Exploratory Biomarker Analysis Using Plasma Angiogenesis-Related Factors and Cell-Free DNA in the TRUSTY Study: A Randomized, Phase II/III Study of Trifluridine/Tipiracil Plus Bevacizumab as Second-Line Treatment for Metastatic Colorectal Cancer.

BACKGROUND: The TRUSTY study evaluated the efficacy of second-line trifluridine/tipiracil (FTD/TPI) plus bevacizumab in metastatic colorectal cancer (mCRC). OBJECTIVE: This exploratory biomarker analysis of TRUSTY investigated the relationship between baseline plasma concentrations of angiogenesis-related factors and cell-free DNA (cfDNA), and the efficacy of FTD/TPI plus bevacizumab in patients with mCRC. PATIENTS AND METHODS: The disease control rate (DCR) and progression-free survival (PFS) were compared between baseline plasma samples of patients with high and low plasma concentrations (based on the median value) of angiogenesis-related factors. Correlations between cfDNA concentrations and PFS were assessed. RESULTS: Baseline characteristics (n = 65) were as follows: male/female, 35/30; median age, 64 (range 25-84) years; and RAS status wild-type/mutant, 29/36. Patients in the hepatocyte growth factor (HGF)-low and interleukin (IL)-8-low groups had a significantly higher DCR (risk ratio [95% confidence intervals {CIs}]) than patients in the HGF-high (1.83 [1.12-2.98]) and IL-8-high (1.70 [1.02-2.82]) groups. PFS (hazard ratio {HR} [95% CI]) was significantly longer in patients in the HGF-low (0.33 [0.14-0.79]), IL-8-low (0.31 [0.14-0.70]), IL-6-low (0.19 [0.07-0.50]), osteopontin-low (0.39 [0.17-0.88]), thrombospondin-2-low (0.42 [0.18-0.98]), and tissue inhibitor of metalloproteinase-1-low (0.26 [0.10-0.67]) groups versus those having corresponding high plasma concentrations of these angiogenesis-related factors. No correlation was observed between cfDNA concentration and PFS. CONCLUSION: Low baseline plasma concentrations of HGF and IL-8 may predict better DCR and PFS in patients with mCRC receiving FTD/TPI plus bevacizumab, however further studies are warranted. CLINICAL TRIAL REGISTRATION NUMBER: jRCTs031180122.

A phase III randomized controlled trial comparing local field with additional prophylactic irradiation in chemoradiotherapy for clinical-T1bN0M0 esophageal cancer: ARMADILLO trial (JCOG1904).

Chemoradiotherapy has been considered as one of the standard treatment options for clinical T1bN0M0 esophageal squamous cell carcinoma with organ preservation. However, 20% of patients develop locoregional recurrence after chemoradiotherapy, which requires salvage treatment including salvage surgery and endoscopic resection. Salvage surgery can cause complications and treatment-related death. Interestingly, chemoradiotherapy with elective nodal irradiation has been reported to reduce the locoregional recurrence of advanced esophageal squamous cell carcinoma. Hence, we are conducting a clinical trial to confirm whether modified chemoradiotherapy with elective nodal irradiation was superiority to that without elective nodal irradiation for the patients with cT1bN0M0 esophageal squamous cell carcinoma. The primary endpoint is major progression-free survival, defined as the time from randomization to the date of death or disease progression, excluding successful curative resection through salvage endoscopic resection. We plan to enroll 280 patients from 54 institutions over 4 years. This trial has been registered in the Japan Registry of Clinical Trials (jRCTs031200067).

Sidedness-Dependent Prognostic Impact of Gene Alterations in Metastatic Colorectal Cancer in the Nationwide Cancer Genome Screening Project in Japan (SCRUM-Japan GI-SCREEN).

The treatment strategies and prognoses of patients with metastatic colorectal cancer (CRC) differ according to the sidedness of the primary tumor. TP53 gain-of-function (GOF) and non-GOF variants have been reported to be differentially associated with prognosis by sidedness. We aimed to evaluate the sidedness-dependent prognostic impact of gene alterations in metastatic CRC. Patients enrolled between April 2017 and March 2019 were included in this study. Those excluded were individuals whose tumor tissues were obtained after chemotherapy and those who were enrolled in the study more than six months after starting first-line chemotherapy. Finally, we assessed 531 patients who underwent complete gene sequencing. The study revealed a significant difference in overall survival between individuals with left-sided CRC (n = 355) and right-sided colon cancer (CC) (n = 176) when considering the TP53 non-GOF variant, KRAS wild-type, NOTCH1 wild-type, NOTCH1 covariant, NOTCH3 sole variant, and MYC amplification. Multivariate analysis on each side revealed that the TP53 GOF and KRAS variants were independent poor prognostic factors for left-sided CRC (p = 0.03 and p < 0.01, respectively), and the TP53 non-GOF variant, BRAF V600E, and MYC amplification for right-sided CC (p < 0.05, p < 0.01, and p = 0.02, respectively). The NOTCH3 sole variant was an independent and favorable prognostic factor for left-sided CRC (p < 0.01). The prognostic significance of gene alterations differed between left-sided CRC and right-sided CC.

