Standard Regimen For First-line Treatment Research Articles

Abstract 6172: Accurate PD-L1 IHC assessment in urothelial carcinoma by an AI algorithm robust across multiple sites, antibody clones, and scanners

Abstract Background: Immunotherapy against PD-L1 is used for treatment of several indications of Urothelial Carcinoma (UC). Recent results indicate that it is likely to become part of the standard first-line treatment regimen for advanced UC in the near future. Accurate readout of Immunohistochemical (IHC) PD-L1 expression is therefore essential to inform UC treatment decisions. However, manual PD-L1-scoring is prone to high inter- and intra-observer variability. Artificial intelligence (AI) may help to improve standardization, accuracy and efficiency of PD-L1 IHC scoring. Yet, previous AI-based approaches struggled to show consistency across images that are diverse with regards to the source institutions, antibody clones, and scanning hardware used. Methods: We developed an AI software for PD-L1 tumor proportion scoring (TPS/TC) on whole-slide images (WSIs) of UC without human supervision. PD-L1 analysis by the software is fully-automated, does not require any adaptation steps, and is concordant with current clinical guidelines. The performance of the software was evaluated on two cohorts of PD-L1 stained UC samples against ground-truth (GT) TPS/TC scores given by human pathologists in clinical routine. The first cohort (n = 53) consisted of samples stained with the 22C3 antibody clone (Agilent) derived from four institutions and three scanner models. It contained both tissue microarray samples and scans of UC resectates. A second validation cohort consisted of n = 83 WSIs stained with the SP263 clone (Ventana), collected from two institutions. Results: For the threshold of TPS≥1% (cut-off established for adjuvant therapy with Nivolumab), agreement rates of AI scores with human GT scores were 92.5% for cohort 1 (22C3) and 96.4% for cohort 2 (SP263). Sensitivity/specificity values were 92.3%/92.9% for cohort 1 and 100%/93.6% for cohort 2. Across both cohorts (n = 136) the agreement rate between AI and human was 94.9%. Conclusions: Across 136 UC samples stained with two PD-L1 antibody clones, and derived from a total of four institutions and three scanner models, the fully automatic AI system showed excellent agreement with human pathologist scores. These results on challenging validation data show the potential of AI applications to standardize and optimize PD-L1 scoring and demonstrate consistency and safety of suitable AI-based systems for application in clinical routine. Citation Format: Niklas Abele, Diego Calvopiña, David Mulder, Patrick Frey, Emre Karakok, Fadime G. Salman, Murat Oktay, Markus Eckstein, Sebastian Springenberg, Arndt Hartmann, Tobias Lang. Accurate PD-L1 IHC assessment in urothelial carcinoma by an AI algorithm robust across multiple sites, antibody clones, and scanners [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6172.

Perioperative immunotherapy for esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is the main prevalent histological subtype and accounts for 85% of esophageal cancer cases worldwide. Traditional treatment for ESCC involves chemotherapy, radiotherapy, and surgery. However, the overall prognosis remains unfavorable. Recently, immune checkpoint blockade (ICB) therapy using anti-programmed cell death-1 (PD-1)/PD-1 ligand (PD-L1) antibodies have not only achieved remarkable benefits in the clinical management of ESCC but have also completely changed the treatment approach for this cancer. In just a few years, ICB therapy has rapidly advanced and been added to standard first-line treatment regimen in patients with ESCC. However, preoperative immunotherapy is yet to be approved. In this review, we summarize the ICB antibodies commonly used in clinical immunotherapy of ESCC, and discuss the advances of immunotherapy combined with chemotherapy and radiotherapy in the perioperative treatment of ESCC, aiming to provide reference for clinical management of ESCC patients across the whole course of treatment.

