A phase Ib/II, multicenter, open-label, dose-escalation, and dose-expansion study evaluating trastuzumab deruxtecan (T-DXd, DS-8201) monotherapy and combinations in patients with HER2-overexpressing gastric cancer (DESTINY-Gastric03).

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. TPS261-TPS261
Author(s):  
Yelena Y. Janjigian ◽  
Natasha Viglianti ◽  
Feng Liu ◽  
Ariadna Mendoza-Naranjo ◽  
Liz Croydon
Keyword(s):  
Gastric Cancer ◽  
Dose Escalation ◽  
Topoisomerase I ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Locally Advanced ◽  
Metastatic Gastric Cancer ◽  
Her2 Status ◽  
Open Label ◽  
Phase 1B

TPS261 Background: For patients (pts) with HER2-overexpressing metastatic gastric cancer, trastuzumab + chemotherapy is a standard first-line option but provides only a modest overall survival (OS) benefit vs chemotherapy. T-DXd is an antibody-drug conjugate consisting of an anti-HER2 antibody, cleavable tetrapeptide-based linker, and a membrane-permeable topoisomerase I inhibitor payload. Results from a phase 1 trial showed promising antitumor activity (confirmed objective response rate [ORR], 43.2%) in pts with heavily pretreated HER2+ metastatic gastric cancer who received T-DXd (5.4 or 6.4 mg/kg; Shitara K, et al. Lancet Oncol. 2019;20:827-836). Here we describe the phase 1b/2 DESTINY-Gastric03 trial (NCT04379596) evaluating T-DXd monotherapy and combinations in pts with HER2-overexpressing gastric cancer. Methods: This is an open-label, multicenter, 2-part, phase 1b/2 study in pts with HER2-overexpressing (immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization positive) locally advanced, unresectable or metastatic gastric or gastroesophageal junction cancer. In part 1 (dose escalation), pts who had received prior trastuzumab-containing therapy will be assigned to 1 of 5 arms: (1) T-DXd + 5-fluorouracil (5-FU); (2) T-DXd + capecitabine (C); (3) T-DXd + durvalumab; (4) T-DXd + 5-FU or C + oxaliplatin (Ox); or (5) T-DXd + 5-FU or C + durvalumab. In part 2 (dose expansion), pts with no prior treatment for metastatic disease will be randomized across 4 arms: (1) T-DXd; (2) trastuzumab + 5-FU or C + Ox or cisplatin; (3) T-DXd + 5-FU or C ± Ox; or (4) T-DXd + 5-FU or C + durvalumab. In part 2, pts will be stratified by HER2 status. Primary endpoints are safety, determination of recommended phase 2 doses (part 1), and investigator-assessed confirmed ORR per RECIST v1.1 (part 2). Secondary endpoints include confirmed ORR (part 1), disease control rate, duration of response, progression-free survival (all per investigator), OS, safety (part 2), pharmacokinetics, and immunogenicity. Clinical trial information: NCT04379596.

Phase III study of first-line zolbetuximab + CAPOX versus placebo + CAPOX in Claudin 18.2+/HER2−advanced or metastatic gastric or gastroesophageal junction adenocarcinoma: GLOW.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS4648-TPS4648
Author(s):  
Manish A. Shah ◽  
Jaffer A. Ajani ◽  
Salah-Eddin Al-Batran ◽  
Yung-Jue Bang ◽  
Daniel Catenacci ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Locally Advanced ◽  
Phase Iii ◽  
Controlled Study ◽  
Her2 Status ◽  
First Line ◽  
Double Blind ◽  
Junction Protein

