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Background Accelerated tumor growth during immunotherapy in pre-existing measurable lesions, hyperprogressive disease (HPD), has been reported. However, progression of non-measurable lesions and new lesions are frequently observed in patients with advanced gastric cancer (AGC). Methods This retrospective study involved AGC patients at 24 Japanese institutions who had measurable lesions and received nivolumab after ≥ 2 lines of chemotherapy. HPD was defined as a ≥ two-fold increase in the tumor growth rate of measurable lesions. The pattern of disease progression was classified according to new lesions in different organs and ascites appeared/increase of ascites. Results Of 245 patients, 147 (60.0%) showed progressive disease (PD) as the best response and 41 (16.7%) showed HPD during nivolumab monotherapy. There was no significant difference in overall survival (OS) between patients with HPD and those with PD other than HPD (median OS 5.0 vs 4.8 months; hazard ratio [HR] 1.0, 95% confidence interval [CI] 0.6–1.5; p = 1.0). Fifty-three patients developed new lesions in different organs and 58 had appearance/increase of ascites; these patients showed shorter OS than those without each of these features (median OS 3.3 vs 7.1 months, HR 1.8, 95% CI 1.2–2.7, p = 0.0031 for new lesions, and 3.0 vs 7.8 months, HR 2.6, 95% CI 1.8–3.8, p Conclusions New lesions in different organs and appearance/increase of ascites, rather than the original definition of HPD, are the patterns of disease progression associated with poor prognosis in AGC patients receiving nivolumab whose best response was PD.

Comprehensive genomic profiling is increasingly used to facilitate precision oncology based on molecular stratification. In addition to conventional tissue comprehensive genomic profiling, comprehensive genomic profiling of circulating tumor DNA has become widely utilized in cancer care owing on its advantages, including less invasiveness, rapid turnaround time, and capturing heterogeneity. However, circulating tumor DNA comprehensive genomic profiling has some limitations, mainly false negatives due to low levels of plasma circulating tumor deoxyribonucleic acid and false positives caused by clonal hematopoiesis. Nevertheless, no guidelines and recommendations fully address these issues. Here, an expert panel committee involving representatives from 12 Designated Core Hospitals for Cancer Genomic Medicine in Japan was organized to develop expert consensus recommendations for the use of circulating tumor deoxyribonucleic acid-based comprehensive genomic profiling. The aim was to generate guidelines for clinicians and allied healthcare professionals on the optimal use of the circulating tumor DNA assays in advanced solid tumors and to aid the design of future clinical trials that utilize and develop circulating tumor DNA assays to refine precision oncology. Fourteen clinical questions regarding circulating tumor deoxyribonucleic acid comprehensive genomic profiling including the timing of testing and considerations for interpreting results were established by searching and curating associated literatures, and corresponding recommendations were prepared based on the literature for each clinical question. Final consensus recommendations were developed by voting to determine the level of each recommendation by the Committee members.

Background No reliable nomogram has been developed until date for predicting the survival in patients with unresectable pancreatic cancer undergoing treatment with gemcitabine plus nab–paclitaxel (GnP) or FOLFIRINOX. Methods This analysis was conducted using clinical data of Japanese patients with unresectable pancreatic cancer undergoing GnP or FOLFIRINOX treatment obtained from a multicenter study (NAPOLEON study). A Cox proportional hazards model was used to identify the independent prognostic factors. A nomogram to predict 6–, 12–, and 18–month survival probabilities was generated, validated by using the concordance index (C–index), and calibrated by the bootstrapping method. And then, we attempted risk stratification for survival by classifying the patients according to the sum of the scores on the nomogram (total nomogram points). Results A total of 318 patients were enrolled. A prognostic nomogram was generated using data on the Eastern Cooperative Oncology Group performance status, liver metastasis, serum LDH, serum CRP, and serum CA19–9. The C–indexes of the nomogram were 0.77, 0.72 and 0.70 for 6–, 12–, and 18–month survival, respectively. The calibration plot showed optimal agreement at all points. Risk stratification based on tertiles of the total nomogram points yielded clear separations of the survival curves. The median survival times in the low–, moderate–, and high–risk groups were 15.8, 12.8 and 7.8 months (P Conclusions Our nomogram might be a convenient and inexpensive tool to accurately predict survival in Japanese patients with unresectable pancreatic cancer undergoing treatment with GnP or FOLFIRINOX, and will help clinicians in selecting appropriate therapeutic strategies for individualized management.

Background/aim The aim of the study was to evaluate gemcitabine plus nanoparticle albumin-bound paclitaxel (GnP) and FOLFIRINOX for recurrent pancreatic cancer (rPC) after resection. Patients and methods Forty-four patients with rPC and 211 with de novo metastatic pancreatic cancer (mPC) who received GnP or FOLFIRINOX as first-line chemotherapy were retrospectively analyzed. Results On crude analysis, the median overall survival (OS) was significantly longer in the rPC group than in the mPC group (14.0 vs. 10.6 months, respectively; p=0.02). However, the difference was not significant on adjusted analysis using the Cox proportional hazards model (adjusted p=0.90). Patients receiving FOLFIRINOX (n=10) and GnP (n=34) in the rPC group had comparable OS (medians, 12.2 vs. 14.4 months, respectively; p=0.82) even after adjusting for covariates using the Cox model (adjusted p=0.18). Conclusion The outcomes of patients in the rPC and mPC groups were comparable following chemotherapy. Both FOLFIRINOX and GnP may be reasonable options for treating rPC.

