scholarly journals P-159 HERIZON: Phase 2 part of the IMU-131 HER2/neu vaccine plus chemotherapy study randomized in patients with HER2/NEU overexpressing metastatic or advanced adenocarcinoma of the stomach or gastroesophageal junction

2021 ◽  
Vol 32 ◽  
pp. S154
Author(s):  
M. Maglakelidze ◽  
D. Ryspayenva ◽  
I. Bulat ◽  
Z. Andric ◽  
I. Nikolic ◽  
...  
Keyword(s):  
Gastroesophageal Junction ◽  
Phase 2 ◽  
Chemotherapy Study

Multicenter phase Ib/II study of second-line trastuzumab, ramucirumab, and paclitaxel in patients with HER2-positive advanced gastric or gastroesophageal junction cancer (HER-RAM study).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4063-4063
Author(s):  
Sun Young Rha ◽  
Chang Gon Kim ◽  
Minkyu Jung ◽  
Hyo Song Kim ◽  
Choong-kun Lee ◽  
...  
Keyword(s):  
Dose Level ◽  
Gastroesophageal Junction ◽  
Second Line ◽  
Phase 2 ◽  
Gi Bleeding ◽  
Her2 Positive ◽  
Phase 1B ◽  
Her 2 ◽  
Level 1 ◽  
Grade 3

4063 Background: We evaluated the safety and efficacy of adding trastuzumab to ramucirumab and paclitaxel (TRP) as a second line treatment in human epidermal growth factor receptor 2 (HER-2)-positive advanced gastric or gastroesophageal junction (G/GEJ) cancer progressed from trastuzumab containing chemotherapy. Methods: Patients with HER-2-positive advanced G/GEJ cancer who progressed after first-line chemotherapy with trastuzumab in combination with fluoropyrimidine and platinum were eligible. Trastuzumab (Herzuma[CT-P6], Celltrion Inc.) 4mg/kg on day 1 followed by 2mg/kg on days 8, 15, and 22, ramucirumab 8mg/kg on days 1 and 15, and paclitaxel (dose level 1: 80mg/m2, dose level -1: 70 mg/m2) on days 1, 8, and 15 of a 28-day cycle was tested. After safety analysis of lead-in safety cohort (phase 1b), phase 2 part was conducted to evaluate the primary endpoint of progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. Results: At the phase 1b part, as there was no dose limiting toxicity in 3 patients at the dose level 1, dose level 1 with full dose combination was determined as recommended phase 2 dose. At the time of data lock on Jan. 31, 2021, 45 patients among enrolled 50 patients were evaluable for response and safety including 3 patients from phase 1b part. Median age was 59 years old (range 30-82) and most patients were male (37/45). At baseline, 33 patients had tumors with HER-2 3+ by immunohistochemistry (IHC) and 12 had those with HER-2 2+ by IHC with ERBB2 amplification by in situ hybridization. With median follow-up duration of 11.6 months, median PFS and OS were 7.2 months (95% confidence interval [CI]: 6.0-8.5 months) and 13.6 months (95% CI: 10.3-16.9 months), respectively. ORR was 55.6% (25/45, complete response = 1, partial response = 24) and DCR was 95.6% (43/45), respectively. Most common hematologic adverse event (AE) was neutropenia (all grade: 64.4%, grade 3/4: 51.1%) with 1 case of febrile neutropenia (2.2%). Most common non-hematologic AE was peripheral sensory neuropathy (all grade: 33.3%, grade 3: 2.2%). Gastrointestinal (GI) bleeding occurred in 4 patients (grade 3 upper GI bleeding: 6.7%, grade 1 lower GI bleeding: 2.2%), whereas GI perforation was not observed. Hypertension occurred in 3 patients (all grade: 6.7%, grade 3: 4.4%). No new or unexpected AEs resulting in treatment cessation were observed with this combination regimen. Conclusions: The continuous use of trastuzumab beyond progression in combination with ramucirumab and paclitaxel showed promising activity and manageable safety profile in HER2 positive G/GEJ cancer patients who progressed after trastuzumab containing chemotherapy. Updated outcomes for ongoing patients will be presented.

