First-Line Advanced Gastric Cancer Research Articles

Early Immune Remodeling Steers Clinical Response to First-Line Chemoimmunotherapy in Advanced Gastric Cancer.

The benefit of 5-FU/platinum with anti-PD-1 in first-line advanced gastric cancer is limited to patient subgroups. Using a trial with sequential anti-PD-1, we show coordinated induction of multicellular TME hubs informs the ability of anti-PD-1 to potentiate T cell-driven responses. Differential TME hub development highlights features that underlie clinical outcomes. This article is featured in Selected Articles from This Issue, p. 695.

PGI3 - Real-World Productivity, Healthcare Resource Utilization (Hru), and Quality of Life (Qol) in Patients With First-Line Advanced Gastric Cancer (Agc) in Korea and Japan

As GC is the fifth most common cancer globally, it is important to better understand the impact of advanced (unresectable/metastatic) disease on patient and caregiver productivity, HRU, and QOL. Real-world data were collected through a cross-sectional survey administered to physicians and patients in Japan and South Korea (Nov 2016 to Mar 2017). For Japanese patients only, health utility and overall health were assessed with the EQ-5D utility index (scores ranging 0 [dead] to 1.0 [full health]) and Visual Analog Scale (VAS; scores ranging 0 to 100, higher scores indicating better overall health), respectively. A total of 95 physicians provided information for 182 patients currently on their first-line active drug treatment for AGC. Median patient age was 67 (32-89) years, most were male (72%), with ECOG PS of 0 (32%) or 1 (48%), primary disease site was gastric vs. gastroesophageal junction (92% vs. 8%), and no prior gastrectomy (81%). Most patients (60%) were retired, unemployed, or on sick leave (15% of these due to AGC). 59% of patients had caregivers, spending an average of 53.5 hours of care/week (SD=38.4). Many caregivers were partners/spouses (81%) who were unable to work or were working less to care for the patient (89%). AGC also had an impact on HRU and EQ-5D scores. In the prior 12 months, patients made an average of 7.9 visits to an oncologist (SD=3.1), and experienced 2.8 GC-related hospitalizations (SD=3.3). Relative to Japanese general population norms for ages 65-74 (EQ-5D index, 0.88; VAS, 76.6), patients had lower health utility and overall health (EQ-5D index: M=0.76, SD=0.21; VAS: M=54.9, SD=20.8) As indicated by real-world data, AGC is associated with productivity loss for both patients and caregivers, significant HRU, and meaningful reductions in patients’ QOL. Novel treatment options are needed to reduce the overall burden of this disease.

Real-world first-line advanced gastric cancer in western and Asian countries: Treatment patterns and impact on quality of life (QOL).

e16018Background: Given the 5-year survival rate for advanced/metastatic gastric cancer (AGC) is only ~5%, it is important to understand real-world first-line (1L) treatment patterns and QOL in the...

Phase III randomized trial comparing 5-fluorouracil and oxaliplatin with or without docetaxel in first-line advanced gastric cancer chemotherapy (GASTFOX study)

IntroductionIn advanced gastric cancer, doublet regimen including platinum salts and fluoropyrimidine is considered as a standard first-line treatment. The addition of docetaxel (75 mg/m2 q3w) to cisplatin (75 mg/m2 q3w) and 5-fluorouracil has been shown to improve efficacy. However, this regimen (DCF) was associated with frequent severe toxicities (including more complicated neutropenia), limiting its use in clinical practice. Interesting alternative docetaxel-based regimens have been developed that need to be validated. AimGASTFOX study is a randomized phase III trial comparing FOLFOX alone or with docetaxel at 50 mg/m2 (TFOX regimen) in first-line treatment for advanced gastric cancer. In both arms, cycle is repeated every 2 weeks until disease progression or unacceptable toxicity. Materials and methodsMain eligibility criteria: histologically proven locally advanced or metastatic gastric or esogastric junction adenocarcinoma, HER negative status, measurable disease, ECOG performance status 0 or 1, and adequate renal, hepatic and bone marrow functions. ResultsThe primary endpoint is radiological/clinical progression-free survival (PFS). A difference of 2 months for the median PFS in favor of TFOX is expected (HR = 0.73) Based on a two-sided α risk of 5% and a power of 90%, 454 events are required to show this difference. Secondary endpoints included overall survival, overall response rate, safety, quality of life and the therapeutic index. ConclusionThis study is planned to include 506 patients to demonstrate the superiority of TFOX over FOLFOX in first-line advanced gastric cancer treatment (NCT03006432).

