Pretreated Advanced Gastric Cancer Research Articles

A phase 1b study of the allosteric extracellular FGFR2 inhibitor alofanib in patients with pretreated advanced gastric cancer.

Alofanib is a small-molecule allosteric extracellular FGFR2 inhibitor. We report safety and preliminary efficacy from the first-in-human phase 1b study of alofanib in heavily pretreated patients with advanced gastric cancer. The standard dose-escalation design 3+3 aimed to establish the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Alofanib was administered daily intravenously 5 days on, 2 days off. There were five dose levels (50-350 mg/m2). All patients received alofanib until disease progression or unacceptable toxicity. 21 patients were enrolled. Patients were predominantly male (71%), 67% had 2 and more metastatic sites, including liver metastases (43%), 19% had ECOG PS 2, and were heavily pretreated (86% had previous 2 and more treatment lines). During dose escalation, no dose-limiting toxicities were observed, and MTD was not defined. 15 (71.4%) patients had at least one adverse event associated with the treatment (TRAE). Grade 3 or higher TRAEs were observed in 6 patients (28.6%). The most common TRAEs included reactions immediately after administration, diarrhea, thrombocytopenia, arthralgia, and headache. The median progression-free survival and overall survival was 3.63 (95% CI 1.58-5.68) and 7.0 (95% CI 3.82-10.18) months, respectively. The 6- and 12-month overall survival rates were 57.1% and 33.3%. Disease control rate was 68% with one durable partial response. The MTD has not been reached and dose of 350 mg/m2, 5 days on, 2 days off has been declared as RP2D. Alofanib showed acceptable tolerability and preliminary signs of clinical activity in the late-line treatment of metastatic gastric cancer. (ClinicalTrials.gov identifier: NCT04071184).

Predictive biomarkers for the efficacy of nivolumab as\u2009\u2265\u20093rd-line therapy in patients with advanced gastric cancer: a subset analysis of ATTRACTION-2 phase III trial

PurposeThe phase 3 ATTRACTION-2 study demonstrated that nivolumab monotherapy improved survival compared to placebo in patients with pretreated advanced gastric cancer (AGC). However, the efficacy of nivolumab seems to be limited to a subset of patients.Materials and methodsThe predictive values of blood neutrophil–lymphocyte ratio (NLR), serum Na, PD-L1 expression, MSI status, tumor EBV infection, and tumor mutation burden (TMB) were investigated in patients with AGC refractory to ≥2 lines of chemotherapy enrolled from Asan Medical Center in ATTRACTION-2 study.ResultsAll 45 patients were analyzed; nivolumab (n = 28) and placebo (n = 17) groups. The objective response rate, median progression-free survival (PFS), and overall survival (OS) were 16.7%, 1.6 months, and 8.1 months in nivolumab group and 0%, 1.6 months and 6.5 months in placebo group. When comparing nivolumab with the placebo group, tumor PD-L1 expression, blood NLR, and serum Na were significant predictive factors of PFS and OS. A multivariate analysis revealed that PD-L1 ( +) and low NLR (≤ 2.9, median) were associated with better PFS. In the nivolumab group, PD-L1 ( +), low NLR, and normal Na (≥ 135 mmol/L) were associated with higher response and disease control rates, while tumor EBV infection and TMB were not.ConclusionTumor PD-L1 expression, blood NLR, and serum Na could be predictive biomarkers for the efficacy of nivolumab in previously treated cases of AGC.

Exploration of predictors of benefit from nivolumab monotherapy for patients with pretreated advanced gastric and gastroesophageal junction cancer: post hoc subanalysis from the ATTRACTION-2 study

