Ramucirumab and paclitaxel in patients with gastric cancer and prior trastuzumab: subgroup analysis from RAINBOW study

2019 ◽  
Vol 15 (23) ◽  
pp. 2723-2731 ◽  
Author(s):  
Ferdinando De Vita ◽  
Christophe Borg ◽  
Gabriella Farina ◽  
Ravit Geva ◽  
Iris Carton ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Subgroup Analysis ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Progression Free Survival ◽  
Combination Group ◽  
Clinical Trial Registration ◽  
Trastuzumab Therapy ◽  
Gastroesophageal Junction Adenocarcinoma ◽  
Registration Number

Aim: This subgroup analysis of the RAINBOW study evaluated the efficacy and safety of ramucirumab in patients with gastric cancer/gastroesophageal junction adenocarcinoma who received prior trastuzumab therapy. Patients & methods: Of adult patients enrolled in the RAINBOW study, 39 had received prior trastuzumab therapy. Of these, 20 patients were treated with ramucirumab plus paclitaxel and 19 patients with placebo plus paclitaxel within the RAINBOW trial. Results: Overall survival was longer with ramucirumab plus paclitaxel (11.4 months; 95% CI: 7.0–17.9) versus placebo plus paclitaxel (7.0 months; 95% CI: 3.4–14.6), hazard ratio: 0.68 (0.33–1.41); p = 0.30. Longer progression-free survival, higher objective response were observed in ramucirumab combination group. Conclusion: Ramucirumab plus paclitaxel demonstrated efficacy benefits with manageable safety profile in a subgroup of patients pretreated with trastuzumab.Clinical trial registration number: NCT01170663.

Effects of apatinib dose interruptions on safety and efficacy in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of stomach or gastroesophageal junction in third- or later-line setting.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 142-142
Author(s):  
Junsheng Wang ◽  
Shukui Qin ◽  
Jin Li ◽  
Wenying Deng ◽  
Lu Wen ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Clinical Trial ◽  
Advanced Gastric Cancer ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Progression Free Survival ◽  
Hazard Ratio ◽  
Safety And Efficacy ◽  
Optimal Dosing ◽  
Line Setting

142 Background: Apatinib, a small molecule VEGFR TKI, has been approved in the treatment of advanced gastric cancer in China. Due to toxicity, many pts underwent temporary interruptions during treatment. We analyzed the data from a phase IV clinical trial of Ahead-G201 to evaluate the relationship between dose interruption, drug safety and efficacy. Methods: At the cutoff date of Jul 10, 2017, Ahead-G201 study enrolled 1037 pts. The adverse events (AEs) and clinical efficacy were evaluated for pts with no, 1, 2 and ≥3 dose interruptions. Results: 336 of 1037 pts underwent dose interruptions during apatinib treatment: 1 interruption in 183 pts; 2 interruptions in 67 pts; and ≥3 interruptions in 86 pts. The toxicity and efficacy for them were listed in Table. For safety, pts with no interruption had the lowest incidence of all AEs (59.3%) and grade 3-4 AEs (30.0%). Pts with ≥3 interruptions had the highest objective response rate (ORR, 20.3%) and disease control rate (DCR, 82.6%). Moreover, these pts got median progression-free survival (mPFS) of 6.6 mos and median overall survival (mOS) of 9.4 mos, which were the longest among 4 groups. Furthermore, multivariate analysis revealed that ≥3 interruptions of apatinib bring much more efficacy benefit both in mPFS (6.6 vs 3.8 mos: hazard ratio, 0.5, 95%CI, 0.3 to 0.7) and mOS (9.4 vs 6.6 mos: hazard ratio, 0.5, 95%CI, 0.3 to 0.8) for pts, than those with no interruption. Conclusions: Current results indicated that dose interruptions are required to manage toxicity and it is necessary to explore an optimal dosing pattern of apatinib in advanced gastric cancer. Clinical trial information: NCT02426034. [Table: see text]

