ALT, alanine aminotransferase; AST, aspartate aminotransferase A partial response was observed in 1pt with CRC (1.25mg/kg) and 1pt with pancreatic cancer (3.75mg/kg). Stable disease at 12 weeks was the best response in 20 pts (41.7%; CRC, n=9/pancreatic, n=11).Table457PTableAEs, n (%)Related to ABBV-621, n (%)All grade (≥5 patients)Grade 3/4Serious1.25mg/kg (n=16)3.75mg/kg (n=16)7.5mg/kg (n=16)Total (N=48)1.25mg/kg (n=16)3.75mg/kg (n=16)7.5mg/kg (n=16)Total (N=48)1.25mg/kg (n=16)3.75mg/kg (n=16)7.5mg/kg (n=16)Total (N=48)Fatigue4 (25.0)3 (18.8)4 (25.5)11 (22.9)00000000Increased ALT1 (6.3)4 (25.0)5 (31.3)10 (20.8)1 (6.3)1 (6.3)1 (6.3)3 (6.3)01 (6.3)01 (2.1)Stomatitis1 (6.3)3 (18.8)5 (31.3)9 (18.8)00000000Increased AST1 (6.3)3 (18.8)4 (25.0)8 (16.7)1 (6.3)1 (6.3)2 (12.5)4 (8.3)01 (6.3)01 (2.1)Decreased appetite2 (12.5)1 (6.3)4 (25.0)7 (14.6)00000000Diarrhea1 (6.3)3 (18.8)3 (18.8)7 (14.6)00000000Nausea2 (12.5)1 (6.3)4 (25.0)7 (14.6)0000001 (6.3)1 (2.1)Vomiting3 (18.8)1 (6.3)3 (18.8)7 (14.6)0000001 (6.3)1 (2.1)Dysgeusia2 (12.5)2 (12.5)1 (6.3)5 (10.4)00000000Pyrexia01 (6.3)4 (25.0)5 (10.4)00000000 Conclusions Administration of ABBV-621 in pts with R/R CRC and pancreatic cancer shows an acceptable safety profile at all DL and evidence of antitumor activity. Clinical trial identification NCT03082209. Editorial acknowledgement Medical writing support was provided by Yanci M. Baker, PhD, from Aptitude Health, Atlanta, GA, and funded by AbbVie. Legal entity responsible for the study AbbVie Inc. Funding AbbVie Inc. Disclosure E. Calvo: Honoraria (self): HM Hospitales Group; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Nanobiotix; Advisory / Consultancy: Janssen-Cilag; Advisory / Consultancy: PsiOxus; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: EUSA Pharma, Inc.; Advisory / Consultancy: AbbVie; Advisory / Consultancy: Celgene; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Guidepoint Global; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche/Genentech; Advisory / Consultancy: Gerson Lehrman Group; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Servier; Advisory / Consultancy: amcure; Leadership role: Foundation INTHEOS; Research grant / Funding (institution): BeiGene; Research grant / Funding (institution), Shareholder / Stockholder / Stock options: START; Shareholder / Stockholder / Stock options: Oncoart Associated; Shareholder / Stockholder / Stock options: International Cancer Consultants. M.J.A. de Jonge: Advisory / Consultancy: Faron Pharmaceutical Ltd. D.W. Rasco: Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Lily; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Millennium; Research grant / Funding (institution): Rexahn; Research grant / Funding (institution): Five Prime Therapeutics; Research grant / Funding (institution): Pharmacyclics; Research grant / Funding (institution), Travel / Accommodation / Expenses: Asana BioSciences; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Aeglea; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Ascentage; Research grant / Funding (institution): MacroGenics; Research grant / Funding (institution): Apexian; Research grant / Funding (institution): Birdie; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Constellation; Research grant / Funding (institution): Syndax; Research grant / Funding (institution): Astex; Research grant / Funding (institution): Compugen; Research grant / Funding (institution): Coordination; Research grant / Funding (institution): GSK; Research grant / Funding (institution): Incyte. V. Moreno: Advisory / Consultancy: Puma Biotechnology; Travel / Accommodation / Expenses: Sanofi; Travel / Accommodation / Expenses: Regeneron. Y. Chang: Shareholder / Stockholder / Stock options, Full / Part-time employment: AbbVie. M. Chiney: Full / Part-time employment, Former employee: AbbVie; Full / Part-time employment, Current employee: Bristol-Myers Squibb. M. Motwani: Shareholder / Stockholder / Stock options, Full / Part-time employment: AbbVie. S. Penugonda: Shareholder / Stockholder / Stock options, Full / Part-time employment: AbbVie. A.M. Petrich: Shareholder / Stockholder / Stock options, Full / Part-time employment: AbbVie. M.J. Ratain: Advisory / Consultancy: Acentage Pharma; Advisory / Consultancy: Cyclacel; Advisory / Consultancy: Aptevo Therapeutics; Advisory / Consultancy: Shionogi; Research grant / Funding (institution): Dicerna; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Genentech/Roche; Licensing / Royalties: UGT1A1 genotyping for irinotecan; Licensing / Royalties: Genomic prescribing system; Officer / Board of Directors: Value in Cancer Care Consortium. P. LoRusso: Advisory / Consultancy: Agios; Advisory / Consultancy: AbbVie; Advisory / Consultancy: Genmab; Advisory / Consultancy: Halozyme; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: CytomX; Advisory / Consultancy: Five Prime; Advisory / Consultancy: Takeda; Advisory / Consultancy: Sotio; Advisory / Consultancy: Cybrexa; Advisory / Consultancy: Agenus.