Although peripheral neuropathy (PN) is a common adverse event in patients treated with oxaliplatin as first-line chemotherapy (1st-OX) for advanced gastric cancer, the effect of PN on the efficacy of paclitaxel at second-line chemotherapy (2nd-PTX) remains unclear. We investigated the association between PN induced by 1st-OX and efficacy of 2nd-PTX in patients with advanced gastric cancer (AGC).The study subjects were patients with AGC who received 1st-OX followed by 2nd-PTX at Gifu University Hospital between January 2015 and December 2019. Primary outcome was time to treatment failure (TTF) of 2nd-PTX. Secondary outcomes included overall survival (OS), response rate and adverse events during the period of 2nd-PTX. The association between incidence of grade ≥2 peripheral neuropathy (G2PN) and TTF or OS was also evaluated using Cox proportional hazards analysis.A total of 54 patients with AGC who received 1st-OX followed by 2nd-PTX were eligible. Incidence rates of G2PN at the start of 2nd-PTX was 20.3% (11/54). Median duration of TTF and OS were not significantly longer in patients with G2PN than in those without it (TTF: 4.7 months vs. 3.7 months, p=0.264, OS: 10.6 months vs. 8.5 months, p=0.706). Cox proportional hazards analysis indicated that there was no significant relationship between the incidence of G2PN and TTF, or between the incidence of G2PN and OS. However, development of grade ≥3 PN was significantly higher in patients with G2PN than in those without it (45.5% vs. 2.3%, p0.001).G2PN induced by 1st-OX may not affect efficacy of 2nd-PTX in patients with AGC but could be a risk for grade ≥3 PN of 2nd-PTX.

Introduction: Original FOLFIRINOX (oFFX) is more toxic than other regimens for patients with metastatic pancreatic cancer (mPC); therefore, a modified FFX (mFFX) regimen with a reduced dosage has been used in Japanese clinical practice. However, very few studies have compared these two regimens. Methods: This study was conducted as part of a multicenter retrospective study of 318 patients with mPC across 14 centers in Japan (NAPOLEON study). To control for potential bias and confounders, we conducted a propensity score-adjusted analysis of patient characteristics and clinical outcomes. Results: oFFX and mFFX were administered to 48 and 54 patients. More patients with younger age and poorer performance status were included in the oFFX group. The overall survival (OS; median, 11.6 vs. 11.3 months; hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.60–1.40; p = 0.67), progression-free survival (PFS) (median, 6.3 vs. 5.7 months; HR, 0.85; 95% CI, 0.56–1.28; p = 0.44), and overall response rate (29 vs. 26%, p = 0.71) were not significantly different for the oFFX and mFFX groups. Thrombopenia and liver dysfunction were significantly more frequent with oFFX than with mFFX. The median received dose intensity of CPT-11 was higher with oFFX than with mFFX (299 vs. 270 mg/m2/week, p < 0.01). The propensity score-adjusted analysis revealed no statistically significant differences in OS and PFS between the two groups. Conclusion: In our data, there was no significant difference in efficacy between mFFX and oFFX, and mFFX has fewer adverse events.

Trifluridine/tipiracil (FTD/TPI) is an orally administrated anticancer drug with efficacy validated for patients with metastatic colorectal cancer (mCRC) or gastric cancer. FTD, a key component of FTD/TPI, exerts antitumor effects via its incorporation into DNA. Using specific antibodies against bromodeoxyuridine, FTD incorporation into DNA is detected in tumors and peripheral blood mononuclear cells (PBMC) of patients with mCRC who are administered FTD/TPI. The proportion of FTD‐positive PBMC fluctuates according to the schedule of treatment, although the association between the proportion of FTD‐positive PBMC and the clinical outcomes of patients is unknown. To answer this question, here we monitored the FTD‐positive PBMC of 39 elderly patients with mCRC enrolled in KSCC1602, a single‐arm phase 2 trial of FTD/TPI plus bevacizumab as a first‐line treatment, for 1 month, during the first cycle of treatment. The median values and interquartile ranges of the percentage of FTD‐positive PBMC on days 8, 15, and 29 were 39.3% (30.7%‐52.2%), 66.9% (40.0%‐75.3%), and 13.5% (5.7%‐26.0%), respectively. Receiver operating characteristic analysis revealed that the percentage of FTD‐positive PBMC on day 8 (the end of the first week of treatment) had moderate ability to accurately diagnose the occurrence of severe neutropenia and leukopenia within 1 month (area under the curve = 0.778 [95% confidence interval, 0.554‐0.993]). This result suggests that excess FTD incorporation into PBMC at the initial phase of FTD/TPI plus bevacizumab treatment is a risk factor for early onset of severe hematological adverse events., Severe hematological adverse events were predicted by FTD incorporation into PBMC during the early phase of FTD/TPI plus bevacizumab treatment. However, FTD‐positive PBMC were not associated with prognosis.

Fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX, FFX) and gemcitabine plus nab-paclitaxel (GnP) are considered standard treatments for patients with metastatic pancreatic cancer. Direct comparisons are not available that establish which is optimal. We conducted a propensity score-adjusted analysis of patients with metastatic pancreatic cancer to identify the therapeutic advantages of these standard therapies. We used clinical data as part of a multicenter retrospective study of patients with unresectable or recurrent pancreatic cancer treated with FFX or GnP (NAPOLEON study). FFX and GnP were initially administered to 102 and 153 patients, respectively. The GnP group comprised more patients of advanced age, worse performance status, lower body mass index, recurrence, and lower albumin concentrations. Median overall survival (OS) and progression-free survival (PFS) were 11.5 months and 5.8 months in the FFX group and 11.1 months and 5.9 months in the GnP group, respectively. Propensity score-adjusted analysis indicated that the administration of FFX or GnP was not independently associated with OS (adjusted hazard ratio [HR] 1.06; 95% confidence interval [CI] 0.76–1.47; P = 0.73). Similarly, the difference in PFS was not significant between groups (adjusted HR 0.93; 95% CI 0.68–1.26; P = 0.62). Gastrointestinal disorders were more common in the FFX group, whereas the frequencies of hematological, nervous system, and skin disorders were higher in the GnP group. The efficacies of FFX and GnP were comparable, although safety profiles differed and should be considered in selecting treatment.

Background/aim We compared the efficacy and safety of second-line FOLFIRI with bevacizumab (Bmab) or aflibercept (AFL) in patients with unresectable metastatic colorectal cancer (mCRC) to clarify selection criteria for anti-angiogenic agents. Patients and methods The subjects were patients with mCRC who received second-line FOLFIRI in combination with Bmab or AFL. The primary endpoint was median overall survival (OS). Secondary endpoints were median time to treatment failure (TTF), overall response rate (ORR) and incidence of adverse events. Results Data from 26 patients in the Bmab group and 19 in the AFL group were analyzed. Median OS was slightly longer in the AFL group compared to the Bmab group, whereas median TTF was similar. ORR tended to be higher in the AFL group. The incidence of ≥grade 2 diarrhea and proteinuria was significantly higher in the AFL group than the Bmab group. Conclusion In patients given combination treatment with FOLFIRI for second-line treatment of mCRC, AFL can increase response rates compared to Bmab, which may contribute to longer survival.

Background A previous Phase I/II study demonstrated that TAS‐102 (trifluridine/tipiracil [FTD/TPI]) plus bevacizumab (Bev) has encouraging efficacy and controllable safety for patients with previously treated metastatic colorectal cancer. Therefore, we designed for assessing the efficacy and safety of FTD/TPI plus Bev in elderly patients with previously untreated metastatic colorectal cancer. Methods This is a multicenter, single‐arm Phase II study included patients ≥70 years old with previously untreated, unresectable metastatic colorectal cancer. Treatment consisted of FTD/TPI plus Bev given every 4 weeks. The primary endpoint was progression‐free survival (PFS), assuming a null hypothesis of a PFS of 5 months. The secondary endpoints were the overall survival (OS), overall response rate (ORR), and adverse events (AEs). Results Between 5 January 2017 and 13 March 2018, 39 patients were enrolled from 18 institutions. The median patient age was 76.0 years (range, 70–88); the ECOG‐PS was 0 in 24 patients and 1 in 15 patients. The median PFS was 9.4 months as a primary endpoint, and the median OS was 22.4 months. The ORR was 40.5% and the disease control rate was 86.5%. Grade 3–4 AEs included neutropenia (71.8%), leukopenia (51.3%), anorexia (15.4%), febrile neutropenia (10.3%), and fatigue (10.3%). Conclusions FTD/TPI plus Bev is an effective and well‐tolerated regimen for elderly patients with previously untreated metastatic colorectal cancer. Capecitabine/bevacizumab can be selected as a subsequent maintenance therapy without irinotecan and oxaliplatin because FTD/TPI has no cross‐resistance with 5‐fluorouracil. Clinical trial registration: UMIN clinical trials registry (UMIN000025241)., We aimed to assess the efficacy and safety of FTD/TPI plus Bev in elderly patients with previously untreated metastatic colorectal cancer. The median PFS was 9.4 months as a primary endpoint, the median OS was 22.4 month, ORR was 40.5% and AEs were manageable. The combination of FTD/TPI plus Bev is an effective and well‐tolerated regimen for elderly patients with previously untreated metastatic colorectal cancer.

In a randomized pivotal global phase III study, S-1 and oxaliplatin 100 mg/m2 (SOX100) combination chemotherapy was as effective as S-1 and cisplatin for advanced gastric cancer (AGC) and showed a favorable safety profile. In this phase II study, we analyzed survival outcomes to assess the efficacy and safety of the SOX regimen with oxaliplatin 130 mg/m2 (SOX130) in AGC. Patients with HER2-negative AGC received 80 mg/m2/day S-1 orally on days 1–14 and 130 mg/m2 oxaliplatin intravenously on day 1 of each 21-day cycle until the criteria for treatment withdrawal were fulfilled. The primary endpoint was the response rate (RR), and the null hypothesis of RR in the current trial was 45%. The secondary endpoints were progression-free survival (PFS) and overall survival (OS). Adverse events (AEs) were recorded according to CTCAE version 4.0. Seventy-one patients were enrolled from June 2015 to November 2016, but eight were excluded for ineligibility. Therefore, all final analyses were conducted with 63 patients. The confirmed RR was 46.0% (90% confidence interval [CI]: 36.1–56.3), and the disease control rate was 77.8% (90% CI: 68.1–85.1). The median PFS and OS were 4.9 (95% CI: 4.2–7.1) and 14.8 (95% CI: 11.1–18.9) months, respectively. Incidences of grade 3–4 AEs > 10% were anorexia (19.0%), peripheral neuropathy (12.7%), nausea (11.1%), and thrombocytopenia (11.1%). This study represents the first evaluation of SOX130 in patients with HER2-negative AGC. SOX130 showed an acceptable safety profile, but the prespecified statistical efficacy targets were not achieved.