Anti-PD-1 Antibody (Tislelizumab) Combined with R-CHOP for the Treatment of Previously Untreated Primary Mediastinal B-Cell Lymphoma: A Prospective Phase II Study

Background: Primary mediastinal B-cell lymphoma (PMBCL) is a rare aggressive B-cell lymphoma of thymic origin. Due to the low incidence rate of PMBCL, there is currently no internationally accepted standard first-line treatment regimen. Dose-adjusted (DA) EPOCH-R which is the more commonly used first-line therapy plan is not so effective because patients usually cannot tolerate it. The R-CHOP regimen is comparable to the R-DA-EPOCH for the first-line treatment of PMBCL in terms of survival and has a better safety profile (Bhatt, V.R. et al, Cancer Treat Rev 2015; Iwanicka el al., Curr Hematol Malig Rep 2014). Meanwhile, patients with PMBCL usually have alterations of 9p24.1, leading to overexpression of PDL-1/2. Previous studies have found that PD-1 monoclonal antibody shows good efficacy in recurrent and refractory PMBCL (Steidl et al., Blood 2011; Zinzani et al., Blood 2017). Tislelizumab, a humanized IgG4 antibody that binds PD-1 with high affinity, minimizes binding to Fcγ receptor 1 (FcγRI) on macrophages by the genetic engineering of Fc segment, abrogating antibody-dependent phagocytosis (ADCP)-induced T-cell clearance. The efficacy and safety of its combination with R-CHOP in previously untreated PMBCL is not yet clear. We speculate that the combination of both may be a new option for the first-line therapy for PMBCL patients with good efficacy and low toxicity. Methods: This is a single-arm, multi-center, phase II clinical study (ChiCTR2100044313). Patients aged 18 years or older with a diagnosis of PMBCL and previously untreated were eligible. Eligible patients received 6 cycles of Tislelizumab (200 mg D1), Rituximab (375 mg/m 2 D1), Cyclophosphamide (750 mg/m 2 D2), Pirarubicin (50 mg/m 2 D2), Vincristine (1.4 mg/m 2, maximum dose 2 mg, D2), Prednisone (100 mg/d D2-6), every 21 days for 1 cycle. Disease response assessments were performed by positron emission tomography and computed tomography (PET-CT) or enhanced CT every two cycles, meanwhile peripheral blood ctDNA was monitored, and treatment-related adverse effects were assessed and recorded. The primary endpoint was objective remission rate (ORR). The secondary endpoints included treatment safety, progression-free survival (PFS) and overall survival (OS), and the exploratory analyses of the correlation between PD-L1 expression in tumor tissues, tumor-associated macrophages (TAM) phenotype in tumor microenvironment and efficacy. Results: From June 2020 to June 2023, 12 patients were enrolled and 9 patients had evaluable efficacy with the median age of 34 years, 3 males and 6 females, all patients had large mediastinal mass at initial diagnosis. 7 patients had PD-L1 expression (VENTANA SP263) above 80% and 2 cases could not be further tested due to insufficient tissue specimens. The ORR was 100%, and the CR rate was 77.8% (7/9) after 6 cycles of treatment. The 5 th and 9 th patient reached PR after 6 cycles of treatment due to irregular hospitalization. And CR was achieved after 2 cycles of regular treatment for the 5 th patient. NGS from formalin-fixed paraffin-embedded (FFPE) and circulating tumor DNA (ctDNA) evaluation from blood were performed across all patients before treatment. 5 patients underwent end of treatment-ctDNA test. Median follow-up 15m (6.8m-26.3m), the third patient was lost to follow-up at 9m. The other patients who achieved CR are still at complete remission. Moreover, we found SOCS1, TNFAIP3 are the most frequently mutated genes in biopsies of PMBCL and only the 5th patient had RHOA mutation which is highly related to PMBCL. The PET-CT and ctDNA assessments were negative in three patients at the end of 6 cycles with 60% concordance, and the 5 th and 9 th patient achieved PR on PET-CT, but the ctDNA assessments were negative. The most common adverse events (AEs) were gastrointestinal reactions, 2 patients experienced grade IV myelosuppression and 1 patient had grade I hyperthyroidism. No treatment-related deaths occurred. Conclusion: Tislelizumab combined with R-CHOP for the treatment of previously untreated PMBCL had good efficacy and sustained response with low toxicity. Longer follow-up is required to access the survival benefit of this regimen. Figure 1: Disease Remission in the Included Patients

Phase III Study Comparing Cisplatin Plus Gemcitabine With Cisplatin Plus Pemetrexed in Chemotherapy-Naive Patients With Advanced-Stage Non-Small-Cell Lung Cancer.