Tislelizumab in combination with chemotherapy in Chinese patients with advanced gastric or gastroesophageal junction (G/GEJ) cancer: Results from one cohort of an ongoing phase 2 study.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 11-11
Author(s):  
Yu-Xian Bai ◽  
En Xiao Li ◽  
Buhai Wang ◽  
Xianglin Yuan ◽  
Nong Xu ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Gastroesophageal Junction ◽  
Chinese Patients ◽  
Phase 2 ◽  
First Line ◽  
Cancer Data ◽  
Cell Clearance ◽  
Phase 2 Study ◽  
Target Disease

11 Background: Tislelizumab, a humanized IgG4 mAb with high affinity and specificity for PD-1, was specifically engineered to minimize FcγR binding on macrophages, thus abrogating antibody-dependent phagocytosis, a potential mechanism of T-cell clearance and resistance to anti-PD-1 therapy. This phase 2 study (NCT03469557) evaluated safety, tolerability, and antitumor activity of first-line tislelizumab plus chemotherapy in Chinese pts with advanced G/GEJ or esophageal cancer; data from the G/GEJ cohort are presented here. Methods: Adult pts with histologically or cytologically confirmed HER2 negative G/GEJ were treated with tislelizumab (200 mg IV Q3W) + oxaliplatin (130 mg/m² IV Q3W for up to 6 cycles) + capecitabine (1000 mg/m² BID, Days 1–14 Q3W). AEs were assessed per CTCAE v4.03; tumor responses were assessed every 9 wks. Results: As of 13 June 2018, 15 G/GEJ pts (median age, 59 yr; M/F, 11/4) were enrolled; median treatment duration was 171 days (range 21-251). AEs in > 2 pts considered related to chemotherapy and/or tislelizumab are detailed in the Table. No fatal AEs occurred. Three pts discontinued treatment due to ascites or increased ALT, AST, or total bilirubin. With a median follow up of 181 days, 46.7% (n = 7) had confirmed PR, 20% (n = 3) had SD, 13.3% (n = 2) with non-target disease only at baseline had non-CR/non-PD, 6.7% (n = 1) had PD, and 13.3% (n = 2) did not have evaluable disease. ORR and DCR were 46.7% (n = 7/15) and 80% (n = 12/15), respectively. Conclusions: First-line tislelizumab plus chemotherapy was generally well tolerated and antitumor activity was observed in pts with advanced G/GEJ cancer. Clinical trial information: NCT03469557. [Table: see text]

Effect of ethnicity and chemotherapy (mFOLFOX6) on zolbetuximab pharmacokinetics in patients with claudin 18.2-positive locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma (G/GEJ).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16078-e16078
Author(s):  
Keun-Wook Lee ◽  
Samuel J Klempner ◽  
Jianning Yang ◽  
Amit Desai ◽  
Akihiro Yamada ◽  
...  
Keyword(s):  
Ethnic Differences ◽  
Phase 1 ◽  
Gastroesophageal Junction ◽  
Locally Advanced ◽  
Serum Drug Concentration ◽  
Phase 2 ◽  
Phase 3 ◽  
Maximum Serum ◽  
Phase 2 Study ◽  
Junction Protein