Renal impairment as a risk factor for trifluridine/tipiracil-induced adverse events in metastatic colorectal cancer patients from the REGOTAS study.

Renal impairment may be associated with an increased risk of hematologic events (AEs) in patients undergoing treatment with trifluridine/tipiracil (FTD/TPI). This study aimed to investigate the specific types of AEs linked to renal impairment in patients with metastatic colorectal cancer (mCRC) receiving FTD/TPI, using real-world data. Among the patients included in the REGOTAS study (a retrospective study of FTD/TPI versus regorafenib), those treated with FTD/TPI were evaluated. Creatinine clearance values of < 30, 30-60, 60-90, and > 90 mL/min were defined as severe, moderate, mild renal impairment, and normal renal function, respectively. Renal impairment was analyzed as a risk factor for grade 3 or higher AEs using a logistic regression model. Overall survival (OS) and progression-free survival (PFS) based on renal impairment were evaluated. A total of 309 patients were included in the analysis, with 124, 130, and 55 patients divided into the normal, mild, and moderate-to-severe groups, respectively. The risk of grade 3 or higher neutropenia was significantly higher in the moderate-to-severe group (odds ratio 3.47; 95% confidence interval 1.45-8.30; P = 0.005), but there was no significant increase in the risk of non-hematologic AEs in any of the groups. The OS and PFS of patients in the mild and moderate-to-severe groups were comparable to those in the normal group. Patients with mCRC and moderate/severe renal impairment receiving FTD/TPI therapy may develop severe neutropenia; however, FTD/TPI remains a viable treatment option due to its clinical benefit.

A Phase II Trial of Trifluridine/Tipiracil in Combination with Cetuximab Rechallenge in Patients with RAS Wild-Type mCRC Refractory to Prior Anti-EGFR Antibodies: WJOG8916G Trial.

BACKGROUND: Trifluridine/tipiracil (FTD/TPI) improved the overall survival in patients with metastatic colorectal cancer (mCRC) who had previously received standard chemotherapies; however, the clinical outcomes remain poor. OBJECTIVE: A multicenter phase II study aimed to assess the efficacy and safety of FTD/TPI plus cetuximab rechallenge. PATIENTS AND METHODS: Patients with histologically confirmed RAS wild-type mCRC refractory to prior anti-epidermal growth factor receptor (anti-EGFR) antibody were enrolled and treated with FTD/TPI (35 mg/m2 twice daily on days 1-5 and 8-12) plus cetuximab (initially 400 mg/m2, followed by weekly 250 mg/m2) every 4 weeks. The primary endpoint was disease control rate (DCR), expecting a target DCR of 65% and null hypothesis of 45% with 90% power and 10% one-sided alpha error. Gene alterations of RAS, BRAF, EGFR, PIK3CA, ERBB2, and MET in pre-treatment circulating tumor DNA were evaluated using the Guardant360 assay. RESULTS: A total of 56 patients (median age 60 years; left-sided tumors 91%; objective partial or complete response during the prior anti-EGFR therapy 61%) were enrolled. The DCR was 54% (80% confidence interval [CI] 44-63; P = 0.12), with a partial response rate of 3.6%. Median progression-free survival (PFS) was 2.4 months (95% CI 2.1-3.7). In the circulating tumor DNA analysis, patients without any alterations of the six genes (n = 20) demonstrated higher DCR (75% vs. 39%; P = 0.02) and longer PFS (median 4.7 vs. 2.1 months; P < 0.01) than those with any gene alterations (n = 33). The most common grade 3/4 hematologic adverse event was neutropenia (55%). No treatment-related deaths occurred. CONCLUSIONS: FTD/TPI plus cetuximab rechallenge did not demonstrate clinically meaningful efficacy in all mCRC patients, but might be beneficial for the molecularly selected population.

