A randomized, placebo-controlled, phase III trial-in-progress to evaluate the efficacy and safety of tislelizumab plus chemotherapy as first-line treatment for unresectable, locally advanced recurrent/metastatic esophageal squamous cell carcinoma (ESCC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS2656-TPS2656
Author(s):  
Jian-Ming Xu ◽  
Ken Kato ◽  
Richard Hubner ◽  
Eric Raymond ◽  
Yihuan Xu ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Single Agent ◽  
Objective Response ◽  
Locally Advanced ◽  
Phase Iii ◽  
Double Blind Study ◽  
Line Treatment ◽  
Efficacy And Safety ◽  
First Line ◽  
First Line Treatment

TPS2656 Background: ESCC remains the predominant histological subtype of, and accounts for most deaths from, esophageal cancer. PD-1 inhibition has demonstrated antitumor activity and was generally well tolerated in patients (pts) with advanced unresectable or metastatic ESCC. Tislelizumab, an investigational anti-PD-1 antibody, was engineered to minimize binding to FcγR on macrophages to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. Results from early phase clinical studies suggest single-agent tislelizumab was generally well tolerated and had antitumor activity in pts with solid tumors, including ESCC. Methods: This phase 3, randomized, placebo-controlled, double-blind study (NCT03783442) is designed to evaluate the efficacy and safety of tislelizumab plus chemotherapy as first-line treatment of unresectable, locally advanced recurrent or metastatic ESCC. Adult pts with histologically confirmed ESCC that had metastatic disease either at first diagnosis or with a ≥6 month treatment-free interval will be eligible. Additional eligibility criteria include measurable/evaluable disease, ECOG performance score ≤1, and no prior anti-PD-(L)-1, PD-L2, or other first-line therapy or palliative radiation treatment ≤4 weeks before treatment. Approximately 480 pts will be randomized 1:1 to receive investigator-chosen chemotherapy (ICC) plus tislelizumab 200 mg IV Q3W or ICC plus placebo. Chemotherapy options include: platinum (cisplatin 60–80 mg/m2 or oxaliplatin 130 mg/m2 IV Q3W) plus 5-FU 750–800 mg/m2 IV daily for 5 days Q3W; or platinum plus capecitabine 1000 mg/m2 orally BID for 14 days Q3W; or platinum + paclitaxel 175 mg/m2 IV Q3W. Progression-free survival and overall survival are coprimary endpoints; secondary endpoints include objective response rate, duration of response, and health-related quality-of-life. Safety will be assessed by monitoring adverse events, physical examinations, vital signs, and electrocardiograms. This study is actively enrolling. Clinical trial information: NCT03783442.

Tislelizumab plus chemotherapy as first-line treatment for unresectable, locally advanced recurrent/metastatic esophageal squamous cell carcinoma.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. TPS462-TPS462
Author(s):  
Harry H. Yoon ◽  
Ken Kato ◽  
Richard Hubner ◽  
Eric Raymond ◽  
Aiyang Tao ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Antitumor Activity ◽  
Esophageal Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Locally Advanced ◽  
Double Blind Study ◽  
Line Treatment ◽  
First Line ◽  
First Line Treatment

TPS462 Background: Esophageal squamous cell carcinoma (ESCC) is the predominant histological subtype of esophageal cancer, particularly in Asian countries. Inhibition of the PD-1/PD-L1 axis has demonstrated antitumor activity in patients with advanced unresectable or metastatic ESCC. Tislelizumab, an investigational humanized IgG4 monoclonal antibody with high affinity and binding specificity for PD-1, was engineered to minimize binding to FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. Results from early phase clinical studies suggest tislelizumab, as a single agent or in combination with chemotherapy, was generally well tolerated and had antitumor activity in patients with solid tumors, including ESCC. Methods: This global, phase 3, randomized, placebo-controlled, double-blind study (NCT03783442) is designed to evaluate the efficacy and safety of tislelizumab plus chemotherapy as first-line treatment of unresectable, locally advanced recurrent or metastatic ESCC. Adult patients with histologically confirmed unresectable ESCC, or locally advanced recurrent/metastatic disease with a ≥6 month treatment-free interval, are eligible; palliative radiation administered > 4 weeks from study initiation is allowed. Patients who received prior anti-PD-(L)1, anti-PD-L2, or first-line therapy are ineligible. Patients (n≈480) will be randomized 1:1 to receive tislelizumab 200 mg IV every 3 weeks (Q3W) plus investigator-chosen chemotherapy (ICC) or placebo plus ICC. ICC options include: platinum (plat; cisplatin 60-80 mg/m2 or oxaliplatin 130 mg/m2 IV Q3W) + 5-FU 750-800 mg/m2 by continuous IV infusion over 24 hours for 5d Q3W; or plat + capecitabine 1000 mg/m2 orally BID for 14d Q3W; or plat + paclitaxel 175 mg/m2 IV Q3W. Progression-free and overall survival are primary endpoints; secondary endpoints include objective response rate, duration of response, and health-related quality of life. Safety will be assessed by monitoring adverse events, physical examinations, vital signs, and electrocardiograms. This study is actively enrolling. Clinical trial information: NCT03783442.

