MYC acetylated lysine residues drive oncogenic cell transformation and regulate select genetic programs for cell adhesion-independent growth and survival.

The MYC oncogenic transcription factor is acetylated by the p300 and GCN5 histone acetyltransferases. The significance of MYC acetylation and the functions of specific acetylated lysine (AcK) residues have remained unclear. Here, we show that the major p300-acetylated K148(149) and K157(158) sites in human (or mouse) MYC and the main GCN5-acetylated K323 residue are reversibly acetylated in various malignant and nonmalignant cells. Oncogenic overexpression of MYC enhances its acetylation and alters the regulation of site-specific acetylation by proteasome and deacetylase inhibitors. Acetylation of MYC at different K residues differentially affects its stability in a cell type-dependent manner. Lysine-to-arginine substitutions indicate that although none of the AcK residues is required for MYC stimulation of adherent cell proliferation, individual AcK sites have gene-specific functions controlling select MYC-regulated processes in cell adhesion, contact inhibition, apoptosis, and/or metabolism and are required for the malignant cell transformation activity of MYC. Each AcK site is required for anchorage-independent growth of MYC-overexpressing cells in vitro, and both the AcK148(149) and AcK157(158) residues are also important for the tumorigenic activity of MYC transformed cells in vivo. The MYC AcK site-specific signaling pathways identified may offer new avenues for selective therapeutic targeting of MYC oncogenic activities.

Tumor Response Predicts Survival Time of Nivolumab Monotherapy for Advanced Gastric Cancer: A Subgroup Analysis of the DELIVER Trial (JACCRO GC-08).

BACKGROUND: This prospective observational study evaluated the real-world effectiveness of nivolumab monotherapy in previously treated advanced gastric cancer (GC). A preplanned 2-year final analysis was performed to confirm survival and tumor behavior with nivolumab monotherapy. PATIENTS AND METHODS: The primary endpoint was overall survival (OS). The data regarding tumor size were prospectively collected and evaluated using the RECIST criteria. Exploratory analyses were performed for survival according to the tumor response and depth of response (DpR) in patients with measurable lesions who were receiving nivolumab monotherapy as third- or later-line therapy. RESULTS: In 487 patients, the median OS and progression-free survival (PFS) were 5.8 (95% CI 5.3-6.9) months and 1.8 (95% CI 1.7-2.0) months, respectively. The response rate (RR) was 14.5% in 282 patients with measurable lesions. In 234 patients treated with third- or later-line, the DpR was found to be associated with PFS and OS in the Spearman analysis (r = 0.55 and 0.44, respectively) as well as using a discrete variable. When the DpR was divided into 5 groups (-20%≥DpR; -20%

Addition of docetaxel to S-1 results in significantly superior 5-year survival outcomes in Stage III gastric cancer: a final report of the JACCRO GC-07 study.

PURPOSE: A phase III trial comparing S-1 and docetaxel with S-1 alone as postoperative chemotherapy for pathologically Stage III gastric cancer was conducted and clarified the superiority of the doublet in terms of 3-year relapse-free survival as the primary endpoint (67.7% versus 57.4%, hazard ratio [HR] 0.715, 95% confidence interval [CI] 0.587-0.871; p = 0.0008). This final report analyzed 5-year survival outcomes along with the incidence and pattern of late recurrences. PATIENTS AND METHODS: Patients with histologically confirmed Stage III gastric cancer who underwent gastrectomy with D2 lymphadenectomy were randomly assigned to receive adjuvant chemotherapy with either S-1 plus docetaxel or S-1 alone. The same 912 patients who were evaluated for 3-year survival outcomes in the previous report were analyzed. RESULTS: Five-year overall survival rate of the S-1 plus docetaxel group (67.91%) was significantly superior to that in the S-1 group (60.27%; HR 0.752, 95% CI 0.613-0.922; p = 0.0059). The incidence of late recurrence at > 3 years after randomization was similar in both groups (7.3% versus 7.2%). Peritoneal dissemination was the most common pattern of late recurrence. Addition of docetaxel significantly suppressed relapse through the lymphatic (6.8% [95% CI 4.52-9.17] versus 15% [95% CI 11.76-18.30]; p < 0.0001) and hematogenous (10.2% [95% CI 7.37-12.94] versus 15.7% [95% CI 12.36-19.01]; p < 0.0137) pathways throughout the 5 years of follow-up. CONCLUSION: The survival benefit of postoperative chemotherapy with S-1 and docetaxel in terms of 5-year overall survival rate was confirmed for patients with pathologically Stage III gastric cancer, although late recurrences were not prevented.