Ramucirumab treatment in patients with gastric cancer/gastroesophageal junction adenocarcinoma: Secondary analysis of efficacy and safety results of 4 dosing regimens in the phase II trial I4T-MC-JVDB.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 117-117
Author(s):  
Jaffer A. Ajani ◽  
Anghel Adrian Udrea ◽  
Tomasz Sarosiek ◽  
Michael Schenker ◽  
Carys Morgan ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Standard Dose ◽  
Gastroesophageal Junction ◽  
Secondary Analysis ◽  
Progression Free Survival ◽  
Efficacy And Safety ◽  
Open Label ◽  
Standard Regimen ◽  
Gastroesophageal Junction Adenocarcinoma ◽  
Grade 3

117 Background: Ramucirumab (RAM) is approved for treatment of advanced gastric cancer or gastroesophageal junction adenocarcinoma with disease progression after prior platinum and/or fluoropyrimidine chemotherapy at 8 mg/kg every 2 weeks (Q2W). Previous phase 3 trials indicated that efficacy of RAM correlated with exposure. While the primary objectives of the open-label RAM monotherapy JVDB study were pharmacokinetics and safety, a secondary analysis was conducted on efficacy and safety of the 3 higher exposure regimens vs. the standard regimen. Methods: Patients ( n = 164) were randomized 1:1:1:1 to 4 treatment arms: 8 mg/kg Q2W (Arm 1), 12 mg/kg Q2W (Arm 2), 6 mg/kg every week (Arm 3), and 8 mg/kg Days 1 and 8 (D1D8) every 3 weeks (Q3W) (Arm 4). Treatment-emergent adverse events (TEAEs) were graded by NCI CTCAE v4.0. Tumor response was assessed by RECIST 1.1. Results: Median (months) progression-free survival (PFS) of the 3 arms and overall survival (OS) of 2 arms was increased compared to the standard regimen (Table). Best overall response was partial response (Arm 2, n = 4; Arm 3, n = 2). The majority of patients experienced ≥1 TEAE (81.4%); 39.1% had ≥1 Grade ≥3 event and 26.7% had ≥1 serious event. The most frequent Grade ≥3 events were fatigue (5.6%), abdominal pain (5.05%), hypertension (5.0%), anemia (4.3%), and vomiting (3.7%). Conclusions: Although the study was not powered for statistical comparisons, some trends toward improved efficacy vs. the standard regimen were observed; the greatest median PFS months and OS improvement was 1 month (Arm 2 vs. Arm 1; PFS = 2.50 vs. 1.45; OS = 6.74 vs. 5.68). Despite higher RAM exposures with the experimental regimens, the safety profile is similar to the standard dose regimen, and no unexpected safety findings were observed. Clinical trial information: NCT02443883. [Table: see text]

Initial dose of apatinib in Chinese patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of stomach or gastroesophageal junction in third- or later-line setting: 500 mg or 850 mg?

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 35-35 ◽  
Author(s):  
Wenying Deng ◽  
Shukui Qin ◽  
Jin Li ◽  
Lu Wen ◽  
Junsheng Wang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Clinical Trial ◽  
Advanced Gastric Cancer ◽  
Initial Dose ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Progression Free Survival ◽  
Chinese Patients ◽  
Best Response ◽  
Line Setting

