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%

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.

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.

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.

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.

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.

Anti programmed death-ligand 1 antibody-related cholangitis without bile duct dilation or stenosis.

Cholangitis has been reported as an immune-related adverse event, although it rarely occurs. Here we report a case of cholangitis due to atezolizumab in a 77-year-old woman who had been treated with atezolizumab and nab-paclitaxel for breast cancer and lung metastasis. On the seventh cycle, she presented with fever and epigastric pain, and computed tomography and endoscopic ultrasound showed slight wall thickening of the common bile duct, and transpapillary bile duct biopsy was performed. Pathologically, CD8+ T cells predominant infiltration was detected in the subepithelium of the bile duct, resulting in the diagnosis of atezolizumab-related cholangitis. The patient's symptoms were resolved immediately after discontinuing atezolizumab. Hepatobiliary enzymes returned to normal 21 days after onset, and bile duct wall thickening disappeared. Cholangitis should be included as the differential diagnosis of liver dysfunction in patients receiving immune checkpoint inhibitors.

Phase II Study of S-1 and Irinotecan Plus Bevacizumab as Second-line Treatment for Patients With Metastatic Colorectal Cancer Resistant to the Fluoropyrimidine-oxaliplatin-cetuximab Regimen.

BACKGROUND/AIM: The usefulness of angiogenesis inhibitors as second-line treatment after the progression of anti-epidermal growth factor receptor antibody drug-containing regimens for RAS wild-type metastatic colorectal cancer (mCRC) has not been fully investigated. Therefore, we conducted a phase II study to verify the efficacy and safety of the combination of S-1 and irinotecan plus bevacizumab (SIRB regimen) as second-line treatment for patients with oxaliplatin and cetuximab-refractory KRAS wild-type mCRC. PATIENTS AND METHODS: Patients with mCRC who had previously received oxaliplatin and cetuximab-containing regimen were eligible for this study. Patients were infused with bevacizumab 7.5 mg/kg and irinotecan 150 mg/m2 intravenously on day 1, whereas S-1 80 mg/m2 was administered orally twice daily until day 15, followed by a 7-day drug holiday period. The primary end point was 6-month progression-free survival (PFS) rate. RESULTS: In total, 17 patients were enrolled in this study. The 6-month PFS rate was 64.7% [95% confidence interval (CI)=41.99-87.43], median PFS was 10.1 months (95%CI=4.11-17.28), and median overall survival was 21.8 months (95%CI=9.79-37.91). The response rate was 23.5% (95%CI=6.81-49.90%). Grade ≥3 adverse events were observed in 10% of patients, and included leukopenia [3 (17.6%)], neutropenia [5 (29.4%)], anorexia [2 (11.8%)], diarrhea [2 (11.8%)], and hypertension [3 (17.6%)]. No treatment-related deaths or febrile neutropenia were observed. CONCLUSION: The SIRB regimen might be a promising second-line treatment option for patients with oxaliplatin and cetuximab-refractory KRAS wild-type mCRC in terms of efficacy and safety.

Initial Safety Analysis of CapeOx for Elderly Patients With Advanced Gastric Cancer Patients: A Phase II Trial.

BACKGROUND: Safety of combination chemotherapy using platinum and fluorouracil has not been evaluated adequately for advanced gastric cancer (AGC) in elderly patients. PATIENTS AND METHODS: We initiated a phase II study to evaluate the efficacy and safety of capecitabine plus oxaliplatin (CapeOX) as first-line therapy for patients with AGC aged ≥70 years. Planned assessment of toxicity was made upon recruitment of the first 20 patients. RESULTS: In five out of 20 patients, unacceptable toxicity was observed, including three patients who were unable to complete the initial two courses due to adverse events. Among the other 15 patients, dose reduction due to toxicity were needed in 10 and treatment delay for adverse events also occurred in 12 patients during the first two courses. CONCLUSION: Early analyses of safety suggest that the CapeOX regimen was not tolerated without dose reduction for elderly patients with AGC in this study.

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 II Study of Third-Line Panitumumab Rechallenge in Patients with Metastatic Wild-Type KRAS Colorectal Cancer Who Obtained Clinical Benefit from First-Line Panitumumab-Based Chemotherapy: JACCRO CC-09.