BackgroundThe phase 3 ATTRACTION-2 study demonstrated that nivolumab monotherapy was superior to placebo for patients with pretreated advanced gastric or gastroesophageal junction cancer, but early progression of tumors in some patients was of concern.MethodsThis post hoc analysis statistically explored the baseline characteristics of the ATTRACTION-2 patients and extracted a single-factor and double-factor combinations associated with early disease progression or early death. In the extracted patient subgroups, the 3-year restricted mean survival times of progression-free survival and overall survival were compared between the nivolumab and placebo arms.ResultsTwo single factors (age and peritoneal metastasis) were extracted as independent predictors of early progression, but none of them, as a single factor, stratified patients into two subgroups with significant differences in restricted mean survival time. In contrast, two double-factor combinations (serum sodium level and white blood cell count; serum sodium level and neutrophil–lymphocyte ratio) stratifying patients into two subgroups with significant differences in the restricted mean survival time were extracted. Additional exploratory analysis of a triple-factor combination showed that patients aged < 60 years with peritoneal metastasis and low serum sodium levels (approximately 7% of all patients) might receive less benefit from nivolumab, and patients aged ≥ 60 years with no peritoneal metastasis and normal serum sodium levels might receive higher benefit.ConclusionsA combination of age, peritoneal metastasis, and serum sodium level might predict benefit from nivolumab as salvage therapy in advanced gastric or gastroesophageal junction cancer patients, especially less benefit for patients having all three risk factors.

Trastuzumab deruxtecan for the treatment of patients with HER2-positive gastric cancer

Trastuzumab deruxtecan (T-DXd) is a novel anti-human epidermal growth factor receptor 2 (HER2) antibody–drug conjugate composed of a monoclonal anti-HER2 antibody and a topoisomerase I inhibitor, DX-8951 derivative (an exatecan derivative). T-DXd showed potential anti-tumor activities in HER2-positive gastric cancer cell lines and xenograft models. In the randomized, phase II trial DESTINY-Gastric01, T-DXd demonstrated a significantly higher objective response rate as a primary endpoint and a longer overall survival as a secondary endpoint in patients with pretreated HER2-positive advanced gastric cancer (AGC). Although adverse events caused by T-DXd were generally manageable, approximately 10% of patients experienced treatment-related interstitial lung disease. Based on the results of the DESTINY-Gastric01 trial, T-DXd was approved for HER2-positive pretreated AGC in Japan. This study reviews the preclinical and clinical data of T-DXd for treating HER2-positive gastric cancer.

Trifluridine/tipiracil for the treatment of metastatic gastric cancer

ABSTRACTIntroduction: Trifluridine/tipiracil is a novel oral cytotoxic chemotherapy consisting of a thymidine-based nucleoside analog, trifluridine, and a thymidine phosphorylase inhibitor, tipiracil. Trifluridine/tipiracil was approved for the treatment of metastatic colorectal cancer refractory to standard therapies. A phase II trial in Japan demonstrated that this therapy has antitumor activity and is tolerated by patients with advanced gastric cancer (AGC); as a result, the phase III TAGS trial (Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer) was initiated.Area covered: Trifluridine/tipiracil has proved effective for heavily pretreated AGC and has thus been approved for use in the United States in February 2019, Japan in August 2019 and the European Union in September 2019. Detail of the phase III TAGS trial is discussed in this review.Expert opinion: Trifluridine/tipiracil after at least two previous courses of systemic chemotherapy improved rates of survival of gastric cancer; thus it has become one of the treatment options in affected patients. Currently, several clinical trials of trifluridine/tipiracil in combination with other anticancer agents such as ramucirumab (an anti-vascular endothelial growth factor receptor 2 monoclonal antibody) for patients with AGC are ongoing.

Cost-effectiveness of trifluridine/tipiracil (TAS102) for heavily pretreated metastatic gastric cancer.

Trifluridine/tipiracil (TAS102), a novel oral cytotoxic chemotherapy, significantly improved overall survival compared with placebo in heavily pretreated advanced gastric cancer. This study aimed to evaluate the cost-effectiveness of TAS102 in the third-line or later treatment for this population from the US payer perspective. A Markov model was developed to simulate advanced gastric cancer, including three health states: progression-free survival (PFS), progressive disease (PD) and death. Model inputs were derived from a randomised, double-blind, placebo-controlled, phase 3 trial (TAGS trial, NCT02500043). Utilities were extracted from public resources. Costs were calculated from an American payer perspective. Sensitivity analyses were conducted to explore the impact of uncertainty. From the US payer perspective, treatment with TAS102 for patients with heavily pretreated advanced gastric cancer was estimated to increase costs by $59,180 compared with the placebo, with a gain of 0.06 quality-adjusted life years (QALYs) for an incremental cost-effectiveness ratio (ICER) of $986,333 per QALY. The costs for progression-free survival of TAS102 group had the greatest impact on the ICERs, as well as the cost of TAS102. Trifluridine/tipiracil (TAS102) is not a cost-effective choice for patients with heavily pretreated metastatic gastric cancer from an American payer perspective.

