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Background Dual-targeted anti-HER2 therapy significantly improves outcomes in HER2-positive breast cancer and could be beneficial in other HER2-positive cancers. JACOB’s end-of study analyses aimed to evaluate the long-term efficacy and safety of pertuzumab plus trastuzumab and chemotherapy for previously untreated HER2-positive metastatic gastric or gastroesophageal junction cancer. Methods Eligible patients were randomized 1:1 to pertuzumab/placebo plus trastuzumab and chemotherapy every 3 weeks. Primary endpoint: overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), duration of response (DoR), and safety. Results The intention-to-treat population comprised 388 patients in the pertuzumab arm and 392 in the placebo arm. The safety population comprised 385 and 388 patients, respectively. Median follow-up was ≥ 44.4 months. Median OS was increased by 3.9 months (hazard ratio 0.85 [95% confidence intervals, 0.72–0.99]) and median PFS by 1.3 months (hazard ratio 0.73 [95% confidence intervals, 0.62–0.85]) in the pertuzumab vs. the placebo arm. ORR was numerically higher (57.0% vs. 48.6%) and median DoR 1.8 months longer with pertuzumab treatment. There was a trend for more favorable hazard ratios in certain subgroups related to HER2 amplification/overexpression. Safety was comparable between arms, except for serious and grade 3–5 adverse events, and any-grade diarrhea, which were more frequent with pertuzumab. Conclusions JACOB did not meet its primary endpoint. Nonetheless, the study continues to demonstrate some, albeit limited, evidence of treatment activity and an acceptable safety profile for pertuzumab plus trastuzumab and chemotherapy in previously untreated HER2-positive metastatic gastric or gastroesophageal junction cancer after long-term follow-up. Trial registration NCT01774786; https://clinicaltrials.gov/ct2/show/NCT01774786.

Prespecified exploratory biomarker analyses of the phase II/III GATSBY study (NCT01641939) assessed whether patient subgroups experienced a survival benefit from trastuzumab emtansine (T-DM1) versus taxane therapy, and to advance understanding of HER2-positive advanced gastric/gastroesophageal junction cancer (AGC) disease biology. Adults with HER2-positive AGC whose disease progressed during/after first-line therapy were enrolled and randomized to receive T-DM1 [Stage 1: 3.6 mg/kg q3w, 2.4 mg/kg qw, or taxane (docetaxel/paclitaxel); Stage 2: 2.4 mg/kg qw or taxane]. Primary efficacy endpoint was overall survival (OS). Prespecified exploratory biomarkers included HER2, HER3, PTEN, PIK3CA mutation status, FcγR, and cMET. Tumor samples from patients who received 2.4 mg/kg T-DM1 (n = 228) or taxane (n = 117) were included. Median OS was longer in subgroups with HER2 immunohistochemistry (IHC) 3+ [9.5 versus 8.3 months for T-DM1 versus taxane; hazard ratio (HR) 0.99 (95% CI 0.68–1.43)] versus HER2 IHC 2+/in situ hybridization-positive [5.2 versus 9.2 months for T-DM1 versus taxane; HR 1.53 (95% CI 0.94–2.50)] tumors. Trends towards increased median OS were also observed in subgroups with > versus ≤ median HER2 mRNA expression, higher versus lower HER2 gene copy number, HER2 gene ratio and H score, and homogenous or nonfocal HER2 IHC staining. T-DM1 was not associated with superior OS versus taxane in any subgroup. Patients with previously treated HER2-positive AGC with higher HER2 expression experienced a better treatment effect from T-DM1 than those with lower HER2 expression and may derive comparable survival benefits from T-DM1 and taxane therapy. NCT01641939 ( https://clinicaltrials.gov/ct2/show/NCT01641939 ).

Hyperprogressive disease (HPD) during treatment with anti-programmed death-1/programmed death-ligand 1 monoclonal antibodies has anecdotally been reported in some types of cancers, but is not well-characterized in patients with advanced gastric cancer (AGC). Total 62 AGC patients treated with nivolumab in a single institution from September 2017 to April 2018 were enrolled in this study. Tumor responses were assessed according to Response Evaluation Criteria in Solid Tumors version 1.1, and HPD was defined as ≥ two fold increase in tumor growth rate. Clinicopathological and molecular characteristics associated with HPD were also investigated. Thirteen of 62 patients (21%) developed HPD after nivolumab treatment. Overall survival (OS) and progression-free survival (PFS) were significantly shorter in patients with HPD than in patients without HPD (median OS: 2.3 months vs. not reached, P