Cisplatin plus gemcitabine is a standard regimen for first-line treatment of advanced non-small-cell lung cancer (NSCLC). Phase II studies of pemetrexed plus platinum compounds have also shown activity in this setting. This noninferiority, phase III, randomized study compared the overall survival between treatment arms using a fixed margin method (hazard ratio [HR] < 1.176) in 1,725 chemotherapy-naive patients with stage IIIB or IV NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 1. Patients received cisplatin 75 mg/m2 on day 1 and gemcitabine 1,250 mg/m2 on days 1 and 8 (n = 863) or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 on day 1 (n = 862) every 3 weeks for up to six cycles. Overall survival for cisplatin/pemetrexed was noninferior to cisplatin/gemcitabine (median survival, 10.3 v 10.3 months, respectively; HR = 0.94; 95% CI, 0.84 to 1.05). Overall survival was statistically superior for cisplatin/pemetrexed versus cisplatin/gemcitabine in patients with adenocarcinoma (n = 847; 12.6 v 10.9 months, respectively) and large-cell carcinoma histology (n = 153; 10.4 v 6.7 months, respectively). In contrast, in patients with squamous cell histology, there was a significant improvement in survival with cisplatin/gemcitabine versus cisplatin/pemetrexed (n = 473; 10.8 v 9.4 months, respectively). For cisplatin/pemetrexed, rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia (P ≤ .001); febrile neutropenia (P = .002); and alopecia (P < .001) were significantly lower, whereas grade 3 or 4 nausea (P = .004) was more common. In advanced NSCLC, cisplatin/pemetrexed provides similar efficacy with better tolerability and more convenient administration than cisplatin/gemcitabine. This is the first prospective phase III study in NSCLC to show survival differences based on histologic type.

Association of thyroid transcription factor-1 (TTF-1) expression with efficacy of PD-1/PD-L1 inhibitors plus pemetrexed and platinum chemotherapy in advanced non-squamous non-small cell lung cancer.

Thyroid transcription factor-1 (TTF-1) expression in advanced non-squamous non-small cell lung cancer (NSCLC) has been associated with the efficacy of pemetrexed plus platinum chemotherapy. However, the relation between TTF-1 expression and efficacy of the combination of programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors plus pemetrexed and platinum chemotherapy, a standard first-line treatment regimen for advanced non-squamous NSCLC, has remained unclear. We retrospectively evaluated TTF-1 expression in tumor tissue of patients with advanced or recurrent non-squamous NSCLC treated with PD-1/PD-L1 inhibitors plus pemetrexed and platinum chemotherapy in the first-line setting. Clinical characteristics and pathological data for each patient were assessed, and progression-free survival (PFS) was evaluated. Bias due to patient background was minimized by application of inverse probability of treatment weighting (IPTW) analysis. A total of 122 patients, 75 (61.5%) of whom were positive for TTF-1 immunostaining in tumor specimens, was included in this multicenter study. At the time of analysis, 89 (73.0%) patients had experienced progression events and 44 (36.1%) had died [median follow-up 14.6 months (range, 0.53-29.5 months)]. PFS was longer for TTF-1-positive patients than for TTF-1-negative patients [median, 12.2 vs. 6.0 months; hazard ratio (HR) =0.63 (95% CI: 0.37-1.06); log-rank P=0.028]. IPTW-adjusted PFS was significantly longer for TTF-1-positive than for TTF-1-negative patients [HR =0.62 (95% CI: 0.46-0.83); log-rank P=0.024]. TTF-1 expression in advanced non-squamous NSCLC can serve as a basis for prediction of PFS in patients treated with PD-1/PD-L1 inhibitors plus pemetrexed and platinum chemotherapy in the first-line setting.

Application of immune checkpoint inhibitors in hepatobiliary cancers

Hepatobiliary cancers are primarily categorized into hepatocellular carcinoma (HCC) and biliary tract cancers (BTC). HCC is one of the most common malignant cancers, with increasing global incidence. Immune checkpoint inhibitors (ICIs) have changed the approach of HCC management in recent years. The combination of atezolizumab and bevacizumab has surpassed sorafenib as the standard regimen for first-line treatment of advanced unresectable HCC. However, the optimal choice for second-line treatment after initial treatment with ICIs lacks clinical trial confirmation. In addition, limited clinical trial data on ICIs combined with locoregional and perioperative therapies have been reported. Unlike HCC, clinical studies have found that immunotherapy is effective only for BTC with specific molecular markers. Moreover, the molecular characteristics governing immune responses and evasion remain unclear. This review provides information on the application of immunotherapy for HCC and prospects over the next few years. In addition, current evidence from clinical trials of BTC has made BTC immunotherapy a research hotspot again. Based on the findings in the literature, future clinical trials are being planned. Furthermore, biomarkers used in immunotherapies for hepatobiliary cancers that may shed light on the management of these diseases in the future were discussed.