Efficacy and safety of toripalimab combination with SOX regimen as a first-line treatment in patients with unresectable locally advanced or recurrent/metastatic gastric/gastroesophageal junction cancer: Preliminary data from a single-armed, exploratory study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16015-e16015
Author(s):  
Xiaolin Lin ◽  
Qing Xia ◽  
Ting Han ◽  
Meng Zhuo ◽  
Haiyan Yang ◽  
...  
Keyword(s):  
Disease Control ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Locally Advanced ◽  
Disease Control Rate ◽  
Line Treatment ◽  
Efficacy And Safety ◽  
First Line ◽  
Gastroesophageal Junction Cancer ◽  
First Line Treatment

e16015 Background: Gastric cancer (GC) is one of the most common malignancies of the digestive system with a poor prognosis and limited treatment option. Currently immunotherapy is approved for the third-line treatment of GC, but there are limited data on first-line treatment. Therefore, this study will further explore the efficacy and safety of the domestic PD-1 antibody toripalimab combined with S-1 plus oxaliplatin (SOX) regimen as the first-line treatment of unresectable locally advanced or recurrent/metastatic gastric/gastroesophageal junction cancer. Methods: A prospective, single-armed, exploratory, investigated initiated trial explores the efficacy and safety of toripalimab combined with SOX regimen as first-line treatment of unresectable locally advanced or recurrent/metastatic gastric/gastroesophageal junction cancer. The primary objectives are objective response rate (ORR). Secondary objectives include disease control rate (DCR), DOR, PFS, and OS. The dosage regimen is: Toripalimab, 240mg D1; oxaliplatin, 130mg/m2, D1 ; S-1, 40mg/m2, bid oral D1-14 days, every 21 days as a cycle and plan 6 cycles of treatment. Tumor responses were assessed radiologically every two cycles. Major eligibility requirements include: unresectable advanced, recurrent or metastatic gastric/gastroesophageal junction cancer with diagnoses confirmed histologically or cytologically, age 18 and 80 years, first-line treatment, at least one measurable lesion according to RECIST 1.1, ECOG 0-1, adequate organ function and HER-2 negative. Results: So far, 17 of planned 20 patients have been enrolled. 14 patients completed 2 cycles of treatment, the ORR rate was 57% (8/14) and the disease control rate (DCR) was 93% (13/14). 10 patients completed 4 cycles of treatment, the ORR rate was 60% (6/10) and the disease control rate (DCR) was 90% (9/10). 7 patients completed 6 cycles of treatment, the ORR rate was 43% (3/7) and the disease control rate (DCR) was 57% (4/7). Common adverse reactions during treatment in 17 patients included rash 17.6% (3/17), diarrhea 41.2% (7/17), hypothyroidism 11.8% (2/17), elevated amylase 35.3% (6/17), decreased platelets 41.2% (7/17), mostly grade I-II. Conclusions: Toripalimab combination with SOX regimen as a first-line treatment demonstrated promising anti-tumor activity in unresectable locally advanced or recurrent/metastatic gastric/gastroesophageal junction cancer patients with a good ORR and controllable safety. Clinical trial information: NCT04202484.

Efficacy and Safety of Trastuzumab as a Single Agent in First-Line Treatment of HER2-Overexpressing Metastatic Breast Cancer

2002 ◽  
Vol 20 (3) ◽  
pp. 719-726 ◽  
Author(s):  
Charles L. Vogel ◽  
Melody A. Cobleigh ◽  
Debu Tripathy ◽  
John C. Gutheil ◽  
Lyndsay N. Harris ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Single Agent ◽  
Objective Response ◽  
Metastatic Breast ◽  
Her2 Overexpression ◽  
Line Treatment ◽  
Efficacy And Safety ◽  
First Line ◽  
First Line Treatment