Trifluridine/tipiracil+bevacizumab (BEV) vs. fluoropyrimidine-irinotecan+BEV as second-line therapy for metastatic colorectal cancer: a randomised noninferiority trial.

BACKGROUND: This open-label, multicentre, phase II/III trial assessed the noninferiority of trifluridine/tipiracil (FTD/TPI) plus bevacizumab vs. fluoropyrimidine and irinotecan plus bevacizumab (control) as second-line treatment for metastatic colorectal cancer (mCRC). METHODS: Patients were randomised (1:1) to receive FTD/TPI (35 mg/m2 twice daily, days 1-5 and days 8-12, 28-day cycle) plus bevacizumab (5 mg/kg, days 1 and 15) or control. The primary endpoint was overall survival (OS). The noninferiority margin of the hazard ratio (HR) was set to 1.33. RESULTS: Overall, 397 patients were enrolled. Baseline characteristics were similar between the groups. Median OS was 14.8 vs. 18.1 months (FTD/TPI plus bevacizumab vs. control; HR 1.38; 95% confidence interval [CI] 0.99-1.93; Pnoninferiority = 0.5920). In patients with a baseline sum of the diameter of target lesions of <60 mm (n = 216, post hoc analyses), the adjusted median OS was similar between groups (FTD/TPI plus bevacizumab vs. control, 21.4 vs. 20.7 months; HR 0.92; 95% CI 0.55-1.55). Grade ≥3 adverse events (FTD/TPI plus bevacizumab vs. control) included neutropenia (65.8% vs. 41.6%) and diarrhoea (1.5% vs. 7.1%). CONCLUSIONS: FTD/TPI plus bevacizumab did not demonstrate noninferiority to fluoropyrimidine and irinotecan plus bevacizumab as second-line treatment for mCRC. CLINICAL TRIAL REGISTRATION: JapicCTI-173618, jRCTs031180122.

Clinical significance of circulating-tumour DNA analysis by metastatic sites in pancreatic cancer.

BACKGROUND: Liquid biopsy is an alternative to tissue specimens for tumour genotyping. However, the frequency of genomic alterations with low circulating-tumour DNA (ctDNA) shedding is shown in pancreatic ductal adenocarcinoma (PDAC). We, therefore, investigated the prevalence of KRAS mutations and ctDNA fraction by the metastatic site in patients with PDAC. METHODS: This study enrolled previously treated PDAC patients from a plasma genomic profiling study; ctDNA analysis was performed using Guardant360 at disease progression before initiating subsequent treatment. RESULTS: In 512 patients with PDAC, KRAS mutations were detected in 57%. The frequency of KRAS mutation in ctDNA differed depending on the metastatic organ; among patients with single-organ metastasis (n = 296), KRAS mutation detection rate was significantly higher in patients with metastasis to the liver (78%). In addition, the median maximum variant allele frequency (VAF) was higher with metastasis to the liver (1.9%) than with metastasis to the lungs, lymph nodes, peritoneum or with locally advanced disease (0.2%, 0.4%, 0.2% and 0.3%, respectively). CONCLUSION: The prevalence of KRAS mutations and maximum VAF were higher in patients with metastasis to the liver than in those with metastasis to other sites. This study indicated the clinical utility of ctDNA analysis, especially in PDAC with liver metastases.

Prospective observational study of zinc deficiency symptoms during first-line chemotherapy for gastric and colorectal cancer.

Background: Zinc deficiency during long-term chemotherapy and its related symptoms, including skin rash, taste disorders, and oral mucositis, have not been sufficiently investigated. Methods: This prospective observational study enrolled patients with gastric and colorectal cancer who underwent standard first-line chemotherapy. According to the Practice Guidelines for Zinc Deficiency, zinc deficiency is defined as a serum level of <60 µg/dL. Serum zinc levels were measured before and after (1, 3, and 6 months) chemotherapy, and symptoms were assessed using the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events version 1.0. Repeated measures were analyzed using a generalized linear mixed model. Results: Of the 61 enrolled patients, 48 who underwent standard first-line chemotherapy with fluoropyrimidine plus oxaliplatin were analyzed. Zinc deficiency was observed in 18 patients (38%) before chemotherapy. The least-squares means of serum zinc levels significantly decreased at 3 and 6 months of chemotherapy in 30 patients without zinc deficiency at the start of chemotherapy (both P<0.01) but not in 18 with zinc deficiency at the beginning. Changes in serum zinc levels during chemotherapy negatively correlated with changes in taste, rash, and itching (all P<0.04) in patients without zinc deficiency before treatment initiation. Conclusions: Serum zinc levels decreased during chemotherapy in zinc-non-deficient patients at the beginning of chemotherapy and correlated with taste changes, skin rash, and itching. Therefore, investigating whether zinc supplementation ameliorates these symptoms is necessary.