35 Background: A fine balance between maintaining efficacy and reducing toxicity is necessary for drug therapies in many cancers. This study seeks to review the data from phase IV clinical trial of Ahead-G201 to help elucidate the optimal initial dose of apatinib in advanced gastric cancer. Methods: Pts data from the Ahead-G201 study at cut-off date of Jul 10, 2017 were extracted to explore the correlation of apatinib initial dose (500 mg vs 850 mg) with safety and clinical efficacy. Results: 864 of eligible pts received apatinib at an initial dose of 500 mg, and 58 pts received at 850 mg. Dose interruption occurred in 258 pts (33.1%) at 500 mg and in 27 pts (46.5%) at 850 mg. For safety, the most common adverse events (AEs) were proteinuria, hypertension and leukocyte decrease in both groups. Moreover, the incidence of all AEs and grade 3-4 AEs in pts at 500 mg was significantly lower than pts at 850 mg (Table). For efficacy, pts at 500 mg achieved an objective response rate (ORR) of 10.8% and a disease control rate (DCR) of 70.6%, at best response, which were 10.3% and 55.2% in pts at 850 mg. Pts at 500 mg got a significantly longer median progression-free survival (mPFS) and median overall survival (mOS) than pts at 850 mg (PFS, 4.6 mos vs 2.2 mos; OS, 6.8 mos vs 4.0 mos). Multivariate analysis indicated that apatinib treatment at an initial dose of 500 mg was significantly associated with longer mOS in advanced gastric cancer pts (6.8 mos vs 4.0 mos: hazard ratio, 0.5; 95%CI, 0.3 to 0.8), compared to initial dose of 850 mg. Conclusions: Compared to receiving apatinib at initial dose of 850mg, oral administration of apatinib starting from 500 mg seemed to bring more clinical benefit for patients with advanced gastric cancer, whilst with lower toxicities. Clinical trial information: NCT02426034. [Table: see text]

Pembrolizumab (pembro) versus standard of care chemotherapy (chemo) in patients with advanced gastric or gastroesophageal junction adenocarcinoma: Asian subgroup analysis of KEYNOTE-062.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4523-4523 ◽  
Author(s):  
Hironaga Satake ◽  
Keun Wook Lee ◽  
Hyun Cheol Chung ◽  
Jeeyun Lee ◽  
Kensei Yamaguchi ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Advanced Gastric Cancer ◽  
Performance Status ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Asian Population ◽  
Progression Free Survival ◽  
Ecog Performance Status ◽  
End Points ◽  
Asian Patients

4523 Background: First-line treatment with pembro or pembro + chemo vs chemo alone was evaluated in patients with PD-L1 combined positive score (CPS) ≥1, HER2-negative advanced gastric cancer in the randomized, active-controlled, phase 3 KEYNOTE-062 study (NCT02494583). We present results from the Asian subpopulation receiving pembro monotherapy or chemo. Methods: Eligible patients were randomly assigned 1:1:1 to pembro 200 mg, pembro + chemo (cisplatin + 5-FU or capecitabine), or placebo + chemo every 3 weeks for ≤35 cycles (~2 years). Randomization was stratified by region, disease status, and fluoropyrimidine treatment. Primary end points for this analysis were overall survival (OS) in patients with CPS ≥1 and patients with CPS ≥10; progression-free survival (PFS) and objective response rate (ORR) were exploratory end points. Data cutoff was March 26, 2019. Results: Globally, 256 patients received pembro monotherapy and 250 received chemo. Pembro was noninferior to chemo for OS in CPS ≥1 per prespecified margins (median OS, 10.6 vs 11.1 months, respectively; HR [99.2% CI], 0.91 [0.69-1.18]). In the Asian population 62 patients received pembro and 61 received chemo; 26 and 22 had CPS ≥10 (Table). Compared with the global population, Asian patients had a higher proportion of ECOG performance status 0, more diagnoses of stomach cancer, and a greater proportion with 0-2 metastatic sites. Median OS was longer with pembro than chemo using both CPS cutoffs (HR [95% CI]: CPS ≥1, 0.54 [0.35-0.82]; CPS ≥10, 0.43 [0.21-0.89]); 12- and 24-month OS rates were higher for pembro using both CPS cutoffs (12-month OS: CPS ≥1, 69% vs 54%; CPS ≥10, 81% vs 68%; 24-month OS: CPS ≥1, 45% vs 23%; CPS ≥10, 54% vs 27%). The HR (95% CI) for PFS was 1.11 (0.76-1.64) for CPS ≥1 and 0.71 (0.36-1.39) for CPS ≥10. Conclusions: In Asian patients with advanced gastric cancer, OS favored pembro in patients with CPS ≥1 and CPS ≥10. Clinical trial information: NCT02494583 . [Table: see text]