Purpose The purpose of this clinical study was to be the first to explore whether ART-123, a recombinant human soluble thrombomodulin, prevents oxaliplatin-induced peripheral neuropathy (OIPN). Methods This randomized, phase IIa trial enrolled stage II/III colon cancer patients who received adjuvant mFOLFOX6 chemotherapy. Participants were randomly allocated to 3 arms in a double-blind manner: placebo (placebo: days 1–3); 1-day ART (ART-123: day 1, placebo: days 2–3); and 3-day ART (ART-123: days 1–3). ART-123 (380 U/kg/day) or placebo was infused intravenously before each 2-week cycle of mFOLFOX6. OIPN was assessed with the Functional Assessment of Cancer Therapy/Gynecological Oncology Group-Neurotoxicity-12 (FACT/GOG-Ntx-12) score by participants and the NCI Common Terminology Criteria for Adverse Events (NCI-CTCAE) by investigators. Results Seventy-nine participants (placebo n = 28, 1-day ART n = 27, 3-day ART n = 24) received study drugs. The least-squares mean FACT/GOG-Ntx-12 scores at cycle 12 from the mixed effect model for repeated measures were 28.9 with placebo, 36.3 with 1-day ART (vs. placebo: 7.3 [95% CI 1.9 to12.8, p = 0.009]), and 32.3 with 3-day ART (vs. placebo: 3.4 [95% CI −.1 to 9.0, p = 0.222]). The cumulative incidence of NCI-CTCAE grade ≥ 2 sensory neuropathy at cycle 12 was 64.3% with placebo, 40.7% with 1-day ART (vs. placebo: −23.5 [95% CI −48.4 to 4.0], p = 0.108), and 45.8% with 3-day ART (vs. placebo: −18.5 [95% CI −44.2 to 9.4], p = 0.264). Common adverse events were consistent with those reported with mFOLFOX6; no severe bleeding adverse events occurred. Conclusion ART-123 showed a potential preventive effect against OIPN with good tolerability. A larger study with 1-day ART is warranted. NCT02792842, registration date: June 8, 2016

Predictive markers for the clinical outcomes of second-line treatment in patients with metastatic colorectal cancer (mCRC) remain unclear. This retrospective biomarker study was conducted to explore predictive markers for patients with KRAS exon 2 wild-type mCRC who were treated with FOLFIRI plus panitumumab (Pani) or bevacizumab (Bev) in the WJOG6210G trial. The associations of early tumor shrinkage (ETS), tumor location, and VEGF-D with progression-free survival (PFS) and overall survival (OS) were analyzed using a Cox proportional hazards model. Spearman’s correlation coefficient was used to analyze the association of depth of response (DpR) with PFS and OS. Serum VEGF-D levels were measured in samples collected before treatment using magnetic bead panel Milliplex xMAP kits. In total, 101 patients (Pani, n = 49; Bev, n = 52) were enrolled in this study. Patients with ETS had longer PFS (Pani: hazard ratio (HR) 0.40, P = 0.009; Bev: HR 0.078, P = 0.0002) and OS (Pani: HR 0.49, P = 0.044; Bev: HR 0.35, P = 0.048) than patients without ETS. The DpR was moderately correlated with PFS and OS in Pani (rs = 0.75, P

Treatment options for patients with advanced gastric cancer (AGC) are limited. One approach to improving survival in patients with AGC is to optimize the available agents via sequential therapy. However, clinical trial reports of first-line chemotherapy indicate that elderly patients and patients with massive ascites are less likely to receive subsequent lines of therapy. In addition, clinical trials of second- and third-line chemotherapy generally exclude these two patient populations because they are likely to have poor performance status and additional issues that are difficult to manage. Good patient management is likely to be key to the successful use of sequential therapy in these two patient populations by minimizing adverse effects to allow patients to derive benefit from the additional treatment. This narrative review summarizes the available information on AGC treatment and patient management in elderly patients and patients with massive ascites. The available data suggest that elderly patients benefit from chemotherapy; however, monitoring toxicity is essential to avoid chemotherapy-related toxicities. Important aspects of patient management for elderly patients include symptom monitoring, nutritional support, and fall prevention. The available data for patients with massive ascites show limited success for a range of treatment approaches, including systemic chemotherapy. The management of ascites is also challenging, with no clear guidance on the preferred strategies. To address these gaps in knowledge, future clinical trials should incorporate more inclusive eligibility criteria to enroll populations of patients with AGC that are more reflective of the real-world population with respect to age, complications, and overall health status.

