The COVID-19 pandemic has significantly disrupted global Supply Chains (SCs), emphasizing the importance of SC resilience, which refers to the ability of SCs to return to their original or more ...desirable state following disruptions. This study focuses on collaboration, a key component of SC resilience, and proposes a novel collaborative structure that incorporates a fictitious agent to manage inventory transshipment decisions between retailers in a centralized manner while maintaining the retailers' autonomy in ordering. The proposed collaborative structure offers the following advantages from SC resilience and operational perspectives: (i) it facilitates decision synchronization for enhanced collaboration among retailers, and (ii) it allows retailers to collaborate without the need for information sharing, addressing the potential issue of information sharing reluctance. Additionally, this study employs non-stationary probability to capture the deeply uncertain nature of the ripple effect and the highly volatile customer demand caused by the pandemic. A new Reinforcement Learning (RL) algorithm is developed to handle non-stationary environments and to implement the proposed collaborative structure. Experimental results demonstrate that the proposed collaborative structure using the new RL algorithm achieves superior SC resilience compared with centralized inventory management systems with transshipment and decentralized inventory management systems without transshipment using traditional RL algorithms.
Patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, two or more previous regimens of chemotherapy have a poor prognosis, and current guidelines do ...not recommend any specific treatments for these patients. We assessed the efficacy and safety of nivolumab, a fully human IgG4 monoclonal antibody inhibitor of programmed death-1 (PD-1), in patients with advanced gastric or gastro-oesophageal junction cancer who had been previously been treated with two or more chemotherapy regimens.
In this randomised, double-blind, placebo-controlled, phase 3 trial done at 49 clinical sites in Japan, South Korea, and Taiwan, eligible patients (aged ≥20 years with unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, standard therapy including two or more previous chemotherapy regimens, with an Eastern Cooperative Oncology Group ECOG performance status of 0–1, and naive to anti-PD-1 therapy or other therapeutic antibodies and pharmacotherapies for the regulation of T cells) were recruited. Patients were randomly assigned (2:1) using an interactive web response system to receive 3 mg/kg nivolumab or placebo intravenously every 2 weeks, stratified by country, ECOG performance status, and number of organs with metastases. Study treatment was continued until progressive disease per investigator assessment or onset of toxicities requiring permanent discontinuation. Patients and investigators were masked to group assignment. The primary endpoint was overall survival in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study treatment. This study is ongoing but not recruiting new patients, and is registered with ClinicalTrials.gov, number NCT02267343.
Between Nov 4, 2014, and Feb 26, 2016, we randomly assigned 493 patients to receive nivolumab (n=330) or placebo (n=163). At the data cutoff (Aug 13, 2016), median follow-up in surviving patients was 8·87 months (IQR 6·57–12·37) in the nivolumab group and 8·59 months (5·65–11·37) in the placebo group. Median overall survival was 5·26 months (95% CI 4·60–6·37) in the nivolumab group and 4·14 months (3·42–4·86) in the placebo group (hazard ratio 0·63, 95% CI 0·51–0·78; p<0·0001). 12-month overall survival rates were 26·2% (95% CI 20·7–32·0) with nivolumab and 10·9% (6·2–17·0) with placebo. Grade 3 or 4 treatment-related adverse events occurred in 34 (10%) of 330 patients who received nivolumab and seven (4%) of 161 patients who received placebo; treatment-related adverse events led to death in five (2%) of 330 patients in the nivolumab group and two (1%) of 161 patients in the placebo group. No new safety signals were observed.
In this phase 3 study, the survival benefits indicate that nivolumab might be a new treatment option for heavily pretreated patients with advanced gastric or gastro-oesophageal junction cancer. Ongoing trials that include non-Asian patients are investigating nivolumab for advanced gastric or gastro-oesophageal junction cancer in various settings and earlier treatment lines.
Ono Pharmaceutical and Bristol-Myers Squibb.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Background
Nivolumab showed improvement in overall survival (OS) in ATTRACTION-2, the first phase 3 study in patients with gastric/gastroesophageal junction (G/GEJ) cancer treated with ≥ 2 ...chemotherapy regimens. The 2-year follow-up results of ATTRACTION-2 are presented herein.
Methods
ATTRACTION-2 was a randomized, double-blind, placebo-controlled, phase 3 trial (49 sites; Japan, South Korea, and Taiwan). The median (min–max) follow-up period was 27.3 (24.1–36.3) months. The primary endpoint was OS. A subanalysis of OS was performed based on best overall response and tumor-programmed death ligand-1 (PD-L1) expression status.