Background INDUCE-1 is a first in human study investigating GSK609 alone (mono) and in combination (combo) with other regimens including pembro. The study consists of dose escalation (DE) and expansion phases. Findings from DE and the PK/PD mono cohort demonstrated that a range of GSK609 doses (≥0.1-1 mg/kg) have biological and clinical activity supporting the mechanism of action of a non-T cell depleting IgG4 ICOS agonist antibody as a clinical target. Methods Eligible patients (pts) for the HNSCC EC had recurrent or metastatic disease, ≤5 prior lines of therapy, measurable disease, and no active autoimmune disease. Pts received 1 mg/kg GSK609 in the mono EC and 0.3 mg/kg GSK609 + 200 mg pembro in the combo EC until disease progression or unacceptable toxicity, up to 2 years (yrs). Disease assessments were performed every 9 weeks (wks) through wk 54 then every 12 wks. Overall response rate (ORR) was assessed for futility in ≥ 10 pts/EC, analyzed by prior PD-1/L1 treatment status (naive vs. experienced). PD-L1 expression was determined by the 22C3 pharmDx assay. Results As of 16 April 2019, 12 of 17 PD-1/L1 experienced pts in the mono and 29 of 34 PD-1/L1 naive pts in the combo HNSCC ECs had at least 1 disease assessment (evaluable population). In the mono EC, median age was 56 yrs (range: 27-73); 88% were male; 82% received ≥1 prior lines in the metastatic setting. In the combo EC, median age was 61 yrs (range: 33-77); 85% were male; 68% received ≥1 prior lines in the metastatic setting. ORR was 8% (95% CI: 0.2%, 38.5%) and 28% (95% CI: 12.7%, 47.2%) in mono (1 of 8 pts) and combo (8 of 29 pts) ECs, respectively. Median PFS in the combo EC was 5.6 months (95% CI: 2.4, NR). Treatment-related adverse events occurring in the overall mono (n = 208) and combo populations (n = 178) were consistent with that previously reported (Hansen, et al. ESMO, 2018). PD-L1 IHC testing is ongoing. Conclusions Preliminary data demonstrate GSK609 has single agent activity in PD-1/L1 experienced HNSCC. The combo of GSK609 with pembro shows promising antitumor activity and a manageable safety profile in pts with previously treated, PD-1/L1 naive HNSCC. Clinical trial identification NCT02723955; March 31, 2016. Legal entity responsible for the study GlaxoSmithKline. Funding GlaxoSmithKline. Disclosure D. Rischin: Advisory / Consultancy, Uncompensated: MSD; Research grant / Funding (institution): MSD; Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Uncompensated: GSK; Research grant / Funding (institution): GSK; Advisory / Consultancy, Uncompensated: BMS; Research grant / Funding (institution): BMS; Advisory / Consultancy, Uncompensated: Regeneron; Research grant / Funding (institution): Roche. A.M.L. Lim: Travel / Accommodation / Expenses: BMS; Research grant / Funding (self): Department of Health (WA) / Raine Medical Research Foundation Clinician Research Fellowship. J. Martin-Liberal: Advisory / Consultancy: BMS; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Roche; Speaker Bureau / Expert testimony: Astellas; Speaker Bureau / Expert testimony: BMS; Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: Pierre Fabre; Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Roche; Travel / Accommodation / Expenses: BMS; Travel / Accommodation / Expenses: Novartis; Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: Pierre Fabre; Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Ipsen. V. Moreno: Advisory / Consultancy: Merck; Advisory / Consultancy: BMS; Travel / Accommodation / Expenses: Regeneron/Sanofi; Travel / Accommodation / Expenses: BMS; Speaker Bureau / Expert testimony, Presentation: BMS; Speaker Bureau / Expert testimony, Presentation: Nanobiotix; Research grant / Funding (self), Educational Grant: Medscape/Bayer. J.M. Trigo Perez: Advisory / Consultancy: Roche; Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: AstraZeneca; Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: BMS; Travel / Accommodation / Expenses: BMS; Advisory / Consultancy: MSD; Travel / Accommodation / Expenses: MSD; Advisory / Consultancy: Boehringer; Travel / Accommodation / Expenses: Boehringer. C. Le Tourneau: Advisory / Consultancy: MSD; Advisory / Consultancy: BMS; Advisory / Consultancy: GSK; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Roche; Advisory / Consultancy: Amgen; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Nanobiotix. D.C. Cho: Advisory / Consultancy: PureTech; Advisory / Consultancy: Torque; Advisory / Consultancy: Nektar Therapeutics; Advisory / Consultancy: HUYA Pharmaceuticals. A.R. Hansen: Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy: Merck; Advisory / Consultancy: GSK; Advisory / Consultancy: BMS; Advisory / Consultancy: Novartis; Advisory / Consultancy: Boston Biomedical; Advisory / Consultancy: Medimmune; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Boehringer-Ingelheim. M. Maio: Honoraria (self), Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses, Non-remunerated activity/ies, Press Conference: BMS; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses, Non-remunerated