A phase II, open-label, randomized study to evaluate the efficacy and safety of andecaliximab combined with nivolumab versus nivolumab alone in subjects with unresectable or recurrent gastric or gastroesophageal junction adenocarcinoma.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 75-75 ◽  
Author(s):  
Manish A. Shah ◽  
Jean-Philippe Metges ◽  
David Cunningham ◽  
Kai-Keen Shiu ◽  
Lucjan Wyrwicz ◽  
...  
Keyword(s):  
Randomized Study ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Progression Free Survival ◽  
Tolerability Profile ◽  
Efficacy And Safety ◽  
Open Label ◽  
T Cell Infiltration ◽  
Gastroesophageal Junction Adenocarcinoma ◽  
Kaplan Meier

75 Background: Andecaliximab (ADX) is a monoclonal antibody that inhibits matrix metalloproteinase 9 (MMP9). Preclinical studies suggest that MMP9 inhibition relieves immune suppression and promotes T-cell infiltration to potentiate checkpoint blockade. Methods: Phase 2, open-label, randomized study of the efficacy and safety of ADX + nivolumab (NIVO) vs. NIVO alone in patients with pre-treated metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. Patients were randomized to either ADX 800 mg IV + NIVO 3 mg/kg IV, or NIVO 3 mg/kg IV alone, and stratified by tumor PD-L1 status. Treatment was administered every 2 weeks. Re-staging CT scans were performed every 8 weeks to evaluate response. Primary endpoint: objective response rate (ORR). Secondary endpoints: progression-free survival (PFS), overall survival (OS), and adverse events (AEs). Results: Of the 144 patients randomized, 141 were treated, 109 (76%) completed tumor assessment. 81% of patients were white, with 69% male and a mean (SD) age of 59 (12) years. ORR (95% CI) was 11.1% (4.9–20.7%) in patients receiving ADX + NIVO, and 6.9% (2.3–15.5%) in those receiving NIVO alone, p = 0.6. Kaplan-Meier estimated median (95% CI) PFS was 1.8 (1.8–2.0) months in patients receiving ADX + NIVO, and 1.9 (1.7–1.9) months in those receiving NIVO alone, p = 0.2. Kaplan-Meier estimated median (95% CI) OS was 7.2 (5.2–9.1) months in patients receiving ADX + NIVO, and 5.9 (3.5–8.6) months in those receiving NIVO alone, p = 0.4. AEs leading to treatment discontinuation occurred in 1 patient in the ADX + NIVO group, and in 1 patient in NIVO-only group. PD-L1 and mismatch repair deficient subgroup analyses will be presented. Exploratory biomarker analyses will be submitted separately. Conclusions: Addition of ADX to NIVO did not improve ORR, PFS, or OS compared with NIVO alone in patients with pre-treated metastatic gastric or GEJ adenocarcinoma. Combination of ADX with NIVO had a favorable safety and tolerability profile. Clinical trial information: NCT02864381.

scholarly journals MAHOGANY: margetuximab combination in HER2+ unresectable/metastatic gastric/gastroesophageal junction adenocarcinoma

2020 ◽  
Author(s):  
Daniel VT Catenacci ◽  
Minori Rosales ◽  
Hyun Cheol Chung ◽  
Harry H Yoon ◽  
Lin Shen ◽  
...  
Keyword(s):  
Cell Function ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Locally Advanced ◽  
Lymphocyte Activation ◽  
First Line ◽  
Her2 Positive ◽  
Open Label ◽  
Clinical Trial Registration ◽  
Gastroesophageal Junction Adenocarcinoma