The potential drug cost impact of nivolumab (N) in patients with advanced/metastatic gastric cancer (GC) or gastroesophageal junction cancer (GEJC) in Canada.

101 Background: Advanced/metastatic GC and GEJC is associated with poor survival outcomes. Systemic treatment options are limited in patients having had at least two lines of chemotherapy. Immune checkpoint inhibitors (ICIs) appear to be a promising therapeutic option in these patients. The role of predictive biomarkers to response to ICIs remains to be fully elucidated. This may ultimately inform the utility and thus potentially the drug cost incurred by ICIs. The ATTRACTION-2 phase III study using N in heavily pretreated advanced GC and GEJC patients improved outcomes. The use of ICIs has an anticipated budgetary impact on health care systems within the context of this potentially funded utilization of N. Methods: An estimation of the N drug cost alone for advanced de novo and relapsed cases diagnosed in 2017 and subsequently treated in the third line in Canada was undertaken. A cost estimate for N treatment in earlier lines was also evaluated. N cost per patient was calculated based on treatment indication, duration of treatment, standard dose/schedule. The analysis was performed in Canadian dollars ($) and assumed complete drug delivery and uncomplicated cycles. The cost of N was obtained from the pan Canadian Oncology Drug Review (PCODR) cost for N in lung cancer. The number of target patients and N utilization was derived from constructed schema to give a budget impact estimate. Results: Estimated N cost per treated patient is $15,770. The N drug cost in the third line setting is estimated at $5.9 million (M) for GC and $2.4M for GEJC, total $8.4M (IQR $3.9M-$18.7M). For first line and second line N in eligible pts respectively: potential drug cost is $23.7M, $11.8M for GC and $9.7M, $4.9M for GEJC. A sensitivity analysis was performed. Conclusions: ICIs potentially add a drug cost burden to the publically funded Canadian healthcare system. As biomarkers predictive of response evolve and patients are treated accordingly, the drug cost burden may lessen. Potential earlier line use and a longer duration of therapy will add to the estimated budgetary impact.

Clinical efficacy of immune checkpoint inhibitors in the treatment of unresectable advanced or recurrent gastric cancer: an evidence-based review of therapies.

Standard treatment options for patients with advanced gastric cancer (GC) offer limited efficacy and are associated with some toxicity, which necessitates the development of more effective therapies for improving the treatment outcomes for this disease. Immunotherapy involving immune checkpoint inhibitors (ICIs) which inhibit the programmed death 1 (PD-1)/programmed death ligand 1 interaction has emerged as a new treatment option. Nivolumab, a human IgG4 monoclonal antibody inhibitor of PD-1, has demonstrated promising clinical activity and induced durable responses in patients with advanced GC. Nivolumab has recently been approved for treating patients with pretreated advanced GC in Japan. In the present review, we summarized current evidence of the clinical efficacy of ICIs in a variety of solid tumors and reported our experience in patients with GC who were treated with nivolumab and the interesting features that were observed in these cases. Certain ICI-specific clinical features such as pseudo- and hyper-progression of tumor and hyper-response to subsequent chemotherapy have been reported in several cancer types. Lastly, we discussed the present scenario regarding research on biomarkers for assessing the clinical benefits of ICI therapies.