TPS4648 Background: Gastric cancer is the fourth leading cause of cancer death worldwide. Capecitabine + oxaliplatin (CAPOX) is a standard first-line treatment for advanced gastric cancer. Claudin (CLDN)18.2 has emerged as a promising targetable biomarker. In healthy tissue, CLDN18.2, a tight junction protein, is confined to gastric mucosa (ie, cells in the pit and base regions of gastric glands). Upon malignant transformation, structural loss in gastric or gastroesophageal junction (G/GEJ) adenocarcinoma cells may allow antibodies more access to previously unavailable CLDN18.2. Zolbetuximab is a chimeric IgG1 monoclonal antibody that specifically binds to CLDN18.2 and mediates cell death through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Results of a phase 2 study (NCT01630083) showed prolonged survival of patients with CLDN18.2-positive (CLDN18.2+) advanced G/GEJ adenocarcinoma treated with zolbetuximab + epirubicin, oxaliplatin, and capecitabine (EOX) vs EOX alone. Methods: This phase 3, double-blind, placebo-controlled study (NCT03653507) will enroll ~500 adult patients from global sites. Patients are required to have CLDN18.2+/HER2− locally advanced unresectable or metastatic G or GEJ adenocarcinoma that is radiographically evaluable per RECIST v1.1. Patients are not permitted to have received prior treatment with chemotherapy for advanced or metastatic G or GEJ adenocarcinoma. Patients will be randomly assigned 1:1 to receive either zolbetuximab plus CAPOX or placebo plus CAPOX. Randomization will be stratified by region (Asia vs non-Asia), number of metastatic sites (0 to 2 vs ≥3), and prior gastrectomy (yes vs no). Zolbetuximab will be administered at a loading dose of 800 mg/m2 IV on Cycle 1 Day 1 followed by 600 mg/m2 IV every 3 weeks. Central testing of tumor tissue will determine CLDN18.2 and HER2 status (if unknown); patients will be considered CLDN18.2+ if ≥75% of tumor cells demonstrate moderate-to-strong membranous immunohistochemical staining. The primary objective is to compare progression-free survival between treatment arms. Secondary endpoints are overall survival; objective response rate; duration of response; and the safety/tolerability, pharmacokinetics, and immunogenicity of zolbetuximab. As of January 31, 2020, 127 sites were active and open to enrollment. Clinical trial information: NCT03653507 .

Efficacy of patupilone in advanced local or metastatic gastric cancer: A phase IIa trial

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4069-4069 ◽  
Author(s):  
K. W. Hsin ◽  
M. Boyer ◽  
M. Ducreux ◽  
M. Liu ◽  
R. Soo ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Disease Progression ◽  
Performance Status ◽  
Objective Response ◽  
Locally Advanced ◽  
Outlet Obstruction ◽  
Metastatic Gastric Cancer ◽  
Open Label ◽  
Disease Stabilization

4069 Background: Although the use of taxanes has produced encouraging response rates in patients with advanced local or metastatic gastric cancer, outcomes remain unsatisfactory. Patupilone (EPO906; epothilone B), a novel microtubule stabilizer, has demonstrated anti-tumor activity against a broad range of tumors in vitro and in animal models. The present trial evaluated the efficacy of patupilone in patients with locally advanced or metastatic gastric cancer. Methods: Patients with confirmed gastric adenocarcinoma (defined by RECIST) received patupilone 2.5 mg/m2/wk by single 5- to 7-minute IV infusion for 3 weeks, followed by 1 week off (4-week cycle). Additional inclusion criteria: WHO performance status ≤2, age ≥18 years, life expectancy ≥3 months, and no major hematologic, renal, or hepatic impairment. The primary objective of this open-label, single-arm, 2-stage, multicenter study was to determine the objective response rate (using RECIST) of treatment with patupilone in this population. Results: All 22 patients enrolled were evaluable. Mean age was 61.1 years, 63.6% were men, and 72.7% were oriental. Of 18 patients (81.8%) who completed the study, 10 (45.5%) had disease progression and 8 (36.4%) died from the disease; of 4 discontinuations, 3 were due to adverse events (AEs) and 1 to abnormal alkaline phosphatase. Overall response: 2 patients had partial responses, 6 disease stabilization, 12 disease progression, and 2 unknown. The duration of response in the 2 partial responders was 176 and 113+ days, with the latter censored at 113 days. The most frequently reported AEs were diarrhea (n = 18), nausea (n = 14), vomiting (n = 13), abdominal pain (n = 10), and fatigue (n = 10). Of these AEs, 9 were grade 3 (4 diarrhea, 3 vomiting, 1 nausea, and 1 fatigue) and 2 were grade 4 (1 nausea and 1 vomiting). Grade 4 AEs also included 1 gastric outlet obstruction and 1 dehydration. Conclusions: Patupilone resulted in an overall tumor response/disease stabilization rate of 36.4%, was well tolerated, and may prove to be a viable alternative to taxane treatment in advanced local/metastatic gastric cancer. [Table: see text]

