Sequential Lateral Lymphatic Metastasis Shows Similar Oncologic Outcomes to Upward Spread in Advanced Rectal Cancer After Preoperative Chemoradiotherapy.

BACKGROUND: Whether lateral pelvic node metastasis should be considered as a regional or systemic disease is a long-standing debate. Although previous Japanese studies have considered it to be locoregional disease, Western countries consider it a systemic disease and do not perform lateral pelvic node dissection after preoperative chemoradiotherapy. OBJECTIVE: To evaluate whether lateral pelvic node metastasis is a systemic or regional disease that is amenable to curative resection. DESIGN: Retrospective analysis of a prospectively collected database. SETTING: This study was conducted at a tertiary cancer center. PATIENTS: There were 616 consecutive patients who underwent curative total mesorectal excision alone or with lateral pelvic node dissection after preoperative chemoradiotherapy for locally advanced rectal cancer between 2011 and 2019. MAIN OUTCOME MEASURES: Three-year disease-free and overall survival. RESULTS: A total of 360 patients underwent total mesorectal excision, and 160 patients underwent total mesorectal excision with lateral pelvic node dissection. There was no difference in the 3-year disease-free survival (DFS; p = 0.844) or overall survival rates ( p = 0.921) between the groups. Patients with lateral pelvic node metastasis showed DFS similar to those with perirectal lymph node metastasis in the total mesorectal excision group. In a subgroup analysis, patients with internal iliac pelvic node metastasis showed a disease-free survival comparable to those with perirectal node involvement, and patients with other lateral pelvic node metastasis showed a DFS similar to those with intermediate node involvement. In the lateral pelvic node dissection group, the lateral pelvic node metastatic rate was 32.5%. On multivariate analysis, fewer than 8 of the unilateral harvested lateral pelvic nodes and advanced ypT stage were significantly associated with poor disease-free survival. LIMITATION: The retrospective design. CONCLUSIONS: Lateral lymphatic metastasis showed oncologic outcomes similar to those of upward spread, especially perirectal lymph nodes metastasis. Large cohort studies with long-term follow-up are required to confirm these results. See Video Abstract . LAS METSTASIS LINFTICAS SECUENCIALES LATERALES MUESTRAN RESULTADOS ONCOLGICOS SIMILARES EN LA PROPAGACIN ASCENDENTE DEL CNCER RECTAL AVANZADO DESPUS DE LA RADIOQUIMIOTERAPIA PREOPERATORIA: ANTECEDENTES:Es un debate muy antiguo si las metástasis en los ganglios pélvicos laterales deben considerarse una enfermedad regional o sistémica. Si bien estudios japoneses anteriores las consideran como una enfermedad locorregional, en los países de occidente se las considera como una enfermedad sistémica por la cual no se realiza disección de ganglios pélvicos laterales después de una radioquimioterapia preoperatoria.OBJETIVOS:Evaluar si la metástasis en los ganglios pélvicos laterales se consideran como enfermedad sistémica o enfermedad regional susceptible de resección curativa.DISEÑO:Análisis retrospectivo de una base de datos recopilada prospectivamente.AJUSTE:Este estudio se realizó en un centro oncológico terciario.PACIENTES:616 pacientes consecutivos se sometieron a excisión total del mesorrecto curativa sola o con disección de los ganglios pélvicos laterales después de radioquimioterapia preoperatoria en casos de cáncer de recto localmente avanzado entre 2011 y 2019.PRINCIPALES MEDIDAS DE RESULTADO:Sobrevida global y libre de enfermedad a 3 años.RESULTADOS:Un total de 360 pacientes se sometieron a excisión total del mesorrecto y 160 pacientes se sometieron a excisión total del mesorrecto con disección de ganglios pélvicos laterales.No hubo diferencias en la sobrevida libre de enfermedad a 3 años (p = 0,844) ni en las tasas de sobrevida general (p = 0,921) entre los grupos. Los pacientes con metástasis en los ganglios pélvicos laterales mostraron una sobrevida libre de enfermedad similar a aquellos con metástasis en los ganglios linfáticos perirrectales que se encontraban en el grupo de excisión total del mesorrecto.En el análisis de subgrupos, los pacientes con metástasis en los ganglios pélvicos ilíacos internos mostraron una sobrevida libre de enfermedad comparable a aquellos con afección de los ganglios perirrectales y los pacientes con otras metástasis en los ganglios pélvicos laterales mostraron una sobrevida libre de enfermedad similar a aquellos con afección de los ganglios intermedios.En el grupo de disección de los ganglios pélvicos laterales, la tasa de metástasis en dichos ganglios fué del 32,5%. En el análisis multivariado, < de 8 ganglios pélvicos laterales resecados unilateralmente y el estadio ypT avanzado se asociaron significativamente con una menor sobrevida libre de enfermedad.LIMITACIÓN:El diseño retrospectivo del estudio.CONCLUSIONES:Las metástasis linfáticas laterales mostraron resultados oncológicos similares a la diseminación ascendente, especialmente las metástasis en los ganglios linfáticos perirrectales. Se requieren grandes estudios de cohortes con seguimiento a largo plazo para confirmar estos resultados. (Traducción-Dr. Xavier Delgadillo ).