Combination of cisplatin/S-1 in the treatment of patients with advanced gastric or gastroesophageal adenocarcinoma: Results of noninferiority and safety analyses compared with cisplatin/5-fluorouracil in the First-Line Advanced Gastric Cancer Study

BackgroundThe aim of developing oral fluorouracil (5-FU) is to provide a more convenient administration route with similar efficacy and the best achievable tolerance. S-1, a novel oral fluoropyrimidine, was specifically designed to overcome the limitations of intravenous fluoropyrimidine therapies. Patients and methodsA multicentre, randomised phase 3 trial was undertaken to compare S-1/cisplatin (CS) with infusional 5-FU/cisplatin (CF) in 1053 patients with untreated, advanced gastric/gastroesophageal adenocarcinoma. This report discusses a post-hoc noninferiority overall survival (OS) and safety analyses. ResultsResults (1029 treated; CS=521/CF=508) revealed OS in CS (8.6 months) was statistically noninferior to CF (7.9 months) [hazard ratio (HR)=0.92 (two-sided 95% confidence interval (CI), 0.80–1.05)] for any margin equal to or greater than 1.05. Statistically significant safety advantages for the CS arm were observed [G3/4 neutropenia (CS, 18.6%; CF, 40.0%), febrile neutropenia (CS, 1.7%; CF, 6.9%), G3/4 stomatitis (CS, 1.3%; CF, 13.6%), diarrhoea (all grades: CS, 29.2%; CF, 38.4%) and renal adverse events (all grades: CS, 18.8%; CF, 33.5%)]. Hand–foot syndrome, infrequently reported, was mainly grade 1/2 in both arms. Treatment-related deaths were significantly lower in the CS arm than the CF arm (2.5% and 4.9%, respectively; P<0.047). ConclusionCS is noninferior to CF with a better safety profile and provides a new treatment option for patients with advanced gastric carcinoma.

Exposure and clearance of bevacizumab in patients with first-line advanced gastric cancer.

2603 Background: Bevacizumab (BEV), rhuMAB VEGF, in combination with chemotherapy (CT) is currently approved in various types of cancer. Recently, BEV+CT was evaluated in 1st line advanced gastric cancer (AGC) in a double-blind randomized phase 3 trial (AVAGAST), but failed to meet the primary OS endpoint (HR=0.87; p=0.1002). BEV pharmacokinetics (PK) is well established by a reference population PK (PPK) model, and BEV PK is consistent across multiple cancer indications. However, BEV PK in AGC was never evaluated. We aimed to assess BEV exposure (EXP) and PK in AGC and to explore the influence of demographic, prognostic and biochemical (DPB) factors. Methods: BEV concentrations (Cp) were measured from plasma samples collected following disease progression from 182 patients (7.5mg/kg Q2W) in AVAGAST. Expected BEV Cp [median and 90% prediction interval (PI)] were simulated using the PPK model and compared to the observed BEV EXP. BEV clearance (CL) in AGC was estimated using NONMEM and compared between subgroups stratified by DPB factors. Results: All DPB factors of AGC are similar to those in other cancers except for lower body weight. No cachexia was observed. BEV Cp was detectable in 162 patients. 85% of observed BEV Cp was below the median BEV Cp simulated using PPK model and 38% below the lower limit of the 90% PI. Median BEV CL in AGC was 4.5 L/day/kg vs. 3 L/day/kg in other cancers. BEV CL was significantly higher (p=0.0012) in patients without prior gastrectomy (4.9 L/day/kg, n=120) than those with gastrectomy (4.1 L/day/kg, n=42). CL appeared to be higher in AGC patients with higher ECOG scores, lower albumin, more metastatic sites, poorer response and later stage AGC. Tumor location (GE Jct vs. Stomach), VEGF-A and ethnicity (Asian vs. Non-Asian) did not correlate with BEV CL. Conclusions: Overall, AGC patients exhibited significantly lower BEV EXP due to a 50% increase in BEV CL vs. other cancers. In addition, BEV is cleared significantly faster in patients without prior gastrectomy. The low BEV EXP in AGC could potentially reduce the effect of BEV in AGC. The underlying mechanism for faster BEV CL in AGC is unknown and warrants further research and potential BEV dose modifications.