The BEETS (JACCRO CC-18) trial: an observational and translational study of BRAF-mutated metastatic colorectal cancer.

For BRAF V600E-mutated metastatic colorectal cancer (mCRC), the BEACON phase 3 trial showed survival benefit of triplet therapy with cetuximab (anti-EGFR antibody), encorafenib (BRAF inhibitor) and binimetinib (MEK inhibitor) as well as doublet therapy with cetuximab and encorafenib over irinotecan-based chemotherapy plus anti-EGFR antibody. Both regimens are standards of care in Japan, but definite biomarkers for predicting efficacy and selecting treatment remain lacking. The mechanisms underlying resistance to these regimens also warrant urgent exploration to further evolve treatment. This prospective observational/translational study evaluated real-word clinical outcomes with cetuximab and encorafenib with or without binimetinib for BRAF-mutated mCRC patients and investigated biomarkers for response and resistance by collecting blood samples before and after treatment. Clinical Trial Registration: UMIN000045530 (https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000051983).

The BEETS trial is a study that looks at how well two combinations of targeted therapies (cetuximab + encorafenib with or without binimetinib) work and how safe they are for patients with advanced colorectal cancer that has a mutation (change) in the BRAF gene. In this trial, patients participate voluntarily instead of being assigned to one of the two therapy groups. When a patient has BRAF-mutated advanced colorectal cancer, it means that the cancer cells in their body have changes in a gene called BRAF. This gene normally produces a protein called BRAF, which is involved in the growth of cells. However, when there is a mutation in this gene, it can cause the production of an overactive BRAF protein, leading to fast and excessive cell growth and division. For patients with BRAF-mutated advanced colorectal cancer, combinations of targeted therapies have been found to be effective as a second- or third-line treatment, based on the results of a phase 3 clinical trial. The main goal of the BEETS trial is to evaluate how well these treatments work and how safe they are when used in real-world clinical practice. Additionally, the study will use laboratory tests (liquid biopsy) to explore new biomarkers that can help predict how well a treatment will work and assist in selecting the most suitable treatment plans. We hope that the findings of this study will contribute to improving the overall management of this specific type of cancer.

Real-world effectiveness of nivolumab in advanced gastric cancer: the DELIVER trial (JACCRO GC-08).

BACKGROUND: There is no large real-world data regarding efficacy and safety of immunotherapy in gastric cancer (GC). Although some tumors can grow rapidly after immunotherapy, the patient proportions and survival outcomes are unclear in GC. METHODS: A multicenter, prospective observational study was performed to evaluate clinical outcomes including survival time, safety, and tumor behavior of nivolumab treatment for patients with advanced GC. Primary endpoint was overall survival (OS), and secondary endpoints included response rate (RR), disease control rate (DCR), progression-free survival (PFS), tumor growth rate (TGR) at first evaluation, and safety. RESULTS: Of 501 enrolled patients, 487 were evaluable (median age 70 years, 71% male, performance status 0/1/2 [42%/44%/14%], 21% HER2-pos, 42% patients with ascites). Median OS was 5.82 months (95% CI 5.29-7.00) with a 1-year survival rate of 30% and median PFS of 1.84 months (95% CI 1.71-1.97). The DCR was 39.4% and the RR was 14.2% (95% CI 10.3-18.8) in 282 patients with measurable lesions. In 219 patients evaluable for TGR, 20.5% were identified as hyperprogressive disease (HPD). OS from the first evaluation of patients with HPD was shorter compared with non-HPD (HR 1.77, 95% CI 1.25-2.51, P = 0.001), but it was not worse than that of patients with progression and non-HPD (HR 1.05, 95% CI 0.72-1.53, P = 0.8). A multivariate analysis revealed the presence of peritoneal metastasis was a prognostic factor for OS and PFS. CONCLUSIONS: Our real-world data demonstrated the comparable survival time to a previous clinical trial and revealed the frequency and prognosis of patients with HPD in advanced GC treated with nivolumab.