Rivoceranib, a VEGFR-2 inhibitor, monotherapy in previously treated patients with advanced or metastatic gastric or gastroesophageal junction cancer (ANGEL study): an international, randomized, placebo-controlled, phase 3 trial.

BACKGROUND: Rivoceranib is an oral, selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2. ANGEL (NCT03042611) was a global, randomized, double-blinded, placebo-controlled, phase 3 study evaluating rivoceranib as 3rd-line or ≥4th-line therapy in patients with advanced/metastatic gastric or gastroesophageal junction (GEJ) cancer. METHODS: Patients had failed ≥2 lines of chemotherapy and were randomized 2:1 to rivoceranib 700 mg once daily or placebo with best supportive care. PRIMARY ENDPOINT: overall survival (OS) in the intention-to-treat population. Secondary endpoints: progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) by blinded independent central review (BICR). RESULTS: In total, 460 patients (rivoceranib n = 308, placebo n = 152) were enrolled. OS was not statistically different for rivoceranib versus placebo (median 5.78 vs. 5.13 months; hazard ratio [HR] 0.93, 95% CI 0.74-1.15; p = 0.4724). PFS by BICR (median 2.83 vs. 1.77 months; HR 0.58, 95% CI 0.47-0.71; p < 0.0001), ORR (6.5% vs. 1.3%; p = 0.0119), and DCR (40.3 vs. 13.2%; p < 0.0001) were improved with rivoceranib versus placebo. In patients receiving ≥4th-line therapy, OS (median 6.34 vs. 4.73 months; p = 0.0192) and PFS by BICR (median 3.52 vs. 1.71 months; p < 0.0001) were improved with rivoceranib versus placebo. The most common grade ≥ 3 treatment-emergent adverse events with rivoceranib were hypertension (17.9%), anemia (10.4%), aspartate aminotransferase increased (9.4%), asthenia (8.5%), and proteinuria (7.5%). CONCLUSIONS: This study did not meet its primary OS endpoint. Compared to placebo, rivoceranib improved PFS, ORR, and DCR. Rivoceranib also improved OS in a prespecified patient subgroup receiving ≥4th-line therapy.

Bemarituzumab plus mFOLFOX6 as first-line treatment in East Asian patients with FGFR2b-overexpressing locally advanced or metastatic gastric/gastroesophageal junction cancer: subgroup of FIGHT final analysis.