A phase Ia/Ib, open label, multicenter, dose-escalation study of BI 907828 (MDM2-p53 antagonist) in adult patients with advanced or metastatic solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS3166-TPS3166 ◽  
Author(s):  
Curtis Robert Chong ◽  
Todd Michael Bauer ◽  
Scott Andrew Laurie ◽  
Manish R. Patel ◽  
Noboru Yamamoto ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Treatment Cycle ◽  
Objective Response ◽  
Locally Advanced ◽  
Negative Regulator ◽  
Recommended Dose ◽  
Open Label ◽  
Number Of Patients ◽  
Phase 1B

TPS3166 Background: Inactivation of tumor protein 53 (TP53) is a central mechanism of tumors to promote survival and proliferation. The murine double minute 2 ( MDM2) oncogene is the primary cellular negative regulator of TP53. Small molecule inhibitors of the MDM2-p53 interaction are currently being evaluated in clinical trials as new anti-cancer drugs, and clinical data published to date support the rationale to target MDM2-amplified tumors. BI 907828 is a potent MDM2-p53 antagonist that has shown efficacy in mouse models of human cancer. Methods: NCT03449381 is a Phase 1a/1b, open-label, multicenter, dose-escalation trial of BI 907828 in patients aged ≥18 years with advanced/metastatic solid tumors. Primary objectives of the Phase 1a (dose-escalation) part are to determine: the maximum tolerated dose (MTD) of BI 907828 based on dose-limiting toxicities (DLTs) during the first treatment cycle; the recommended dose for expansion (RDE); safety and tolerability. Patients in Arm A will receive one dose of BI 907828 every 21 days, and patients in Arm B one dose on Days 1 and 8, every 28 days. Secondary objectives include pharmacokinetics (PK), pharmacodynamics (PD) [GDF-15 induction in plasma], and preliminary anti-tumor activity. Primary endpoints are the number of patients with DLTs during the first treatment cycle, and the MTD. Phase 1a will include ≈50 evaluable patients with locally advanced or metastatic solid tumors with either a known TP53 wild type (wt) status or unknown TP53 status, regardless of MDM2 amplification status at the time of study entry. The main objectives of Phase 1b (expansion cohorts) are to assess efficacy, safety, and PK profiles at the RDE, and to determine the recommended dose for Phase 2. The primary endpoint is objective response, where best response is determined according to RECIST v1.1, or RANO criteria for patients with glioblastoma. Phase 1b will include up to 150 evaluable patients with TP53 wt tumors, assigned to four different cohorts, including non-squamous NSCLC, soft tissue sarcoma, glioblastoma, urothelial carcinoma, and solid tumors with brain metastases. As of 8th February 2019, 11 patients have been enrolled. Clinical trial information: NCT03449381.

Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma: A randomized, phase II, multicenter, open-label study (DESTINY-Gastric01).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4513-4513 ◽  
Author(s):  
Kohei Shitara ◽  
Yung-Jue Bang ◽  
Satoru Iwasa ◽  
Naotoshi Sugimoto ◽  
Min-hee Ryu ◽  
...  
Keyword(s):  
Topoisomerase I ◽  
Phase 1 ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Progression Free Survival ◽  
Her2 Status ◽  
Antibody Drug Conjugate ◽  
Her2 Positive ◽  
Open Label ◽  
Grade 3