Peritoneal metastasis as a predictive factor for nab-paclitaxel in patients with pretreated advanced gastric cancer: an exploratory analysis of the phase III ABSOLUTE trial

BackgroundIn the ABSOLUTE trial, weekly nanoparticle albumin-bound paclitaxel (w-nab-PTX) showed non-inferiority to weekly solvent-based paclitaxel (w-sb-PTX) for overall survival (OS). Thus, w-nab-PTX might be an option for second-line chemotherapy in advanced gastric cancer (AGC). However, predictive factors for efficacies of these agents have not been evaluated.MethodsPatients previously enrolled in the ABSOLUTE trial were divided into apparent peritoneal metastasis group (PM group) and no apparent peritoneal metastasis group (no PM group) based on baseline imaging evaluated by RECIST ver. 1.1 criteria and amount of ascites. OS, progression-free survival, and overall response rate were compared between two arms in each group.ResultsThis study included 240 and 243 patients in the w-nab-PTX and w-sb-PTX arms, respectively. In the PM group, the w-nab-PTX arm (n = 88) had longer OS than the w-sb-PTX arm (n = 103), and median survival time (MST) of 9.9 and 8.7 months [hazard ratio (HR) 0.63; 95% CI 0.45–0.88; P = 0.0060], respectively. In the no PM group, the w-nab-PTX arm (n = 140) had shorter OS than the w-sb-PTX arm (n = 152), and MST of 11.6 and 15.7 months (HR 1.40; 95% CI 1.06–1.86; P = 0.0180), respectively. After adjusting for prognostic factors, the HR for OS in the w-nab-PTX arm versus the w-sb-PTX arm was 0.59 (95% CI 0.42–0.83; P = 0.0023; PM group) and 1.34 (95% CI 1.01–1.78; P = 0.0414; no PM group), with significant interaction between treatment efficacy and presence of peritoneal metastasis (P = 0.0003).ConclusionsThe presence of apparent peritoneal metastasis might be a predictive factor for selecting w-nab-PTX for pretreated AGC patients.Trial registration numberJapicCTI-132059.

Regorafenib: lights and shadows of antiangiogenic therapies in gastric cancer

Gastric cancer stands among the most common causes of cancer death worldwide (1). Median overall survival (OS) for patients with advanced disease is approximately 1 year and chemotherapy still represents the milestone of treatment in most patients (2). While first-line chemotherapy has a well-established role in gastric cancer management, during the past few years several trials clearly demonstrated a significant OS benefit for second-line therapy compared with best supportive care (BSC) alone (3); however, as the gain in survival is at best modest in absolute terms, a careful clinical selection is needed to identify patients who could benefit from salvage therapies (4). Moreover, no standard treatment exists after second-line failure. Thus, searching for new therapeutic opportunities in pretreated advanced gastric cancer patients is imperative for researchers and clinicians.

A pilot study of apatinib reversing paclitaxel resistance in heavily pretreated advanced gastric cancer (AGC).

89 Background: In vitro or vivo, apatinib can reverse ABC-mediated multidrug resistance not only by inhibiting their transport function, but also by downregulating ABC expression. Methods: The patients with advanced gastric adenocarcinoma were resistant to paclitaxel-containing regimen (disease progression during or within 3 months after chemotherapy) and had measurable lesions received apatinib 850 mg, po, qd combined with paclitaxel alone (80 mg/m2 d1, d8, and d15, repeated 4-weekly) or POF (reported in 2007, 2008, 2009, 2010 ASCO, paclitaxel 135 mg/m2, oxaliplatin 85 mg/m2, and leucovorin 400 mg/m2, d1; 5-FU 2400 mg/m2 for 46h, repeat 2-weekly). The choice of regimen was left to clinician discretion in term of performance status and whether the agent that will be given has been resistant. Results: From 14th August 2015 to 1st March 2016, seven patients were eligible. The median age was 49 years (range, 43 to 67 years), 5 were males and 2 were females. The prior chemotherapeutic agents were summarized in table. Four patients had disease progression during apatinib. Two PRs, four SDs (unconfirmed), and one early death were observed. At a median follow-up of 238 days, the median progression-free survival was 124 days, the median survival was 194 days (range, 33 to 398+ days). Grade 3 to 4 neutropenia, anaemia, hypertension, fatigue, stomatitis was one patient respectively. No treatment-related death occurred. Conclusions: This study showed promising result that apatinib reverses paclitaxel resistance in heavily pretreated AGC. Clinical trial information: NCT02697838. [Table: see text]

Abstract CT058: Phase I study of LY2874455, a fibroblast growth factor (FGF) receptor inhibitor, in patients with advanced cancer