BACKGROUND: In the FIGHT study (NCT03694522) bemarituzumab, a humanized monoclonal antibody selective for fibroblast growth factor receptor 2b (FGFR2b), plus mFOLFOX6 showed clinically meaningful efficacy in patients with FGFR2b-positive (2+/3+ membranous staining by immunohistochemistry) locally advanced unresectable/metastatic gastric/gastroesophageal cancer (G/GEJC). A meaningful proportion of patients in FIGHT were enrolled in East Asia, reflecting global epidemiology of G/GEJC. METHODS: This subgroup analysis of the global, phase 2, double-blind FIGHT study included all patients enrolled in East Asian sites. Patients were randomized 1:1 to bemarituzumab-mFOLFOX6 (15 mg/kg and one 7.5 mg/kg dose on cycle 1, day 8) or matching placebo-mFOLFOX6. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate, and safety. Efficacy was evaluated after a minimum follow-up of 24 months. RESULTS: The East Asian subgroup comprised 89 patients (57% of overall study population); 45 were randomized to bemarituzumab-mFOLFOX6 and 44 to placebo-mFOLFOX6. Median PFS (95% confidence interval [CI]) was 12.9 months (8.8-17.9) with bemarituzumab-mFOLFOX6 and 8.2 months (5.6-10.3) with placebo-mFOLFOX6 (HR 0.50, 95% CI 0.29-0.87); median OS (95% CI) was 24.7 months (13.8-33.1) vs 12.9 months (9.3-21.4), respectively (HR 0.56, 95% CI 0.32-0.96). Treatment benefit was more pronounced in patients with FGFR2b-positive G/GEJC in ≥ 10% of tumor cells. No new safety signals were reported. CONCLUSION: In East Asian patients with FGFR2b-positive advanced/metastatic G/GEJC enrolled in the global FIGHT study, bemarituzumab-mFOLFOX6 showed clinically meaningful outcomes over placebo-mFOLFOX6.

Preoperative sequential short-course radiation therapy and FOLFOX chemotherapy versus long-course chemoradiotherapy for locally advanced rectal cancer: a multicenter, randomized controlled trial (SOLAR trial).

BACKGROUND: Preoperative (chemo)radiotherapy has been widely used as an effective treatment for locally advanced rectal cancer (LARC), leading to a significant reduction in pelvic recurrence rates. Because early administration of intensive chemotherapy for LARC has more advantages than adjuvant chemotherapy, total neoadjuvant therapy (TNT) has been introduced and evaluated to determine whether it can improve tumor response or treatment outcomes. This study aims to investigate whether short-course radiotherapy (SCRT) followed by intensive chemotherapy improves oncologic outcomes compared with traditional preoperative long-course chemoradiotherapy (CRT). METHODS: A multicenter randomized phase II trial involving 364 patients with LARC (cT3-4, cN+, or presence of extramural vascular invasion) will be conducted. Patients will be randomly assigned to the experimental or control arm at a ratio of 1:1. Participants in the experimental arm will receive SCRT (25 Gy in 5 fractions, daily) followed by four cycles of FOLFOX (oxaliplatin, 5-fluorouracil, and folinic acid) as a neoadjuvant treatment, and those in the control arm will receive conventional radiotherapy (45-50.4 Gy in 25-28 fractions, 5 times a week) concurrently with capecitabine or 5-fluorouracil. As a mandatory surgical procedure, total mesorectal excision will be performed 2-5 weeks from the last cycle of chemotherapy in the experimental arm and 6-8 weeks after the last day of radiotherapy in the control arm. The primary endpoint is 3-year disease-free survival, and the secondary endpoints are tumor response, overall survival, toxicities, quality of life, and cost-effectiveness. DISCUSSION: This is the first Korean randomized controlled study comparing SCRT-based TNT with traditional preoperative LC-CRT for LARC. The involvement of experienced colorectal surgeons ensures high-quality surgical resection. SCRT followed by FOLFOX chemotherapy is expected to improve disease-free survival compared with CRT, with potential advantages in tumor response, quality of life, and cost-effectiveness. TRIAL REGISTRATION: This trial is registered at Clinical Research Information under the identifier Service KCT0004874 on April 02, 2020, and at Clinicaltrial.gov under the identifier NCT05673772 on January 06, 2023.

Oncological impact of intraperitoneal chemotherapy after cytoreductive surgery for patients with colorectal peritoneal metastasis: A bi-institutional retrospective analysis.

