327 Study of anti-PD-1 antibody multimodal combination as first-line treatment on time window of advanced solid tumor

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A353-A353
Author(s):  
Jian Shi ◽  
Baoen Shan ◽  
Junyan Wang ◽  
Jiayin Liu ◽  
Rongfeng Liu ◽  
...  
Keyword(s):  
Cell Death ◽  
Time Window ◽  
Line Treatment ◽  
Advanced Solid Tumor ◽  
Plasma Drug ◽  
First Line ◽  
Standard Chemotherapy ◽  
Drug Concentrations ◽  
First Line Treatment ◽  
Plasma Drug Concentrations

BackgroundImmune checkpoint inhibitors (ICIs) targeting the programmed cell death-1(PD-1) has dramatically shifted the therapeutic paradigm of advanced tumor. However, a large proportion of patients do not achieve durable responses with anti-PD-1 monotherapy. Strategically combining immunotherapies with other systemic therapies to harness potential synergies is critical for maximizing their clinical activity and realizing the greatest benefits for patients with cancer. Chemotherapy drugs induce a form of tumor cell death that is immunologically active, thereby inducing an adaptive immune response specific for the tumor. Apatinib (VEGFR2 inhibitor) in combination with an anti-PD-1 has demonstrated synergistic antitumor effects. In our previous research, steady-state of apatinib (250 mg qd) plasma drug concentration was achieved by day 3. Camrelizumab and sintilimab are humanized anti-PD-1 antibody. We aim to assess time window, efficacy and safety of patients who receive anti-PD-1 antibody multimodal combination as first-line treatment of advanced solid tumor.MethodsThis multicentre, open-label, exploratory cohort study. Eligible patients were aged 18–70 years, and had histologically or cytologically confirmed advanced solid tumors, an Eastern Cooperative Oncology Group performance status of 0 or 1, and received no previous anti-tumor treatment for advanced disease. 180 patients were assigned to three group: Camrelizumab/sintilimab (200 mg,iv,d4,q3w,24 months) plus standard chemotherapy (d1-3), Camrelizumab/sintilimab (200 mg,iv,d4,q3w,24 months) plus apatinib (250 mg, po, d1,qd), Camrelizumab/sintilimab (200 mg,iv,d7,q3w,24 months) plus standard chemotherapy(d1-3) and apatinib (250 mg,po, d1,qd). Tumor tissue and matched blood of all patients will be collected for NGS-based 727 genes panel assay, and the blood samples will be collected until disease progression. Meanwhile, plasma drug concentrations were detected by daily measurement of trough and peak concentrations(d0, 1, 2, 3, 21, 42, 63). The primary endpoint of this study is progression free survival (PFS), and the secondary endpoints include objective response rate (ORR), disease control rate (DCR), overall survival (OS) and safety. In addition, exploratory analysis was performed to comprehensively assess the relationship between gene status and efficacy, plasma drug concentrations and biological effects. This study is registered with ClinicalTrials.gov, number NCT04282278.ResultsN/AConclusionsN/ATrial RegistrationClinicalTrials. gov, number NCT04282278.Ethics ApprovalThe study was approved by the Fourth Hospital of Hebei Medical University Institution’s Ethics Board, approval number 2020012.

scholarly journals Immune Checkpoint Inhibition in Oesophago-Gastric Carcinoma

2021 ◽  
Vol 14 (2) ◽  
pp. 151
Author(s):  
Anica Högner ◽  
Peter Thuss-Patience
Keyword(s):  
Cell Death ◽  
Gastric Carcinoma ◽  
Programmed Cell Death ◽  
Immune Checkpoint ◽  
Disease Free Survival ◽  
Line Treatment ◽  
Second Line ◽  
First Line ◽  
The Usa ◽  
First Line Treatment