Association of ERBB2 Copy Number and Gene Coalterations With Trastuzumab Efficacy and Resistance in Human Epidermal Growth Factor Receptor 2-Positive Esophagogastric and Gastric Cancer.

PURPOSE: ERBB2 copy number (CN), measured using next-generation sequencing, is a predictive biomarker for trastuzumab efficacy in human epidermal growth factor receptor 2 (HER2)-positive advanced esophagogastric and gastric cancer (AGC). We aimed to investigate the association of ERBB2 amplification and gene coalterations with response and resistance to trastuzumab-combined chemotherapy. METHODS: The SCRUM-Japan GI-SCREEN was a comprehensive genomic profiling project of GI cancer tissues using Oncomine Cancer Research Panel and Oncomine Comprehensive Assay. From 885 patients with AGC who successfully underwent gene profiling, 74 with ERBB2 amplification (CN ≥ 4.0) and who received first-line trastuzumab-combined chemotherapy were selected, and ERBB2 CN and gene coalterations were assessed. RESULTS: ERBB2 CN did not differ in tumor response to trastuzumab-combined chemotherapy (one-way analysis of variance test, P = .37). Multivariate analysis using the Cox proportional hazard model revealed that ERBB2 CN (continuous log2-converted CN, hazard ratio, 0.76; 95% CI, 0.62 to 0.93; P < .01) and receptor/oncogene amplifications in the HER2 signaling pathway (hazard ratio, 2.5; 95% CI, 1.2 to 5.3; P = .01) were significant predictors for progression-free survival (PFS). ERBB2 variants coexisted in five patients (7%) and were missense mutations. Two patients with low variant allele frequencies (VAFs; 8%, 12%) showed high ERBB2 CN (55, 80) and durable response (≥ 20 months), whereas three patients with high VAFs (66%-90%) showed low ERBB2 CN (8-11) and no response with short PFS (1-10 months). CONCLUSION: ERBB2 CN and gene coamplification in the HER2 signaling pathway were positive and negative predictors of PFS in trastuzumab-treated HER2-positive AGC patients, respectively. HER2-positive AGC patients with a high VAF of ERBB2 showed poor outcomes and may need HER2 tyrosine kinase inhibitors and trastuzumab deruxtecan.

Clinical Outcomes of S-1 Monotherapy and Modified FOLFIRINOX Therapy after Gemcitabine plus Nab-paclitaxel Therapy in Unresectable Pancreatic Cancer.

Objective S-1 and modified FOLFIRINOX (mFFX) were often used as the second-line chemotherapies after failure of gemcitabine plus nab-paclitaxel (GnP) in unresectable pancreatic cancer (UPC) until nanoliposomal irinotecan plus 5-fluorouracil/leucovorin therapy was approved as an alternative in Japan in 2020. However, the clinical outcomes of S-1 and mFFX after GnP have scarcely been reported. Therefore, we retrospectively studied them. Methods We extracted the clinical data of 86 patients with UPC who received second-line chemotherapy after GnP between 2015 and 2020. Among the patients who had a good organ functions and no massive ascites, 41 patients treated with S-1 and 21 treated with mFFX were enrolled. Results Compared to S-1, mFFX tended to be used for younger patients with a good general condition (median age, 63 vs. 71 years, p<0.01; and performance status 0, 67% vs. 37%, p<0.05). The median progression-free and overall survival were similar between the S-1 (3.7 and 7.2 months, respectively) and mFFX (3.3 and 7.4 months, respectively) groups. The response rate in patients with measurable lesions was 4% (n=1/23) in the S-1 group and 17% (n=2/12) in the mFFX group. The incidence of grade 3 or 4 adverse events was 20% in the S-1 group and 57% (neutrophil count decreased in 43%) in the mFFX group (p<0.01). Conclusion S-1 and mFFX were both acceptable second-line chemotherapies after GnP therapy for UPC, although attention should be paid to myelosuppression during mFFX treatment. Further studies involving nanoliposomal irinotecan plus 5-fluorouracil/leucovorin therapy are necessary to facilitate the selection of the optimal regimen for each patient.