activity/ies, Press Conference: Merck; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Eli Lilly; Honoraria (institution): AstraZeneca; Honoraria (institution): Patients’ fee to the University Hospital of Siena. A. Italiano: Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy: Epizyme; Advisory / Consultancy: ImmuneDesign; Advisory / Consultancy: Eli Lily; Advisory / Consultancy: Novartis; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): PharmaMar. J.R. Bauman: Advisory / Consultancy: Pfizer. M. Chisamore: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co. Inc. H. Zhou: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxoSmithKline. C. Ellis: Full / Part-time employment: GlaxoSmithKline; Shareholder / Stockholder / Stock options: GlaxoSmithKline. M. Ballas: Full / Part-time employment: GlaxoSmithKline; Shareholder / Stockholder / Stock options: GlaxoSmithKline. A. Hoos: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxoSmithKline. E. Angevin: Advisory / Consultancy: GSK; Advisory / Consultancy: MSD; Advisory / Consultancy: Medimmune; Advisory / Consultancy: Celgene; Travel / Accommodation / Expenses: AbbVie; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Sanofi; Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: MedImmune; Travel / Accommodation / Expenses: BMS; Travel / Accommodation / Expenses: Celgene; Travel / Accommodation / Expenses: Innate Pharma. All other 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.

Background ErbB3, a heterodimeric partner of EGFR or ErbB2, is activated by heregulin binding in various cancers. ISU104, blocking ErbB3 activation and dimerization, showed anti-tumor effects in various preclinical models as mono- or combination-therapy. Methods In the part 1, we enrolled the patients with advanced solid tumor who were refractory to standard treatments. Study was conducted with a standard 3 + 3 dose escalation scheme at 5 different doses (1, 3, 5, 10, 20 mg/kg/day). Dose-limiting toxicities (DLTs) were evaluated during the 1st Cycle of 28 days. Thereafter, ISU104 was given weekly, and tumor response was assessed every 8 weeks. Blood samples for pharmacokinetics (PK) and immunogenicity studies were performed. Results In the part 1, 15 patients (13 males, 2 females) were enrolled. Median age was 54 (range 36–96). No DLT was observed even at the maximum dose (20mg/kg/day). The most common drug-related adverse events (AEs) were oral mucositis (n = 3), pruritus (n = 2), diarrhea (n = 2), and fatigue (n = 2), but of which were grade 1. Only two grade 3 AEs were noted; asthenia (n = 1) and anemia (n = 1). Thirteen subjects were assessable; 7 stable diseases and 1 partial response (table). One responder lasted up to 40 weeks. Drug clearances tend to decrease (0.77±0.41 ml/h/kg at 1 mg/kg; 0.20±0.03 ml/h/kg at 20 mg/kg) and half-lives to increase (44.50±5.74 h at 1 mg/kg; 269.86±19.08 h at 20 mg/kg) as dose is increased. PK analysis and modeling suggested target-mediated clearance of ISU104 and saturation of target binding at 3 mg/kg, and the dosing regimen for the part 2 of the current study, which would be 20 mg/kg tri-weekly. Table . 454PD Cancer type Hypopharynx Hypopharynx * Rectal Breast Palate Rectal Submandibular Parotid Colon NSCLC Esophagus Tonsil Esophagus Best response PR SD SD SD SD SD SD SD PD PD PD PD PD Maximum change in tumor size (target lesion) (%) -60.5 -21.9 -21.4 -8.1 0.5 2.8 3.6 6.9 13.2 13.5 17.4 28.1 73.7 * Double primary with esophagus Conclusions Intravenous administrations of ISU104 were well tolerated up to 20 mg/kg/day without DLT, and showed disease control rate of 60.0%. Safety and efficacy of ISU104 as mono- or combination-therapy and potential biomarkers will be further explored in head and neck, colorectal and breast cancers. Clinical trial identification NCT03552406. Legal entity responsible for the study ISU Abxis. Funding KDDF: Korea Drug Development Fund. Disclosure B. Keam: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: MSD; Advisory / Consultancy: Genexin; Research grant / Funding (self): ONO; Research grant / Funding (self): MSD; Research grant / Funding (institution): AstraZeneca. T.M. Kim: Research grant / Funding (institution): AstraZeneca. K. Park: Advisory / Consultancy: Astellas Pharma; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: Lilly; Advisory / Consultancy: Hanmi; Advisory / Consultancy: Kyowa Hakko Kirin; Advisory / Consultancy: Norvatis; Advisory / Consultancy: Ono Pharmaceutical; Advisory / Consultancy: Roche; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: GlaxoSmithKline; Advisory / Consultancy: MSD; Speaker Bureau / Expert testimony: AZD. J.S. Ahn: Advisory / Consultancy: Samsung Bioepis; Honoraria (institution): Menarini; Honoraria (institution): Amgen; Honoraria (institution): Pfizer; Honoraria (institution): AstraZeneca; Honoraria (institution): Roche; Honoraria (institution): Janssen; Honoraria (institution): MSD; Honoraria (institution): Bristol-Myers Squibb-Ono Pharmaceutical; Honoraria (institution): Eisai; Honoraria (institution): Boehringer Ingelheim. J. Juhn: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: ISU Abxis. S. Kim: Full / Part-time employment: ISU Abxis. S. Hong: Shareholder / Stockholder / Stock options, Full / Part-time employment: ISU ABXIS. M. Ahn: Honoraria (institution), Advisory / Consultancy: AstraZeneca; Honoraria (institution), Advisory / Consultancy: BMS; Honoraria (institution), Advisory / Consultancy: MSD; Honoraria (institution): ONO; Honoraria (institution), Advisory / Consultancy: Roche; Advisory / Consultancy: TAKEDA; Advisory / Consultancy: Novartis; Advisory / Consultancy: Alpha pharmaceutical. All other authors have declared no conflicts of interest.