4513 Background: T-DXd is an antibody-drug conjugate composed of an anti-HER2 antibody, cleavable tetrapeptide-based linker, and topoisomerase I inhibitor. In a phase 1 trial of T-DXd (5.4 or 6.4 mg/kg), the objective response rate (ORR) was 43.2% (19/44) and median progression-free survival (mPFS) was 5.6 mo in patients with advanced HER2+ gastric cancer (GC). DESTINY-Gastric01 (DS8201-A-J202; NCT03329690) is an open-label, multicenter, randomized, phase 2 study of T-DXd in HER2-expressing advanced GC or GEJ adenocarcinoma; results are from the primary analyses for ORR and interim overall survival (OS) in HER2+ patients. Methods: Patients with centrally confirmed HER2+ (IHC 3+ or IHC 2+/ISH+ on archival tissue) GC that progressed on ≥ 2 prior lines were randomized 2:1 (T-DXd 6.4 mg/kg q3w or physician’s choice [PC] irinotecan or paclitaxel). All patients received prior HER2 therapy. Stratification factors were region, ECOG PS (0;1), and HER2 status. The primary endpoint was unconfirmed ORR by independent central review. Secondary endpoints were OS (alpha controlled), PFS, disease control rate (DCR), duration of response (DOR), and safety. Results: 187 patients received T-DXd (n = 125) or PC (n = 62 [55 irinotecan; 7 paclitaxel]); 79.7% Japan, 20.3% Korea. Patients had a median of 2 prior lines of therapy, and 44.4% had ≥ 3. At data cutoff (8 Nov 2019), 22.4% of T-DXd and 4.8% of PC patients remained on treatment. ORR was 51.3% (61/119; 11 CR and 50 PR) with T-DXd vs 14.3% (8/56; all PR) with PC ( P < .0001); confirmed ORR, 42.9% vs 12.5% ( P < .0001); DCR, 85.7% vs 62.5% ( P = .0005); mDOR, 11.3 vs 3.9 mo; mPFS, 5.6 vs 3.5 mo (HR, 0.47 [95% CI, 0.31-0.71]; P = .0003). OS was significantly prolonged with T-DXd (mOS, 12.5 vs 8.4 mo; HR, 0.59 [95% CI, 0.39-0.88]; P = .0097; prespecified O'Brien Fleming boundary, P = .0202); 12-month OS, 52.1% vs 28.9%. Grade ≥ 3 AEs occurred in 85.6% of patients with T-DXd vs 56.5% with PC; the most common were neutrophil count decreased (51.2%; 24.2%), anemia (37.6%; 22.6%), and white blood cell count decreased (20.8%; 11.3%). 12 patients (9.6%) had T-DXd–related interstitial lung disease (ILD; 2 grade 3, 1 grade 4, no grade 5) vs 0 with PC. 1 drug-related death (pneumonia [non-ILD] in the T-DXd arm) occurred. Conclusions: T-DXd demonstrated statistically significant and clinically meaningful improvements in ORR and OS compared with standard chemotherapy (paclitaxel or irinotecan) in patients with HER2+ advanced gastric or GEJ adenocarcinoma. Clinical trial information: NCT03329690 .

Phase I study of concomitant pemetrexed and cisplatin plus radiation in patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) carcinomas.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 145-145
Author(s):  
Hani M. Babiker ◽  
Andrew I. Kovoor ◽  
Myke R. Green ◽  
Tomislav Dragovich ◽  
Thomas David Brown ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Gastroesophageal Junction ◽  
Locally Advanced ◽  
Stage Iv ◽  
Complete Response ◽  
Stage Iii ◽  
Weekly Schedule ◽  
Open Label ◽  
Weekly Cisplatin