Abstract Background: The fibroblast growth factor (FGF) and FGF receptor pathway has been implicated in several cancers. Inhibition of this pathway has led to the attenuation of tumor growth in preclinical models1. This phase I, first in human dose (FIH) study evaluated safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of LY2874455, an oral FGF receptor inhibitor. Methods: This study had 2 open-label parts. Part A: standard 3+3 patient dose escalation study, identified 16 mg BID as the recommended dose2. Part B: dose expansion study, evaluated 16 mg BID dose in patients (pts) with pretreated advanced gastric cancer (GC) or non-small cell lung carcinoma (NSCLC), who also had ECOG performance status 0-2 and adequate organ function. Treatment continued until disease progression or intolerability. We report here results from Part B of the study. Results: Overall 27 pts in the NSCLC cohort and 31 pts in the GC cohort were treated. Median age was 58.5 years: majority of pts were Asian (89.7%). Pts had received a median of 4 previous lines of chemotherapy. FGFR1 amplification status in the NSCLC group: 29.6% were negative, 7.4% were positive, and status was unknown in 63.0%. For GC pts: 80.6% negative for FGFR2 amplification, 6.5% positive, and status unknown in 12.9%. Both cohorts each received a median of 2 cycles. All 58 pts experienced at least 1 treatment emergent adverse event (TEAE) possibly related to study drug, with 39 pts (67.2%) experiencing at least 1 Grade 3 or 4 TEAE possibly related to study drug. The most common drug-related AEs included: hyperphosphatemia (79.3%), diarrhea (77.6%), anorexia (72.4%), and fatigue (51.7%). Eighteen pts (31.0%) experienced at least 1 serious adverse event (SAE), and 9 pts had SAE possibly related to study drug related. SAEs possibly related to study drug were: fatigue (n = 4), anorexia (n = 3), heamoptysis, central serous retinopathy, keratoconjunctivitis sicca, diarrhea, and hyponatremia. Eleven pts discontinued due to AE or SAE. In the GC cohort, 1 patient, who was FGFR2 amplification negative, had a partial response, and 6 FGFR2 negative pts had stable disease (SD), with 1 patient on treatment for 9 cycles. None of the NSCLC pts responded, but 4 pts had SD (FGFR1 positive n = 2; FGFR1 negative n = 2). Conclusion: Treatment with LY2874455 had a manageable toxicity profile, and preliminary findings suggest anti-tumor activity in gastric cancer. 1. Hattori Y, Itoh H, Uchino S, Hosokawa K, Ochiai A, Ino Y, et al. Immunohistochemical detection of K-sam protein in stomach cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 1996;2:1373-81. 2. Tie, J., et al. “A phase I trial of LY2874455, a fibroblast growth factor receptor inhibitor, in patients with advanced cancer.” Proceedings of the 105th annual meeting of the American Association for Cancer Research 2014;74(19 Suppl):Abstract nr CT215. Citation Format: Jeanne Tie, Yung-Jue Bang, Young Suk Park, Yoon-Koo Kang, David Monteith, Kimberly Hartsock, Oday Hamid, Donald E. Thornton, Michael Michael. Phase I study of LY2874455, a fibroblast growth factor (FGF) receptor inhibitor, in patients with advanced cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT058.

Doublet Versus Single Agent as Second-Line Treatment for Advanced Gastric Cancer: A Meta-Analysis of 10 Randomized Controlled Trials.