Background Anti-PD-1 monoclonal antibody, nivolumab, has shown efficacy for advanced gastric cancer (AGC). However, the specific immune cell subsets predominantly activated during the period of anti-PD-1 therapy for AGC have not been clarified. Methods Peripheral blood of 30 AGC patients treated with nivolumab was prospectively obtained before the initial and second administrations and at the time of progressive disease (PD). The proportions of immune cell subsets and the serum concentrations of cytokines were systematically analysed by flow cytometry. Associations of subsets and serum cytokines with therapeutic effects were evaluated. Results After the initial administration, significant increases in activated central/effector memory, activated effector T cells, and activated T-helper 1 subsets were observed. At the time of PD, activated regulatory T cells, LAG3-positive CD4+/CD8+ T cells, and TIM3-positive CD4+/CD8+ T cells increased significantly. Significant positive correlations were shown between progression-free survival and proportions of LAG3-positive CD4+/CD8+ T cells and of OX40-positive CD4+/CD8+ T cells (log-rank p = 0.0008, 0.0003, 0.0035 and 0.0040). Conclusions Nivolumab therapy enhances activation of central/effector memory and effector subsets of CD4+/CD8+ T cells. The expression levels of LAG-3 and OX40 on T cells correlated with the efficacy of nivolumab therapy and could be reasonable biomarkers for anti-PD-1 therapy.

The mainstream first-line chemotherapy for advanced/recurrent gastric cancer (ARGC) is combination therapy including platinum-based agents. With the progressive aging of the society, the incidence of gastric cancer in elderly patients is increasing. However, elderly patients cannot tolerate these agents because of renal dysfunction or low quality of life. The KSCC1701 study explored the efficacy and safety of S-1 + ramucirumab in elderly patients with ARGC.Chemotherapy-naive patients aged ≥70 years with ARGC were eligible. Patients received S-1 (40-60 mg twice daily for 4 weeks in 6-week cycles) and ramucirumab (8 mg/kg every 2 weeks) until disease progression. The primary end-point was the 1-year overall survival (OS) rate. The anticipated lower threshold of 1-year survival was set at 40% in light of previous S-1-based regimens. The secondary end-points included progression-free survival (PFS), OS, the overall response rate (ORR) and safety.Between September 2017 and November 2019, 48 patients (34 men and 14 women) were enrolled in this study. The median patient age was 77.5 years, and all patients had a performance status of 0 (n = 20) or 1 (n = 28). The 1-year OS rate was 65.2%, which met the primary end-point. The median survival time and median PFS were 16.4 and 5.8 months, respectively. The ORR was 41.9%. The most frequent grade 3/4 (≥15%) adverse events were neutropenia, anorexia and anaemia.Considering these findings, S-1 + ramucirumab appears to be an excellent treatment option for elderly patients with ARGC. (250 words). This trial has been registered with the Japan Registry of Clinical Trials Registry under the number jRCTs071180066.

Background The ML18174 study, which showed benefits of bevacizumab (BEV) continuation beyond progression (BBP) for metastatic colorectal cancer (mCRC), excluded patients with first-line progression-free survival (PFS) shorter than 3 months. The present study was conducted to evaluate the efficacy of second-line chemotherapy after early disease progression during first-line chemotherapy containing bevacizumab. Methods The subjects of this study were mCRC patients who experienced disease progression Results Sixty-one patients were identified as subjects of this study. Baseline characteristics were numerically different between BBP (n = 37) and non-BBP (n = 25) groups, such as performance status (0–1/> 2/unknown: 89/8/3 and 56/40/4%), RAS status (wild/mutant/unknown: 32/54/16 and 76/16/8%). Response rate was 8.6% in BBP group and 9.1% in non-BBP group (p = 1.00). Median PFS was 3.9 months in BBP group and 2.8 months in non-BBP group (HR [95%CI]: 0.79 [0.46–1.34], p = 0.373, adjusted HR: 0.87 [0.41–1.82], p = 0.707). Median overall survival was 8.5 months in BBP group and 5.4 months in non-BBP group (HR 0.66 [0.38–1.12], p = 0.125, adjusted HR 0.53 [0.27–1.07], p = 0.078). Conclusion In mCRC patients who experienced early progression in first-line chemotherapy, second-line chemotherapy showed poor clinical outcomes regardless use of anti-angiogenic agents.

Objectives FOLFIRINOX (FFX, a combination of oxaliplatin, irinotecan, fluorouracil, and leucovorin) and gemcitabine plus nab-paclitaxel (GnP) have been used as standard, first-line treatments for advanced pancreatic cancer. However, no study has compared the efficacy of the 2 regimens. This study retrospectively compared the efficacy and safety of the 2 regimens in patients with locally advanced pancreatic cancer. Methods We reviewed the records of patients with locally advanced pancreatic cancer who started FFX or GnP as first-line chemotherapy as part of a multicenter retrospective study in patients with unresectable pancreatic cancer treated with FFX or GnP (NAPOLEON study). Results Sixteen of the 63 patients were treated with FFX, and the other 47 patients were treated with GnP between December 2013 and March 2017. There were no significant differences in median overall survival rate between the GnP (15.5 months) and FFX (14.3 months, P = 0.60) groups or median progression-free survival rate between the GnP (8.8 months) and FFX (8.1 months, P = 0.51) groups. Both treatments were generally well tolerated, although anorexia was more severe in the FFX group than in the GnP group. Conclusions The effects of FFX and GnP were similar but resulted in different toxicities, which could guide agent choice.

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. 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. 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. 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.