145 Background: For the treatment of esophageal and GEJ carcinomas, weekly cisplatin (20-30 mg/m2 weekly; total dose approximately 100 mg/m2) has demonstrated efficacy and tolerability. Pemetrexed (PEM) in combination with carboplatin and concomitant radiation has also shown activity for treatment of esophageal or lung carcinomas on a tri-weekly schedule, despite tolerability when administered weekly. This is the first phase I trial sought to establish the MTD of bi-weekly PEM in combination with weekly cisplatin and radiation in patients with locally advanced/metastatic esophageal and GEJ carcinomas. Methods: This is a phase I single institution, open-label dose-escalation trial (Fibonacci 3+3). Patients with stage III/IV esophageal cancer received PEM on weeks 1, 3, and 5 at doses of 300, 500, 750 mg/m2 concurrently with weekly cisplatin (20 mg/m2) and 28 daily fractions of radiation (total 50.4 Gy). If 1 or fewer DLTs were observed, the next cohort of patients received an escalated dose. If two or more patients develop DLTs, then dose escalation halted. Primary endpoint was to determine MTD; secondary endpoints included tolerability and preliminary anti-tumor activity using RECIST (Version 1.0). Results: 8 patients enrolled; median age was 72 (range 56-81); 50% were male; ECOG range was 0-2; 50% of patients had adenocarcinoma (AC), remaining patients had squamous cell carcinoma (SCC); 63% and 37% of patients were stage III and IV, respectively. Dose-escalation proceeded to 750 mg/m2 dose. The MTD was determined to be 500 mg/m2 bi-weekly following grade 4 dehydration and esophagitis at 750 mg/m2. DLTs observed were grade 4 thrombosis and grade 3 neutropenia at 300 and 500 mg/m2, respectively. Complete response was observed in 50% of patients (75% stage III SCC), partial response in 25% of patients (100% Stage IV AC), and disease progression in 1 patient (Stage III AC). 38% of patients proceeded to surgery. Conclusions: The combination of bi-weekly pemetrexed 500 mg/m2 and weekly cisplatin concomitantly with radiation demonstrates efficacy in patients with advanced or metastatic GEJ carcinomas with manageable safety profile. Clinical trial information: NCT00701857.

Phase Ib trial of cabozantinib (C) in combination with atezolizumab (A) in patients (pts) with advanced hepatocellular carcinoma (HCC), gastric or gastroesophageal junction cancer (GC/GEJC), or colorectal cancer (CRC).

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. TPS478-TPS478 ◽  
Author(s):  
Kristen Renee Spencer ◽  
Giridharan Ramsingh ◽  
Nehal Mohamed ◽  
Sumanta K. Pal ◽  
Lorenza Rimassa
Keyword(s):  
Dose Escalation ◽  
Checkpoint Inhibitors ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Advanced Hepatocellular Carcinoma ◽  
Synergistic Activity ◽  
Advanced Hcc ◽  
Expansion Stage ◽  
Previously Treated ◽  
Phase 1B

TPS478 Background: C is an inhibitor of tyrosine kinases involved in tumor growth, angiogenesis, and immune regulation, including MET, VEGFR, and TAM family kinases (Tyro3, AXL, MER). Preclinical and clinical studies suggest that C promotes an immune-permissive tumor environment which may enhance response to checkpoint inhibitors such as the anti-PD-L1 mAb A. C significantly improved overall survival vs placebo in previously treated advanced HCC, and the combination of A and bevacizumab has shown synergistic activity in advanced HCC. Checkpoint inhibitors have shown clinical activity in advanced CRC primarily in pts with high microsatellite instability (MSI); combination with immune-modulating agents may enhance activity in pts with stable or low MSI. Likewise, combination therapy may improve response in pts with GC/GEJC resistant to standard chemotherapy. Here, we present the study design of an ongoing phase 1b trial which includes cohorts with advanced HCC, GC/GEJC, or CRC. Methods: This global, phase 1b, open-label trial will assess the safety, tolerability, preliminary efficacy, and pharmacokinetics of C in combination with A (NCT03170960). The study consists of a dose-escalation stage and an expansion stage. In the dose-escalation stage (3+3 design), a recommended C dose for combination with a standard dose of A will be established. In the expansion stage, 18 cohorts will be enrolled at the recommended dose of C + A including 3 cohorts with gastrointestinal cancers: (1) advanced HCC not previously treated with systemic therapy; (2) advanced GC/GEJC after progression on platinum- or fluoropyrimidine-containing therapy; and (3) advanced CRC after progression on fluoropyrimidine combined with oxaliplatin or irinotecan. Pts will continue treatment as long as they experience clinical benefit as judged by the investigator or until unacceptable toxicity. The primary objective of the expansion stage is the objective response rate for each cohort. Exploratory objectives include correlation of tumor and plasma biomarkers, immune cell profiles, and MSI status with clinical outcome. Clinical trial information: NCT03170960.