BACKGROUND AND OBJECTIVES: There is a paucity of evidence on the value of intraperitoneal chemotherapy (IPC) following cytoreductive surgery (CRS) for colorectal peritoneal metastasis. This study aimed to evaluate the association between mitomycin C-IPC and survival outcomes following CRS. METHODS: The institutional databases of two tertiary hospitals were reviewed to identify patients who underwent CRS for colorectal peritoneal metastasis. The outcomes of patients who underwent CRS without IPC were compared with those of patients who underwent CRS plus early postoperative intraperitoneal chemotherapy (EPIC) or CRS plus hyperthermic intraperitoneal chemotherapy (HIPEC). The primary endpoints were cancer-specific survival (CSS), progression-free survival (PFS), and peritoneal PFS (P-PFS). RESULTS: In 149 patients with peritoneal metastasis alone, EPIC and HIPEC use was significantly associated with better CSS, PFS, and P-PFS in the multivariate analysis. CSS was also significantly associated with perioperative systemic chemotherapy. Among 42 patients with both peritoneal and extraperitoneal metastases, CSS was independently related to the completeness of cytoreduction score, location of extraperitoneal metastasis, and grade 3-4 complications. CONCLUSIONS: Mitomycin C-IPC after CRS was associated with better survival outcomes than CRS alone in patients with resectable peritoneal metastasis of colorectal cancer. This study found that IPC had beneficial effects regarding P-PFS in patients with both peritoneal and extraperitoneal metastases.

Circulating Tumor DNA as a Predictive Biomarker for Clinical Outcomes With Margetuximab and Pembrolizumab in Pretreated HER2-Positive Gastric/ Gastroesophageal Adenocarcinoma.

PURPOSE: To assess the ability of circulating tumor DNA (ctDNA)-based testing to identify patients with HER2 (encoded by ERBB2)-positive gastric/gastroesophageal adenocarcinoma (GEA) who progressed on or after trastuzumab-containing treatments were treated with combination therapy of anti-HER2 and anti-PD-1 agents. METHODS: ctDNA analysis was performed retrospectively using plasma samples collected at study entry from 86 patients participating in the phase 1/2 CP-MGAH22-05 study (NCT02689284). RESULTS: Objective response rate (ORR) was significantly higher in evaluable ERBB2 amplification-positive vs - negative patients based on ctDNA analysis at study entry (37% vs 6%, respectively; P = .00094). ORR was 23% across all patients who were evaluable for response. ERBB2 amplification was detected at study entry in 57% of patients (all HER2 positive at diagnosis), and detection was higher (88%) when HER2 status was determined by immunohistochemistry fewer than 6 months before study entry. ctDNA was detected in 98% (84/86) of patients tested at study entry. Codetected ERBB2-activating mutations were not associated with response. CONCLUSIONS: Current ERBB2 status may be more effective than archival status at predicting clinical benefit from margetuximab plus pembrolizumab therapy. ctDNA testing for ERBB2 status prior to treatment will spare patients from repeat tissue biopsies, which may be reserved for reflex testing when ctDNA is not detected.

KEYSTEP-008: phase II trial of pembrolizumab-based combination in MSI-H/dMMR metastatic colorectal cancer.

Robust clinical activity has been observed with the immune checkpoint inhibitor pembrolizumab in patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC). However, given the response rate of 45% and a median progression-free survival of 16.5 months with first-line pembrolizumab demonstrated in KEYNOTE-177, there is room for improvement. Targeting a second immune receptor, such as CTLA-4, LAG-3, TIGIT, or ILT-4 may improve efficacy of PD-1 inhibition. Here we describe the design and rationale for the open-label, randomized, phase II KEYSTEP-008 trial, which will evaluate the efficacy and safety of pembrolizumab-based combination therapy compared with pembrolizumab monotherapy in chemotherapy-refractory (cohort A) or previously untreated (cohort B) MSI-H/dMMR mCRC. Clinical Trial Registration: NCT04895722 (ClinicalTrials.gov).

Ramucirumab plus paclitaxel as a second-line treatment in HER2-positive gastric cancer: subgroup analysis of a nationwide, real-world study in Korea (KCSG-ST19-16).