Three-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 plus docetaxel versus S-1 alone in stage III gastric cancer: JACCRO GC-07.

PURPOSE: The second planned interim analysis (median follow-up 12.5 months) in a phase III trial of postoperative adjuvant chemotherapy for stage III gastric cancer revealed significant improvement in relapse-free survival (RFS) for S-1 plus docetaxel over S-1 alone. Although enrollment was terminated on the recommendation of the independent data and safety monitoring committee, we continued follow-up and herein report on 3-year RFS, the primary endpoint. PATIENTS AND METHODS: Patients with histologically confirmed stage III gastric cancer who underwent gastrectomy with D2 lymphadenectomy were randomly assigned to receive adjuvant chemotherapy with either S-1 plus docetaxel or S-1 alone. In the S-1 plus docetaxel group, S-1 was given orally for 2 weeks followed by 1 week of rest for seven courses, and docetaxel was given intravenously on day 1 of the second to seventh courses. The combination therapy was followed by S-1 monotherapy for up to 1 year. RESULTS: The 3-year RFS rate of the S-1 plus docetaxel group was 67.7%. This was significantly superior to that of 57.4% in the S-1 group (hazard ratio [HR] 0.715, 95% CI 0.587-0.871, P = 0.0008). This translated into a significant benefit in the 3-year overall survival (OS) rate in the S-1 plus docetaxel group (77.7% versus 71.2%, HR 0.742, 95% CI 0.596-0.925, P = 0.0076). CONCLUSION: On 3-year follow-up data, postoperative adjuvant therapy with S-1 plus docetaxel was confirmed to improve both RFS and OS and can be recommended as a standard of care for patients with stage III gastric cancer treated by D2 dissection.

Phase 2 study of irinotecan plus cetuximab rechallenge as third-line treatment in KRAS wild-type metastatic colorectal cancer: JACCRO CC-08.

BACKGROUND: Regorafenib or trifluridine/tipiracil as third-line treatment have limited efficacy in metastatic colorectal cancer (mCRC). METHODS: This Phase 2 trial evaluated the efficacy and safety of irinotecan plus cetuximab rechallenge as third-line treatment in KRAS wild-type mCRC patients who achieved clinical benefit with first-line cetuximab-containing therapy. The primary endpoint was 3-month progression-free survival (PFS) rate. A sample size was calculated; 30 patients with a 3-month PFS rate of 45% deemed promising and 15% unacceptable. Patients with greater and less than the cut-off value of cetuximab-free intervals (CFIs) were classified into the long and short CFI groups, respectively, in subgroup analyses. RESULTS: Among 34 eligible patients who received treatment at least once, 3-month PFS rate was 44.1% (95% confidence interval, 27.4-60.8%). The median PFS and overall survival (OS) were 2.4 and 8.2 months, respectively. The response and disease control rates were 2.9 and 55.9%, respectively. PFS and OS were significantly longer in the long- than in the short CFI group. CONCLUSIONS: Irinotecan plus cetuximab rechallenge as third-line treatment for KRAS wild-type mCRC was safe and had promising activity, especially in those with a long CFI, warranting further investigation in a Phase 3 randomised trial. CLINICAL TRIAL REGISTRATION: UMIN000010638.

DELIVER (JACCRO GC-08) trial: discover novel host-related immune-biomarkers for nivolumab in advanced gastric cancer.