Systemic ALCL Treated in Routine Clinical Practice: Outcomes Following First-Line Chemotherapy from a Multicentre Cohort.

IntroductionBrentuximab vedotin (BV)-CHP is the new standard regimen for first-line treatment of systemic anaplastic large cell lymphoma (sALCL). We undertook a retrospective analysis of consecutive patients diagnosed with sALCL, treated in routine practice, to serve as a benchmark analysis for comparison BV-CHP efficacy in routine practice.MethodsPatients aged 16 years or older with sALCL treated in seven UK and Australian centres and from 14 additional centres from the UK Haematological Malignancy Research Network database (n = 214). Treatment allocation was clinician choice and included best supportive care (BSC). Main outcomes were time to treatment failure (TTF) and overall survival (OS). Multivariable analysis for predictors of both TTF and OS was also undertaken.ResultsThe median age 52 years (range 16–93), 18% ECOG ≥ 3 and 40% of cases were ALK positive. CHOP (cyclophosphamide, adriamycin, vincristine, prednisolone) was employed in 152 (71%) of patients and CHOEP (CHOP + etoposide) in 4% of patients. For CHOP-treated patients overall response rate (ORR) was 65% and complete response (CR) 47%. Only 9% of patients underwent autologous stem cell transplant (ASCT). With 57 months median follow-up, 4-year TTF and OS were 41.2% (95% CI 33.1–49.1) and 58.9% (95% CI 50.3–66.5) respectively. Multivariable analysis showed ALK+ status was independently associated with superior TTF (HR 0.36, 95% CI 0.21–0.63) but not OS (0.44, 95% CI 0.18–1.07).DiscussionWe present a retrospective analysis with mature follow-up of one of the largest multicentre populations of sALCL available, comparable to similar large retrospective studies. ALK status remains a strong predictor of outcomes.ConclusionThese data serve as a robust benchmark for BV-CHP as the new standard of care for sALCL. Similar real-world evidence with BV-CHP will be desirable to confirm the findings of ECHELON-2.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-021-01764-0.

P-65 Locally advanced/metastatic gastric cancer: Real-world data on first-line treatment with oxaliplatin and cisplatin-based doublets

In metastatic gastric cancer (mGC), palliative chemotherapy has shown benefit compared with best supportive care (BSC) and combination chemotherapy showed a survival benefit over single-drug therapies. However, no standard first-line treatment regimen is currently accepted. Anthracycline and docetaxel-based triplets are not superior to fluoropyrimidine-containing doublets and a recent meta-analysis showed benefit of oxaliplatin (OX)- over cisplatin (CIS)-based doublets. Capecitabine proved non-inferior to fluorouracil in the REAL-2 trial and subsequent meta-analyses.

Hemoglobin Levels and Red Blood Cells Distribution Width Highlights Glioblastoma Patients Subgroup With Improved Median Overall Survival.

Glioblastoma multiforme (GBM) is known for its dismal prognosis, though its dependence on patients' readily available RBCs parameters is not fully established. In this work, 170 GBM patients, diagnosed and treated in Soroka University Medical Center (SUMC) over the last 12 years were retrospectively inspected for their survival dependency on pre-operative RBCs parameters. Besides KPS and tumor resection supplemented by oncological treatment, age under 70 (HR = 0.4, 95% CI 0.24–0.65, p = 0.00073), low hemoglobin level (HR = 1.79, 95% CI 1.06–2.99, p = 0.031), and Red Cell Distribution Width (RDW) < 14% (HR = 0.57, 95% CI 0.37–0.88, p = 0.018) were found to be prognostic of patients' overall survival in multivariate analysis, accounting for a false discovery rate of < 5% due to multiple hypothesis testing. According to these results, a stratification tree was made, from which a favorable route highlighted a subgroup of nearly 30% of the cohorts' patients whose median overall survival was 21.1 months (95% CI 16.2–27.2)—higher than the established chemo-radiation standard first-line treatment regimen overall median survival average of about 15 months. The beneficial or detrimental effect of RBCs parameters on GBM prognosis and its possible causes is discussed.