BACKGROUND: Regorafenib and trifluridine/tipiracil are standard third-line chemotherapies for colorectal cancer patients, but their efficacy is limited. Anti-epidermal growth factor receptor antibody rechallenge has been reported to be promising for patients who have obtained clinical benefit from first-line cetuximab-based chemotherapy. Moreover, panitumumab showed non-inferior efficacy to cetuximab. OBJECTIVE: This study assessed the efficacy and safety of third-line panitumumab rechallenge in patients with metastatic KRAS exon 2 wild-type metastatic colorectal cancer who obtained clinical benefit from first-line panitumumab-based chemotherapy. PATIENTS AND METHODS: This was a prospective, multicenter, phase II trial conducted from October 2013 to August 2017. Major eligibility criteria included KRAS exon 2 wild-type and achievement of complete response, partial response, or continued stable disease for at least 6 months in first-line panitumumab-based therapy. Irinotecan plus panitumumab treatment was continued until disease progression or unacceptable toxicity was observed. The primary endpoint was the 3-month progression-free survival (PFS) rate. RESULTS: Twenty-five patients were enrolled in this study. Their median age was 66.5 years, and the 3-month PFS rate was 50.0% (95% confidence interval 30.0-70.0). The median PFS and overall survival were 3.1 months and 8.9 months, respectively. The response rate and disease control rate were 8.3% and 50.0%, respectively. Common grade 3/4 adverse events were acneiform rash (17%), hypomagnesemia (13%), and dry skin (13%). No treatment-related deaths occurred. CONCLUSION: Irinotecan plus panitumumab rechallenge is a promising third-line treatment regimen in patients with metastatic wild-type KRAS colorectal cancer. CLINICAL TRIAL IDENTIFICATION: UMIN000015916.

18F-FDG-PET/CT as an imaging biomarker for regorafenib efficacy in metastatic colorectal cancer (JACCRO CC-12).

INTRODUCTION: Regorafenib is a multikinase inhibitor approved for the treatment of metastatic colorectal cancer (mCRC). Despite providing a statistically significant survival benefit, a substantial number of patients fail to respond to or continue with treatment, which has resulted in an unmet clinical need for a biomarker of regorafenib efficacy. METHODS: The JACCRO CC-12 study was a prospective, multicenter, single-arm phase II trial designed to evaluate the usefulness of [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) as an imaging biomarker of regorafenib in patients with mCRC that progressed after standard chemotherapies. FDG-PET and contrast-enhanced computed tomography (CT) were performed before and after treatment with regorafenib 160 mg once daily 3 weeks on/1 week off. The primary end point was the change in the maximum standardized uptake value in the lesion with the highest uptake at pre-treatment FDG-PET. The secondary end points included overall survival (OS), progression-free survival (PFS), the objective response rate (ORR), safety, and the correlation between FDG-PET and CT. RESULTS: Twenty patients were enrolled from November 2014 to March 2016, 17 of whom were evaluated for metabolic and morphological changes. Metabolic response with FDG-PET was partial response (PR) in one case (5.9%), stable disease (SD) in four (23.5%), and progressive disease (PD) in 12 (70.6%). The metabolic response rate was 5.9%. On CT imaging, no complete response or PR was observed, and the ORR was 0%. Median PFS and OS were 1.7 and 9.8 months, respectively. The median PFS of patients who achieved PR or SD by FDG-PET was 3.7 months, whereas that of those assessed as PD was 1 month (p = 0.13). The median OS of patients who achieved PR or SD by FDG-PET was 13.0 months, whereas that of patients assessed as PD was 10.6 months (p = 0.43). Frequent adverse events were palmar-plantar erythrodysesthesia syndrome, hypertension, loss of appetite, and fatigue. CONCLUSIONS: In this study, FDG-PET failed to demonstrate usefulness as an early imaging biomarker of regorafenib in patients with mCRC.

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.

Higher Systemic Exposure to Unbound Active Metabolites of Regorafenib Is Associated With Short Progression-Free Survival in Colorectal Cancer Patients.

Regorafenib treatment improves survival of patients with metastatic colorectal cancer, but it is also characterized by detrimental side effects that may require modified dosing or interval schedules. Regorafenib is metabolized by cytochrome P450 3A4 in the liver to its active metabolites, M-2 and M-5. We examined area under the unbound plasma concentration-time curve (AUCu) to these compounds to establish pharmacokinetic bases for individualized dosing strategies. The plasma protein binding of M-2 and M-5 was approximately 10-fold lower than that of regorafenib, whereas AUCu values for active metabolites on both days 1 and 15 were significantly higher than that of regorafenib. Patients with higher AUCu values of M-2 or M-5 on day 1 showed significantly shorter progression-free survival than others, likely due, at least in part, to treatment discontinuation as a result of adverse events, especially occurred during first cycle.

RAS Mutations in Circulating Tumor DNA and Clinical Outcomes of Rechallenge Treatment With Anti-EGFR Antibodies in Patients With Metastatic Colorectal Cancer.