Background In the current oncology new drug development, evaluation of the proof of concept (POC) in first in human trials (FIH) is essential. The serial tumor biopsy (i.e., pre-treatment biopsy and post-treatment biopsy) has supported us investigating POC, and had substantial potential to explore the target indication as well as optimizing the developmental strategy. However, regardless of protocol requirement, it has been often invasive to cancer patients and resulted in uninspired outcome, due to its tumor location or patients’ condition. We evaluated our performance of serial tumor biopsies in FIH trials. Methods From July 1995 to April 2019, we retrospectively reviewed the FIH trials conducted at our center and analyzed the acquisition rate of serial tumor biopsies as well as the pathological diagnostic accuracy. The acquisition rate was calculated as the number of samples taken per the number of samples required in their protocol. Results Of phase I trials (n = 147) including 46 FIH trials, 12 FIH trials (n = 80) since 2015 were mandatory for serial tumor biopsies (including single tumor biopsy in 3 trials). Out of the 108 biopsies taken, the primary tumor site were as follows; colorectal (n = 20), lung (n = 16), pancreas (n = 11), breast (n = 5) and others (n = 28). In regards to technical procedure, ultrasound-guided needle biopsy (n = 46), bronchoscopy (n = 33), percutaneous biopsy (n = 19), CT-guided needle biopsy (n = 8) and endoscopy (n = 2) were performed. The biopsy sites were liver (n = 37), lung (n = 24), lymph nodes (n = 24), skin and soft tissue (n = 17) and others (n = 6). The acquisition rate of tumor biopsies mandatory in the 12 FIH trials was 96.4% (95%CI: 91.2 – 98.6%), and 79 out of 85 samples could achieve definite pathological diagnosis with the accuracy rate of 92.9% (95%CI: 85.4-96.7%). Paired pathological diagnosis were also available with the rate of 88.5% (95%CI: 71.0-96.0%). The major reason missing biopsy (n = 19) was the study termination due to the disease progression (68.4%). Two adverse events of grade 2 were experienced during biopsies. Conclusions This analysis demonstrated the outstanding performance of serial tumor biopsy in FIH trials. We consider it properly contributes to the global standard in early drug development. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure T. Shimizu: Advisory / Consultancy: Takeda Oncology; Honoraria (self): Ono Pharmaceutical; Honoraria (self): ONO Pharma Taiwan CO.; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Chugai Pharmaceutical; Research grant / Funding (self): Takeda Oncology; Research grant / Funding (self): PharmaMar; Research grant / Funding (self): Bristol-Myers Squibb Japan; Research grant / Funding (self): Daiichi Sankyo; Research grant / Funding (self): SymBio Pharmaceuticals; Research grant / Funding (self): Five Prime Therapeutics; Research grant / Funding (self): 3D Medicine; Research grant / Funding (self): Chordia Therapeutics; Research grant / Funding (self): AbbVie; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Eli Lilly; Research grant / Funding (self): Novartis. N. Yamamoto: Advisory / Consultancy, Research grant / Funding (self): Eisai; Advisory / Consultancy, Research grant / Funding (self): Takeda; Advisory / Consultancy: Otsuka Pharmaceutica; Speaker Bureau / Expert testimony, Research grant / Funding (self): Bristol-Myers Squibb Japan; Speaker Bureau / Expert testimony, Research grant / Funding (self): Pfizer; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony, Research grant / Funding (self): Lilly Japan; Speaker Bureau / Expert testimony, Research grant / Funding (self): Ono Pharmaceutical; Speaker Bureau / Expert testimony, Research grant / Funding (self): Chugai Pharmaceutical; Research grant / Funding (self): Taiho Pharmaceutical; Research grant / Funding (self): Astellas Pharma; Research grant / Funding (self): Novartis; Research grant / Funding (self): Daiichi Sankyo; Advisory / Consultancy, Research grant / Funding (self): Boehringer Ingelheim; Research grant / Funding (self): Kyowa Hakko Kirin; Research grant / Funding (self): Bayer; Research grant / Funding (self): AbbVie; Research grant / Funding (self): Janssen Pharma; Research grant / Funding (self): MSD; Research grant / Funding (self): MERCK. All other authors have declared no conflicts of interest.