Immune checkpoint inhibitors enrich the therapeutic landscape in oesophago-gastric carcinoma. With regard to oesophageal squamous cell carcinoma (ESCC), the selective PD-1 (programmed cell death receptor 1)-inhibitor nivolumab improves disease-free survival in the adjuvant therapy setting (CHECKMATE-577). In first-line treatment, ESCC patients (pts) benefit in overall survival (OS) from the PD-1-inhibitor pembrolizumab in combination with chemotherapy (KEYNOTE-590). In the second-line setting, nivolumab (ATTRACTION-03) and pembrolizumab (KEYNOTE-181) demonstrate a benefit in OS compared with chemotherapy. These data resulted in the approval of nivolumab for the second-line treatment of advanced ESCC pts regardless of PD-L1 (programmed cell death ligand 1) status in Europe, Asia, and the USA, and pembrolizumab for pts with PD-L1 CPS (combined positivity score) ≥ 10 in Asia and the USA. Further approvals can be expected. In gastro-oesophageal junction and gastric cancer, the addition of nivolumab to chemotherapy in first-line treatment improves OS in pts with advanced disease with PD-L1 CPS ≥ 5 (CHECKMATE-649). Additionally, pembrolizumab was non-inferior to chemotherapy for OS in PD-L1 CPS ≥ 1 pts (KEYNOTE-062). In third-line treatment, nivolumab shows benefits in OS regardless of PD-L1 expression (ATTRACTION-02) with approval in Asia, and pembrolizumab prolonged the duration of response in PD-L1 positive pts (KEYNOTE-059) with approval in the USA. We discuss the recent results of the completed phase II and III clinical trials.

Combination of trastuzumab and taxane-containing intensified chemotherapy in first-line treatment of HER2-positive advanced gastric cancer

2020 ◽  
pp. 030089162096982
Author(s):  
Mustafa Gürbüz ◽  
Erman Akkuş ◽  
Abdullah Sakin ◽  
Semiha Urvay ◽  
Atike Gökçen Demiray ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Advanced Gastric Cancer ◽  
Gastric Adenocarcinoma ◽  
Locally Advanced ◽  
Line Treatment ◽  
First Line ◽  
Standard Chemotherapy ◽  
Her2 Positive ◽  
Intensified Chemotherapy ◽  
First Line Treatment

Purpose: Taxane-containing combinations are recommended for the first-line therapy of advanced gastric cancer. It is not known which chemotherapy regimen is the best with trastuzumab for HER2-positive patients. The aim of this study was to compare taxane-containing intensified chemotherapy versus standard chemotherapy in combination with trastuzumab in the first-line treatment of HER2-positive advanced gastric adenocarcinoma. Methods: This study is a retrospective multicenter study of the Turkish Oncology Group. A total of 130 HER2-positive patients with inoperable locally advanced, recurrent, or metastatic gastric adenocarcinoma being given chemotherapy plus trastuzumab as the first-line treatment were included from 16 different oncology centers. Trastuzumab combination with intensified chemotherapy including taxane or standard chemotherapy was compared in terms of progression-free survival (PFS), overall survival (OS), and toxicity. Results: There were 108 patients in the standard and 22 patients in the intensified chemotherapy group. PFS of the standard and intensified group were 5.6 months (95% confidence interval [CI] 4.8–6.4) and 5.3 months (95% CI 2.6–8), respectively ( p = 0.70). OS of the standard and intensified group were 11.1 months (95% CI 8.3–13.9) and 15.2 months (95% CI 12.7–17.7), respectively ( p = 0.03). Repeated analysis excluding patients given any previous therapy revealed similar results. The intensified group had more fever and febrile neutropenia. Conclusion: Trastuzumab combination with intensified chemotherapy provides better OS in first-line treatment of HER2-positive advanced gastric cancer. Further large-scale studies should be performed in HER2-positive patients.

Prognostic impact of human epidermal growth factor-2 (HER2) status on overall survival (OS) of advanced gastric cancer (AGC) patients (pts) treated with standard chemotherapy without trastuzumab as a first-line treatment: A Japanese multicenter collaborative retrospective study.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 4075-4075
Author(s):  
Tomohiro Nishina ◽  
Nozomu Fuse ◽  
Takeshi Kuwata ◽  
Shigenori Kadowaki ◽  
Eiji Shinozaki ◽  
...  
Keyword(s):  
Performance Status ◽  
Gastroesophageal Junction ◽  
Her2 Status ◽  
Prognostic Impact ◽  
Line Treatment ◽  
First Line ◽  
Standard Chemotherapy ◽  
Ecog Performance Status ◽  
Significant Difference ◽  
First Line Treatment