BackgroundPrimary 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 MethodsWe 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.ResultsA 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).ConclusionsIn the present study, PTL is not a prognostic and predictive factor in patients with mCRC under later-line REG or FTD/TPI therapy.

Trastuzumab (T-mab) combined with cisplatin and fluoropyrimidines is a standard first-line treatment for HER2+ advanced gastric cancer (AGC). We conducted the first phase II trial among four Japanese study groups to assess the efficacy and safety of T-mab + S-1 and oxaliplatin (T-SOX130) for HER2+ AGC or recurrent gastric cancer. Patients with IHC 3+ or IHC 2+/FISH+ tumors received 80 mg/m2 (80–120 mg/day) oral S-1 on days 1–14, 130 mg/m2 intravenous oxaliplatin on day 1, and intravenous T-mab (8 mg/kg loading dose, 6 mg/kg thereafter) on day 1 of a 21-day cycle. The primary endpoint was centrally assessed response rate (RR). Adverse events were based on the Common Terminology Criteria for Adverse Events (CTCAE) Ver.4.0. We enrolled 42 patients from June 2015 to May 2016. Efficacy and safety analyses were conducted for 39 patients. The data cutoff was May 31, 2018. The confirmed RR was 82.1% (32/39; 90% CI 70.0–90.0); the disease control rate was 87.2% (34/39; 95% CI 73.3–94.4). Nine patients underwent curative surgery after T-SOX130. Median Time to treatment failure (TTF), Progression-free survival (PFS) and Overall survival (OS) was 5.7 (95% CI 4.6–7.0), 7.0 (95% CI 5.5–14.1), and 27.6 (95% CI 15.6–Not reached) months, respectively. Incidences of grade 3–4 adverse events > 10% were thrombocytopenia (17.9%), anorexia (17.9%), anemia (12.8%), neutropenia (10.3%), and hyponatremia (10.3%). T-SOX130 showed promising response and survival with a favorable safety profile and should be considered for patients with HER2+ AGC.

Capmatinib is a highly specific, potent and selective MET inhibitor. This was an open‐label, multicenter, dose‐escalation, phase I study conducted in Japanese patients with advanced solid tumors (not selected based on their MET status). The primary objective was to determine the maximum tolerated dose (MTD) and/or highest studied dose being safe. Secondary objectives included safety, pharmacokinetics and preliminary antitumor activity. Dose escalation was guided by a Bayesian Logistic Regression Model dependent on dose‐limiting toxicities (DLT) in cycle 1. Of 44 adult Japanese patients with confirmed advanced solid tumors enrolled, 29 received capmatinib capsules (doses ranging from 100 mg once daily [q.d.] to 600 mg twice daily [b.i.d.]) and 15 received tablets (200 mg b.i.d. and 400 mg b.i.d.). DLT occurred in two patients: grade 2 suicidal ideation (600 mg b.i.d. capsule) and grade 3 depression (400 mg b.i.d. tablet). MTD was not reached. The highest studied dose determined to be safe as tablet was 400 mg b.i.d., whereas it is not yet determined for capsules. Most common adverse events suspected to be drug‐related were increased blood creatinine, nausea, decreased appetite, vomiting and diarrhea. Following repeated daily dosing up to day 15 by q.d. or b.i.d. regimen using capsules, median time to reach maximum plasma drug concentration (T max) was 1.0‐4.0 hours; absorption was more rapid after dosing using tablets, with median T max of 1.0 hour on both days 1 and 15. Eight patients had a best overall response of stable disease. These data support further clinical development of capmatinib.

Microbiome analysis has attracted attention in recent years as a tool to monitor individual health status. In particular, gut microbiota is closely related to autoimmunity, and detailed study of gut microbiota may enable prediction of the health status of individuals.Here, we aimed to conduct a detailed study to identify gastric cancer-specific gut microbiota and compare the data between patients with gastric cancer and healthy individuals. Toward this, we extracted DNA from feces of patients with advanced gastric cancer enrolled in the observational/translational study, the DELIVER trial (JACCRO GC-08: UMIN000030850) which evaluated clinical outcomes of nivolumab and developed host-related biomarkers for nivolumab in 500 patients with advanced gastric cancer, and obtained their sequence data at an average of 5 Gbps using whole-genome shotgun sequencing. We then performed genus classification and functional pathway analysis using Kyoto Encyclopedia of Genes and Genomes (KEGG).We analyzed differences in bacterial composition using the data of 476 Japanese patients with advanced gastric cancer (median age 70y, median BMI 20.0, 71% male, 37.0% of patients with relapse, 55.5% with previous gastrectomy) and public database of 106 healthy cases. Bifidobacterium, Anaerostipes, and Parabacteroides were predominant in the healthy individuals, whereas Streptococcus, Lactobacillus, and Odoribacter were predominant in patients with advanced gastric cancer. Furthermore, the KEGG pathway analysis showed that butanoate and pyruvate metabolism were enriched in the healthy individuals, whereas factors such as ABC transporters and ribosomes were enriched in the patients with advanced gastric cancer. Clustering analysis broadly classified the patients with advanced gastric cancer and healthy individuals into two clusters, and the clustering using pathway data enabled clearer classification of the patients with advanced gastric cancer and healthy individuals than the clustering using flora analysis. Additionally, the healthy individuals had higher bacterial flora diversity compared to the patients with advanced gastric cancer.We thus successfully identified the molecular characteristic of microbial genera and functional pathways in the gut in patients with advanced gastric cancer. We conclude that fecal metagenomic shotgun sequencing analysis might be used to detect gastric cancer. Citation Format: Ryo Matoba, Hiroshi Iijima, Yasuhiro Sakamoto, Ryohei Kawabata, Atsushi Ishiguro, Yusuke Akamaru, Yosuke Kito, Hiroshi Yabusaki, Jin Matsuyama, Masazumi Takahashi, Akitaka Makiyama, Takahisa Suzuki, Masahiro Tsuda, Hisateru Yasui, Jun Hihara, Toru Masuzawa, Hiroyuki Okuda, Junji Kawada, Shuhei Suzuki, Hisato Kawakami, Takako Eguchi Nakajima, Kei Muro, Wataru Ichikawa, Masashi Fujii, Yu Sunakawa. Molecular characteristics of gut microbiota in patients with gastric cancer: The DELIVER trial (JACCRO GC-08) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5957.