Results of the JAVELIN Gastric 100 phase 3 trial: avelumab maintenance following first-line (1L) chemotherapy (CTx) vs continuation of CTx for HER2− advanced gastric or gastroesophageal junction cancer (GC/GEJC).

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 278-278 ◽  
Author(s):  
Markus H. Moehler ◽  
Mikhail Dvorkin ◽  
Mustafa Ozguroglu ◽  
Min-hee Ryu ◽  
Alina Simona Muntean ◽  
...  
Keyword(s):  
Gastroesophageal Junction ◽  
Objective Response ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Clinical Activity ◽  
Primary Analysis ◽  
Open Label ◽  
Phase 3 ◽  
Post Induction

278 Background: We report the primary analysis of JAVELIN Gastric 100, which compared avelumab (anti–PD-L1) maintenance after 1L CTx vs continued CTx in patients (pts) with GC/GEJC. Methods: In this global, open-label, phase 3 trial (NCT02625610), eligible pts had previously untreated, unresectable, locally advanced/metastatic (LA/M) HER2− GC/GEJC. Pts without progressive disease (PD) after 12 weeks of 1L oxaliplatin/fluoropyrimidine induction were randomized 1:1 to avelumab 10 mg/kg Q2W switch maintenance or continued CTx, stratified by region (Asia vs non-Asia). Primary endpoint was overall survival (OS) post induction in all randomized or PD-L1+ (≥1% of tumor cells, 73-10 assay) pts. Results: 805 pts received induction CTx and 499 pts were randomized (avelumab, n = 249; CTx, n = 250). At data cutoff (Sep 13, 2019), minimum follow-up was 18 months. In the avelumab and CTx arms, median OS post induction/randomization was 10.4 months (95% CI 9.1-12.0) vs 10.9 months (95% CI 9.6-12.4), hazard ratio (HR) 0.91 (95% CI 0.74-1.11; p = 0.1779); 24-month OS rates were 22.1% (95% CI 16.8-28.0) vs 15.5% (95% CI 10.8-20.9), respectively. The HR for OS in PD-L1+ pts (n = 54) was 1.13 (95% CI 0.57-2.23). No OS trend was seen in Asian pts (n = 114; HR 0.90 [95% CI 0.59-1.36]) or other subgroups, except for a potential benefit with avelumab in pts with no metastatic sites at randomization (n = 60; HR 0.52 [95% CI 0.28-0.98]). Progression-free survival was similar between arms (HR 1.04 [95% CI 0.85-1.28]). In the avelumab vs CTx arms, objective response rates (post randomization only) were 13.3% (95% CI 9.3-18.1) vs 14.4% (95% CI 10.3-19.4), and 12-month rates for duration of response were 62.3% (95% CI 40.9-77.9) vs 28.4% (95% CI 13.2-45.7), respectively. Treatment-related adverse event rates (all grades/grade ≥3) were 61.3%/12.8% with avelumab and 77.3%/32.8% with CTx. Conclusions: Avelumab maintenance showed clinical activity and favorable safety vs continued CTx in pts with LA/M GE/GEJC; however, JAVELIN Gastric 100 did not meet its primary objective of demonstrating superior OS in the randomized or PD-L1+ population. Clinical trial information: NCT02625610.