NOTCH gene alterations in metastatic colorectal cancer in the Nationwide Cancer Genome Screening Project in Japan (SCRUM-Japan GI-SCREEN).

PURPOSE: Activated Notch receptor signaling has been implicated in tumor growth and progression in colorectal cancer (CRC). However, the pathogenic relevance of NOTCH gene alterations remains unclear. The aim of this study was to clarify mutational landscapes and assess their clinical significance in patients with metastatic CRC. METHODS: Pre-chemotherapy tumor tissues obtained from 1154 metastatic CRC patients in the Nationwide Cancer Genome Screening Project in Japan between April 2017 and March 2019 were studied using the Oncomine Comprehensive Assay. RESULTS: The frequencies of NOTCH1, NOTCH2, and NOTCH3 nonsynonymous sequence variants were 11.5%, 4.4%, and 10.4%, respectively. The majority of variants were missense of unknown significance that were distributed across all domains of all three NOTCH genes. The gain-of-function mutations in NOTCH reported in multiple malignancies were not identified. The NOTCH amplification rate was less than 1%. No NOTCH fusions were detected. In patients who were registered before, or within 1 year of, first-line chemotherapy, overall survival for 51 patients with only NOTCH3 variants was significantly longer than for 540 patients with no NOTCH variants (median, 40.2 months vs 27.7 months; P = 0.04). Multivariate analysis revealed that variant NOTCH3 was an independent prognostic factor for increased survival (hazard ratio 0.61, 95% confidence interval, 0.39-0.94; P = 0.03) besides poor prognostic factors associated with mutant TP53, KRAS, and BRAF, as well as amplified MYC. CONCLUSION: NOTCH genes are unlikely to harbor driver mutations and amplifications in patients with metastatic CRC. NOTCH3 variant should be further investigated as a favorable prognostic marker.

Nanoparticle albumin-bound paclitaxel and ramucirumab versus paclitaxel and ramucirumab as second-line chemotherapy for unresectable advanced or recurrent gastric cancer: a multicenter, propensity score-matched analysis (CROSS SELL study).

BACKGROUND: Paclitaxel plus ramucirumab (PTX + RAM) is the standard second-line chemotherapy for unresectable advanced or recurrent gastric cancer (AGC). Nanoparticle albumin-bound paclitaxel (nab-PTX) is an improved, more convenient form of PTX and is non-inferior to PTX. Although some retrospective and single-arm phase II studies regarding nab-PTX + RAM have been reported, comparative studies are lacking. Here, we compared the efficacy and toxicity of nab-PTX + RAM and PTX + RAM using propensity score matching. METHODS: Clinical data of 265 patients treated for AGC with nab-PTX + RAM or PTX + RAM were retrospectively collected. Nab-PTX was administered at dosages of 100 mg/m2, replacing PTX in the standard PTX + RAM regimen. Progression-free survival (PFS), overall survival (OS), and toxicity were compared using 1:1 propensity score matching. RESULTS: In total, 190 (72%) patients were matched. The median PFS was 5.3 [95% confidence interval (CI) 4.4-6.3] and 4.7 (95% CI 3.2-5.3) months in the nab-PTX + RAM and PTX + RAM groups, respectively [hazard ratio (HR) = 0.76, 95% CI 0.56-1.03, p = 0.07]. The median OS was 11.5 (95% CI 9.2-15.0) and 9.9 (95% CI 8.0-12.7) months, respectively (HR = 0.78, 95% CI 0.56-1.07, p = 0.12). Grade 3 and 4 neutropenia was observed more frequently in the nab-PTX + RAM group (72% vs. 56%, p = 0.03). No treatment-related deaths occurred. CONCLUSIONS: Nab-PTX + RAM exhibited more favorable trends in terms of PFS and OS but was more myelosuppressive than PTX + RAM. As neutropenia is commonly manageable toxicity, nab-PTX + RAM presents a treatment alternative for AGC. Further studies including randomized, controlled studies are warranted.

Risk factors and efficacy outcomes of early-onset severe neutropenia due to paclitaxel or nanoparticle albumin-bound paclitaxel combined with ramucirumab in advanced gastric cancer: a multicenter retrospective cohort study.