PURPOSE: Several trials have evaluated the efficacy of rechallenge treatment with anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) in patients with metastatic colorectal cancer (mCRC). A recent trial indicated that RAS status in circulating tumor DNA (ctDNA) may potentially predict patients with RAS wild-type mCRC resistant to anti-EGFR mAb who would benefit from rechallenge treatment, and the findings should be further investigated. MATERIAL AND METHODS: We enrolled patients whose plasma samples were collected in prospective phase II trials, the JACCRO CC-08 (n = 36) and CC-09 (n = 25), which evaluated rechallenge chemotherapy with anti-EGFR mAb for KRAS wild-type mCRC. RAS in ctDNA was analyzed at the time points of baseline, 8 weeks, and progression using OncoBEAM RAS CRC kit. RESULTS: Sixteen patients were enrolled in this study, with a response rate of 0% and a disease control rate (DCR) of 62.5%. RAS mutations were found at baseline in six patients. The DCR was 33% in patients with RAS mutations in ctDNA, whereas it was 80% in patients without RAS mutation at baseline. Patients with RAS mutation at baseline had significantly shorter progression-free survival (PFS) and overall survival (OS) than those without RAS mutation (median PFS, 2.3 v 4.7 months; hazard ratio [HR], 6.2; P = .013; median OS, 3.8 v 16.0 months; HR, 12.4; P = .0028). Six of 10 patients without RAS mutation at baseline acquired RAS mutations at progression. Postprogression survival after rechallenge treatment was numerically shorter in patients with RAS mutation at progression. CONCLUSION: RAS status in ctDNA was significantly associated with clinical outcomes in patients with mCRC receiving rechallenge treatment with anti-EGFR mAb. These findings could support the clinical utility of OncoBEAM RAS CRC kits for anti-EGFR mAb rechallenge in RAS wild-type mCRC.

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.

Addition of Docetaxel to Oral Fluoropyrimidine Improves Efficacy in Patients With Stage III Gastric Cancer: Interim Analysis of JACCRO GC-07, a Randomized Controlled Trial.

PURPOSE: S-1 is a standard postoperative adjuvant chemotherapy for patients with stage II or III gastric cancer in Asia. Neoadjuvant or perioperative strategies dominate in Western countries, and docetaxel has recently shown significant survival benefits when combined with other standard regimens in advanced cancer and perioperative settings. PATIENTS AND METHODS: This randomized phase III study was designed to prove the superiority of postoperative S-1 plus docetaxel over S-1 alone for R0 resection of pathologic stage III gastric cancer. The sample size of 1,100 patients was necessary to detect a 7% increase in 3-year relapse-free survival as the primary end point (hazard ratio, 0.78; 2-sided α = .05; ß = .2). RESULTS: The second interim analysis was conducted when the number of events reached 216 among 915 enrolled patients (median follow-up, 12.5 months). Analysis demonstrated the superiority of S-1 plus docetaxel (66%) to S-1 (50%) for 3-year relapse-free survival (hazard ratio, 0.632; 99.99% CI, 0.400 to 0.998; stratified log-rank test, P < .001), and enrollment was terminated as recommended by the independent data and safety monitoring committee. Incidences of grade 3 or greater adverse events, particularly neutropenia and leukopenia, were higher in the S-1 plus docetaxel group, but all events were manageable. CONCLUSION: Addition of docetaxel to S-1 is effective with few safety concerns in patients with stage III gastric cancer. The present findings may also be applicable in countries in which perioperative adjuvant chemotherapy or chemoradiation is not standard.

Tumor Sidedness and Enriched Gene Groups for Efficacy of First-line Cetuximab Treatment in Metastatic Colorectal Cancer.

Molecular differences in tumor locations may contribute to the sidedness-specific response to cetuximab in metastatic colorectal cancer (mCRC). We investigated genes associated with the response to cetuximab treatment depending on tumor sidedness. Our study included 77 patients with mCRC (13/63, right/left) with KRAS exon 2 wild-type tumors from phase II trials of first-line therapy with cetuximab. Expression levels of 2,551 genes were measured in tissue samples by HTG EdgeSeq Oncology Biomarker Panel. Univariate Cox regression analysis using log2 values of counts per million (CPM) was conducted in each sidedness to assess associations with clinical outcomes, and to define the optimal cut-off point for clinically significant genes. In addition, a gene set enrichment analysis (GSEA) was performed to identify significant gene pathways in each sidedness. Sixty-nine patients were assessable for gene expression data. Overexpression of BECN1 [log2(CPM) ≥ 6.8] was associated with favorable survival, regardless of tumor sidedness. High expression of NOTCH1 [log2(CPM) ≥ 7.5] predicted significantly longer progression-free survival (PFS; median 14.7 vs. 11.1 months, HR 0.43, P = 0.01) and overall survival (OS; median 42.8 vs. 26.5 months, HR 0.35, P = 0.01) in left side but not in right side. The GSEA showed that regulation of DNA replication gene set correlated with favorable survival in the left, whereas the subcellular component and leukocyte migration gene sets were associated with good survival in the right. In conclusion, genes contributing to the efficacy of cetuximab treatment may differ according to the sidedness in mCRC. NOTCH1 may potentially discriminate favorable responders to cetuximab in patients with left-sided tumors.