e16078 Background: Zolbetuximab is a chimeric IgG1 monoclonal antibody that targets Claudin 18.2 (CLDN18.2), a tight junction protein that is normally confined to gastric mucosa but is retained in G/GEJ. A phase 2 (NCT01630083, FAST) trial demonstrated significantly prolonged survival with zolbetuximab + EOX (epirubicin, oxaliplatin, capecitabine) vs EOX in G/GEJ. Two global phase 3 studies are ongoing, comparing zolbetuximab + chemotherapy vs chemotherapy as first-line treatment in CLDN18.2-positive G/GEJ. This study assessed the influence of ethnic differences and chemotherapy on the pharmacokinetics (PK) of zolbetuximab in patients (pts) with G/GEJ and the potential effect of zolbetuximab on chemotherapy PK. Methods: In the Japanese phase 1 and global phase 2 studies, adult pts with CLDN18.2-postitive G/GEJ received zolbetuximab 800 mg/m2 IV on Cycle 1 Day 1 (Cycle 1 Day 3 in Cohort 2 of phase 2) then 600 mg/m2 Q3W. Phase 1 and Cohort 1A of the phase 2 study assessed zolbetuximab monotherapy in 21-day cycles. Cohort 2 of the phase 2 study assessed zolbetuximab + mFOLFOX (5-FU, folinic acid, oxaliplatin; 4 cycles) in 42-day cycles (Q2W from Cycle 1 Day 1). Blood samples for zolbetuximab PK following single and multiple doses, and for chemotherapy (5-FU and oxaliplatin) PK alone or with zolbetuximab were collected. Maximum serum drug concentration (Cmax) and area under the concentration-time curve from 0-21 days (AUC0-21) were assessed. Potential ethnic differences in zolbetuximab exposures across Japanese, other Asian (Korean and Taiwanese), and Western pts, and the potential drug-drug interaction between zolbetuximab and chemotherapy were evaluated. Results: Zolbetuximab concentration profiles and PK parameters were generally comparable across Japanese, other Asian, and Western populations (Table). Zolbetuximab PK properties were similar between monotherapy and combination therapy cohorts (Table). Chemotherapy PK was comparable with and without zolbetuximab. Conclusions: The analyses suggest no apparent ethnic differences in zolbetuximab PK across Japanese/Asian and Western pts and no PK interactions between zolbetuximab and mFOLFOX6. These results support the use of zolbetuximab and mFOLFOX without the need for dose adjustment in global phase 3 trials. Clinical trial information: NCT03505320, NCT03528629. [Table: see text]

Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma: Final overall survival (OS) results from a randomized, multicenter, open-label, phase 2 study (DESTINY-Gastric01).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4048-4048
Author(s):  
Kensei Yamaguchi ◽  
Yung-Jue Bang ◽  
Satoru Iwasa ◽  
Naotoshi Sugimoto ◽  
Min-Hee Ryu ◽  
...  
Keyword(s):  
Median Survival ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Phase 2 ◽  
Standard Chemotherapy ◽  
Primary Analysis ◽  
Her2 Positive ◽  
Open Label ◽  
Grade 3

4048 Background: T-DXd is an antibody–drug conjugate comprising an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a topoisomerase I inhibitor. DESTINY-Gastric01 (DS8201-A-J202; ClinicalTrials.gov, NCT03329690) is an open-label, multicenter, randomized, phase 2 trial of T-DXd in patients with HER2-positive advanced gastric cancer (GC) or GEJ adenocarcinoma. In the primary analysis (101 OS events; median survival follow-up, 12.3 mo), T-DXd showed statistically significant benefit vs standard chemotherapy in objective response rate (ORR) and OS (Shitara K, et al. N Engl J Med. 2020;382:2419-2430); here, we present the final OS analysis as well as updated efficacy and safety. Methods: Patients (pts) with locally advanced or metastatic, centrally confirmed HER2-positive (IHC3+ or IHC2+/ISH+ on archival tissue) GC or GEJ cancer that had progressed after ≥2 previous lines of therapy including trastuzumab were randomly assigned 2:1 (T-DXd 6.4 mg/kg Q3W or physician’s choice [PC] irinotecan [I] or paclitaxel [P]). Pts were stratified by country, ECOG performance status (0, 1), and HER2 status. Primary end point was ORR by independent central review. Key secondary end points were OS, duration of response (DOR), progression-free survival (PFS), disease control rate (DCR), confirmed ORR, and safety. Final OS analysis was performed at 133 OS events. Results: 187 pts received T-DXd (n = 125) or PC (n = 62 [55 I; 7 P]); 79.7% of pts were Japanese and 20.3% were Korean. Pts had a median of 2 prior lines of therapy, and 44.4% had ≥3. At data cutoff (June 3, 2020), 8% of T-DXd and 0% of PC pts remained on treatment (median survival follow-up, 18.5 mo). OS was improved with T-DXd vs PC (median OS, 12.5 vs 8.9 mo; hazard ratio [HR], 0.60 [95% CI, 0.42-0.86]); 12-month OS, 52.2% vs 29.7%. ORR was 51.3% (61/119; 11 CR; 50 PR) with T-DXd vs 14.3% (8/56; all PR) with PC ( P < 0.0001); confirmed ORR, 42.0% (50/119; 10 CR; 40 PR) vs 12.5% (7/56; all PR) ( P = 0.0001); DCR, 86.6% vs 62.5% ( P = 0.0003); confirmed median DOR, 12.5 vs 3.9 mo; median PFS, 5.6 vs 3.5 mo (HR, 0.47 [95% CI, 0.31-0.71]; P = 0.0003). Grade ≥3 AEs occurred in 85.6% of T-DXd pts vs 56.5% with PC; the most common were neutrophil count decreased (49.6%, 22.6%), anemia (38.4%, 22.6%), and white blood cell count decreased (20.8%, 11.3%). 16 pts (12.8%) had T-DXd–related interstitial lung disease (ILD; 13 grade 1/2, 2 grade 3, 1 grade 4, no grade 5) vs 0 with PC. As reported in the primary analysis, there was 1 T-DXd–related death from pneumonia (non-ILD). Conclusions: With additional follow-up after the primary analysis, T-DXd continued to demonstrate OS benefit and clinically relevant improvement in ORR compared with standard chemotherapy, and a manageable safety profile, in HER2-positive advanced GC or GEJ adenocarcinoma. Clinical trial information: NCT03329690.