Phase II study of biweekly docetaxel and cisplatin combination chemotherapy in first-line advanced gastric cancer

15601 Background: Docetaxel and cisplatin, as single agents, have demonstrated activity in patients with advanced gastric cancer. Docetaxel and cisplatin have shown a different toxicity profile; consequently the combination of these drugs could be a safe and effective treatment. Therefore, we conducted a phase II study to assess efficacy and toxicity of a biweekly regimen of docetaxel plus cisplatin in patients with advanced gastric cancer who have never been treated with palliative chemotherapy. Methods: Fifty-two patients with advanced gastric cancer were enrolled, histologically confirmed of gastric adenocarcinoma, at least one measurable lesion, ECOG PS ≤2, no prior palliative chemotherapy and adequate bone marrow, renal and hepatic function. Docetaxel 50 mg/m2 and cisplatin 50 mg/m2 were administered every two weeks until progression disease, unbearable toxicity or a maximum of 12 cycles. The objective response was evaluated according to RECIST criteria and toxicity was assessed according to the NCI-CTC 2.0. Results: In total, 392 cycles were administered (median 8, range 1–12 cycles), with a median dose intensity of 91% for docetaxel and cisplatin. The median age was 66 years (range 37–84), 71% were male, 6.5% had ECOG 0 and 78.3% ECOG 1. The objective response rate was 37.0% (95% CI, 23.0–50.9) with one complete response and 16 partial responses, over 46 evaluable patients. Sixteen patients had stable disease. Median time to progression was 5.5 months (95% CI, 4.0–7.0) and median overall survival 8.9 months (95% CI: 6.0–11.9). The most common grade 3–4 toxicities per cycle were neutropenia (5.9%), anaemia (1.8%), asthenia (1.8%), vomiting (1.0%), nausea (0.8%) and thrombocytopenia (0.8%). Conclusions: Biweekly administration of docetaxel and cisplatin in advanced gastric cancer has a manageable toxicity profile and shows a promising antitumor activity as a first-line therapy. No significant financial relationships to disclose.

Docetaxel, Cisplatin, and Fluorouracil; Docetaxel and Cisplatin; and Epirubicin, Cisplatin, and Fluorouracil As Systemic Treatment for Advanced Gastric Carcinoma: A Randomized Phase II Trial of the Swiss Group for Clinical Cancer Research

This randomized phase II trial evaluated two docetaxel-based regimens to see which would be most promising according to overall response rate (ORR) for comparison in a phase III trial with epirubicin-cisplatin-fluorouracil (ECF) as first-line advanced gastric cancer therapy. Chemotherapy-naïve patients with measurable unresectable and/or metastatic gastric carcinoma, a performance status <or= 1, and adequate hematologic, hepatic, and renal function randomly received <or= eight 3-weekly cycles of ECF (epirubicin 50 mg/m(2) on day 1, cisplatin 60 mg/m(2) on day 1, and fluorouracil [FU] 200 mg/m(2)/d on days 1 to 21), TC (docetaxel initially 85 mg/m(2) on day 1 [later reduced to 75 mg/m(2) as a result of toxicity] and cisplatin 75 mg/m(2) on day 1), or TCF (TC plus FU 300 mg/m(2)/d on days 1 to 14). Study objectives included response (primary), survival, toxicity, and quality of life (QOL). ORR was 25.0% (95% CI, 13% to 41%) for ECF, 18.5% (95% CI, 9% to 34%) for TC, and 36.6% (95% CI, 23% to 53%) for TCF (n = 119). Median overall survival times were 8.3, 11.0, and 10.4 months for ECF, TC, and TCF, respectively. Toxicity was acceptable, with one toxic death (TC arm). Grade 3 or 4 neutropenia occurred in more treatment cycles with docetaxel (TC, 49%; TCF, 57%; ECF, 34%). Global health status/QOL substantially improved with ECF and remained similar to baseline with both docetaxel regimens. Time to response and ORR favor TCF over TC for further evaluation, particularly in the neoadjuvant setting. A trend towards increased myelosuppression and infectious complications with TCF versus TC or ECF was observed.