Aim: Nivolumab has survival benefit in patients with previously treated advanced gastric cancer; however, about 60% of the patients did not respond to nivolumab, raising the necessity of its predictive biomarkers. Gut microbiome has been shown to be associated with efficacy of anti-PD-1 antibody in various types of cancers, but little is known about gastric cancer. Design: This is an observational/translational study to evaluate clinical outcomes of nivolumab and to discover novel immune-related biomarkers (gut microbiome, genetic polymorphism, gene expression and metabolome in plasma) in gastric cancer, using fecal and blood samples at two points before and after treatment. Candidate factors will be explored in first 200 patients and then validated in last 300 patients. Trial registration: UMIN000030850.

Predictive value of TLR7 polymorphism for cetuximab-based chemotherapy in patients with metastatic colorectal cancer.

The TLR7 and TLR9 signalings are implicated in the regulation of the immune system through type-I interferon induction. Preclinical studies have demonstrated the immunomodulatory and antitumor effects of TLR7 and TLR9 agonists in combination with cetuximab. We tested the hypothesis that genetic variations in TLR7 and TLR9 and their downstream molecules IRF5 and IRF7 were associated with outcomes in metastatic colorectal cancer (mCRC) patients receiving cetuximab-based chemotherapy. Six single nucleotide polymorphisms (SNPs) in TLR7, TLR9, IRF5 and IRF7 were tested for the association with RR, PFS, and OS in KRAS-wild type mCRC patients. Patients treated with FOLFIRI + cetuximab or FOLFIRI + bevacizumab in the FIRE-3 trial served as a discovery set (FIRE3-Cet, n = 244) or a control set (FIRE3-Bev, n = 246), respectively. Patients treated with FOLFOX or SOX + cetuximab in the JACCRO-CC05/06 trial served as a validation set (JACCRO, n = 76). Genomic DNA isolated from tumor tissue samples was analyzed by PCR-based direct sequencing. In the discovery cohort, patients with the TLR7 rs3853839 G/G variant showed a trend toward longer PFS than those with any C variants (median 10.0 vs. 11.8 months, HR 1.39, p = 0.092). This preliminary association was confirmed in the validation cohort, and those with the G/G genotype showed a PFS benefit compared with others (univariate: 9.1 vs. 11.6 months, HR 2.04, p = 0.005, multivariate: HR 2.02, 95% CI: 1.14-3.55, p = 0.015). This association was not observed in the control cohort. Our findings suggest that TLR7 rs3853839 predicts the outcome of cetuximab-based chemotherapy in mCRC patients.

Impact of insulin-like growth factor-1 receptor and amphiregulin expression on survival in patients with stage II/III gastric cancer enrolled in the Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer.

BACKGROUND: Exploratory biomarker analysis was conducted to identify factors related to the outcomes of patients with stage II/III gastric cancer using data from the Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer, which was a randomized controlled study comparing the administration of an orally active combination of tegafur, gimeracil, and oteracil with surgery alone. METHODS: Formalin-fixed paraffin-embedded surgical specimens from 829 patients were retrospectively examined, and 63 genes were analyzed by quantitative real-time RT-PCR after TaqMan assay-based pre-amplification. Gene expression was normalized to the geometric mean of GAPDH, ACTB, and RPLP0 as reference genes, and categorized into low and high values based on the median. The impact of gene expression on survival was analyzed using 5-year survival data. The Benjamini and Hochberg procedure was used to control the false discovery rate. RESULTS: IGF1R and AREG were most strongly correlated with overall survival, which was significantly worse in high IGF1R patients than low IGF1R patients, but better in high AREG patients than low AREG patients. The hazard ratio for death in the analysis of overall survival (S-1 vs. surgery alone) was reduced in the high IGF1R group compared with the low IGF1R group and in the low AREG group compared with the high AREG group. There were no significant interaction effects. CONCLUSION: IGF1R gene expression was associated with poor outcomes after curative resection of stage II/III gastric cancer, whereas AREG gene expression was associated with good outcomes. No significant interaction effect on survival was evident between S-1 treatment and gene expression.