Background Netrin-1, a dependence receptor ligand, is overexpressed in many cancers and leads to resistance to cell death. In preclinical studies, targeting netrin-1 with the humanized anti-netrin-1 antibody NP137 inhibits tumor growth and metastasis. Methods Adults with advanced, refractory solid tumors received NP137 IV Q2W, starting at 1 mg/kg. Dose was escalated using a rapid titration design followed by a model-based design with 3-6 pts per cohort; Additional patients (pts) were enrolled in 4 biomarker cohorts, at dose levels that had been declared safe, starting at 6 mg/kg, and underwent paired biopsies for pharmacodynamics (PD) purposes. Results Nineteen pts were enrolled in 7 dose levels (1 to 20 mg/kg). No DLTs were observed but 11 (58%) had infusion related reactions (IRR) of grade 1-2 severity, all at doses of 4 mg/kg and above. Twenty-three pts were enrolled in the biomarker cohorts (up to 6 pts per cohort), and 18 (78%) experienced IRR. To date, 9 of 42 pts (21%) experienced at least one grade ≥ 3 drug related AE and 9 pts had at least one related SAEs (total of 14 SAEs including 10 IRRs and ischemic stroke, back pain, hyponatremia, pneumonia, n = 1 each). Among 36 pts with at least one follow-up RECIST 1.1 assessment, 1 pt with endometrial carcinoma had a confirmed PR (> 6 months to date, >50%, 14mg/kg) and 6 pts had SD at 3 months including one long-lasting SD over 1 year (cervical carcinoma, 6mg/kg) with a shrinkage > 30% in an irradiated lesion. To date, 3 pts are still on treatment (median duration: 43.0 days [7.0; 476.0]). Serum NP137 concentrations had biphasic disposition characteristic of both target and non-target-mediated clearances. PK data up to 5 consecutive cycles showed no evidence of NP137 accumulation. No ADAs were noted. RNAseq data on paired biopsies suggests that NP137 triggers a shift toward a more epithelial phenotype. Based on available data, 14mg/kg Q2W was selected as the RP2D. Recruitment in the extension phase is ongoing in gynecological tumors. Conclusions NP137 was well-tolerated, with mild to moderate IRR as the most frequent treatment-related AEs and showed encouraging signs of clinical activity. Updated data will be presented at the meeting. Clinical trial identification NCT02977195. Legal entity responsible for the study Centre Leon Berard. Funding Netris Pharma. Disclosure P. Cassier: Honoraria (self), Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Research grant / Funding (institution), Travel / Accommodation / Expenses: Lilly; Honoraria (self), Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Abbvie; Honoraria (self), Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche. Y. Courbebaisse: Full / Part-time employment: Netris Pharma. S. Depil: Advisory / Consultancy: Cellectis; Advisory / Consultancy: Netris Pharma; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: PDCLine Pharma; Advisory / Consultancy: Erytech; Advisory / Consultancy: Servier. J. Delord: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): BMS; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Novartis; Honoraria (self), Research grant / Funding (self): Roche/Genentech; Advisory / Consultancy: EMD Serono; Research grant / Funding (self): AstraZeneca. I.L. Ray-Coquard: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Astr-Zeneca; Honoraria (self), Advisory / Consultancy: Clovis; Honoraria (self), Advisory / Consultancy: Tesaro; Honoraria (self), Advisory / Consultancy: PharmaMar; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Research grant / Funding (self): MSD; Advisory / Consultancy: Pfizer; Advisory / Consultancy: GenMab. B. Ducarouge: Full / Part-time employment: Netris Pharma. P. Mehlen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Netris Pharma. J. Blay: Non-remunerated activity/ies, uncompensated scientific advice: Netris Pharma. All other authors have declared no conflicts of interest.