Standard-of-care, first-line therapy for patients with advanced human epidermal growth factor receptor 2 (HER2)-positive gastric/gastroesophageal junction adenocarcinoma is chemotherapy plus trastuzumab, a monoclonal antibody (mAb) targeting HER2. Margetuximab is an Fc-optimized mAb that binds HER2. Retifanlimab, a humanized IgG4 mAb, binds to PD-1 and blocks its interaction with PD-L1/2. Tebotelimab, an IgG4κ bispecific DART® molecule, binds PD-1 and lymphocyte activation gene 3 concomitantly, disrupting these nonredundant inhibitory pathways to further restore exhausted T-cell function. Here, we describe the design and rationale of the randomized, open-label, Phase II/III MAHOGANY trial evaluating margetuximab plus retifanlimab with/without chemotherapy and margetuximab plus tebotelimab with chemotherapy in first-line unresectable metastatic/locally advanced gastroesophageal junction adenocarcinoma. Primary end points include objective response rate, overall survival and safety/tolerability. Clinical trial registration: NCT04082364 (ClinicalTrials.gov)

scholarly journals First-line pembrolizumab/placebo plus trastuzumab and chemotherapy in HER2-positive advanced gastric cancer: KEYNOTE-811

2020 ◽  
Author(s):  
Hyun Cheol Chung ◽  
Yung-Jue Bang ◽  
Charles S Fuchs ◽  
Shu-Kui Qin ◽  
Taroh Satoh ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Advanced Gastric Cancer ◽  
Treatment Options ◽  
Gastroesophageal Junction ◽  
Phase Iii ◽  
First Line ◽  
Her2 Positive ◽  
Double Blind ◽  
Clinical Trial Registration ◽  
Gastroesophageal Junction Adenocarcinoma

Treatment options for patients with HER2-positive advanced gastric cancer are limited, and the prognosis for these patients is poor. Pembrolizumab has demonstrated promising antitumor activity in patients with advanced gastric or gastroesophageal junction adenocarcinoma as monotherapy, in combination with chemotherapy and in combination with trastuzumab. Combining pembrolizumab with trastuzumab and chemotherapy may therefore provide a benefit for patients with advanced HER2-positive gastric cancer. Here we aimed to describe the design of and rationale for the randomized, double-blind, placebo-controlled Phase III KEYNOTE-811 study, which will evaluate the efficacy and safety of pembrolizumab or placebo in combination with trastuzumab and chemotherapy as first-line treatment for patients with advanced HER2-positive gastric or gastroesophageal junction adenocarcinoma. Clinical trial registration: NCT03615326 ( ClinicalTrials.gov )

scholarly journals Safety and tolerability of andecaliximab as monotherapy and in combination with an anti-PD-1 antibody in Japanese patients with gastric or gastroesophageal junction adenocarcinoma: a phase 1b study

2022 ◽  
Vol 10 (1) ◽  
pp. e003518
Author(s):  
Akie Kimura Yoshikawa ◽  
Kensei Yamaguchi ◽  
Kei Muro ◽  
Atsuo Takashima ◽  
Takashi Ichimura ◽  
...  
Keyword(s):  
Gastroesophageal Junction ◽  
Objective Response ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Japanese Patients ◽  
Her2 Status ◽  
Clinical Activity ◽  
Gastroesophageal Junction Adenocarcinoma ◽  
Programmed Death 1 ◽  
Phase 1B