Postmarketing surveillance study of erlotinib plus gemcitabine for pancreatic cancer in Japan: POLARIS final analysis.

OBJECTIVE: Erlotinib plus gemcitabine is approved in Japan for the treatment of metastatic pancreatic cancer. The POLARIS surveillance study investigated safety (focusing on interstitial lung disease [ILD]) and efficacy of erlotinib plus gemcitabine in Japanese pancreatic cancer patients. METHODS: Patients receiving erlotinib plus gemcitabine for pancreatic cancer in Japan between July 2011 and August 2012 were enrolled. ILD-like events were independently confirmed by a review committee. Overall survival (OS) and progression-free survival (PFS) were assessed, and risk factors for ILD occurrence were analyzed by multivariate Cox regression analysis. RESULTS: Safety data were available for 843 patients and efficacy data for 841. Adverse drug reactions were reported in 83.5% of patients, no new safety signals were identified. ILD events were confirmed by the review committee in 52 patients (6.2%), with two fatal cases (0.2%). Median time from initial erlotinib treatment to ILD events was 70.5 days. Of the 52 patients with ILD events, 86.5% improved or fully recovered from ILD (median time 24 days). Multivariate analysis identified previous or concurrent lung disease (hazard ratio [HR], 2.2; 95% confidence interval [CI], 1.0-4.5; P = 0.0365) and ≥3 organs with metastases (HR, 4.2; 95% CI, 2.2-8.2; P < 0.0001) as potential ILD risk factors. Accumulated OS rate at 28 weeks was 68.2%, and median PFS was 92 days (95% CI, 86-101). CONCLUSIONS: Erlotinib plus gemcitabine has an acceptable safety and efficacy profile in pancreatic cancer; however, patients should be assessed for previous/concurrent lung disease and metastatic burden, before and during treatment.

The risk of adverse events of CPT- 11.

Irinotecan is a camptothecin analog used worldwide for a broad range of solid tumors, including colorectal cancer. It can cause severe adverse drug reactions, such as neutropenia or diarrhea. Recent pharmacogenetic studies on irinotecan have revealed the impact of UGT1A1 polymorphisms on severe adverse effects. The concurrence of UGT1A1*28 and UGT1A1*6, even when heterozygous, markedly alters the disposition of irinotecan, potentially increasing toxicity. For patients showing homozygosity for UGT1A1*28, *6 or compound heterozygosity for UGT1A1*6 and *28, dose reduction of irinotecan is strongly recommended. But dose reduction criteria or effect of dose reduction have not been clarified. If prediction accuracy of expression risk of adverse reaction improve, It is expected to be possible to appro- priate therapeutic indications and drug selection, dose setting.

MYC interacts with the human STAGA coactivator complex via multivalent contacts with the GCN5 and TRRAP subunits.

MYC is an oncogenic DNA-binding transcription activator of many genes and is often upregulated in human cancers. MYC has an N-terminal transcription activation domain (TAD) that is also required for cell transformation. Various MYC TAD-interacting coactivators have been identified, including the transcription/transformation-associated protein (TRRAP), a subunit of different histone acetyltransferase (HAT) complexes such as the human "SPT3-TAF9-GCN5 Acetyltransferase" (STAGA) complex involved in MYC transactivation of the TERT gene. However, it remains unclear whether TRRAP and/or other subunits are directly contacted by MYC within these macromolecular complexes. Here, we characterize the interactions of MYC TAD with the STAGA complex. By protein crosslinking we identify both TRRAP and the GCN5 acetyltransferase as MYC TAD-interacting subunits within native STAGA. We show that purified GCN5 binds to an N-terminal sub-domain of MYC TAD (residues 21-108) and that the interaction of GCN5 and STAGA with this sub-domain is dependent on two related sequence motifs: M2 within the conserved MYC homology box I (MBI), and M3 located between residues 100-106. Interestingly, specific substitutions within the M2/3 motifs that only moderately reduce the intracellular MYC-STAGA interaction and do not influence dimerization of MYC with its DNA-binding partner MAX, strongly inhibit MYC acetylation by GCN5 and reduce MYC binding and transactivation of the GCN5-dependent TERT promoter in vivo. Hence, we propose that MYC associates with STAGA through extended interactions of the TAD with both TRRAP and GCN5 and that the TAD-GCN5 interaction is important for MYC acetylation and MYC binding to certain chromatin loci.