Camrelizumab combined with capecitabine and oxaliplatin followed by camrelizumab and apatinib as first-line therapy for advanced or metastatic gastric or gastroesophageal junction cancer: Updated results from a multicenter, open label phase II trial.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4031-4031 ◽  
Author(s):  
Lin Shen ◽  
Zhi Peng ◽  
Yan-Qiao Zhang ◽  
Jia Wei ◽  
Feng Wang ◽  
...  
Keyword(s):  
Gastroesophageal Junction ◽  
Objective Response ◽  
Progression Free Survival ◽  
Sequential Therapy ◽  
Metastatic Gastric Cancer ◽  
First Line ◽  
Open Label ◽  
First Line Therapy ◽  
Line Therapy ◽  
Open Label Phase

4031 Background: Capecitabine plus oxaliplatin (CAPOX) is one of the standard first-line treatments for advanced or metastatic gastric cancer. Camrelizumab (SHR-1210, an anti–PD-1 antibody) shows promising anti-tumor activity in patients (pts) with advanced or metastatic gastric or gastroesophageal junction (G/GEJ) cancer. Camrelizumab combined with CAPOX for untreated G/GEJ cancer was assessed as a part of an ongoing multicenter, open-label phase 2 trial (cohort 1), and encouraging preliminary results were reported. Here, we present the updated safety and efficacy data. Methods: In this cohort, systemic treatment naïve pts with HER2– advanced or metastatic G/GEJ adenocarcinoma were given camrelizumab 200 mg on Day 1, capecitabine 1000 mg/m2 bid on Days 1–14 and oxaliplatin 130 mg/m2 on Day 1 of each 21-day-cycle for 4 to 6 cycles followed by camrelizumab 200 mg every 3 weeks plus apatinib 375 mg qd until disease progression or intolerable toxicity. The primary endpoint was objective response rate. Results: At data cutoff (Jan 20, 2019), 43 of the 48 enrolled pts were evaluable. Partial response was observed in 28 pts (65%), and 19 (44%) were confirmed. Stable disease in 14 pts and progressive disease in 10 pts were reported. Median estimates for duration of response and progression-free survival were not reached. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 9 pts (21%), included neutropenia, diarrhea, rash and elevated ALT, whereas none of the TRAEs was fatal. Ten pts without progression after 4–6 cycles of camrelizumab and CAPOX combination therapy all received camrelizumab plus apatinib as sequential therapy, and no new safety signals were observed. Conclusions: The updated results confirmed that camrelizumab plus CAPOX followed by camrelizumab plus apatinib was well tolerated with noteworthy responses as first-line therapy in advanced or metastatic G/GEJ cancer pts. Expansion of this cohort in a phase 3 study are under way. Clinical trial information: NCT03472365.

Margetuximab (M) combined with anti-PD-1 (retifanlimab) or anti-PD-1/LAG-3 (tebotelimab) +/- chemotherapy (CTX) in first-line therapy of advanced/metastatic HER2+ gastroesophageal junction (GEJ) or gastric cancer (GC).

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. TPS264-TPS264
Author(s):  
Daniel V.T. Catenacci ◽  
Minori Koshiji Rosales ◽  
Hyun Cheol Chung ◽  
Harry H. Yoon ◽  
Lin Shen ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Function ◽  
Checkpoint Inhibitors ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Locally Advanced ◽  
Standard Of Care ◽  
Open Label ◽  
Double Positive ◽  
Line Therapy