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.

Radiological criteria for selecting candidates for neoadjuvant chemotherapy for gastric cancer: an exploratory analysis from the PRODIGY study.

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.

Determinants of clinical outcomes of gastric cancer patients treated with neoadjuvant chemotherapy: a sub-analysis of the PRODIGY study.

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.

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.

BACKGROUND: The 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. METHODS: This 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. RESULTS: Two 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. CONCLUSIONS: A 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.

Nivolumab in previously treated advanced gastric cancer (ATTRACTION-2): 3-year update and outcome of treatment beyond progression with nivolumab.

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.

Initial experience of preoperative short-course radiotherapy followed by oxaliplatin-based consolidation chemotherapy for locally advanced rectal cancer.

PURPOSE: We analyzed the safety and feasibility of preoperative short-course radiotherapy (SCRT) followed by consolidation chemotherapy for patients with locally advanced rectal cancer (LARC). METHODS: From April 2018 to May 2019, 19 patients with LARC were treated with SCRT followed by three cycles of consolidation chemotherapy with leucovorin, fluorouracil, and oxaliplatin (FOLFOX6) before surgery. Adjuvant chemotherapy relied on oxaliplatin. Tumor response, patient compliance, and toxicities were analyzed. RESULTS: The median age was 60 years (range 44-71), and 16 of the patients were male. The median tumor height was 5 cm (range 0-9) from anal verge. All patients received a total dose of 25 Gy in five fractions. The number of cycles of FOLFOX6 before surgery was three in 17, four in one, five in one. Five patients required dose reductions in consolidation chemotherapy. The median interval between initiation of SCRT and surgery was 10.6 weeks (range 8.6-16.4). A pathologic complete response was seen in two patients (11%). Grade III toxicities to the preoperative treatment were seen in five patients (26%): diarrhea in two, a decreased white blood cell count in one, and anemia in two. Postoperative complications arising within 30 days developed in five patients (26%). During the median follow-up period of 20.4 months, there was no tumor recurrence. CONCLUSION: Preoperative SCRT followed by oxaliplatin-based consolidation chemotherapy showed acceptable toxicity and feasibility in patients with LARC. Prospective randomized trials are warranted to verify the efficacy and safety of this treatment strategy compared with conventional long-course concurrent chemoradiotherapy.

Margetuximab plus pembrolizumab in patients with previously treated, HER2-positive gastro-oesophageal adenocarcinoma (CP-MGAH22-05): a single-arm, phase 1b-2 trial.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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). FUNDING: MacroGenics.

Exploratory subgroup analysis of patients with prior trastuzumab use in the ATTRACTION-2 trial: a randomized phase III clinical trial investigating the efficacy and safety of nivolumab in patients with advanced gastric/gastroesophageal junction cancer.

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.

A phase 3 study of nivolumab in previously treated advanced gastric or gastroesophageal junction cancer (ATTRACTION-2): 2-year update data.

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.

Adenosine Induces EBV Lytic Reactivation through ADORA1 in EBV-Associated Gastric Carcinoma.

Cordyceps species are known to contain numerous bioactive compounds, including cordycepin. Extracts of Cordyceps militaris (CME) are used in diverse medicinal purposes because of their bioactive components. Cordycepin, one of the active components of CME, exhibits anti-proliferative, pro-apoptotic, and anti-inflammatory effects. Cordycepin structurally differs from adenosine in that its ribose lacks an oxygen atom at the 3' position. We previously reported that cordycepin suppresses Epstein⁻Barr virus (EBV) gene expression and lytic replication in EBV-associated gastric carcinoma (EBVaGC). However, other studies reported that cordycepin induces EBV gene expression and lytic reactivation. Thus, it was reasonable to clarify the bioactive effects of CME bioactive compounds on the EBV life cycle. We first confirmed that CME preferentially induces EBV gene expression and lytic reactivation; second, we determined that adenosine in CME induces EBV gene expression and lytic reactivation; third, we discovered that the adenosine A1 receptor (ADORA1) is required for adenosine to initiate signaling for upregulating BZLF1, which encodes for a key EBV regulator (Zta) of the EBV lytic cycle; finally, we showed that BZLF1 upregulation by adenosine leads to delayed tumor development in the EBVaGC xenograft mouse model. Taken together, these results suggest that adenosine is an EBV lytic cycle inducer that inhibits EBVaGC development.