Impact of the expression of thymidylate synthase and dihydropyrimidine dehydrogenase genes on survival in stage II/III gastric cancer.

BACKGROUND: The efficacy of 5-fluorouracil (5FU)-based therapy, which remains the cornerstone of gastrointestinal cancer treatment, depends upon the expression of enzymes involved in pyrimidine metabolism, including thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP), and orotate phosphoribosyltransferase (OPRT). We analyzed the expression of these genes in patients enrolled in the Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer (ACTS-GC) and their possible roles as biomarkers for treatment outcomes. METHODS: Formalin-fixed, paraffin-embedded specimens were available for 829 of a total of 1,059 (78.3 %) patients. TS, DPD, TP, and OPRT expression was measured by RT-PCR in manually microdissected tumor specimens and normalized to the reference gene, ß-actin. The expression level of each gene was categorized as low or high using cutoffs at the 33.3rd, 50th, or 66.7th percentiles. RESULTS: The hazard ratio (HR) for overall survival (OS) after S-1 treatment versus surgery alone was significantly lower in high (>66.7th percentile; HR = 0.370; 95 % CI 0.221-0.619) compared to low (<66.7th percentile; HR = 0.757; 95 % CI 0.563-1.018) TS expression groups (P = 0.015). Similarly, the HR for OS after S-1 therapy versus surgery alone was significantly lower in high (>33.3rd percentile; HR = 0.520, 95 % CI 0.376-0.720) compared to low (<33.3rd percentile; HR = 0.848, 95 % CI 0.563-1.276) DPD expression groups (P = 0.065). There was no interaction between TP or OPRT expression and OS. CONCLUSIONS: This large biomarker study showed that high TS and DPD gene expression in tumors was associated with enhanced benefit from postoperative adjuvant S-1 treatment in gastric cancer. There was no interaction between TP and OPRT expression and S-1 treatment.

Study protocol of the B-CAST study: a multicenter, prospective cohort study investigating the tumor biomarkers in adjuvant chemotherapy for stage III colon cancer.

BACKGROUND: Adjuvant chemotherapy for stage III colon cancer is internationally accepted as standard treatment with established efficacy. Several oral fluorouracil (5-FU) derivatives with different properties are available in Japan, but which drug is the most appropriate for each patient has not been established. Although efficacy prediction of 5-FU derivatives using expression of 5-FU activation/metabolism enzymes in tumors has been studied, it has not been clinically applied. METHODS/DESIGN: The B-CAST study is a multicenter, prospective cohort study aimed to identify the patients who benefit from adjuvant chemotherapy with each 5-FU regimen, through evaluating the relationship between tumor biomarker expression and treatment outcome. The frozen tumor specimens of patients with stage III colon cancer who receives postoperative adjuvant chemotherapy are examined. Protein expression of thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD), epidermal growth factor receptor (EGFR), and vascular endothelial growth factor (VEGF) are evaluated using enzyme-linked immunosorbent assay (ELISA). mRNA expression of TP, DPD, thymidylate synthase (TS) and orotate phosphoribosyl transferase (OPRT) are evaluated using reverse transcription polymerase chain reaction (RT-PCR). The patients' clinical data reviewed are as follow: demographic and pathological characteristics, regimen, drug doses and treatment duration of adjuvant therapy, types and severity of adverse events, disease free survival, relapse free survival and overall survival. Then, relationships among the protein/mRNA expression, clinicopathological characteristics and the treatment outcomes are analyzed for each 5-FU derivative. DISCUSSION: A total of 2,128 patients from the 217 institutions were enrolled between April 2009 and March 2012. The B-CAST study demonstrated that large-scale, multicenter translational research using frozen samples was feasible when the sample shipment and Web-based data collection were well organized. The results of the study will identify the predictors of benefit from each 5-FU derivative, and will contribute to establish the "personalized therapy" in adjuvant chemotherapy for colon cancer. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00918827, UMIN Clinical Trials Registry (UMIN-CTR) UMIN000002013.