Docetaxel, cisplatin and leucovorin/fluorouracil in first-line advanced gastric cancer and adenocarcinoma of the esophagogastric junction: Results of the phase II GASTRO-TAX-1 trial

4561 Background: Phase II and III trials combining docetaxel, cisplatin and fluorouracil (DCF) every 3 weeks (wks) have shown superior efficacy but high rates of hematological toxicity in advanced gastric cancer. To reduce toxicity while containing the efficacy of DCF, we conducted a protocol using split doses of docetaxel (T), cisplatin (P), leucovorin (L), fluorouracil (F) (T-PLF). Methods: Chemo-naive patients (pts) with advanced gastroesophageal adenocarcinomas received T 50 mg/m2, P 50 mg/m2 day 1, 15, 29 and L 500 mg/m2 plus F 2,000 mg/m2 d1, 8, 15, 22, 29, 36 qd49. Because significant reductions to &lt;80% of initial drug doses became necessary in 80% of pts, the regimen was amended after the first 15 pts. After the amendment the agents were administered as follows: T 40 mg/m2, P 40 mg/m2, L 200 mg/m2, F 2,000 mg/m2. The primary objective was the overall response rate (ORR) according to RECIST. Results: From 03/04 to 08/05 we included 60 pts: median age 53 yrs, (26–76); 24 pts had locally advanced tumors (LA) and 36 pts had metastatic disease (MET). Pts received a median of 2 (range 0–4) cycles. Reductions to &lt;80% of drug doses were reported in 80% versus 60% of pts pre/post amendment. Reported adverse events were: neutropenia 23%, febrile neutropenia 5%, diarrhea 20%, nausea 8%, emesis 8% and fatigue 20%. The ORR according to RECIST was 46.6% (95%CI 33.3–61.4). Only 6.6% were primarily progressive. 23/24 pts with LA underwent secondary resection (96%). Complete resections (R0) were achieved in 87%. After a median follow-up of 25.5 months, median overall survival (OS) is 17.9 months (95%CI 11.5 -24.3). Median TTP is 9.4 months (95% CI 8.3–10.5). For pts with MET, median TTP is 8.1 months and median OS is 15.1 months. Conclusion: The T-PLF regimen is highly active, safe and has a favorable toxicity profile. [Table: see text]

Extended safety and efficacy data on S‐1 plus cisplatin in patients with untreated, advanced gastric carcinoma in a multicenter phase II study

S-1 is a promising oral fluoropyrimidine. The authors obtained extended Phase II safety and efficacy data in a multicenter setting for the S-1 plus cisplatin combination: The experimental arm of the global Phase III First-Line Advanced Gastric Cancer Study (FLAGS) is being compared with 5-fluorouracil/cisplatin. Eligible patients had untreated, histologically confirmed advanced gastric cancer (AGC), a Karnofsky performance status (KPS) > or =70%, adequate organ function, and provided written consent. Patients received S-1 (25 mg/m(2) twice daily on Days 1 through 21) plus cisplatin (75 mg/m(2) on Day 1) every 28 days. The confirmed overall response rate (CORR) also was designated by an external review. The time to progression (TTP), median survival (MS), and safety were assessed. All 72 patients were assessed for safety and survival, and 64 patients were assessed for CORR. The median KPS was 90%. The median number of treatment cycles was 4. The CORR was 55% (95% confidence interval [95% CI], 42-67%). The median duration of response was >5 months. At 6 months, only an estimated 38% of patients had cancer progression. The estimated MS was 10.4 months (95% CI, 8.6-12.9 months). At least 1 serious adverse event occurred in 44% of patients. The frequent grade 3 or 4 toxicities (using the National Cancer Institute Common Toxicity Criteria), which occurred in >10% of patients, included fatigue/asthenia (24%), emesis (17%), nausea (15%), diarrhea (13%), and neutropenia (19%). Complicated neutropenia (1.4%) and grade 4 diarrhea (1.4%) were rare. The current extended data confirmed that S-1 combined with cisplatin had a highly desirable safety profile. The efficacy against AGC, according to an external review, was encouraging. FLAGS is expected to complete its accrual of 1050 patients by December 2007.