Results
Overall, 493 of 601 screened patients were randomized (2:1) to receive nivolumab (330) or placebo (163). OS (median 95% confidence interval; CI) was significantly longer in the nivolumab group (5.26 4.60–6.37 vs 4.14 3.42–4.86 months in placebo group) at the 2-year follow-up (hazard ratio 95% CI, 0.62 0.51–0.76;
P
< 0.0001). A higher OS rate was observed in the nivolumab vs placebo group at 1 (27.3% vs 11.6%) and 2 years (10.6% vs 3.2%). The OS benefit was observed regardless of tumor PD-L1 expression. Among patients with a complete or partial response (CR or PR) in the nivolumab group, the median OS (95% CI) was 26.6 (21.65—not applicable) months; the OS rates at 1 and 2 years were 87.1% and 61.3%, respectively. No new safety signals were identified.
Conclusions
Nivolumab treatment resulted in clinically meaningful long-term improvements in OS in patients with previously treated G/GEJ cancer. The long-term survival benefit of nivolumab was most evident in patients with a CR or PR.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background
In this exploratory analysis from the PRODIGY study, we aimed to define the radiological criteria to identify patients with gastric cancer who may derive maximal clinical benefit from ...neoadjuvant chemotherapy.
Patients and methods
There were 246 patients allocated to receive surgery followed by adjuvant S-1 (SC group) and 238 allocated to receive neoadjuvant chemotherapy (CSC group). As the PRODIGY’s radiological method of lymph node (LN) evaluation considers short diameter and morphology (the size and morphology method), a method considering only short diameter was also employed. In the SC group, the correlation between radiologic and pathologic findings was analyzed. The hazard ratio (HR) for the progression-free survival (PFS) of the CSC group was analyzed in subgroups with different cT/N stages.
Results
cT4 disease showed a sensitivity of 85.6% for detecting pT4 and had a low proportion of pathologic stage (pStage) I disease (4.5%). Among the criteria determined by different cT/N stages by each method of LN positivity, those involving cT4Nany or cT4N + by both methods had a minimal proportion of pStage I disease (≤ 5%), while cT4Nany by both methods and cT4N + by the size and morphology method exhibited ≥ 75.9% sensitivity for detecting pStage III disease. The relative risk reduction in PFS of the CSC group was greatest in patients meeting the cT4Nany criterion defined by both methods (HR 0.67, 95% confidence interval 0.48–0.93).
Conclusions
The cT4Nany criterion, regardless of the radiological method used for LN evaluation, may help select patients with resectable gastric cancer for neoadjuvant chemotherapy.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Margetuximab, a novel, investigational, Fc-engineered, anti-HER2 monoclonal antibody, is designed to more effectively potentiate innate immunity than trastuzumab. We aimed to evaluate the safety, ...tolerability, and antitumour activity of margetuximab plus pembrolizumab (an anti-PD-1 monoclonal antibody) in previously treated patients with HER2-positive gastro-oesophageal adenocarcinoma.
CP-MGAH22–05 was a single-arm, open-label, phase 1b–2 dose-escalation and cohort expansion study done at 11 academic centres in the USA and Canada and 15 centres in southeast Asia (Korea, Taiwan, and Singapore) that enrolled men and women aged 18 years or older with histologically proven, unresectable, locally advanced or metastatic, HER2-positive, PD-L1-unselected gastro-oesophageal adenocarcinoma, with an Eastern Cooperative Oncology Group performance status of 0 or 1, who had progressed after at least one previous line of therapy with trastuzumab plus chemotherapy in the locally advanced unresectable or metastatic setting. In the dose-escalation phase, nine patients were treated: three received margetuximab 10 mg/kg intravenously plus pembrolizumab 200 mg intravenously every 3 weeks and six received the recommended phase 2 dose of margetuximab 15 mg/kg plus pembrolizumab 200 mg intravenously every 3 weeks. An additional 86 patients were enrolled in the phase 2 cohort expansion and received the recommended phase 2 dose. The primary endpoints were safety and tolerability, assessed in the safety population (patients who received at least one dose of either margetuximab or pembrolizumab) and the objective response rate as assessed by the investigator according to both Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, in the response-evaluable population (patients with measurable disease at baseline and who received the recommended phase 2 dose of margetuximab and pembrolizumab). This trial is registered with ClinicalTrials.gov, NCT02689284. Recruitment for the trial has completed and follow-up is ongoing.
Between Feb 11, 2016, and Oct 2, 2018, 95 patients were enrolled. Median follow-up was 19·9 months (IQR 10·7–23·1). The combination therapy showed acceptable safety and tolerability; there were no dose-limiting toxicities in the dose-escalation phase. The most common grade 3–4 treatment-related adverse events were anaemia (four 4%) and infusion-related reactions (three 3%). Serious treatment-related adverse events were reported in nine (9%) patients. No treatment-related deaths were reported. Objective responses were observed in 17 (18·48%; 95% CI 11·15–27·93) of 92 evaluable patients.