Nab-paclitaxel plus gemcitabine as first line therapy in metastatic pancreatic cancer patients relapsed after gemcitabine adjuvant treatment.

Nab-paclitaxel plus gemcitabine (Nab-Gem) represents one of the standard regimen for first-line treatment of metastatic pancreatic adenocarcinoma (mPDAC). However, few data are available in mPDAC relapsed after gemcitabine as adjuvant treatment. Our study aims to evaluate the efficacy and feasibility of Nab-Gem as first-line treatment for mPDAC patients previously treated with adjuvant treatment. We retrospectively analyzed the safety and efficacy data of 36 patients, who received first-line Nab-Gem after gemcitabine as adjuvant treatment. All patients received gemcitabine after radical surgery. Median disease-free survival was 12months (95% CI 9.7-14.3); at relapse, all patients received Nab-Gem. We observed an objective response rate and disease control rate of 11.1% and 63.9%, respectively. With a median follow-up of 47months, median progression-free survival was 5months (95% CI 1.0-9.0), whereas median overall survival (OS) was 13months (95% CI 5.5-20.5). Median OS was higher in patients with a relapse ≥ 7months after the end of adjuvant treatment than in patients relapsed < 7months (14 vs. 8months, respectively, p: 0.52). Our results show that first-line Nab-Gem is feasible and effective in patients previously treated with gemcitabine as adjuvant treatment.

Serum CYFRA21-1 is Correlated with the Efficacy of Epidermal Growth Factor Receptor-tyrosine Kinase Inhibitor in Non-small Cell Lung Cancer Patients Harboring EGFR Mutations

背景与目的表皮生长因子受体-酪氨酸激酶抑制剂(epidermal growth factor receptor-tyrosine kinase inhibitors, EGFR-TKIs)是EGFR基因突变晚期非小细胞癌(non-small cell lung cancer, NSCLC)患者一线标准治疗方案, 但是临床实践中, 疗效差异较大。本项实验拟研究治疗前血清细胞角蛋白19片段(cytokeratin-19 fragments, CYFRA21-1)和癌胚抗原(carcinoembryonic antigen, CEA)的水平是否与EGFR-TKIs疗效有关。方法回顾性分析194例EGFR基因突变阳性且接受EGFR-TKIs治疗的NSCLC患者的治疗前的血清CYFRA21-1和CEA水平与EGFR-TKIs疗效及生存时间的关系。结果血清水平CYFRA21-1增高和正常的无进展生存时间(progression-free survival, PFS)分别为7.0个月和11.9个月(P < 0.001);总生存(overall survival, OS)分别为12.6个月和28.0个月(P < 0.001)。腺癌中, 血清水平增高和正常的PFS分别为7.0个月和12.0个月(P < 0.001), OS分别为13.1个月和28.1个月(P < 0.001)。鳞癌中, 血清CYFRA21-1水平高低与生存时间无关。治疗前血清CEA水平高低与生存时间无关。结论在EGFR突变肺腺癌患者, 治疗前血清水平CYFRA21-1增高组EGFR-TKIs治疗的PFS和OS均较正常组短。EGFR突变肺腺癌患者, 治疗前血清CYFRA21-1水平可以作为预测EGFR-TKIs治疗的疗效指标。

Combined treatment of Nimotuzumab and rapamycin is effective against temozolomide-resistant human gliomas regardless of the EGFR mutation status.