Background: Paclitaxel or nanoparticle albumin-bound paclitaxel combined with ramucirumab (PTX/nab-PTX + RAM) is widely used as second-line chemotherapy for advanced gastric cancer (AGC), but severe neutropenia often develops with this regimen. Although previous studies have reported that severe neutropenia is a favorable prognostic factor in cancer chemotherapy, it is unclear in AGC patients receiving PTX/nab-PTX + RAM. In addition, the risk factors for early-onset of severe neutropenia (EOSN) still remain unknown. Methods: Among patients with AGC treated with PTX/nab-PTX (on day 1, 8, and 15) + RAM (on day 1 and 15) every 4 weeks as second-line therapy from January 2017 to June 2020, those with grade 0 or 1 neutropenia before the treatment were retrospectively studied. Blood tests were performed on the day of treatment each time, and disease progression was primarily determined by computed tomography every 8±2 weeks. EOSN was defined as grade 4 neutropenia that occurred during the first 28 days. The risk factors for EOSN were investigated using multivariate logistic regression analysis. Progression-free survival (PFS) and overall survival (OS) in patients with and without EOSN were investigated using multivariate analysis with a Cox proportional hazards model. Results: The clinical data of 244 patients were analyzed. EOSN was observed in 51 (20.9%) patients. Multivariate analysis identified the following five risk factors for EOSN: age ≥65 years [odds ratio (OR), 2.75], presence of primary tumor (OR, 2.82), presence of peritoneal metastasis (OR, 2.52), grade 1 neutropenia (OR, 3.32), and high serum level of alkaline phosphatase (OR, 2.34). The PFS was significantly longer in patients with EOSN than in those without EOSN [adjusted hazard ratio (HR), 0.61; 95% CI, 0.41-0.92] and the OS tended to be longer in patients with EOSN than in those without EOSN (adjusted HR, 0.73; 95% CI, 0.47-1.12). HR was adjusted with patient background factors and blood test data considered important as predictive or prognostic factors. Conclusions: EOSN may be associated with favorable outcomes in patients with AGC treated with PTX/nab-PTX + RAM. We should carefully try to treat them keeping the risk factors in mind.

Clinical Impact of Primary Tumor Location in Metastatic Colorectal Cancer Patients Under Later-Line Regorafenib or Trifluridine/Tipiracil Treatment.

BACKGROUND: Primary tumor location (PTL) is an important prognostic and predictive factor in the first-line treatment of metastatic colorectal cancer (mCRC). Although regorafenib (REG) and trifluridine/tipiracil (FTD/TPI) have been introduced recently, the clinical impact of PTL in these treatments is not well understood. MATERIALS AND METHODS: We retrospectively evaluated patients with mCRC who were registered in a multicenter observational study (the REGOTAS study). The main inclusion criteria were Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2, refractory or intolerant to fluoropyrimidines, oxaliplatin, irinotecan, angiogenesis inhibitors, anti-epidermal growth factor receptor therapy (if RAS wild-type), and no prior use of REG and FTD/TPI. The impact of PTL on overall survival (OS) was evaluated using Cox proportional hazard models based on baseline characteristics. RESULTS: A total of 550 patients (223 patients in the REG group and 327 patients in the FTD/TPI group) were included in this study, with 122 patients with right-sided tumors and 428 patients with left-sided tumors. Although the right-sided patients had significantly shorter OS compared with the left-sided patients by univariate analysis (p = 0.041), a multivariate analysis revealed that PTL was not an independent prognostic factor (hazard ratio, 0.95; p = 0.64). In a subgroup analysis, the OS was comparable between the REG and FTD/TPI groups regardless of PTL (p for interactions = 0.60). CONCLUSIONS: In the present study, PTL is not a prognostic and predictive factor in patients with mCRC under later-line REG or FTD/TPI therapy.

Clinical Outcomes Following Trifluridine/Tipiracil Treatment for Patients With Metastatic Colorectal Cancer Ineligible for Regorafenib Treatment.

BACKGROUND/AIM: In later-line treatment of metastatic colorectal cancer (mCRC), trifluridine/tipiracil is often selected because regorafenib is difficult to use in patients with comorbidities such as thrombosis, hemorrhage, or cardiac events. However, the safety and efficacy of trifluridine/tipiracil in these patients is not clear. PATIENTS AND METHODS: The clinical outcomes of trifluridine/tipiracil were retrospectively investigated in patients who were ineligible for regorafenib because of comorbidities. RESULTS: Among the 27 patients who received trifluridine/tipiracil, many had comorbidities of deep venous thrombosis or hemorrhage. The median overall survival was 12.4 months, and the median progression-free survival was 2.8 months. The median overall survival was 7.7 months in 19 patients without subsequent regorafenib. Grade 3 or higher toxicities were found in 51% of patients. No treatment discontinuation because of comorbidities was observed. CONCLUSION: Trifluridine/tipiracil can be safely administered while maintaining efficacy in patients who were ineligible for regorafenib.