scholarly journals Randomized, open-label, phase 2 study of andecaliximab plus nivolumab versus nivolumab alone in advanced gastric cancer identifies biomarkers associated with survival

2021 ◽  
Vol 9 (12) ◽  
pp. e003580
Author(s):  
Manish A Shah ◽  
David Cunningham ◽  
Jean-Philippe Metges ◽  
Eric Van Cutsem ◽  
Zev Wainberg ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Growth Factor ◽  
Advanced Gastric Cancer ◽  
Transforming Growth Factor ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Gene Signature ◽  
Phase 2 ◽  
Her2 Positive ◽  
Open Label

BackgroundMatrix metalloproteinase-9 (MMP9) selectively cleaves extracellular matrix proteins contributing to tumor growth and an immunosuppressive microenvironment. This study evaluated andecaliximab (ADX), an inhibitor of MMP9, in combination with nivolumab (NIVO), for the treatment of advanced gastric cancer.MethodsPhase 2, open-label, randomized multicenter study evaluating the efficacy, safety, and pharmacodynamics of ADX+NIVO versus NIVO in patients with pretreated metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and adverse events (AEs). We explored the correlation of efficacy outcomes with biomarkers.Results144 patients were randomized; 141 were treated: 81% white, 69% male, median age was 61 years in the ADX+NIVO group and 62 years in the NIVO-alone group. The ORR was 10% (95% CI 4 to 19) in the ADX+NIVO group and 7% (95% CI 2 to 16) in the NIVO-alone group (OR: 1.5 (95% CI 0.4 to 6.1; p=0.8)). There was no response or survival benefit associated with adding ADX. AE rates were comparable in both treatment groups; the most common AEs were fatigue, decreased appetite, nausea, and vomiting. Programmed cell death ligand 1, interferon-γ (IFN), and intratumoral CD8+ cell density were not associated with treatment response or survival. The gene signature most correlated with shorter survival was the epithelial-to-mesenchymal gene signature; high transforming growth factor (TGF)-β fibrosis score was negatively associated with OS (p=0.036). Gene expression analysis of baseline tumors comparing long-(1+ years) and short-term (<1 year) survivors showed that GRB7 was associated with survival beyond 1 year. Human epidermal growth factor receptor 2 (HER2)-positive disease was associated with significantly longer survival (p=0.0077). Median tumor mutation burden (TMB) was 2.01; patients with TMB ≥median had longer survival (p=0.0025) and improved PFS (p=0.016). Based on a model accounting for TMB, TGF-β fibrosis, and HER2, TMB was the main driver of survival in this patient population.ConclusionCombination of ADX+NIVO had a favorable safety profile but did not improve efficacy compared with NIVO alone in patients with pretreated metastatic gastric or GEJ adenocarcinoma. HER2 positivity, higher TMB or GRB7, and lower TGF-β were associated with improved outcomes.Trial registration numberNCT02864381 or GS-US-296–-2013.