BackgroundThe treatment of glioblastoma multiforme (GBM) is an unmet clinical need. The 5-year survival rate of patients with GBM is less than 3%. Temozolomide (TMZ) remains the standard first-line treatment regimen for gliomas despite the fact that more than 90% of recurrent gliomas do not respond to TMZ after repeated exposure. We have also independently shown that many of the Asian-derived glioma cell lines and primary cells derived from Singaporean high-grade glioma patients are indeed resistant to TMZ. This issue highlights the need to develop new effective anti-cancer treatment strategies. In a recent study, wild-type epidermal growth factor receptor (wtEGFR) has been shown to phosphorylate a truncated EGFR (known as EGFRvIII), leading to the phosphorylation of STAT proteins and progression in gliomagenesis. Despite the fact that combination of EGFR targeting drugs and rapamycin has been used before, the effect of mono-treatment of Nimotuzumab, rapamycin and combination therapy in human glioma expressing different types of EGFR is not well-studied. Herein, we evaluated the efficacy of dual blockage using monoclonal antibody against EGFR (Nimotuzumab) and an mTOR inhibitor (rapamycin) in Caucasian patient-derived human glioma cell lines, Asian patient-derived human glioma cell lines, primary glioma cells derived from the Mayo GBM xenografts, and primary short-term glioma culture derived from high-grade glioma patients.MethodsThe combination effect of Nimotuzumab and rapamycin was examined in a series of primary human glioma cell lines and glioma cell lines. The cell viability was compared to TMZ treatment alone. Endogenous expressions of EGFR in various GBM cells were determined by western blotting.ResultsThe results showed that combination of Nimotuzumab with rapamycin significantly enhanced the therapeutic efficacy of human glioma cells compared to single treatment. More importantly, many of the Asian patient-derived glioma cell lines and primary cells derived from Singaporean high-grade gliomas, which showed resistance to TMZ, were susceptible to the combined treatments.ConclusionsIn conclusion, our results strongly suggest that combination usage of Nimotuzumab and rapamycin exert higher cytotoxic activities than TMZ. Our data suggest that this combination may provide an alternative treatment for TMZ-resistant gliomas regardless of the EGFR status.

Su1187 Randomised, Multicenter Clinical Trial: Comparison of 10-Day Standard Triple Therapy and Non-Bismuth-Containing Concomitant Therapy for Helicobacter pylori Infection in Korea (Interim Result)

Background Clarithromycin-based standard triple therapy for the first-line treatment of Helicobacter pylori (H. pyloi) has not achieved acceptable eradication rates in some parts of the world, especially in China. This is driven, in part, by clarithromycin resistance. The plant alkaloid berberine and allicin were known to significantly inhibit proliferation of H. pylori in vitro. Moreover, they also seemed to be potentially effective agent for H. pylori eradication in vivo. Whether berberine or allicin treatment could replace clarithromycin as the first-line treatment for Helicobacter pylori infection is unknown. We compared the efficacy of berberine-, allicinor clarithromycin-based triple therapy for 14 days in first-line treatment. Methods For this single-center, randomized trial, we recruited 336 patients (≥18 years old) with H pylori infection from PLA General Hospital between April and December, 2013. Using a permuted block randomization with a block size of six, we randomly allocated eligible patients to receive one of the following regimens (1:1:1): standard triple regimen of clarithromycin 500 mg, omeprazole 20 mg and amoxicillin 1000 mg taken twice a day for 14 days; berberine-based triple regimen of berberine, 300mg 3 times a day and omeprazole 20 mg, amoxicillin 1000 mg twice a day for 14 days; or allicin-based regimen of allicin 8 mg 3 times a day and omeprazole 20 mg, amoxicillin 1000 mg twice a day for 14 days. Investigators were mask to treatment allocation. Eradication was assessed by 13C urea breath test at least 1 month after the treatment. Our primary outcome was probablity of H pylori eradication. The prior patients' consent and approval were obtained from Institutional Review Board of the Chinese PLA General Hospital (Number 2013FC-TSYS-1009). Results We enrolled a total of 336 participants: 112 to each group. In the intention-to-treat population, H. pylori eradication rate was higher with berberine-based therapy (80.4%, 95% CI 73.087.7) than with standard-based therapy (67.0%, 95% CI 58.3-75.7) and allicin-based therapy(65.2%, 95% CI 56.4-74.0). In the per-protocol population, eradication rate was 70.8% (95% CI 62.1-79.4; 75 of 106 patients) in standard triple therapy, 84.1% (95% CI 77.291.0; 90 of 107 patients) in berberine-based therapy, and 73% (95% CI 64.3-81.7; 73 of 100 patients) in allicin-based therapy. Safety profiles for each treatments was similar andmain adverse events were gastrointestinal disorders. Conclusion Berberine-based triple regimen (berberine, amoxicillin and PPI) can achieve a > 80% ITT success rate with similar safety and tolerability to standard regimen for first-line treatment of H. pylori infection.