Randomized phase III trial of capecitabine/cisplatin (XP) vs. continuous infusion of 5-FU/cisplatin (FP) as first-line therapy in patients (pts) with advanced gastric cancer (AGC): Efficacy and safety results

LBA4018 Background: The oral fluoropyrimidine capecitabine has proven efficacy and safety in colorectal and breast cancer. Phase II data in AGC suggested that XP would show comparable efficacy to a standard FP regimen, with potential safety and convenience advantages. This phase III study evaluated XP vs. FP in first-line AGC. Methods: Pts with previously untreated measurable AGC received either oral capecitabine (1000mg/m2 bid d1–14) + cisplatin (80mg/m2 i.v. d1) q3w (XP arm) or 5-FU (800mg/m2/d continuous infusion, d1–5) + cisplatin (80mg/m2 i.v. d1) q3w (FP arm). XP requires 1 day per 3 weeks in hospital; FP requires 5 days. Pts were treated until disease progression or unacceptable toxicity. Primary endpoint: non-inferiority (NI) in progression-free survival (PFS), defined as upper limit of 95% CI of hazard ratio (HR) &lt;1.4 (first test) and &lt;1.25 (second test). Results: From Apr 03 to Jan 05, 316 pts were enrolled in 46 centers/13 countries. Arms were well balanced: median age (years, range) XP (56, 26–74), FP (56, 22–73); median Karnofsky PS 80 (range 70–100) in both arms; male/female (%): XP (64/36) FP (69/31). Median no. of cycles was 5 (XP and FP). Median follow-up is 22.1 months. Primary endpoint was met: HR 0.81 (95% CI 0.63–1.04). XP was superior to FP in terms of overall response rate (ORR, RECIST). Efficacy is presented in the table. Most common treatment-related grade 3/4 adverse events (XP vs. FP) were: neutropenia (16 vs. 19%), vomiting (7 vs. 9%), stomatitis (2 vs. 7%), diarrhea (5 vs. 5%), and anemia (5 vs. 3%). Other grade 3/4 events occurred in &lt;5% of pts. The rate of all-grade hand-foot syndrome was low (22 vs. 4%). Conclusions: XP showed highly significant non-inferiority for PFS and significant superiority for ORR vs. FP with similar safety. These findings suggest that capecitabine should become the fluoropyrimidine of choice for AGC, given the efficacy, reduced hospitalization time and simplified regimen. No significant financial relationships to disclose. [Table: see text]

Extended safety and efficacy data on S-1 plus cisplatin in patients with advanced gastric carcinoma in a multi-center phase II study

4083 Background: We obtained additional phase II safety and efficacy data in a multi-center setting on an active regimen of S-1 plus cisplatin; the experimental arm of the global phase III First-Line Advanced Gastric cancer Study (FLAGS). Methods: Eligible patients had untreated advanced gastric cancer (AGC), histologic proof, KPS ≥70%, adequate organ function, and gave written consent. Patients received S-1 (25mg/m2 p.o. bid on days 1–21) plus cisplatin (75mg/m2 i.v. on day 1) every 28 days. All reported confirmed overall response rate (C-ORR), response durations, and time-to-progression (TTP) are externally reviewed. Results: All 72 patients were assessed for safety and 64 for efficacy. The median age was 56 years and median KPS was 90%. Median no. of cycles was 4. C-ORR was 50% (95% CI, 37%-63%). Median duration of response is &gt;6 months. At 6 months, only 35% of patients have had cancer progression. Median survival (n=72) is 10.5 months (95% CI, 9.3 to NR). At least one SAE occurred in 43% of patients. The frequent grade 3 or 4 adverse events (occurring in &gt;10% of patients) included: fatigue/asthenia (26%), vomiting (21%), nausea (18%), diarrhea (17%), neutropenia (18%), anorexia (11%), and dehydration (11%). Febrile neutropenia (1.4%) and grade 4 diarrhea (1.4%) were rare. Conclusions: These extended data confirm that S-1 plus cisplatin has a very desirable safety profile and impressive efficacy data in AGC. FLAGS will complete accrual of &gt;700 patients by March of 2007. (Supported by Taiho Pharma-USA). [Table: see text]