scholarly journals 433 A phase 2 study of evorpacept (ALX148) in combination with pembrolizumab and chemotherapy in patients with advanced head and neck squamous cell carcinoma (HNSCC); ASPEN-04

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A463-A463
Author(s):  
Beatriz Cirauqui ◽  
Ezra Cohen ◽  
Bhumsuk Keam ◽  
Jean-Pascal Machiels ◽  
Sjoukje Oosting ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Squamous Cell ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Cell Activity ◽  
Neck Squamous Cell Carcinoma ◽  
List Type ◽  
Phase 2

BackgroundAnticancer immunity relies on the release of tumor antigens and subsequent activation of the innate and adaptive immune systems. After cytotoxic chemotherapy induces neoantigen release, myeloid checkpoint inhibitors can help potentiate innate immune cell activity including antigen presentation. CD47 is a marker of self that interacts with SIRPα on myeloid immune cells and is upregulated by tumors to evade immune responses. Evorpacept is a high affinity CD47-blocking fusion protein with an inactive Fc region designed to safely enhance standard anticancer therapeutics. Pembrolizumab, a T cell checkpoint inhibitor that activates cytotoxic lymphocytes, is a standard option for patients with previously untreated recurrent/metastatic (R/M) HNSCC, both as a monotherapy and in combination with 5FU + platinum. Through increased activation of the immune system, a combination of evorpacept + pembrolizumab + 5FU/platinum might have more anti-tumor activity in R/M HNSCC than current standard therapeutic approaches. This combination approach could be particularly beneficial to R/M HNSCC patients with low PD-L1 expression, where anti-PD-(L)1 therapy historically has diminished efficacy. The combination of evorpacept + pembrolizumab + 5FU/platinum has undergone preliminary testing in the ongoing Phase 1 ASPEN-01 study,1 demonstrating initial clinical response and tolerability. In previously untreated, PD-L1-unselected R/M HNSCC patients treated with evorpacept + pembrolizumab + 5FU/platinum, patients experienced objective responses, including complete response. The ASPEN-04 study will assess the efficacy and safety of evorpacept in combination with pembrolizumab and chemotherapy in previously untreated patients with PD-L1-unselected R/M HNSCC.MethodsASPEN-04 (figure 1) is an ongoing non-comparative, open-label, randomized Phase 2 global study of evorpacept + pembrolizumab + chemotherapy (5FU + either carboplatin or cisplatin) or pembrolizumab + chemotherapy in patients with PD-L1-unselected metastatic or unresectable recurrent HNSCC who have not yet been treated for their advanced disease. After an initial safety lead-in cohort, ~106 patients will be randomized to receive evorpacept + pembrolizumab + chemotherapy or pembrolizumab + chemotherapy. Minimization factors used to randomize patients include geography, PD-L1 combined positive score, and HPV (p16) status. Patients in the evorpacept treatment arm will receive evorpacept 45 mg/kg IV Q3W. All patients will receive pembrolizumab 200 mg IV Q3W (maximum of 35 cycles) and standard administration of 5FU and platinum agents. The primary endpoint in this Simon two-stage trial design is objective response rate using RECIST v1.1. Key secondary endpoints include duration of response, progression-free survival, overall survival, and safety. Exploratory endpoints will characterize pharmacodynamic properties.Abstract 433 Figure 1ASPEN-04 Study SchemaAcknowledgementsWe would like to thank all the participating patients, their families, and site research teams.Trial RegistrationClinicalTrials.gov identifier, NCT04675333ReferencesKeun-Wook Lee, Hyun Cheol Chung, Won Seog Kim, et al. ALX148, a CD47 blocker, in combination with standard chemotherapy and antibody regimens in patients with gastric/gastroesophageal junction (GC) cancer and head and neck squamous cell carcinoma (HNSCC); ASPEN-01. Poster presented at: Society for Immunotherapy of Cancer Annual Meeting; November 2020.Ethics ApprovalThe study was approved by all participating institutions’ Ethics and/or Review Boards.

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