Su1190 Berberine-,Allicin-or Clarithromycin-Based Triple Therapy for the First-Line Treatment of Helicobacter pylori Infection: an Open-Label, Randomized Trial

Background Clarithromycin-based standard triple therapy for the first-line treatment of Helicobacter pylori (H. pyloi) has not achieved acceptable eradication rates in some parts of the world, especially in China. This is driven, in part, by clarithromycin resistance. The plant alkaloid berberine and allicin were known to significantly inhibit proliferation of H. pylori in vitro. Moreover, they also seemed to be potentially effective agent for H. pylori eradication in vivo. Whether berberine or allicin treatment could replace clarithromycin as the first-line treatment for Helicobacter pylori infection is unknown. We compared the efficacy of berberine-, allicinor clarithromycin-based triple therapy for 14 days in first-line treatment. Methods For this single-center, randomized trial, we recruited 336 patients (≥18 years old) with H pylori infection from PLA General Hospital between April and December, 2013. Using a permuted block randomization with a block size of six, we randomly allocated eligible patients to receive one of the following regimens (1:1:1): standard triple regimen of clarithromycin 500 mg, omeprazole 20 mg and amoxicillin 1000 mg taken twice a day for 14 days; berberine-based triple regimen of berberine, 300mg 3 times a day and omeprazole 20 mg, amoxicillin 1000 mg twice a day for 14 days; or allicin-based regimen of allicin 8 mg 3 times a day and omeprazole 20 mg, amoxicillin 1000 mg twice a day for 14 days. Investigators were mask to treatment allocation. Eradication was assessed by 13C urea breath test at least 1 month after the treatment. Our primary outcome was probablity of H pylori eradication. The prior patients' consent and approval were obtained from Institutional Review Board of the Chinese PLA General Hospital (Number 2013FC-TSYS-1009). Results We enrolled a total of 336 participants: 112 to each group. In the intention-to-treat population, H. pylori eradication rate was higher with berberine-based therapy (80.4%, 95% CI 73.087.7) than with standard-based therapy (67.0%, 95% CI 58.3-75.7) and allicin-based therapy(65.2%, 95% CI 56.4-74.0). In the per-protocol population, eradication rate was 70.8% (95% CI 62.1-79.4; 75 of 106 patients) in standard triple therapy, 84.1% (95% CI 77.291.0; 90 of 107 patients) in berberine-based therapy, and 73% (95% CI 64.3-81.7; 73 of 100 patients) in allicin-based therapy. Safety profiles for each treatments was similar andmain adverse events were gastrointestinal disorders. Conclusion Berberine-based triple regimen (berberine, amoxicillin and PPI) can achieve a > 80% ITT success rate with similar safety and tolerability to standard regimen for first-line treatment of H. pylori infection.

Randomized phase III study of S-1 plus oxaliplatin versus S-1 plus cisplatin for first-line treatment of advanced gastric cancer.

60 Background: S-1 plus cisplatin (SP) is the standard first-line treatment regimen for advanced gastric cancer (AGC) in Japan. S-1 plus oxaliplatin (SOX) for AGC showed promising efficacy and safety outcomes in the previous phase II study. We aimed to evaluate the non-inferiority of SOX to SP for AGC. Methods: Patients (Pts) with unresectable advanced or recurrent gastric cancer were randomly assigned to SOX (oral S-1 40 mg/m2 b.i.d. for 14 days plus oxaliplatin 100 mg/m2 iv on day 1, q3w) or SP (oral S-1 40 mg/m2 b.i.d. for 21 days plus cisplatin 60 mg/m2iv on day 8, q5w). Eligibility criteria included PS 0-2, age 20 years or older, adequate major organ functions. Primary endpoints were non-inferiority in progression-free survival (PFS) as compared with SP and relative efficacy in overall survival among the groups. Main secondary endpoints included response rate (RR), safety, and length of hospital stay (LOS) per cycle. The primary analysis for PFS was planned after 456 PFS events occurred. Results: Six hundred eighty five pts enrolled were randomly assigned to SOX (n=342) or SP (n=343) between Jan. 2010 and Oct. 2011. The evaluable pts for safety and efficacy were 673 (SOX/SP, 335/338) and 642 (SOX/SP, 318/324), respectively. The median PFS was 5.5 months for SOX vs. 5.4 months for SP (hazard ratio [HR] =1.004; 95% confidence interval [CI], 0.840-1.199). The upper limit of the 95% CI for HR was not above the margin of 1.30 and met the predefined criterion for non-inferiority. RR was 55.7% for SOX and 52.2% for SP (P=0.374). Grade 3 or 4 toxicities in SOX v. SP were neutropenia 19.5% v. 41.5%, thrombocytopenia 9.5% v. 10.4%, febrile neutropenia 0.9% v. 6.9%, hyponatremia 7.1% v. 15.2%, sensory neuropathy 4.4% v. 0%, respectively. Serious adverse events were occurred in 29.3 % for SOX and 37.9% for SP. Eight treatment-related deaths were reported in SP (2.4%) and four in SOX (1.2%). The median LOS per cycle was 0.85 day for SOX and 6.00 days for SP (P&lt;0.0001). Conclusions: SOX showed non-inferiority to SP in PFS and the treatment was well tolerated, with benefit in terms of outpatient-based treatment in pts with AGC. SOX is considered as a new standard regimen for the first-line treatment of AGC on an outpatient basis. Clinical trial information: JapicCTI 101021.