These findings serve as proof of concept of synergistic antitumour activity with the combination of an Fc-optimised anti-HER2 agent (margetuximab) along with anti-PD-1 checkpoint blockade (pembrolizumab).
MacroGenics.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
ATTRACTION-2 demonstrated that nivolumab improved overall survival (OS) vs placebo in patients with advanced gastric cancer treated with ≥ 2 chemotherapy regimens. However, its long-term ...efficacy and outcome of treatment beyond progression (TBP) with nivolumab have not been clarified.
Methods
The 3-year follow-up data were collected. A subset analysis was performed to explore the efficacy of TBP by assessing postprogression survival (PPS) after the first event of disease progression.
Results
Overall, 493 patients were randomized (2:1) to receive nivolumab (
n
= 330) or placebo (
n
= 163). With a median follow-up of 38.5 (range 36.1–47.5) months, OS of the nivolumab group was significantly longer compared to the placebo group (median 5.3 vs 4.1 months; 3-year survival rate, 5.6% vs 1.9%; hazard ratio HR, 0.62 95% confidence interval (CI) 0.50–0.75,
P
< 0.0001). The median OS of responders (
n
= 32) who achieved complete response or partial response was 26.7 months and the 3-year survival rate was 35.5% in the nivolumab group. Overall, 109 patients in the nivolumab group and 37 patients in the placebo group received TBP. PPS tended to be longer in the nivolumab group vs placebo group (median 5.8 vs 4.5 months; HR 95% CI, 0.69 0.47–1.01,
P
= 0.057). In contrast, PPS was similar between both treatment groups in non-TBP patients (median 2.3 vs 2.2 months; HR 0.90,
P
= 0.42).
Conclusions
Long-term efficacy of nivolumab was confirmed at the 3-year follow-up, and a survival benefit of TBP with nivolumab was suggested. Biomarkers for selecting patients suitable for TBP with nivolumab should be identified in the future.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background
A subgroup analysis of data from a nationwide study (KCSG-ST19-16) was performed to evaluate the efficacy and safety of second-line ramucirumab plus paclitaxel treatment in patients with ...human epidermal growth factor receptor 2 (HER2)-positive advanced gastric or gastro-esophageal junction (GEJ) adenocarcinoma.
Methods
The KCSG-ST19-16 study enrolled a total of 1063 patients from 56 hospitals in South Korea with advanced gastric or GEJ adenocarcinoma, who had received second-line treatment with ramucirumab plus paclitaxel. HER2 status was known for 994 (93.5%) of these patients, who were thus included in the subgroup analysis.
Results
In total, 163 of 994 patients (16.4%), had HER2-positive gastric or GEJ adenocarcinoma. The objective response rate to ramucirumab plus paclitaxel treatment was significantly higher in patients with HER2-positive disease compared to those with HER2-negative disease (23.0% 95% confidence interval (CI), 15.9–30.1 vs. 15.1% 95% CI, 12.3–17.9,
p
= 0.025). The median progression-free survival was longer in patients with HER2-positive versus HER2-negative disease, but the difference was not statistically significant (4.3 months 95% CI, 3.7–5.3 vs 3.7 months 95% CI, 3.4–4.0,
p
= 0.054). There was no statistically significant difference in median overall survival (OS) between the groups (9.8 months 95% CI, 8.9–12.3 vs 10.1 months 95% CI, 9.2–10.9,
p
= 0.564).
Conclusions
In patients with HER2-positive gastric or GEJ adenocarcinoma, the objective response rate to second-line treatment with ramucirumab plus paclitaxel was significantly higher compared to patients with HER2-negative disease. However, an increased response to treatment was not associated with an improvement in OS.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background
In this post hoc analysis of the PRODIGY study, we aimed to investigate factors associated with survival outcomes and provide evidence for designing optimal perioperative treatment ...strategies for gastric cancer patients receiving neoadjuvant chemotherapy.
Patients and methods
A total of 212 patients in the neoadjuvant chemotherapy group of the PRODIGY study were included as the study population. The prognostic impact of clinicopathologic factors, including the initial radiological clinical stage (cStage) and post-neoadjuvant chemotherapy pathological stage (ypStage), was analyzed.