Background Anti-HER2 therapy has not demonstrated a survival advantage in the second-line setting of patients with HER2-positive gastric cancer. We conducted this study to assess changes in HER2 status and to identify possible biomarkers for acquired resistance after the use of trastuzumab as the first-line therapy. Patients and methods Patients with advanced or recurrent HER2-positive gastric adenocarcinoma who were diagnosed with progressive disease after the first-line trastuzumab-based therapy and developed pathologically confirmed adenocarcinoma within 3 months after completion of trastuzumab-based therapy were enrolled in this study. We collected re-biopsied samples from the HER2-positive patients who had developed resistance to trastuzumab and re-evaluated their HER2 status. Amplification of EGFR and c-met, as well as PIK3CA mutation, were comparatively analysed when samples were available. Results Among 33 eligible patients, loss of HER2 was identified in 20 patients (60.6%) with refractory disease. Immunohistochemistry showed that the rate of HER2 overexpression was greatly reduced after therapy (pre-HER2 3+: 24 [72.7%] vs. post-HER2 3+: 13 [39.4%]). We found that the use of fixatives other than 10% neutral buffered formalin significantly reduced the HER2-positive rate. EGFR amplification, c-met amplification and PIK3CA mutation before and after trastuzumab-based therapy were observed in 10.3% and 3.8%, 17.9% and 4.2% and 4.0% and 4.2% of cases, respectively. Conclusion Re-evaluation of HER2 status is needed to determine the appropriate use of anti-HER2–targeted therapy after disease progression. Our results also highlight the importance of formalin fixation conditions for HER2 testing.

BackgroundThe ML18174 study, which showed benefits of bevacizumab (BEV) continuation beyond progression (BBP) for metastatic colorectal cancer (mCRC), excluded patients with first-line progression-free survival (PFS) shorter than 3 months. The present study was conducted to evaluate the efficacy of second-line chemotherapy after early disease progression during first-line chemotherapy containing bevacizumab.MethodsThe subjects of this study were mCRC patients who experienced disease progression ResultsSixty-one patients were identified as subjects of this study. Baseline characteristics were numerically different between BBP (n = 36) and non-BBP (n = 25) groups, such as performance status (0-1/>2: 89/11 and 56/44%), RAS status (wild/mutant/unknown: 28/56/16 and 76/16/8%). Response rate was 5.9% in BBP group and 9.1% in non-BBP group (p = 0.642). Median PFS was 3.7 months in BBP group and 2.8 months in non-BBP group (HR [95%CI]: 0.83 [0.49–1.41], p = 0.489, adjusted HR: 0.97 [0.48–1.96], p = 0.932). Median overall survival was 7.6 months in BBP group and 5.4 months in non-BBP group (HR 0.70 [0.41–1.19], p = 0.191, adjusted HR 0.65 [0.34–1.25], p = 0.195).ConclusionIn patients experienced early progression in first-line chemotherapy, their outcomes of second-line chemotherapy were poor regardless of whether they were in BBP or non-BBP group.

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.

Perioperative chemotherapy is the standard of care for locally advanced gastric cancer (LAGC). This phase II study investigated the efficacy and safety of S-1 and oxaliplatin (SOX) as neoadjuvant chemotherapy (NAC) for LAGC and esophagogastric junction cancer (EGJC). Patients completed up to three cycles of SOX130 (oxaliplatin 130 mg/m2 on day 1, oral S-1 40–60 mg twice daily for 2 weeks every 3 weeks), followed by gastrectomy and D2 lymphadenectomy. The primary endpoint was the pathological response rate (pRR). The anastomosis leakage rate was the secondary endpoint in patients with EGJC, and other secondary endpoints were the R0 resection, overall survival (OS), and relapse-free survival (RFS) rates. Between April 2016 and July 2017, 47 patients (24 EGJC, 23 LAGC) were enrolled in this study. Forty-two patients (89.4%, 95% confidence interval [CI] = 76.9–96.5) underwent surgery, and R0 resection was achieved in 41 patients. The pRR was 59.5% (90% CI = 45.7–72.3). The major grade 3 or 4 toxicities were appetite loss in six patients (12.8%), thrombocytopenia in five patients (10.6%), and neutropenia and diarrhea in three patients (6.4%) each. The rate of severe anastomotic leakage (Clavien–Dindo classification grade III or higher) in 20 EGJC was 25.0% (90% CI = 10.4–45.6). The 3-year OS and RFS rate were 62.9% (95% CI = 47.2–75.1) and 53.2% (95% CI = 38.1–66.2), respectively. SOX130 demonstrated substantial benefit for LAGC and EGJC. However, special attention should be paid to anastomotic leakage during surgery for EGJC.