Background AVAGAST was an international, randomized, placebo-controlled phase III study of chemotherapy with or without bevacizumab as first-line therapy for patients with advanced gastric cancer. We performed exploratory analyses to evaluate regional differences observed in the trial. Methods Analyses were performed in the placebo plus chemotherapy arm (intention-to-treat population). Chemotherapy was cisplatin 80 mg/m2 for six cycles plus capecitabine (1000 mg/m2 orally bid days 1–14) or 5-fluorouracil (800 mg/m2/day continuous IV infusion days 1–5) every 3 weeks until disease progression or unacceptable toxicity. Results Overall, 387 patients were assigned to placebo plus chemotherapy (eastern Europe/South America, n = 118; USA/western Europe, n = 81; Korea/other Asia, n = 94; Japan, n = 94). At baseline, poor performance status, liver metastases, and larger tumors were most frequent in eastern Europe/South America and least frequent in Japan. Patients received subsequent chemotherapy after disease progression as follows: eastern Europe/South America (14%); USA/western Europe (37%); Korea/other Asia (61%); and Japan (77%). Hazard ratios for overall survival versus USA/western Europe were 1.47 (95% CI, 1.09–1.99) for eastern Europe/South America, 0.91 (95% CI, 0.67–1.25) for Korea/other Asia, and 0.87 (95% CI, 0.64–1.19) for Japan. Conclusions Regional differences in the healthcare environment may have contributed to the differences in overall survival observed in the AVAGAST study.

The ability to differentiate between mucosal (M) or microinvasive submucosal (SM1: depth of less than 500 µm) and invasive submucosal (SM2: depth of 500 µm or more) cancer is paramount when choosing the method of treatment for early gastric cancer (EGC). The "non-extension sign" relates to a localized increase in thickness and rigidity due to massive submucosal invasion by a cancer. The present study sought to assess the ability of conventional endoscopy (CE) to correctly identify SM2 cancer using only the non-extension sign.This is a retrospective study based on a prospectively collected database. EGCs had been diagnosed according to invasion depth as M-SM1 or SM2. In terms of the endoscopic diagnostic criterion, lesions positive for the non-extension sign were classified as SM2 cancers, while those negative for the non-extension sign were classified as M-SM1 cancers. Histopathological findings were used as the gold standard.We examined a total of 863 lesions from 704 patients, comprising 104 true-positive, 733 true-negative, 9 false-positive, and 17 false-negative lesions. This yielded a sensitivity of 92.0 % (95 % confidence interval (CI), 87.0-97.0 %), a specificity of 97.7 % (95 % CI, 96.7-98.8 %), a positive predictive value of 85.9 % (95 % CI, 79.7-92.1 %), a negative predictive value of 98.8 % (95 % CI, 98.0-99.6 %), and a diagnostic accuracy of 96.9 % (95 % CI, 95.8-98.1 %).The non-extension sign may be useful for accurately determining the suitability of minimally invasive endoscopic treatment. Nevertheless, considering the limitations of retrospective analysis, a further prospective study is warranted to confirm the diagnostic reliability of the non-extension sign.

Background Cancer stem cells (CSCs) have enhanced mechanisms of protection from oxidative stress. A variant form of CD44 (CD44v), a major CSC marker, was shown to interact with xCT, a subunit of cystine–glutamate transporter, which maintains high levels of intracellular reduced glutathione (GSH) which defend the cell against oxidative stress. Sulfasalazine (SSZ) is an inhibitor of xCT and was shown to suppress the survival of CD44v-positive stem-like cancer cells both in vitro and in vivo. To find the dose of SSZ which can safely reduce the population of CD44v-positive cells in tumors, a dose-escalation study in patients with advanced gastric cancer was conducted.

We evaluated the safety and efficacy of ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients previously treated for advanced gastric or gastroesophageal junction adenocarcinoma in Japanese and Western subgroups from the RAINBOW trial.Patients received ramucirumab at 8 mg/kg or placebo (days 1 and 15) plus paclitaxel at 80 mg/m(2) (days 1, 8, and 15 of a 28-day cycle). End points were compared between treatment arms within Japanese (N = 140) and Western (N = 398) populations.The incidence of adverse events of grade 3 or higher was higher for ramucirumab plus paclitaxel in both populations (Japanese population, 83.8 % vs 52.1 %; Western population, 79.1 % vs 61.9 %). Neutropenia was the commonest adverse event of grade 3 or higher, with a higher incidence for ramucirumab plus paclitaxel (Japanese population, 66.2 % vs 25.4 %; Western population, 32.1 % vs 14.7 %). The incidence of febrile neutropenia was low and was similar between treatment arms in both populations. The overall survival hazard ratio was 0.88 (95 % confidence interval, 0.60-1.28) in the Japanese population and 0.73 (95 % confidence interval, 0.58-0.91) in the Western population. The progression-free survival hazard ratio was 0.50 (95 % confidence interval, 0.35-0.73) in the Japanese population and 0.63 (95 % confidence interval, 0.51-0.79) in the Western population. The objective response rate was higher for ramucirumab plus paclitaxel in both populations (Japanese population, 41.2 % vs 19.4 %; Western population, 26.8 % vs 13.0 %), as was the 6-month survival rate (Japanese population, 94.1 % vs 71.4 %; Western population, 66.0 % vs 49.0 %).Safety profiles of the ramucirumab plus paclitaxel arm were similar between populations, though there was a higher incidence of neutropenia in Japanese patients. Progression-free survival and objective response rate improvements were observed for ramucirumab plus paclitaxel in both populations. CLINICALTRIALS.NCT01170663.