Survival Benefit of Crossover Administration of Regorafenib and Trifluridine/Tipiracil Hydrochloride for Patients With Metastatic Colorectal Cancer: Exploratory Analysis of a Japanese Society for Cancer of the Colon and Rectum Multicenter Observational Study (REGOTAS).

Background: The survival benefits of regorafenib (REG) and trifluridine/tipiracil hydrochloride (TFTD) have been demonstrated in chemorefractory patients with metastatic colorectal cancer (mCRC). However, the effects of crossover administration of REG and TFTD on patient survival remain unclear. The present study evaluated the association between exposure to REG and TFTD and overall survival (OS) in patients with mCRC using data from the REGOTAS study. Patients and Methods: We analyzed patients registered in the REGOTAS study, which retrospectively compared the efficacy and safety of use of REG or TFTD as later-line chemotherapy for chemorefractory mCRC patients. We compared the survival outcomes of cohort A (treated using both REG and TFTD) and cohort B (treated using either REG or TFTD). Results: A total of 550 patients (cohort A, n = 252; cohort B, n = 298) met the inclusion criteria. The median OS was significantly increased in cohort A compared with cohort B [9.6 months (95% confidence interval (CI), 8.9-10.9 months) vs. 5.2 months (95% CI, 4.4-6.0 months), P < 0.001]. Multivariate analysis revealed that cohort A was independently associated with a significant increase in OS [A vs. B: Hazard ratios (HR), 0.58; 95% CI, 0.47-0.72; P < 0.001]. Subgroup analysis adjusted using multivariate Cox model revealed a consistently better trend in most subgroups for cohort A compared with cohort B. Conclusions: Our study revealed prolonged survival in patients treated with REG and TFTD. Therefore, all active agents, including REG and TFTD, should be made available to mCRC patients.

A randomized, double-blind, phase II study of oral histone deacetylase inhibitor resminostat plus S-1 versus placebo plus S-1 in biliary tract cancers previously treated with gemcitabine plus platinum-based chemotherapy.

PURPOSE: Effective second-line chemotherapy options are limited in treating advanced biliary tract cancers (BTCs). Resminostat is an oral histone deacetylase inhibitor. Such inhibitors increase sensitivity to fluorouracil, the active form of S-1. In the phase I study, addition of resminostat to S-1 was suggested to have promising efficacy for pre-treated BTCs. This study investigated the efficacy and safety of resminostat plus S-1 in second-line therapy for BTCs. METHODS: Patients were randomly assigned to receive resminostat or placebo (200 mg orally per day; days 1-5 and 8-12) and S-1 group (80-120 mg orally per day by body surface area; days 1-14) over a 21-day cycle. The primary endpoint was progression-free survival (PFS). Secondary endpoints comprised overall survival (OS), response rate (RR), disease control rate (DCR), and safety. RESULTS: Among 101 patients enrolled, 50 received resminostat+S-1 and 51 received placebo+S-1. Median PFS was 2.9 months for resminostat+S-1 vs. 3.0 months for placebo+S-1 (HR: 1.154, 95% CI: 0.759-1.757, p = 0.502); median OS was 7.8 months vs. 7.5 months, respectively (HR: 1.049, 95% CI: 0.653-1.684, p = 0.834); the RR and DCR were 6.0% vs. 9.8% and 70.0% vs. 78.4%, respectively. Treatment-related adverse events (TrAEs) of grade ≥ 3 occurring more frequently (≥10% difference) in the resminostat+S-1 than in the placebo+S-1 comprised platelet count decreased (18.0% vs. 2.0%) and decreased appetite (16.0% vs. 2.0%). CONCLUSIONS: Resminostat plus S-1 therapy improved neither PFS nor OS for patients with pre-treated BTCs. Addition of resminostat to S-1 was associated with higher incidence of TrAEs, but these were manageable (JapicCTI-183883).

Multicenter Phase I/II Study of Nivolumab Combined with Paclitaxel Plus Ramucirumab as Second-line Treatment in Patients with Advanced Gastric Cancer.