The purpose of this study was to perform a meta-analysis of randomized controlled trials (RCTs) to compare the efficacy and safety of doublet versus single agent as second-line treatment for advanced gastric cancer (AGC).A comprehensive literature search was performed to identify relevant RCTs. All clinical studies were independently identified by 2 authors for inclusion. Demographic data, treatment regimens, objective response rate (ORR), and progression-free survival (PFS) and overall survival (OS) were extracted and analyzed using Comprehensive Meta-Analysis software (Version 2.0).Ten RCTs involving 1698 pretreated AGC patients were ultimately identified. The pooled results demonstrated that doublet combination therapy as second-line treatment for AGC significantly improved OS (hazard ratio [HR] 0.87, 95% confidence interval [CI]: 0.78–0.97, P = 0.011), PFS (HR 0.79, 95% CI: 0.72–0.87, P < 0.001), and ORR (relative risk [RR] 1.57, 95% CI: 1.27–1.95, P < 0.001). Sub-group analysis according to treatment regimens also showed that targeted agent plus chemotherapy significantly improve OS, PFS, and ORR. However, no significant survival benefits had been observed in doublet cytotoxic chemotherapy when compared with single cytotoxic agent. Additionally, more incidences of grade 3 or 4 myelosuppression toxicities, diarrhea, and fatigue were observed in doublet combination groups, while equivalent frequencies of grade 3 or 4 thrombocytopenia and nausea were found between the 2 groups.In comparison with single cytotoxic agent alone, the addition of targeted agent to mono-chemotherapy as salvage treatment for pretreated AGC patients provide substantial survival benefits, while no significant survival benefits were observed in doublet cytotoxic chemotherapy regimens.

Long Survival with Metronomic Therapy for Heavily Pretreated Advanced Gastric Cancer: Case Report

A 79-year-old patient with metastatic gastric cancer who failed with two previous lines of chemotherapy has for the last 9 months received third-line chemotherapy with oral cyclophosphamide. This has resulted in an extraordinary long-term progression-free survival of 11 months. Toxicity has been low and well tolerated. Oral cyclophosphamide seems to be potentially active agent for salvage chemotherapy in gastric carcinoma patients who failed with prior lines of chemotherapy.

A phase 2 study of fluorouracil/leucovorin in combination with paclitaxel and oxaliplatin as a salvage treatment in patients with refractory or relapsed advanced gastric cancer

The aim of this study was to evaluate the efficacy and safety of paclitaxel plus oxaliplatin plus fluorouracil/leucovorin (POF) as salvage chemotherapy in pretreated advanced gastric cancer. Fifty-two pretreated patients with the advanced gastric cancer were eligible for this study. The POF regimen consisted of a 3-hour infusion of paclitaxel (135 mg/m2) followed by oxaliplatin (85 mg/m2) and leucovorin (400 mg/m2), administered simultaneously over a 2-hour infusion period, followed by an infusion of fluorouracil (2400 mg/m2) over a 46-hour period, every 14 days. From an intention-to-treat analysis, overall response rate and stable disease rate were 28·8 and 38·5%, respectively. The median time to progression and overall survival were 4·1 and 7·9 months, respectively. Grade 3 or 4 neutropaenia, thrombocytopaenia, fatigue, and neuropathy were 38·5, 15·4, 17·3, and 15·4%, respectively. The POF regimen is active in pretreated advanced gastric cancer as salvage chemotherapy, with a favourable toxicity profile.

Randomised phase II study comparing dose-escalated weekly paclitaxel vs standard-dose weekly paclitaxel for patients with previously treated advanced gastric cancer

Background:This randomised phase II trial compared dose-escalated weekly paclitaxel (wPTX) vs standard-dose wPTX for patients with previously treated advanced gastric cancer (AGC).Methods:Ninety patients were randomised to a standard dose of wPTX (80 mg m−2) or an escalated dose of wPTX (80–120 mg m−2) to assess the superiority of overall survival (OS) with a one-sided alpha error of 0.3 and a power of 0.8.Results:The median OS showed a trend towards longer survival in the dose-escalated arm (11.8 vs 9.6 months; hazard ratio (HR), 0.75; one-sided P=0.12), although it was statistically not significant. The median progression-free survival (PFS) was significantly longer in the dose-escalated arm (4.3 vs 2.5 months, HR, 0.55; P=0.017). Objective response rate was 30.3% with dose escalation and 17.1% with standard dose (P=0.2). The frequency of all grades of neutropenia was significantly higher with dose escalation (88.7% vs 60.0%, P=0.002); however, no significant difference was observed in the proportion of patients experiencing grade 3 or more (40.9% vs 31.1%, P=0.34).Conclusion:Dose-escalated wPTX in patients with pretreated AGC met our predefined threshold of primary end point, OS (P<0.3); however, it did not show a significantly longer OS. Progression-free survival was significantly better with dose escalation.