The correlation between progression-free survival (PFS) or time to progression (TTP) and overall survival (OS) has been evaluated in patients with advanced gastric cancer (AGC) who received first-line chemotherapy. No corresponding analysis has been done in patients who have undergone second-line chemotherapy.We evaluated the correlation between PFS, TTP, objective response rate (ORR), disease control rate (DCR), and OS in patients with AGC who underwent second-line chemotherapy. Correlations were evaluated by Spearman rank correlation coefficient (ρ).Sixty-four trials, including 10 randomized studies, were selected for analysis. Median PFS/TTP moderately correlated with OS (ρ = 0.56). The correlation tended to be stronger in non-Asian trials (ρ = 0.74) than in Asian trials (ρ = 0.37). ORR and DCR did not strongly correlate with OS (ρ = 0.38 for ORR; ρ = 0.54 for DCR). The hazard ratio of PFS and OS in each of the arms of the 10 randomized studies also showed a low correlation (ρ = 0.36).PFS/TTP, ORR, and DCR did not correlate sufficiently with OS to be used as surrogate endpoints in patients with AGC who have undergone second-line chemotherapy. Further research is needed based on individual patient data from ongoing randomized trials.

Sorafenib inhibits several receptor tyrosine kinases involved in tumor progression and angiogenesis. S-1, an oral fluorouracil antitumor drug, plus cisplatin (CDDP) is the standard regimen for advanced gastric adenocarcinoma (AGC) in Japan. The purpose of this phase I study was to evaluate the safety, pharmacokinetics, and preliminary efficacy of sorafenib in combination with S-1 plus CDDP.Patients with histologically confirmed previously untreated AGC were evaluated for eligibility and treated with sorafenib (400 mg bid, days 1-35), S-1 (40 mg/m(2) bid, days 1-21), and CDDP (60 mg/m(2), day 8). Treatment was continued until disease progression or unacceptable toxicity. Pharmacokinetics for sorafenib, 5-FU, and CDDP were investigated in cycle 1.Thirteen patients were enrolled and received at least one dose of the study treatment. No specific or serious adverse event was newly reported in this study. Five patients had partial response and 8 had stable disease as the best response. Pharmacokinetic analysis showed no significant differences in the exposures of sorafenib when administered alone or in combination with S-1 and CDDP.The present phase I study demonstrates the acceptable toxicity and preliminary efficacy of combined treatment with S-1, CDDP, and sorafenib.

The Response Evaluation Criteria in Solid Tumors (RECIST) was revised in 2009, based on a large dataset of 6512 patients from 16 trials. However, no gastric cancer patients were included in those data. The purpose of this study was to clarify the difference between RECIST version 1.0 and version 1.1 in advanced gastric cancer.From 2004 to 2009, 129 consecutive patients with advanced gastric cancer received S-1 plus cisplatin as first-line treatment at the National Cancer Center Hospital East. Ninety-seven of these patients who had had baseline and post-treatment computed tomography scans performed were included in this study. Measurements of tumors were conducted retrospectively.At the baseline of first-line chemotherapy, 172 lymph nodes in 54 patients were considered to be candidate target lesions by RECIST version 1.0. However, only 38% of the lymph nodes were classified as target lesions by RECIST version 1.1, with 47% classified as non-target lesions and 15% classified as non-pathological. By RECIST version 1.0, the proportion of patients with target lesions at the baseline of first-line chemotherapy was 67% (65/97), and this percentage was significantly reduced according to RECIST version 1.1 (53%; 51/97) (McNemar's exact test, P0.001). The findings at the baseline of second-line chemotherapy were similar (reduced from 62 to 49%; McNemar's exact test, P = 0.002). Overall response rates of first-line chemotherapy were 52% (34/65) according to RECIST version 1.0 and 55% (28/51) according to version 1.1.The revision of RECIST significantly reduced the proportion of patients classified with target lesions at the baselines of first-line and second-line chemotherapies. No obvious difference in overall response rates was observed.