PURPOSE: To evaluate the efficacy and safety of first-line, single-agent trastuzumab in women with HER2-overexpressing metastatic breast cancer. PATIENTS AND METHODS: One hundred fourteen women with HER2-overexpressing metastatic breast cancer were randomized to receive first-line treatment with trastuzumab 4 mg/kg loading dose, followed by 2 mg/kg weekly, or a higher 8 mg/kg loading dose, followed by 4 mg/kg weekly. RESULTS: The objective response rate was 26% (95% confidence interval [CI], 18.2% to 34.4%), with seven complete and 23 partial responses. Response rates in 111 assessable patients with 3+ and 2+ HER2 overexpression by immunohistochemistry (IHC) were 35% (95% CI, 24.4% to 44.7%) and none (95% CI, 0% to 15.5%), respectively. The clinical benefit rates in assessable patients with 3+ and 2+ HER2 overexpression were 48% and 7%, respectively. The response rates in 108 assessable patients with and without HER2 gene amplification by fluorescence in situ hybridization (FISH) analysis were 34% (95% CI, 23.9% to 45.7%) and 7% (95% CI, 0.8% to 22.8%), respectively. Seventeen (57%) of 30 patients with an objective response and 22 (51%) of 43 patients with clinical benefit had not experienced disease progression at follow-up at 12 months or later. The most common treatment-related adverse events were chills (25% of patients), asthenia (23%), fever (22%), pain (18%), and nausea (14%). Cardiac dysfunction occurred in two patients (2%); both had histories of cardiac disease and did not require additional intervention after discontinuation of trastuzumab. There was no clear evidence of a dose-response relationship for response, survival, or adverse events. CONCLUSION: Single-agent trastuzumab is active and well tolerated as first-line treatment of women with metastatic breast cancer with HER2 3+ overexpression by IHC or gene amplification by FISH.

A phase III trial to compare efficacy and safety of lenvatinib in combination with everolimus or pembrolizumab vs sunitinib alone in first-line treatment of patients (Pts) with metastatic renal cell carcinoma (RCC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS4595-TPS4595 ◽  
Author(s):  
Robert J. Motzer ◽  
Viktor Grünwald ◽  
Thomas E. Hutson ◽  
Camillo Porta ◽  
Thomas Powles ◽  
...  
Keyword(s):  
Growth Factor ◽  
Karnofsky Performance Status ◽  
Single Agent ◽  
Objective Response ◽  
Growth Factor Receptor ◽  
Phase Iii ◽  
Vegf Receptor ◽  
Line Treatment ◽  
First Line ◽  
First Line Treatment

TPS4595 Background: Lenvatinib (LEN) is a multikinase inhibitor of vascular endothelial growth factor (VEGF) receptor 1–3, fibroblast growth factor receptor 1–4, platelet-derived growth factor receptor alpha, and RET and KIT. Based on a phase 2 study (Motzer et al. Lancet Oncol 2015), LEN was approved in combination with everolimus (EVE) for treatment of metastatic RCC following 1 prior VEGF-targeted therapy. A phase 1b/2 study of LEN in combination with pembrolizumab (PEM) in pts with RCC LEN is also underway. We report the design of a multicenter, open-label, phase 3 trial of LEN plus EVE or PEM vs sunitinib (SUN; a standard therapy for RCC) as first-line treatment for advanced RCC. Methods: Pts aged ≥ 18 years with confirmed advanced RCC diagnosis, ≥ 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, Karnofsky Performance Status ≥ 70, controlled blood pressure, and adequate blood coagulation, renal, hepatic, and bone marrow function are eligible. Pts will be randomized 1:1:1 to receive LEN 18 mg/day + EVE 5 mg/day, LEN 20 mg/day + PEM 200 mg every 3 weeks, or SUN 50 mg/day (on a schedule of 4 weeks on treatment followed by 2 weeks off) until disease progression, unacceptable toxicity, withdrawal of consent, or study end. The primary endpoint is to show superiority of LEN+EVE or LEN+PEM over single-agent SUN as first-line treatment for advanced RCC in improving progression-free survival (PFS). Secondary endpoints include comparison of objective response rate, overall survival, PFS on next-line therapy, health-related quality of life, and safety and tolerability in pts receiving LEN+EVE or LEN+PEM vs SUN. Exploratory endpoints include PFS in the LEN+PEM arm using immune-related RECIST, comparison of duration of response, disease control rate, and clinical benefit rate in pts treated with LEN+EVE or LEN+PEM vs SUN, and analysis of the relationship between blood biomarkers and outcome. No interim analysis is planned for efficacy or futility. Enrollment of 735 pts is planned to achieve 90% power at 2-sided α = 0.05 to detect a difference in ≥ 1 of the primary comparisons. Clinical trial information: NCT02811861.