Everolimus for Previously Treated Advanced Gastric Cancer: Results of the Randomized, Double-Blind, Phase III GRANITE-1 Study

The oral mammalian target of rapamycin inhibitor everolimus demonstrated promising efficacy in a phase II study of pretreated advanced gastric cancer. This international, double-blind, phase III study compared everolimus efficacy and safety with that of best supportive care (BSC) in previously treated advanced gastric cancer. Patients with advanced gastric cancer that progressed after one or two lines of systemic chemotherapy were randomly assigned to everolimus 10 mg/d (assignment schedule: 2:1) or matching placebo, both given with BSC. Randomization was stratified by previous chemotherapy lines (one v two) and region (Asia v rest of the world [ROW]). Treatment continued until disease progression or intolerable toxicity. Primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), overall response rate, and safety. Six hundred fifty-six patients (median age, 62.0 years; 73.6% male) were enrolled. Median OS was 5.4 months with everolimus and 4.3 months with placebo (hazard ratio, 0.90; 95% CI, 0.75 to 1.08; P = .124). Median PFS was 1.7 months and 1.4 months in the everolimus and placebo arms, respectively (hazard ratio, 0.66; 95% CI, 0.56 to 0.78). Common grade 3/4 adverse events included anemia, decreased appetite, and fatigue. The safety profile was similar in patients enrolled in Asia versus ROW. Compared with BSC, everolimus did not significantly improve overall survival for advanced gastric cancer that progressed after one or two lines of previous systemic chemotherapy. The safety profile observed for everolimus was consistent with that observed for everolimus in other cancers.

Randomized phase II study comparing dose-escalated weekly paclitaxel versus standard dose weekly paclitaxel for patients with previously treated advanced gastric cancer.

4076 Background: Retrospective analyses of neutropenia during chemotherapy of weekly paclitaxel (wPTX) suggested better overall survival (OS) among patients with neutropenia. We conducted a randomized phase II trial comparing dose-escalated wPTX with dose adjustments determined by degree of neutropenia versus standard-dose wPTX for patients with previously treated advanced gastric cancer (AGC). Methods: Ninety-patients with AGC that progressed during one or more previous chemotherapy regimens were randomized to a standard dose of wPTX (80 mg/m2, standard dose arm) or an escalated dose of wPTX (80 mg/m2 on day 1, 100 mg/m2 on day 8, and 120 mg/m2 on day 15 unless severe toxicity nor neutropenia&lt;1.5 x 109/L is observed, escalated dose arm) to assess superiority with a one-sided alpha of 0.3 and a power of 0.8. Results: The primary endpoint of median OS showed a trend towards longer survival in the dose-escalated arm (11.8 vs. 9.6 months; hazard ratio [HR], 0.75; 95% CI, 0.45-1.22; one-sided P=0.12). Median progression-free survival (PFS) was significantly longer in the dose-escalated arm (4.3 vs. 2.5 months, HR, 0.55; 95% CI, 0.34-0.90; P=0.017). Objective response rate was 30.3% with dose-escalation and 17.1% with standard dose (P=0.2). The disease control rate (DCR) was significantly higher with dose-escalation (78.8% vs. 48.6%, P=0.009). Subset-analysis according to stratification factors including ECOG PS, presence of measurable lesions and lines of previous chemotherapy indicated that OS benefit of the dose escalation is more prominent in PS 0-1 patients (N=81, median 13.6 vs. 9.8 months, HR 0.68, 95% CI 0.41-1.11) than PS2 patients with significant interaction (p=0.01) Conclusions: Dose escalated wPTX was associated with sufficiently longer OS in patients with pretreated AGC. In addition, significant longer PFS and higher DCR associated with dose-escalation and subset analysis according PS warrant further investigations in phase III trials, especially in patients with favorable PS patients. Clinical trial information: UMIN000004055.