Background The Trastuzumab for Gastric Cancer (ToGA) study is the first international trial to include Japanese patients with human epidermal growth factor 2 (HER2) positive advanced/metastatic gastric or gastroesophageal junction cancer. ToGA showed that trastuzumab plus chemotherapy (capecitabine/cisplatin or 5-fluorouracil/cisplatin) improved overall survival in the overall population (hazard ratio 0.74). Regional differences in outcome in favor of Japanese populations were observed in other studies; therefore, subgroup analyses of ToGA may contribute to the evaluation of the potential benefits of this regimen in Japanese patients. Methods We performed subgroup analyses on 101 Japanese patients enrolled into ToGA (trastuzumab plus chemotherapy, n = 51; chemotherapy, n = 50). Results Median overall survival in the Japanese subgroup was 15.9 months (95% confidence interval 12–25) for trastuzumab plus chemotherapy and 17.7 months (95% confidence interval 12–24) for chemotherapy (hazard ratio 1.00; 95% confidence interval 0.59–1.69). After adjusting for prespecified covariates, the estimated hazard ratio for overall survival was 0.68 (95% confidence interval 0.36–1.27). Further post hoc and exploratory examinations supported the robustness of the adjusted hazard ratios. Conclusions After adjusting for imbalanced patient backgrounds between arms, overall survival of Japanese patients with human epidermal growth factor 2 positive advanced/metastatic gastric or gastroesophageal junction cancer who received trastuzumab plus chemotherapy was improved compared with patients who received chemotherapy alone.

Preclinical studies have shown that mitomycin C (MMC) acts synergistically with irinotecan (CPT-11). In this phase II study, we evaluated the efficacy and toxicity of MMC/CPT-11 therapy as second-line chemotherapy for patients with fluoropyrimidine-resistant advanced gastric cancer.Eligible patients had evidence of tumor progression despite prior treatment with fluoropyrimidine-based regimens or had relapsed within 6 months after completion of therapy with adjuvant fluoropyrimidines. Treatment consisted of MMC (5 mg/m(2)) and CPT-11 (150 mg/m(2)) administered i.v. every 2 weeks. The primary endpoint was the response rate (RR). Our hypothesis was that this combination therapy was efficacious when the lower boundary of the 95% confidence interval (CI) of the RR exceeded 20% of the threshold RR.Between April 2002 and July 2003, 45 eligible patients were registered and analyzed. Among the 45 patients, 40 (89%) had previously received chemotherapy for metastasis and 24 (53%) had a performance status (PS) of 0. Thirteen partial responses were obtained among the 45 patients, resulting in an overall RR of 29% (95% CI, 16-42%). The median time to progression was 4.1 months, and the median survival time was 10 months, with a 1-year survival rate of 36%. Grade 4 neutropenia was observed in 29% of the patients, whereas febrile neutropenia occurred in 9%. The incidence rates of grade 3 nausea and diarrhea were 13 and 2%, respectively.Although this study did not achieve the per-protocol definition of activity, the progression-free survival and overall survival appeared to be promising, with acceptable tolerability. Thus, MMC/CPT-11 therapy as second-line chemotherapy for fluoropyrimidine-resistant advanced gastric cancer presents a potential treatment option in patients with a good PS.

According to the results of two recent randomized studies of treatment for metastatic gastric cancer in Japan, S-1 could replace infusional 5-fluorouracil and S-1 plus cisplatin showed a significant survival advantage over S-1 monotherapy, with a favorable toxicity profile. However, no globally accepted standards have been established yet and we have to wait for the results of other ongoing international studies, including studies of S-1 and its combinations, to achieve such standards. There are two major approaches to achieve further progress in the treatment of advanced gastric cancer. The first is to optimize the use of conventional cytotoxic agents (regimens) in the continuum of treatment for this disease. Several randomized studies of such regimens as second-line treatments are being planned in Japan, for which definitions of eligibility criteria and primary endpoints should be fully discussed in the design of the protocols. The second approach is to incorporate new active agents, particularly molecular targeting agents. Several molecular targeting agents that have shown survival advantages in patients with other tumor types are now under investigation for the treatment of gastric cancer in international randomized studies, including Japan and Korea. The next generation of targeting agents is also being evaluated in early clinical studies. Biological research has become essential for developing new targeting agents. For such biological studies, the tumor tissues of gastric cancer are easily obtainable via endoscopy, and such studies may constitute new frontiers in biological therapy. We expect that these studies will provide not only further clinical advantages but that they will also lead to tailored medicine.