PURPOSE: We conducted a phase I/II study to investigate the safety and efficacy of nivolumab with paclitaxel plus ramucirumab. PATIENTS AND METHODS: Patients with advanced gastric cancer (AGC) refractory to first-line chemotherapy were included. Patients received nivolumab (3 mg/kg on days 1 and 15) combined with paclitaxel (80 mg/m2 on days 1, 8, and 15) and ramucirumab (8 mg/kg on days 1 and 15) every 4 weeks. After feasibility evaluation in six patients (phase I), 37 additional patients were enrolled in the phase II part with the primary endpoint of 6-month progression-free survival (PFS) rate with two-sided 80% confidence interval (CI). The combined positive score (CPS) was defined as the number of programmed death-ligand 1-positive cells divided by the total number of viable tumor cells multiplied by 100. RESULTS: Forty-three patients were enrolled. Of these, 60.5% had CPS ≥ 1. Dose-limiting toxicities were observed in two patients, and the recommended dose was determined as level 1. Thirty-nine (90.7%) patients experienced treatment-related adverse events (AEs) grade ≥3 and 14 (32.6%) patients experienced immune-related AEs grade ≥3. The overall response rate was 37.2% (95% CI, 23.0%-53.5%) and the 6-month PFS rate was 46.5% (80% CI, 36.4%-55.8%; P = 0.067). Median survival time was 13.1 months (95% CI, 8.0-16.6 months): 13.8 months (95% CI, 8.0-19.5 months) in patients with CPS ≥ 1 and 8.0 months (95% CI, 4.8-24.1 months) in patients with CPS < 1. CONCLUSIONS: Nivolumab with paclitaxel plus ramucirumab demonstrated promising antitumor activity with manageable toxicities as second-line treatment for AGC.

[Tolerability of Definitive Chemoradiotherapy in Elderly Patients with Esophageal Cancer].

Definitive chemoradiotherapy(CRT)for esophageal cancer is the standard treatment and alternative to surgery. However, the tolerability of CRT in elderly patients is not well known. In this study, we retrospectively analyzed 60 patients with esophageal cancer who were treated with CRT(5-FU 700 mg/m2, cisplatin 70 mg/m2, radiation 60 Gy)at our hospital between January 2015 and September 2017. The patients were divided into 2 groups: an elderly group comprising 16 patients aged >75 years and a non-elderly group comprising 44 patients aged <74 years. The relative dose intensity of cisplatin in the elderly group was significantly lower than that in the non-elderly group. Radiotherapy was successfully executed in both groups. More patients in the elderly(25%)than the non-elderly group(7%)developed pneumonitis, and all patients who developed severe pneumonitis in the elderly group died. Application of definitive CRT and irradiation methods in elderly patients with a subpleural reticular shadow should be carefully considered before initiating therapy.

Prognostic scores for evaluating the survival benefit of regorafenib or trifluridine/tipiracil in patients with metastatic colorectal cancer: an exploratory analysis of the REGOTAS study.

BACKGROUND: Although regorafenib or trifluridine/tipiracil (FTD/TPI) has been recognized as a later-line standard treatment in patients with metastatic colorectal cancer (mCRC), not all patients have beneficial outcomes. This study aimed to develop a prognostic scoring system for evaluating the overall survival (OS) benefit. METHODS: Patients included in the REGOTAS study, which comprised 489 patients (regorafenib group: 199; FTD/TPI group: 290 patients), were evaluated. OS was analyzed using multivariate Cox proportional model. The prognostic score was calculated using the worst four individual factors weighted by hazard ratio, and the total scores were categorized as low-, moderate-, and high-OS benefit. RESULTS: The worst four factors in the regorafenib group were AST > 40 IU/dL (point, + 3), CRP ≥ 1.0 mg/dL (+ 2), number of metastatic organ site ≥ 3 (+ 2), and duration from initiation of 1st-line chemotherapy < 18 months (+ 2), while they were AST (+ 2), CRP (+ 2), CA19-9 > 37.0 U/mL (+ 2), and ECOG PS ≥ 1 (+ 2) in the FTD/TPI group. These corresponded to a total prognostic score of > 5, 2-4, and 0 points in the regorafenib group and 8, 2-6, and 0 points in the FTD/TPI group. The median OS in the low, moderate, and high OS benefit group was 3.3 (95% CI 3.0-3.7), 8.1 (95% CI 6.4-9.7), and 12.6 months (95% CI 10.6-14.6) in the regorafenib group and 2.8 (95% CI 2.0-3.5), 7.5 (95% CI 6.6-8.3), and 15.4 months (95% CI 9.7-21.2) in the FTD/TPI group. CONCLUSION: These prognostic scores are useful for identifying patients with mCRC who will obtain survival benefits from these drugs.