Correlation of multiple endpoints in the first-line chemotherapy of advanced gastric cancer: Pooled analysis of individual patient data from Japanese Phase III trials.

BACKGROUND: Individual-level surrogates are important for management in patients treated for advanced gastric cancer (AGC). This study aimed to comprehensively investigate the correlation of multiple clinical endpoints in the first-line chemotherapy of AGC. METHODS: Individual patient data (IPD) were collected from four Japanese Phase III trials comparing S-1-based first-line chemotherapies (SPIRITS, START, GC0301/TOP-002, and G-SOX trials). Patients without Response Evaluation Criteria in Solid Tumors (RECIST)-based radiological assessments were excluded. Spearman's rank correlation coefficient was tested for correlation among overall survival (OS), progression-free survival (PFS), and postprogression survival (PPS). OS, PFS, and PPS were compared between responders (best response: complete response or partial response) and nonresponders (best response: stable disease or progressive disease). RESULTS: The study included a total of 1492 patients. Eighty percent of the patients (n = 1190) received subsequent chemotherapies after the failure of each trial's treatment protocol. PFS moderately correlated with OS (Spearman correlation coefficient = 0.66, p < 0.005), whereas the correlation between PPS and OS was strong (Spearman correlation coefficient = 0.87, p < 0.005). Responders had significantly longer OS (median, 17.7 vs. 9.1 months, p < 0.005), PFS (median, 6.9 vs. 2.8 months, p < 0.005), and PPS (median, 10.5 vs. 6.0 months, p < 0.005) than nonresponders. CONCLUSIONS: Our results reacknowledged the mild surrogacy of PFS and importance of postprogression treatments in patients with AGC receiving first-line chemotherapy. Consistent longer survival outcomes in better RECIST categories suggested that tumor response might be a useful individual-level surrogate.

Soluble programmed cell death ligand 1 predicts prognosis for gastric cancer patients treated with nivolumab: Blood-based biomarker analysis for the DELIVER trial.

BACKGROUND: The clinical value of soluble forms of programmed cell death-1 (sPD-1), PD ligand 1 (sPD-L1) and cytotoxic T lymphocyte-associated protein-4 (sCTLA-4) for gastric cancer (GC) patients treated with nivolumab monotherapy has remained unknown. METHODS: Blood samples collected before nivolumab treatment from 439 GC patients enrolled in the DELIVER (Japan Clinical Cancer Research Organisation GC-08) trial were analysed for sPD-1, sPD-L1 and sCTLA-4. Corresponding baseline clinical data were also retrieved. RESULTS: Higher plasma levels of sPD-1 (hazard ratio [HR] = 1.27, p = 0.020), sPD-L1 (HR = 1.86, p < 0.001) and sCTLA-4 (HR = 1.33, p = 0.008) were significantly associated with shorter overall survival (OS), whereas only higher sPD-L1 levels was significantly associated with shorter progression-free survival (HR = 1.30, p = 0.008). The sPD-L1 concentration was significantly associated with the Glasgow prognostic score (GPS) (p < 0.001), but both sPD-L1 (HR = 1.67, p < 0.001) and GPS (HR = 1.39, p = 0.009 for GPS 0 versus 1; HR = 1.95, p < 0.001 for GPS 0 versus 2) were independently associated with OS. Patients with a GPS of 0 and low sPD-L1 thus showed the longest OS (median, 12.0 months) and those with a GPS of 2 and high sPD-L1 showed the shortest OS (median, 3.1 months), yielding a HR of 3.69 (p < 0.001). CONCLUSION: Baseline sPD-L1 levels have the potential to predict survival for advanced GC patients treated with nivolumab, with the prognostic accuracy of sPD-L1 being improved by its combination with GPS.