TPS264 Background: Trastuzumab (T), a monoclonal antibody (mAb) targeting HER2, is standard of care 1st-line therapy for advanced HER2+ GEJ/GC patients. M, an investigational Fc-engineered anti-HER2 mAb, targets the same HER2 epitope but with higher affinity for both 158V (high binding) and 158F (low binding) alleles of activating Fc receptor CD16A. Data suggest margetuximab coordinately enhances both innate and adaptive immunity, including antigen-specific T-cell responses to HER2. PD-1 and LAG-3 are T-cell checkpoint molecules that suppress T-cell function. Retifanlimab (also known as MGA012 or INCMGA00012) is a humanized, hinge-stabilized, IgG4 Κ anti-PD-1 mAb blocking binding of PD-L1 or PD-L2 to PD-1. Tebotelimab (also known as MGD013) is a humanized Fc-bearing bispecific tetravalent DART® protein that binds to both PD-1 and LAG-3, inhibiting their respective ligand binding. We previously reported that a CTX-free regimen of M+PD-1 blockade was well tolerated in GEJ/GC patients, and induced a 44% objective response rate (ORR) in a double-positive biomarker population. This was 2- to 3-fold greater than in historical controls with checkpoint inhibitors alone. This registration-directed trial assesses efficacy, safety, and tolerability of M+checkpoint inhibition ± CTX in metastatic/locally advanced, treatment-naïve, HER2+ GEJ/GC patients. Methods: This is a 2-cohort, adaptive open-label phase 2/3 study (NCT04082364). The first single arm, CTX-free cohort A, evaluates M+retifanlimab in HER2+ (immunohistochemistry [IHC] 3+) and PD-L1+ (excluding microsatellite instability high) patients. After 40 patients are evaluated for response/safety, additional patients will be enrolled if the threshold for continuation is met. In randomized cohort B, HER2+ (IHC 3+ or 2+/fluorescent in situ hybridization+) patients are enrolled irrespective of PD-L1 status. Part 1 of cohort B randomizes patients to 1 of 4 arms (50 patients each): control arm (T+CTX) or 1 of 3 experimental arms (M+CTX; M+CTX+retifanlimab; M+CTX+tebotelimab). CTX is investigator’s choice XELOX or mFOLFOX-6. Part 2 of cohort B consists of control (T+CTX) vs 1 experimental arm (M+CTX) + either retifanlimab or tebotelimab, depending on results from part 1; with 250 patients each. The primary efficacy endpoint for cohort A (both parts) is ORR per RECIST 1.1; for cohort B part 2 it is overall survival. Clinical trial information: NCT04082364.

Phase 1b dose escalation study to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of GS-3583, a FLT3 agonist Fc fusion protein, in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS3147-TPS3147
Author(s):  
Joshua Brody ◽  
John A. Thompson ◽  
Anthony W. Tolcher ◽  
Michelle R. Kuhne ◽  
Xi (Rochelle) Huang ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Standard Therapy ◽  
Locally Advanced ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Dose Escalation Study ◽  
Immunoglobulin G4 ◽  
Phase 1B

TPS3147 Background: Productive antitumor immune responses in nonclinical models depend on a type of dendritic cell (DC), conventional DC subtype 1 (cDC1), which in the context of cancer, primes tumor-reactive T cells through presentation of tumor-derived antigens. FMS-related tyrosine kinase 3 ligand (FLT3L) is a hematopoietic growth factor that binds to and activates FLT3 on terminally differentiated DCs. Activated FLT3 promotes proliferation, inhibits cell death, and is required for the differentiation, expansion, and maintenance of DCs in peripheral and lymphoid organs. GS-3583 is a fusion protein composed of the extracellular domain of recombinant human FLT3L fused to an engineered fragment crystallizable (Fc) region of human immunoglobulin G4. GS-3583 has PK properties that support sustained cDC in patients and potential combination with established immunotherapies. This phase 1b, open-label, multicenter, dose-finding study will evaluate safety, tolerability, PK, and preliminary efficacy of GS-3583 monotherapy in patients with advanced solid tumors (NCT04747470). Methods: Approximately 33 adults aged ≥18 years with a histologically or cytologically confirmed locally advanced or metastatic malignant solid tumor that is refractory to or intolerant of standard therapy or for which no standard therapy is available will be enrolled. The study employs a 3+3 dose escalation design in which GS-3583 is administered intravenously for up to 52 weeks or until progressive disease or unacceptable toxicity. Up to five dose escalation cohorts have been planned. The maximum tolerated dose is the highest dose with incidence of DLT in < 33% of 6 or more patients in the first 28 days of GS-3583 dosing; recommended phase 2 dose will be determined. Assessments include safety, PK, pharmacodynamics including cDCs, immunogenicity, and efficacy by RECIST 1.1 in CT/MRI imaging conducted every 8 weeks. Accrual at approximately 3-4 centers in the US is ongoing. Clinical trial information: NCT04747470.

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