4075 Background: The prognostic impact of HER2 status on OS of AGC pts treated with standard chemotherapy without trastuzumab for first-line treatment remains controversial. This study investigated whether HER2 status is an independent prognostic factor for AGC pts. Methods: Formalin-fixed paraffin-embedded tumor samples from 293 eligible pts were examined for HER2 by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH). Eligible criteria included: 1) histologically confirmed gastric or gastroesophageal junction adenocarcinoma, 2) unresectable or recurrent cancer, 3) treated with S-1 plus cisplatin as first-line chemotherapy, 4) age: ≥20, 5) ECOG performance status score: 0-2 and 6) with archived tumor sample. HER2+ was defined as IHC 3+ or IHC 2+/FISH+. Results: Of 293 pts, 43 (15%) were HER2+. Baseline pt characteristics between HER2+ and HER2- pts were significantly different by histology (intestinal/diffuse, 65%/35% vs. 39%/61%; p=0.001), measurable disease by RECIST v1.0 (91% vs. 69%; p=0.003), No. of metastatic sites (≥2, 72% vs. 46%; p=0.003) and presence of liver metastasis (56% vs. 31%; p=0.003). After median follow-up time of 48.9 months with 270 (92%) death events, there was no significant difference in OS between HER2+ and HER2- pts (median, 11.7 vs. 13.7 months; hazard ratio [HR] 1.11, 95% CI 0.79–1.55; log rank p=0.550). After adjusting other prognostic factors with Cox hazard model, HER2+ was still not prognostic for OS (HR 0.890, 95% CI 0.627–1.262, p=0.513). Conclusions: HER2 status has no significant prognostic impact on OS of AGC pts treated with S-1 plus cisplatin without trastuzumab as a first-line treatment.

Tisotumab vedotin versus investigator’s choice chemotherapy in second- or third-line recurrent or metastatic cervical cancer (innovaTV 301/ENGOT-cx12/GOG 3057, trial in progress).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS5596-TPS5596
Author(s):  
Ignace Vergote ◽  
Bradley J. Monk ◽  
Robert L. Coleman ◽  
Leslie M. Randall ◽  
Keiichi Fujiwara ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Cervical Cancer ◽  
Cell Death ◽  
Disease Progression ◽  
Treatment Options ◽  
Human Monoclonal Antibody ◽  
Objective Response ◽  
Line Treatment ◽  
First Line ◽  
First Line Treatment

TPS5596 Background: Doublet chemotherapy (paclitaxel plus either platinum or topotecan) with bevacizumab (if eligible) is recommended for first-line treatment of recurrent (not amenable to curative therapy) or metastatic cervical cancer (r/mCC; Tewari 2014). In the second-line setting, there are limited data for currently available treatment options. Tisotumab vedotin (TV) is an investigational antibody-drug conjugate (ADC) composed of a tissue factor (TF)-directed human monoclonal antibody covalently linked to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable linker. TV is directed to cells expressing TF and releases MMAE upon internalization, resulting in cell cycle arrest and apoptotic cell death. TV has anti-tumor activity on multiple tumor types and kills tumor cells by direct cytotoxicity, bystander cytotoxicity, antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and in a manner consistent with immunogenic cell death. In a recent phase 2 pivotal trial (innovaTV 204), TV demonstrated a clinically meaningful objective response rate (ORR) of 24% and median duration of response (DOR) of 8.3 months, as well as a manageable and tolerable safety profile with most adverse events being mild to moderate, in r/mCC patients with disease progression on or after chemotherapy. These findings support further investigation of TV in patients with r/mCC who progress on available first-line treatment options. Methods: The innovaTV 301 trial (NCT04697628) is a global, randomized, open-label, phase 3 clinical trial evaluating the efficacy and safety of TV in patients with previously treated r/mCC. Eligible patients must be ≥18 years, have r/mCC, and have experienced disease progression after receiving 1-2 prior lines of therapy (either standard of care systemic chemotherapy doublet or platinum-based therapy [if eligible; paclitaxel+cisplatin+bevacizumab, paclitaxel+carboplatin+bevacizumab, or paclitaxel+topotecan/nogitecan+bevacizumab]). Approximately 482 patients will be randomized 1:1 to receive 21-day cycles of either TV (2.0 mg/kg IV once every 3 weeks) or investigator’s choice of chemotherapy: topotecan (1 or 1.25 mg/m2 IV; Day 1 [D1] to D5 of each cycle), vinorelbine (30 mg/m2 IV; D1 and D8 of each cycle), gemcitabine (1000 mg/m2 IV; D1 and D8 of each cycle), irinotecan (100 or 125 mg/m2 IV; weekly for 28days, then every 42 days), or pemetrexed (500 mg/m2 IV, D1 of each cycle). The primary endpoint of this trial is overall survival. Key secondary endpoints are progression-free survival, ORR, time to response, DOR, safety, and quality of life outcomes. The study is currently enrolling and will have sites open in the US, EU, Japan, Latin America, Taiwan, Singapore, and South Korea. Clinical trial information: NCT04697628.

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