Background TAS-117 is a novel highly potent and selective oral allosteric AKT inhibitor. This study investigated the safety, efficacy, pharmacokinetics, pharmacodynamics, and pharmacogenomics profiles of TAS-117 in patients (pts) with advanced solid tumors, for whom no standard treatment remains. Methods The primary objective was to evaluate the safety profile of TAS-117, including the identification of the maximum tolerated dose (MTD) and the recommended dose (RD) with regimen (RR) in a 21-day cycle. Dose escalation was assessed in a once-daily repeated dosing regimen (QD), starting at 4 mg/day, with an accelerated titration design. Dose-limiting toxicity (DLT) was evaluated in a first cycle. After RD and RR were determined, pts with endometrial cancer (EC) harboring PIK3CA or AKT gene alterations or ovarian clear cell carcinoma (OCC) were enrolled for further safety evaluation. Results TAS-117 was administered QD (n = 12) and in a 4 days on/3 days off regimen (4d/3d) (n = 10). The dose was escalated to 24 mg/day in QD dosing and 32 mg/day in 4d/3d; the MTD was not reached. The DLT was a grade 3 rash maculo-papular at 32 mg/day in 4d/3d dosing. The RD and RR were determined as TAS-117 24 mg/day and 4d/3d. As of 24 Apr 2019, 42 pts (15 with PIK3CA-mutated (mt) EC, 7 with AKT-altered EC, and 20 with OCC) were enrolled, and safety profiles were investigated. The common (≥30%) treatment-related adverse events (TRAEs) were rash maculo-papular (grade 3, observed in 42.5% of pts), stomatitis, hyperglycemia, white blood cell decrease, and neutrophil count decreased. Common TRAEs, especially rash maculo-papular, were manageable with dose reduction, dose interruption, or symptomatic therapy. TAS-117 exposure tended to increase in a dose-dependent matter. In efficacy-evaluable pts, objective responses were observed in 1 pt with PIK3CA-mt EC and 5 pts with OCC. The disease control rate was 61.5% in 13 pts with PIK3CA-mt EC, 80.0% in 5 pts with AKT-altered EC, and 37.5% in 16 pts with OCC. Conclusions TAS-117 had a manageable safety profile with clinical antitumor activity in pts with advanced solid tumors. Further investigation of the drug in a combination therapy is in preparation. Clinical trial identification JapicCTI-152780. Legal entity responsible for the study Taiho Pharmaceutical Co., Ltd. Funding Has not received any funding. Disclosure S. Takahashi: Honoraria (self), Research grant / Funding (self): Eisai; Honoraria (self): Bristol-Myers-Squibb; Honoraria (self), Research grant / Funding (self): Taiho; Honoraria (self): Bayer; Research grant / Funding (self): MSD; Research grant / Funding (self): Astrazeneka; Research grant / Funding (self): Quintiles; Research grant / Funding (self): IQVIA; Research grant / Funding (self): Daiichi-Sankyo; Research grant / Funding (self): Ono pharmaceutical. D. Aoki: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Taiho Pharmaceutical Co., Ltd.; Honoraria (self), Advisory / Consultancy: AstraZeneca K.K.; Honoraria (self), Research grant / Funding (institution): Chugai Pharmaceutical Co., Ltd.; Honoraria (self), Advisory / Consultancy: MSD K.K.. K. Yonemori: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eisai; Honoraria (self), Research grant / Funding (institution): Taiho; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Ono; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Chugai; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): ICON Japan; Research grant / Funding (institution): Kissei; Research grant / Funding (institution): Kyowa Hakko Kirin; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Nippon Kayaku; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): 3D MATRIX. H. Hara: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Chugai Pharma; Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck Serono; Honoraria (self): Yakult Honsha; Honoraria (self), Research grant / Funding (institution): Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Takeda; Honoraria (self): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): MSD; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Dainippon Sumitomo Pharma; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): LSK BioPharma; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Incyte. K. Hasegawa: Honoraria (self), Research grant / Funding (self): Daiichi-Sankyo; Honoraria (self): Chugai; Honoraria (self): Nippon Kayaku; Honoraria (self): Bayer; Honoraria (self): AstraZeneca; Advisory / Consultancy: MSD; Research grant / Funding (self): OncoTherapy Science; Research grant / Funding (self): Yakult Honsha. K. Takehara: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Kyowa Kirin; Speaker Bureau / Expert testimony: Taiho; Speaker Bureau / Expert testimony: Nippon Kayaku; Speaker Bureau / Expert testimony: Janssen; Speaker Bureau / Expert testimony: Treumo; Speaker Bureau / Expert testimony: Ono; Speaker Bureau / Expert testimony: Daiichi Sankyo; Speaker Bureau / Expert testimony: Chugai Pharma; Speaker Bureau / Expert testimony: Eisai. K. Harano: Honoraria (self): Eisai; Honoraria (self), Advisory / Consultancy: Taiho; Honoraria (self): AstraZeneca; Honoraria (self), Non-remunerated activity/ies: Chugai; Advisory / Consultancy: Takeda. E. Noguchi: Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self), Research grant / Funding (institution): Nippon Kayaku; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Chugai; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): ICON Japan; Research grant / Funding (institution): Kissei; Research grant / Funding (institution): Kyowa Hakko Kirin; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Ono; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Taiho; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): 3D MATRIX. T. Doi: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Chugai; Advisory / Consultancy, Research grant / Funding (institution): Merck Serono; Advisory / Consultancy: Otsuka; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy: Amgen; Advisory / Consultancy, Research grant / Funding (institution): Kyowa Hakko Kirin; Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy: AstraZeneka; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy, Research grant / Funding (institution): Daiichisankyo; Advisory / Consultancy, Research grant / Funding (institution): Dainippon Sumitomo; Advisory / Consultancy, Research grant / Funding (institution): Takeda; Advisory / Consultancy, Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Taiho, Zenyaku Kogyo, Astellas; Research grant / Funding (institution): Janssen, Eisai, Sanofi; Research grant / Funding (institution): NanoCarrier, Quintiles, Pfizer; Research grant / Funding (institution): Bristol-myers; Research grant / Funding (institution): Bristol-Myers-Squibb. All other authors have declared no conflicts of interest.