Anlotinib combined with pemetrexed and carboplatin as first-line treatment in advanced nonsquamous non-small cell lung cancer (NSCLC): ALTER L012.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21040-e21040
Author(s):  
Qiming Wang ◽  
Xiuli Yang ◽  
Tianjiang Ma ◽  
Qiumin Yang ◽  
Chenghui Zhang ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Line Treatment ◽  
First Line ◽  
Treatment Naïve ◽  
Nsclc Patients ◽  
First Line Treatment

e21040 Background: The anti-angiogenic drug bevacizumab combined with chemotherapy has achieved positive results in previous studies. In particular, the median progression-free survival (PFS) for EGFR-negative patients was increased to 8.3 months in the BEYOND study. Unlike bevacizumab, anlotinib is a novel multitarget tyrosine kinase inhibitor and can be conveniently orally administered. In the phase III trial ALTER 0303, anlotinib significantly improved overall survival (OS) and PFS in advanced NSCLC patients. This exploratory study aims to establish the efficacy and safety of anlotinib in combination with pemetrexed and carboplatin as first-line treatment in advanced non-squamous NSCLC. Methods: This is a multi-center, single-arm clinical trial. Adults with treatment-naive, histologically confirmed stage IIIB-IV non-squamous NSCLC, ECOG 0-1, and without known sensitizing EGFR/ALK alterations are included. Patients received anlotinib (12 mg p.o., QD, d1 to 14, 21 days per cycle) combined with pemetrexed (500 mg/m2, iv, d15-21, Q3W) + carboplatin (AUC = 5, iv, d15-21, Q3W) for 4 cycles followed by anlotinib and pemetrexed maintenance until disease progression (PD). The primary endpoint was PFS. Secondary endpoints were OS, objective response rate (ORR), disease control rate (DCR) and safety. Results: Between Mar 2019 and Dec 2020, 40 patients were enrolled in six centers and 31 of them have received at least one tumor assessment. Median age was 62 (33, 75); 66.7% male, 11.1% brain metastasis. At data cutoff (Dec 31, 2020), patients were followed up for a median of 8.26 months. Median PFS was 10.5 months (95% CI: NE, NE); ORR was 67.7% (0 CR, 21 PR), DCR was 96.8% (0 CR, 21 PR, 9 SD) and median OS was NE. The most common Grade ≥ 3 AEs were hypertension 22.2%, neutropenia 19.44%, myelosuppression 11.1%, thrombocytopenia 8.33%, leukopenia 5.56%, hand-foot syndrome 5.56% and there were no Grade 5 toxicities. Conclusions: This study finds that anlotinib plus pemetrexed and carboplatin can significantly improve PFS and ORR compared to standard chemotherapy for treatment-naive non-squamous NSCLC patients. The combination was well tolerated, and the AEs were manageable. The follow-up time is not sufficient, and the OS outcomes need further evaluation. Clinical trial information: NCT03790228.

Phase III Multicenter Randomized Trial of Oxaliplatin Added to Chronomodulated Fluorouracil–Leucovorin as First-Line Treatment of Metastatic Colorectal Cancer

2000 ◽  
Vol 18 (1) ◽  
pp. 136-136 ◽  
Author(s):  
S. Giacchetti ◽  
B. Perpoint ◽  
R. Zidani ◽  
N. Le Bail ◽  
R. Faggiuolo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Objective Response ◽  
Sensory Neuropathy ◽  
Phase Iii ◽  
Line Treatment ◽  
Survival Times ◽  
First Line ◽  
Grade 3 ◽  
First Line Treatment

PURPOSE: To study how adding oxaliplatin (l-OHP) to chronomodulated fluorouracil (5-FU)–leucovorin (LV) affected the objective response rate, as first-line treatment of metastatic colorectal cancer. PATIENTS AND METHODS: Two hundred patients from 15 institutions in four countries were randomly assigned to receive a 5-day course of chronomodulated 5-FU and LV (700 and 300 mg/m2/d, respectively; peak delivery rate at 0400 hours) with or without l-OHP on the first day of each course (125 mg/m2, as a 6-hour infusion). Each course was repeated every 21 days. Response was assessed by extramural review of computed tomography scans. RESULTS: Grade 3 to 4 toxicity from 5-FU–LV occurred in ≤ 5% of the patients (≤ 1% of the courses). Grade 3 to 4 diarrhea occurred in 43% of the patients given l-OHP (10% of the courses), and less than 2% of the patients had severe hematotoxicity. Thirteen percent of the patients had moderate functional impairment from peripheral sensory neuropathy. Sixteen percent of the patients receiving 5-FU–LV had an objective response (95% confidence interval [CI], 9% to 24%), compared with 53% of those receiving additional l-OHP (95% CI, 42% to 63%) (P < .001). The median progression-free survival time was 6.1 months with 5-FU–LV (range, 4.1 to 7.4 months) and 8.7 months (7.4 to 9.2 months) with l-OHP and 5-FU–LV (P = .048). Median survival times were 19.9 and 19.4 months, respectively. CONCLUSION: By chronomodulating 5-FU–LV, we were able to add l-OHP without compromising dose-intensities. l-OHP significantly improved the antitumor efficacy of this regimen.