IS3-6 - Multicenter Randomized Phase II Study of Weekly Docetaxel Alone Versus Weekly Docetaxel Plus Oxaliplatin as a Second-Line Chemotherapy in Patients with Advanced Gastric Cancer: Preliminary Response and Safety Results

ABSTRACT Background Gastric cancer is a frequent malignancy with worldwide estimated incidence of 990'000 cases, representing 7.8% of all cancers in 2008. There are limited data suggesting a benefit for doublet second-line chemotherapy in advanced gastric cancer. Methods The eligibility criteria were patients 1) with prior exposure to cisplatin based chemotherapy and advanced or recurrent stomach cancer 2) with pathologically proven gastric adenocarcinoma, 3) with an ECOG performance status 0 to 2, 4) with measurable lesions. Each treatment cycle was consisted of docetaxel 36 mg/m2 in docetaxel mono therapy group and docetaxel 36 mg/m2, oxaliplatin 80 mg/m2 in docetaxel/oxaliplatin doublet therapy group on days 1, 8. The primary end point of this study was response rate, and secondary end points included toxicity, progression free and overall survival. Results Fifty two patients were enrolled; median age was 63 years; male (n = 42) and female (n = 10); docetaxel mono therapy (n = 27) and docetaxel/oxalliplatin doublet therapy (n = 25). The median number of cycles administered was 2.5 (range,1-9). Fourty eight patients were assessable for efficacy. Four partial responses, 7 stable diseases in mono therapy group (RR; 4/27, 14.8%) and 1 complete remission, 4 partial responses, 13 stable diseases in double therapy group (RR; 5/25, 20.0%) were confirmed (P = 0.198). Median progression free survival was 1.97 months in the mono therapy group and 4.93 months in doublet therapy group (P = 0.007). Median overall survival was 11.57 months in the mono therapy group and 8.13 months in doublet therapy group (P = 0.650). Grade 3 or 4 adverse events were reported in 11 of 52 patients; G3 pain were in 2 patients and G3 pneumonia was in 1 patient in mono group, G3/4 neutropenia were 5 patients in the combination group, G3 nausea, vomiting, general weakness was 1 patient each group in combination group. Conclusions Weekly docetaxel/oxaliplatin doublet therapy showed superior progression free survival to monotherapy group as second line therapy in cisplatin pretreated advanced gastric cancer patients.

Combined analysis of randomized controlled trial (RCT) and patient-preference trial (PPT) evaluating second-line chemotherapy (SLC) in advanced gastric cancer (AGC).

4064 Background: While prolonged overall survival (OS) from SLC compared to best supportive care (BSC) has recently been demonstrated for AGC (Park et al, ASCO 2011), the prognosis of pretreated AGC remains poor. We assessed whether patient preference, willing to participate onto RCT, or other parameters contributed to this OS improvement. Methods: In the phase III trial, pretreated AGC patients (n=372) were first offered RCT. If a patient agreed to participate, randomly assigned 2:1 to SLC or BSC (n=202). If refused RCT, but agreed to receive treatment of their preference, they were offered SLC or BSC (PPT; n=170). OS of RCT participants was compared to that of whole patient population according to prognostic subgroups. In addition, analyses of OS unadjusted for multiple comparisons were conducted across predefined subgroups. Results: Median OS was 6.3 months among 254 patients treated with SLC and 3.3 months among 118 patients treated with BSC (HR, 0.507; 95% CI, 0.405 to 0.637; one-sided p&lt;0.001). Compared to the RCT patients, younger age group, those with an ECOG performance status (PS) of 0, and with one prior chemotherapy were under-represented in the PPT patients. OS was comparable between RCT (5.0 months) and PPT (4.4 months) patients even after controlling for major prognostic factors (log-rank p=0.322). The OS benefit for SLC was preserved when analyzed according to baseline parameters. Parameters that were associated significantly with a prolonged OS included a PS of 0, the chemotherapy-free interval ≥3 months, and one prior chemotherapy. When the analysis was adjusted for these three parameters, patients who received SLC still had improved OS (HR, 0.554; 95% CI, 0.441 to 0.696; p&lt;0.001). Conclusions: The 54% participation rate obtained in the current study represents the best achievable rate for this kind of phase III RCT involving BSC only arm. Even if we consider differences in the baseline characteristics between RCT and PPT patients, it is concluded that the RCT results can be generalized for the patient population and provided additional evidence supporting the use of SLC in patients with pretreated AGC.