BackgroundMatrix metalloproteinase 9 (MMP9) is implicated in protumorigenic processes. Targeting either stromal or epithelial MMP9 reduces the incidence of metastasis. Andecaliximab is a monoclonal antibody that targets MMP9 with high affinity and selectivity. However, no study has examined whether the inhibition of T-cell programmed death 1 (PD-1) in the presence of andecaliximab increases activated lymphocyte infiltration into the tumor, thereby increasing antitumor activity more than that in anti-PD-1 monotherapy. In this study, we assessed the safety, pharmacokinetics (PK), exploratory biomarkers, and preliminary efficacy of andecaliximab as monotherapy and in combination with nivolumab in Japanese patients with advanced or recurrent gastric or gastroesophageal junction (GEJ) adenocarcinoma.MethodsThis phase 1b study comprised four cohorts enrolling Japanese patients with gastric or GEJ adenocarcinoma. This paper concerns cohorts 1 and 4; cohorts 2 and 3 will be reported subsequently. Cohort 1 enrolled patients with human epidermal growth factor receptor 2 (HER2)-negative tumors (n=8) who received andecaliximab monotherapy (800 mg by intravenous infusion every 2 weeks (Q2W)), and cohort 4 enrolled patients irrespective of their HER2 status (n=10) who received 800 mg of andecaliximab in combination with nivolumab Q2W. Safety, dose-limiting toxicities (DLTs), PK, pharmacodynamics, and biomarkers were assessed in both cohorts.ResultsPK of andecaliximab in Japanese patients with gastric or GEJ adenocarcinoma was similar to that reported in non-Japanese patients with advanced solid tumors. Andecaliximab monotherapy and in combination with nivolumab demonstrated no DLTs in cohort 1 and 4, respectively. Toxicities were manageable and well tolerated in both cohorts. The median progression-free survival was 1.4 months (90% CI, 0.5 to 5.4) and 4.6 months (90% CI, 0.9 to not reached) in cohorts 1 and 4, respectively. The objective response rate was 50% (90% CI, 22% to 78%) in cohort 4, and in some patients, the combination therapy was effective regardless of the biomarker status.ConclusionsThe andecaliximab–nivolumab combination demonstrated a manageable safety profile and promising clinical activity in patients with advanced gastric adenocarcinoma.NCT02862535.

Safety and efficacy of apatinib in elderly patients with advanced or metastatic gastric cancer in the post-marketing phase IV study: Subgroup analysis by age (Ahead-G201).

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 126-126
Author(s):  
Lu Wen ◽  
Shukui Qin ◽  
Jin Li ◽  
Wenying Deng ◽  
Junsheng Wang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Subgroup Analysis ◽  
Cox Regression ◽  
Objective Response ◽  
Progression Free Survival ◽  
Metastatic Gastric Cancer ◽  
Increased Risk ◽  
Post Marketing ◽  
Metastatic Sites ◽  
Phase Iv

126 Background: Old age is a potential negative predictor, and thus is of interest. Data from the ongoing post-marketing Phase IV trial were collected to assess the effect of age on apatinib treatment in 2000+ patients (pts) with chemotherapy-refractory advanced or metastatic gastric cancer. Methods: This subgroup analysis was stratified by age (<65 or ≥65 yrs). Both incidence of adverse events (AEs) and clinical outcomes were compared. Results: 725 pts <65 yrs and 312 pts ≥65 yrs were enrolled (data cut-off 2017/7/10). Differences in gender, ECOG PS, BMI, disease duration and metastatic sites were observed. 68.6% and 39.7% of pts aged ≥65 yrs experienced AEs of any grade and grade ≥3, which were not different with 70.2% and 40.0% of pts aged <65 yrs. The common AE profile was similar, but elderly pts had a higher incidence of hypertension, diarrhea and bilirubin increase (Table). Pts ≥65 yrs showed a higher objective response rate (12.2% vs. 9.9%) and longer overall survival (7.82 vs. 6.05 mos); however, there was no statistical difference. The disease control rate (79.6% vs. 65.4%; p=0.002) and progression free survival (PFS) (5.71 vs. 3.22 mos; p<0.001) of pts ≥65 yrs were significantly superior to pts <65 yrs. Multivariate Cox regression model confirmed that age ≥65 yr was a positive prognostic factor for PFS independent of baseline and treatment characteristics (HR: 0.67 [95%CI, 0.50–0.88]). Conclusions: Pts ≥65 yr is not at increased risk of overall AEs, but hypertension, diarrhea and bilirubin increase should be closely monitored. The PFS benefit in elderly pts will be validated. Clinical trial information: NCT02426034. [Table: see text]