A Multicenter, Phase II Trial of Schedule Modification for Nab-Paclitaxel in Combination with Ramucirumab for Patients with Previously Treated Advanced Gastric or Gastroesophageal Junction Cancer: The B-RAX Trial (JACCRO GC-09).

BACKGROUND: This study investigated whether schedule modification of bi-weekly nanoparticle albumin-bound paclitaxel (nab-PTX) plus ramucirumab (RAM) is efficacious against gastric cancer (GC) or gastroesophageal junction cancer (GJC). PATIENTS AND METHODS: Patients with unresectable GC or GJC who were previously treated with fluoropyrimidine-containing regimens received nab-PTX (100 mg/m2) on days 1, 8, and 15 and RAM (8 mg/kg) on days 1 and 15 of a 28-day cycle. Based on the incidence of severe adverse events (AEs) during the first cycle, patients were modified to bi-weekly therapy from the second cycle. The primary endpoint was progression-free survival (PFS) in the bi-weekly therapy population. Based on the hypothesis that bi-weekly nab-PTX plus RAM would improve PFS from 4.5 to 7.0 months, 40 patients were required for power of 0.8 with a one-sided α of 0.05. RESULTS: Of the 81 patients enrolled, 47 patients (58%) were assigned to bi-weekly therapy. Patient characteristics were Eastern Cooperative Oncology Group performance status of 1 (19%) and diffuse type (45%). Median PFS was 4.7 months (95% confidence interval [CI] 3.7-5.6 months) and overall response rate was 25% (95% CI 11-39%). Severe AEs of grade 3 or worse were mainly neutropenia (83%) and hypertension (23%). EQ-5D scores were maintained during the treatment. In patients who continued standard-schedule therapy, median PFS was 2.7 months (95% CI 1.8-4.0 months). CONCLUSIONS: The primary endpoint for PFS was statistically not met, but modification of nab-PTX plus RAM to a bi-weekly schedule might be a feasible treatment option as second-line treatment for advanced GC/GJC patients, especially elderly patients, with severe AEs during the first cycle.

A phase I study of infusional 5-fluorouracil, leucovorin, oxaliplatin and irinotecan in Japanese patients with advanced colorectal cancer who harbor UGT1A1*1/*1,*1/*6 or *1/*28.

OBJECTIVE: To evaluate the safety and efficacy of combination chemotherapy with 5-fluorouracil (5-FU), leucovorin, irinotecan and oxaliplatin (FOLFOXIRI) in Japanese patients with advanced colorectal cancer. METHODS: This phase I dose-finding study was designed to determine the maximum tolerated dose (MTD), recommended dose (RD) or both of FOLFOXIRI. Patients with UDP-glucuronosyltransferase (UGT) 1A1*6/*6, *28/*28 and *6/*28 genotypes were excluded, because these UGT1A1 genotypes are linked to severe neutropenia in Japanese. RESULTS: A total of 10 Japanese patients with advanced colorectal cancer were studied. The MTD of FOLFOXIRI in these Japanese patients was 165 mg/m(2) irinotecan, 85 mg/m(2) oxaliplatin and 2,400 mg/m(2) 5-FU. Accordingly, the RD of FOLFOXIRI was determined to be 150 mg/m(2) irinotecan, 85 mg/m(2) oxaliplatin and 2,400 mg/m(2) 5-FU. Toxic effects, evaluated until the completion of 4 cycles, were manageable. Grade 3-4 neutropenia occurred in 27% of cycles, but there was no febrile neutropenia. Among the 9 assessable patients, the objective response rate was 89%. CONCLUSIONS: We thus determined the RD of FOLFOXIRI in Japanese patients with advanced colorectal cancer who do not have UGT1A1*28/*28, *6/*6 or *6/*28 genotypes. Our results indicate that FOLFOXIRI is a well-tolerated regimen for these Japanese patients.