Quercetin Synergistically Inhibit EBV-Associated Gastric Carcinoma with Ganoderma lucidum Extracts.

Mycotherapy has been shown to improve the overall response rate during cancer treatment and reduce some chemotherapy-related adverse events. Ganoderma lucidum is a traditional mushroom used for pharmaceutical purposes. G. lucidum extracts (GLE) showed potential antitumor activities against several cancers. These tumor inhibitory effects of GLE were attributed to the suppression of the proliferation and metastasis of cancer cells. Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) is defined as the monoclonal proliferation of carcinoma cells with latent EBV infection. The inhibitory effects of GLE against EBVaGC are questionable. The aim of this study was to investigate GLE as potential antitumor agents and a counterpart of quercetin (QCT) for the cotreatment in suppressing EBVaGC development. Therefore, this study conducted antitumor assays using a EBVaGC xenograft mice model and found that GLE could suppress tumor development. These inhibitory effects were significantly augmented by the low concentration of the quercetin (QCT) cotreatment in the xenograft mice. The addition of GLE in low concentrations synergistically reinforced QCT-induced apoptosis and EBV lytic reactivation. GLE contains various polysaccharides and triterpenes, such as ganoderic acid. Interestingly, the addition of ganoderic acid A (GAA) could produce similar bioactive effects like GLE in QCT-mediated antitumor activity. The GAA addition in low concentrations synergistically reinforced QCT-induced apoptosis and EBV lytic reactivation. GAA was sufficiently effective as much as GLE. Therefore, our results suggested that QCT-supplemented GLE could be a potential food adjunct for the prevention of EBVaGC development.

Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: Ono Pharmaceutical and Bristol-Myers Squibb.

Intratumoural PD-L1 expression is associated with worse survival of patients with Epstein-Barr virus-associated gastric cancer.

BACKGROUND: This study investigated the clinical relevance and prognostic impact of the overall expression of programmed cell death protein ligand-1 (PD-L1) and programmed cell death protein ligand-2 (PD-L2), in patients with Epstein-Barr virus-associated gastric cancer (EBVaGC). METHODS: After reviewing 1318 consecutive cases of surgically resected or endoscopic submucosal dissected gastric cancers, the expression status of PD-L1 and PD-L2 in 120 patients with EBVaGC identified by EBV-encoded RNA in situ hybridisation was retrospectively analysed using immunohistochemistry (IHC). For each IHC marker, positivity was separately in intraepithelial tumour cells (iTu-) and immune cells in the tumour stroma area (str-). RESULTS: Among 116 eligible patients, 57 (49.1%) and 66 patients (56.9%) were determined as iTu-PD-L1-positive and str-PD-L1-positive, respectively, whereas 23 (21.6%) and 45 patients (38.8%) were determined as iTu-PD-L2 positive and str-PD-L2 positive, respectively. Intraepithelial tumour cell PD-L1 positivity was found to be significantly associated with lymph node (LN) metastasis (P=0.012) and a poor disease-free survival (DFS) (P=0.032), yet not overall survival (P=0.482). In a multivariate analysis, iTu-PD-L1 positivity was independently associated with a poor DFS (P=0.006, hazard ratio=12.085). In contrast, str-PD-L2-positivity was related to a lower T category (P=0.003), absence of LN metastasis (P=0.032) and perineural invasion (P=0.028). Intraepithelial tumour cell and str-PD-L2 positivity showed a trend towards an improved DFS, although not significant (P=0.060 and P=0.073, respectively). CONCLUSIONS: Intraepithelial tumour cells PD-L1 expression can be used to predict a poor outcome in patients with EBVaGC and can represent a rational approach for PD-1/PD-L pathway-targeted immunotherapy.