Results
The median age was 58 years. The majority of patients (77.4%) had cStage III disease, and about 10% and 25% had ypStage 0 and I disease, respectively. According to the initial cStage, progression-free survival (PFS) and overall survival (OS) were significantly different (
P
< 0.01). PFS and OS were also different according to the ypStage (
P
< 0.01). In multivariate analyses, cStage IIIC disease (vs. cStage II) and ypStage II and III disease (vs. ypStage 0/I) were independent factors for poor survival outcomes. Based on the patterns of PFS and OS according to both cStage and ypStage, three patient groups were defined. These groups showed distinct PFS and OS (
P
< 0.01) with 5-year PFS rates of 95.7%, 77.9%, and 31.3% and 5-year OS rates of 95.7%, 82.4%, and 42.5%, respectively.
Conclusions
Both initial cStage and ypStage were independent factors for survival outcomes of gastric cancer patients treated with neoadjuvant chemotherapy. Efforts should be made to develop optimal peri-operative treatment strategies for patients at different risks according to cStage and ypStage.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Purpose
This study attempted to reveal the prognostic impact of microsatellite instability-high (MSI-H) colon cancer with tumor-infiltrating immune cells (TIICs) and immune checkpoint protein ...expression, which are good candidates for immunotherapy.
Materials and methods
The study included 89 patients with MSI-H colon cancer who underwent curative surgery at Kyungpook National University Chilgok Hospital. The expression status of specific inhibitory receptors, such as CD274 (programmed death-ligand 1, PD-L1), PDCD1 (programmed cell death 1, PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), lymphocyte-activation gene 3 (LAG3), and indolamine 2′3′-dioxygenase 1 (IDO1), was retrospectively analyzed using immunohistochemistry (IHC).
Results
Among the 89 patients, CD274, LAG3, and IDO1 expressions in TIICs were observed in 68.6% (61 cases), 13.5% (12), and 28.1% (25) of patients, respectively. Meanwhile, CD274, CTLA4, and IDO1 were expressed in tumor cells of 24.7% (22 cases), 4.5% (4), and 72.0% (64) of patients, respectively. During the median follow-up duration of 39 months, 14 (15.7%) patients experienced disease recurrence. Among the five immune checkpoint proteins, CD274, LAG3, and IDO1 expressions in TIICs were significantly associated with a better disease-free survival (DFS) in a univariate analysis (
P
= 0.028, 0.037, and 0.030 respectively). Moreover, co-expression of CD274, LAG3, and IDO1 in TIICs showed an even better survival for DFS (
P
= 0.010). In a multivariate survival analysis, CD274, LAG3, and IDO1 expressions in TIICs remained as independent prognostic factors for a better DFS.
Conclusion
CD274, LAG3, and IDO1 expressions in TIICs showed a better prognosis for patients with MSI-H colon cancer. Thus, the potential therapeutic implications of these immune checkpoint molecules should be further investigated.
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EMUNI, FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background
Data on immune checkpoint inhibitor efficacy in patients with human epidermal growth factor receptor 2-positive (HER2+) advanced gastric/gastroesophageal junction (G/GEJ) cancer are ...lacking. Because HER2 status was not captured in the ATTRACTION-2 trial, we used patients with prior trastuzumab use (Tmab+) as surrogate for HER2 expression status to evaluate the efficacy and safety of nivolumab as third- or later-line therapy in these patients.
Methods
In ATTRACTION-2, a randomized, double-blind, placebo-controlled, phase 3 multicenter trial, patients were randomized (2:1) to receive nivolumab (3 mg/kg) or placebo every 2 weeks until disease progression or toxicity requiring study discontinuation. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and safety were assessed.
Results
Of 493 enrolled patients, 81 (nivolumab,
n
= 59; placebo,
n
= 22) were Tmab+ and 412 (nivolumab,
n
= 271; placebo,
n
= 141) were Tmab−. In both groups, patients receiving nivolumab showed a longer median OS vs placebo (Tmab+, 8.3 95% confidence interval, 5.3–12.9 vs 3.1 1.9–5.3 months, hazard ratio, 0.38 0.22–0.66;
P
= 0.0006; Tmab−, 4.8 4.1–6.0 vs 4.2 3.6–4.9 months, 0.71 0.57–0.88;
P
= 0.0022). PFS was longer in both groups receiving nivolumab vs placebo (Tmab+, 1.6 1.5–4.0 vs 1.5 1.3–2.9 months, 0.49 0.29–0.85;
P
= 0.0111; Tmab−, 1.6 1.5–2.4 vs 1.5 1.5–1.5 months, 0.64 0.51–0.80;
P
= 0.0001).
Conclusions
Nivolumab was efficacious and safe as third- or later-line therapy regardless of prior trastuzumab use in patients with advanced G/GEJ cancer.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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