JUPITER-02: Randomized, double-blind, phase III study of toripalimab or placebo plus gemcitabine and cisplatin as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (NPC).

2021 ◽  
Vol 39 (18_suppl) ◽  
pp. LBA2-LBA2
Author(s):  
Rui-hua Xu ◽  
Hai-Qiang Mai ◽  
Qiu-Yan Chen ◽  
Dongping Chen ◽  
Chaosu Hu ◽  
...  
Keyword(s):  
Interim Analysis ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Phase Iii ◽  
Line Treatment ◽  
First Line ◽  
Double Blind ◽  
Grade 3 ◽  
First Line Treatment

LBA2 Background: Gemcitabine-cisplatin (GP) chemotherapy is the standard 1st line treatment for locally advanced, recurrent or metastatic (r/m) NPC. Toripalimab, a humanized IgG4K monoclonal antibody specific for PD-1, provided durable responses in patients (pts) with r/m NPC as monotherapy in the ≥2nd line setting (POLARIS-02 study). The results of JUPITER-02, a randomized, placebo-controlled, double-blinded Phase III trial of toripalimab in combination with GP chemotherapy as first-line treatment for r/m NPC are summarized. Methods: Pts with advanced NPC with no prior chemotherapy in the r/m setting were randomized (1:1) to receive toripalimab 240 mg or placebo d1 in combination with gemcitabine 1000 mg/m2 d1, d8 and cisplatin 80 mg/m2 d1 every 3 weeks (Q3W) for up to 6 cycles, followed by monotherapy with toripalimab or placebo Q3W until disease progression, intolerable toxicity, or completion of 2 years of treatment. Stratification factors were ECOG PS (0 vs. 1) and extent of disease (recurrent vs. primary metastatic) at enrollment. Progression-free survival (PFS) and response were assessed by independent review committee (IRC) per RECIST v1.1. The primary endpoint was PFS by IRC in the ITT population. Secondary end points included ORR, DOR and OS. There was one prespecified interim analysis of PFS at 130 PFS events with a planned final analysis at 200 PFS events. Results: 289 pts were randomized: 146 to the toripalimab arm and 143 to the placebo arm. By May 30, 2020 as the interim analysis cutoff date, the median treatment duration was 39 weeks in the toripalimab arm and 36 weeks in the placebo arm. A significant improvement in PFS was detected for the toripalimab arm compared to the placebo arm (HR = 0.52 [95% CI: 0.36-0.74] two-sided p = 0.0003), with median PFS of 11.7 vs. 8.0 months. The 1-year PFS rates were 49% and 28% respectively. An improvement in PFS was observed across relevant subgroups, including all PD-L1 subgroups. The ORR was 77.4% vs. 66.4% (P = 0.033) and the median DOR was 10.0 vs. 5.7 months (HR = 0.50 [95% CI: 0.33-0.78]). As of Jan 15, 2021, OS was not mature, with 25 deaths in the toripalimab arm and 35 in the placebo arm (HR = 0.68 [95% CI: 0.41-1.14], P = 0.14). The incidence of Grade ≥3 adverse events (AEs) (89.0% vs 89.5%); AEs leading to discontinuation of toripalimab/placebo (7.5% vs 4.9%); and fatal AEs (2.7% vs 2.8%) were similar between two arms; however, immune-related (irAEs) (39.7% vs. 18.9%) and Grade ≥3 irAEs (7.5% vs. 0.7%) were more frequent in the toripalimab arm. Conclusions: The addition of toripalimab to GP chemotherapy as 1st-line treatment for pts with advanced NPC provided superior PFS and ORR and longer DOR than GP alone with a manageable safety profile. These results support the use of toripalimab with GP chemotherapy as the new standard care for this population. Clinical trial information: NCT03581786.

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