Background TP-0903 is a novel, oral small molecule AXL kinase inhibitor impacting oncogenesis and resistance. AXL is upregulated in many solid tumors and influences the mesenchymal phenotype, which drives resistance to targeted cancer therapeutics, traditional chemotherapies, and immuno-oncology agents. Methods A dose escalation study was performed to examine the safety and clinical activity of TP-0903 in patients with advanced solid tumors. Patients received oral TP-0903 once daily for 21 of 28-day cycles. Nine dose levels were explored using modified 3 + 3 dose escalation rules. The primary objective of the trial was to identify the maximum tolerated dose of TP-0903 prior to expanding into refractory colorectal, platinum refractory/resistant ovarian cancer and TP-0903 in combination with immunotherapy or EGFR tyrosine kinase inhibitor in immunotherapy-resistant tumors or non-small cell lung cancers. Potential biomarkers were evaluated using liquid biopsies and pre-and post-dose tumor biopsies will be reported. Results Thirty-six patients were enrolled between December 2016 and April 2019 receiving 1.5 to 37mg/m2 over 9 cohorts. The most frequently observed >Gr3 AEs were thrombocytopenia (3), anemia (2), nausea (2), syncope (2), and vomiting (2), all manageable with supportive care. Grade 4 thrombocytopenia was the dose limiting toxicity observed in one patient in cohort 8 (28 mg/m2), reoccurring as grade 3 thrombocytopenia in 2 patients in cohort 9 (37mg/m2) without meeting DLT criteria. Patients are currently still ongoing in cohort 9. Eleven patients, (11/36, 30.6%), had stable disease with a median duration of 3.7 months (range 1.6 to 7.4+ months). Baseline serum soluble AXL of all enrolled patients was determined by immunoassay and indicated higher levels in patients with documented stable disease vs. progressive disease (p = 0.0332). Conclusions The oral small molecule AXL kinase inhibitor TP-0903 is well tolerated with a manageable safety profile. Hematologic toxicity was observed as a DLT. Future studies will evaluate the role of TP0903 in selected disease cohorts as monotherapy and in combination. Serum soluble AXL will be evaluated as a potential predictive biomarker of response. Clinical trial identification NCT: 02729298. Legal entity responsible for the study Tolero Pharmaceuticals, Inc. Funding Tolero Pharmaceuticals, Inc. Disclosure J. Sarantopoulos: Research grant / Funding (institution): Tolero. G. Fotopoulos: Research grant / Funding (institution): Tolero Pharmaceuticals. F.Y. Tsai: Advisory / Consultancy: Tempus Lab; Officer / Board of Directors, Co-Founder: Caremission LLC; Shareholder / Stockholder / Stock options: Salarius Pharmaceuticals. M.S. Beg: Research grant / Funding (institution): Tolero Pharmaceuticals. A.A. Adjei: Research grant / Funding (institution): Tolero Pharmaceuticals. Y. Lou: Research grant / Funding (institution): Tolero Pharmaceuticals; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Stem Centrx; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): Vaccinex; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): MacroGenics. M. Seetharam: Research grant / Funding (institution): Tolero Pharmaceuticals. M.A. Villalona-Calero: Research grant / Funding (institution): Tolero Pharmaceuticals; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Bristol Meyers; Research grant / Funding (institution): Novocure; Research grant / Funding (institution): Guardant. J. Melear: Research grant / Funding (institution): Tolero Pharmaceuticals. M. Janat-Amsbury: Full / Part-time employment: Tolero Pharmaceuticals. H. Beever: Full / Part-time employment: Tolero Pharmaceuticals. L. Mouritsen: Full / Part-time employment: Tolero Pharmaceuticals. M. Wade: Full / Part-time employment: Tolero Pharmaceuticals. B.V. Bryan: Full / Part-time employment: Tolero Pharmaceuticals. D.J. Bearss: Leadership role, Full / Part-time employment: Tolero Pharmaceuticals.