Phase II study of zolbetuximab plus pembrolizumab in claudin 18.2: Positive locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma (G/GEJ)—ILUSTRO Cohort 3.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. TPS260-TPS260
Author(s):  
Samuel J Klempner ◽  
Jaffer A. Ajani ◽  
Salah-Eddin Al-Batran ◽  
Yung-Jue Bang ◽  
Daniel V.T. Catenacci ◽  
...  
Keyword(s):  
Performance Status ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Open Label ◽  
Eligibility Criteria ◽  
Gastroesophageal Junction Adenocarcinoma ◽  
Junction Protein

TPS260 Background: Five-year survival with advanced G/GEJ is poor, and limited biomarkers exist to inform optimal treatment selection. Pembrolizumab, an anti–programmed death-1 receptor (PD-1) antibody, is approved for advanced/metastatic PD-ligand 1–positive (PD-L1+) G/GEJ that progressed after ≥2 lines of therapy. The transmembrane tight junction protein claudin 18.2 (CLDN18.2) is normally confined to gastric mucosa but is often overexpressed in G/GEJ with roughly one-third of patients (pts) having high expression (≥75%). Zolbetuximab, a chimeric IgG1 monoclonal antibody, binds to CLDN18.2 and mediates cancer cell death through antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity. Phase 2 (NCT01630083) results showed prolonged survival with zolbetuximab + epirubicin, oxaliplatin, and capecitabine (EOX) vs EOX alone in G/GEJ. Results of nonclinical studies showed enhanced antitumor activity with zolbetuximab + anti-murine PD-1 antibody, and it was hypothesized that a combination with pembrolizumab (new Cohort 3) might augment ADCC and antitumor immune response in CLDN18.2 overexpressing G/GEJ. Methods: This phase 2 open-label study (NCT03505320) will enroll ~112 adult pts from 22 sites in 5 countries into 3 cohorts; this abstract describes Cohort 3 (~62 pts). Key eligibility criteria are advanced/metastatic G/GEJ, measurable disease (RECIST v1.1), adequate organ function and performance status, and high/intermediate (Cohort 3A) or high (Cohort 3B) expression of CLDN18.2. Central testing of tumor tissue will determine CLDN18.2 expression; pts are considered CLDN18.2 positive (CLDN18.2+) if ≥75% (high) or ≥50% to < 75% (intermediate) of tumor cells demonstrate moderate-to-strong membranous IHC staining. Patients in Cohort 3B are required to be PD-L1+, defined as a combined positive score ≥1 (IHC staining per the Dako 22C3 PD-L1 assay). Patients will receive zolbetuximab + pembrolizumab in the third/later line in Cohort 3A and third line in Cohort 3B. In Cohort 3A (safety cohort), zolbetuximab will be administered at a loading dose of 800 mg/m2 IV on Day 1 Cycle 1 followed by 600 mg/m2 IV every 3 weeks; a reduction from 600 mg/m2 every 3 weeks is permitted. Pembrolizumab 200 mg IV will be administered on Day 1 of each 21-day cycle. Cohort 3B (expansion cohort) zolbetuximab dose is determined from results of Cohort 3A. Imaging will occur every 6 weeks for 24 weeks and every 12 weeks thereafter. The primary endpoint is objective response rate; additional endpoints include duration of response, disease control rate, and progression-free survival by independent review committee and investigator assessment. Pharmacokinetics, safety/tolerability, quality of life, and immunogenicity will be assessed. The study is currently recruiting pts. Clinical trial information: NCT03505320.

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