Irinotecan is inactive as a first-line treatment, but plays an important part in gastric cancer treatment

Based on the results of the GC0301/TOP002 (S-1 versus irinotecan plus S-1) randomized control study, which were reported in this journal–Gastric Cancer [1]–can we conclude that irinotecan is not important in gastric cancer treatment? Currently, the answer to this question may be ‘‘yes’’, because irinotecan-based regimens did not meet any primary endpoint as a first-line treatment in three randomized control studies, including the GC0301/TOP002 study [1–3]. When these clinical studies were planned, standard treatment in the field of gastric cancer was absent; there was no appropriate, universal control. At that time, the National Comprehensive Cancer Network proposed 5-fluorouracil (FU)-based or cisplatin-based combinations as acceptable standard therapy. 5-FU alone or S-1 (an oral fluoropyrimidine) was standard therapy in Japan, but 5-FU plus cisplatin (CF) was also used frequently. CF was frequently employed in Korea, Japan, many South American countries, and many European countries. Epirubicin plus CF (ECF) was considered the standard in a few European countries and possibly in Canada. Thus, a 5-FU-based or cisplatin-based combination was an appropriate control in the West and, for that matter, in most of the world. Based on this background, the control arms varied among studies. Three randomized control studies (1 in Europe/the United States, 2 in Japan) were conducted to verify the efficacy of irinotecan-based regimens as a first-line treatment. A study in Europe and the United States was first reported. In these countries, irinotecan was emphasized as a new active agent for gastric cancer. This study was planned as a phase II/III trial [1]. In the phase II part, irinotecan combined with an infusional 5-FU Arbeitsgemeinschaft Internistische Onkologie (AIO) regimen [irinotecan/5-FU (IF)] was selected over irinotecan combined with cisplatin on the basis of the risk/benefit ratio. At the time, the IF regimen was considered to be the most active irinotecan-based regimen available in the West. In the phase III part, the usefulness of IF in comparison with CF was examined with respect to the time to progression (TTP) as a primary endpoint. When reviewing the antitumor effects of IF and CF in this study, the response rates (RRs) were 31.8 and 25.8%, respectively. The TTP was 5.0 and 4.2 months, respectively. The median survival time (MST) was 9.0 and 8.7 months, respectively. The toxicity profile of IF was also markedly more favorable than that of CF. However, with respect to the primary endpoint, TTP, the usefulness of IF in comparison with CF could not be demonstrated. In the protocol, it was also impossible to verify the non-inferiority of IF. Based on the results of this study, IF may not become a standard regimen for first-line treatment; the first study was unsuccessful in the West. Combination therapy with irinotecan and cisplatin (IC) was initially investigated as a first-line treatment in the JCOG9912 study, which was conducted by the Japan Clinical Oncology Group (JCOG); in this study, the usefulness of combination therapy with IC in comparison with the continuous intravenous infusion of 5-FU (5-FUci) was examined [2]. The RR and time to treatment failure (TTF) were significantly more favorable with IC. However, with respect to the primary endpoint, overall survival (OS), the usefulness of combination therapy with IC in comparison with 5-FUci was not demonstrated to be statistically significant (p = 0.055). Clinical studies not only in Europe and the United States but also in Japan failed to propose combination therapy with IC as a standard treatment. When reviewing the survival curve for this combination therapy