Background ImmTAC® bispecific molecules are unique TCR–anti-CD3 agents that redirect T cells against intracellular antigens, in contrast to antibody-based therapies, which are limited to extracellular antigens. The most advanced ImmTAC, tebentafusp (IMCgp100), against melanocyte-associated lineage antigen gp100, has shown monotherapy responses in advanced melanoma, a solid tumor. In contrast, bispecific antibodies have shown activity in hematologic cancers but appear less active in solid tumors. ImmTAC molecules recognize a specific peptide presented on a defined Class I HLA molecule via an affinity enhanced, engineered, soluble TCR. Through the addition of an anti-CD3 scFv domain fused to the TCR targeting domain, an ImmTAC can redirect T cell activity against cancer cells, regardless of the specificity of the T cell. IMCnyeso is an ImmTAC against NY-ESO-1/LAGE-1A, which are cancer testis antigens expressed in a variety of solid malignancies, but with very low or absent normal tissue expression. Trial design IMCnyeso-101 is a multi-center, open-label, first-in-human study of IMCnyeso in HLA-A*02:01-positive patients with NY-ESO-1- and/or LAGE-1A-positive advanced NSCLC, synovial sarcoma, melanoma, or urothelial carcinoma. The study includes dose escalation (Bayesian logistic regression models) and expansion for IMCnyeso monotherapy (QW), followed by expansion into indication specific arms to test for signs of efficacy in defined patient cohorts. Primary endpoints are establishing MTD/RP2D and safety and tolerability. Secondary endpoints include: characterization of PK and ADA, efficacy by RECIST v1.1 (PFS, ORR and DOR) and OS. The dose escalation portion of the study is in progress. The trial continues to enroll; NCT number NCT03515551. Clinical trial identification NCT03515551. Legal entity responsible for the study Immunocore. Funding Immunocore. Disclosure J. Lopez: Research grant / Funding (institution), During the conduct of the study: Immunocore, Roche, Genentech; Advisory / Consultancy, Outside the submitted work: Novartis (personal fees); Research grant / Funding (institution), Outside the submitted work: MSD; Research grant / Funding (institution), Outside the submitted work (grant and non-financial support): Basilea; Advisory / Consultancy, Research grant / Funding (institution), Outside the submitted work: Genmab. T. Sato: Advisory / Consultancy: Immunocore; Advisory / Consultancy: IDEAYA Biosciences; Advisory / Consultancy: Neon Therapeutics, Inc. F. Thistlethwaite: Honoraria (self), Achilles Therapeutics. B. Van Tine: Honoraria (institution), Advisory / Consultancy: Immunocore ; Advisory / Consultancy: Epizyme; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy: CytRX; Advisory / Consultancy, Speaker Bureau / Expert testimony: Janssen; Speaker Bureau / Expert testimony: Caris; Advisory / Consultancy: Immune Design; Advisory / Consultancy: Daiichi Sankyo; Speaker Bureau / Expert testimony: Adaptimmune; Advisory / Consultancy: Plexxicon; Advisory / Consultancy: Bayer; Advisory / Consultancy, Research grant / Funding (self): Pfizer; Research grant / Funding (self): Merck; Research grant / Funding (self): Tracon. J.A. Rodon: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy: Eli Lilly; Honoraria (self), Advisory / Consultancy: Orion Pharmaceuticals; Advisory / Consultancy: Servier Pharma; Honoraria (self), Advisory / Consultancy: Peptomyc; Honoraria (self): Merck Sharp; Advisory / Consultancy: Merck Sharp & Dome; Advisory / Consultancy: Kelun Pharma/Klus Pharma; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Roche Pharma; Advisory / Consultancy: Elipses Pharma; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Spectrum Pharmaceuticals; Research grant / Funding (institution): Tocagen; Research grant / Funding (institution): Symphogen; Research grant / Funding (institution): BioAtla; Research grant / Funding (institution): GenMab; Research grant / Funding (institution): CytomX; Research grant / Funding (institution): Kelun-Biotech; Research grant / Funding (institution): Takeda-Millenium; Research grant / Funding (institution): Glaxosmithkline; Research grant / Funding (institution): Ipsen. J. Dukes: Shareholder / Stockholder / Stock options, Full / Part-time employment: Immunocore Ltd. R. Easton: Shareholder / Stockholder / Stock options, Full / Part-time employment: Immunocore. S. Marshall: Shareholder / Stockholder / Stock options, Full / Part-time employment: Immunocore. All other authors have declared no conflicts of interest.