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.

Simple Summary Microsatellite instability-high (MSI-H) is an established biomarker for response to immune checkpoint inhibitors (ICIs). ICIs are not usually administered in the first-line setting for MSI-H tumors including gastric cancer (GC), although such tumors tend to be less responsive to cytotoxic chemotherapy compared with microsatellite-stable tumors. On the basis of evidence suggesting that nivolumab plus low-dose ipilimumab can improve survival in MSI-H colorectal cancer, we plan to investigate the efficacy and safety of this regimen for MSI-H GC, which accounts for ~5% of all GC cases. The NO LIMIT study (WJOG13320G/CA209-7W7) is an investigator-initiated, single-arm, open-label, 14-center phase 2 trial of nivolumab plus low-dose ipilimumab for MSI-H GC in the first-line setting. Its primary objective is to determine the overall response rate for the study treatment as assessed by blinded independent central review. The planned number of subjects is 28. Abstract Nivolumab (NIVO) plus low-dose ipilimumab (IPI) has shown a promising survival benefit in first-line treatment of microsatellite instability-high (MSI-H) colorectal cancer. We hypothesized that this regimen might also be beneficial for MSI-H gastric cancer (GC), which accounts for ~5% of all GC cases. NO LIMIT (WJOG13320G/CA209-7W7) is an investigator-initiated, single-arm, open-label, 14-center phase 2 trial of NIVO plus low-dose IPI for MSI-H GC in the first-line setting. Eligibility criteria include unresectable advanced, recurrent, or metastatic gastric or esophagogastric junction cancer with a histologically confirmed diagnosis of adenocarcinoma; confirmed MSI-H status with the MSI-IVD Kit (FALCO); no prior systemic anticancer therapy; an Eastern Cooperative Oncology Group performance status of 0 or 1; and a measurable lesion per RECIST 1.1. The primary objective of the study is to determine the overall response rate (ORR) for the NIVO+IPI regimen as assessed by blinded independent central review. Secondary end points include progression-free survival, overall survival, duration of response, safety, tolerability, and biomarkers. The number of patients was set at 28 on the basis of the threshold and expected ORR values of 35 and 65%, respectively, with a one-sided alpha error of 0.025 and power of 0.80. Subjects will receive treatment with nivolumab (240 mg) biweekly in combination with ipilimumab (1 mg/kg) every 6 weeks. The results of this study should clarify the therapeutic potential of NIVO+IPI for MSI-H GC in the first-line setting. Trial registration: JapicCTI-205400.

The objectives were to describe treatment sequences for advanced colorectal cancer (CRC), use of second-line FOLFIRI (leucovorin, 5-fluorouracil, irinotecan) plus antiangiogenic drug (bevacizumab, ramucirumab, aflibercept beta) therapy, and the factors associated with the duration of antitumor drug treatment from second-line antiangiogenic therapy in Japan. This retrospective observational study was conducted using a Japanese hospital-based administrative database. Patients were enrolled if they started adjuvant therapy (and presumably experienced early recurrence) or first-line treatment for advanced CRC between May 2016 and July 2019, and were analysed until September 2019. Factors associated with overall treatment duration from second-line treatment with FOLFIRI plus antiangiogenic drugs were explored with multivariate Cox regression analysis. The most common first-line treatments were FOLFOX (leucovorin, 5-fluorouracil, oxaliplatin) or CAPOX (capecitabine, oxaliplatin) with bevacizumab (presumed RAS-mutant CRC) and FOLFOX with panitumumab (presumed RAS-wild type CRC). The most common second-line treatments were FOLFIRI-based. Many patients did not transition to subsequent lines of therapy. For second-line treatment, antiangiogenic drugs were prescribed more often for patients with presumed RAS-mutant CRC, right-sided CRC, and independent activities of daily living (ADL). The median duration of second-line FOLFIRI plus antiangiogenic drug treatment was 4.5 months; 66.2% of patients transitioned to third-line therapy. Low body mass index and not fully independent ADL were significantly associated with shorter overall duration of antitumor drug treatment from second-line therapy. Left-sided CRC, presumed RAS-wild type CRC, previous use of oral fluoropyrimidines and use of proteinuria qualitative tests, antihypertensives, or anticholinergics during second-line therapy were significantly associated with longer treatment. Treatment of advanced CRC in Japan is consistent with both international and Japanese guidelines, but transition rates to subsequent therapies need improvement. In addition to antitumor drug treatment, better ADL, higher body mass index, management of hypertension, and proteinuria tests were associated with continuation of sequential therapy that included antiangiogenic drugs.

Background No reliable nomogram has been developed until date for predicting the survival in patients with unresectable pancreatic cancer undergoing treatment with gemcitabine plus nab-paclitaxel (GnP) or FOLFIRINOX (FFX).Methods This analysis was conducted using clinical data of patients with unresectable pancreatic cancer undergoing GnP or FFX treatment obtained from a multicenter study (NAPOLEON study). A Cox proportional hazards model was used to identify the independent prognostic factors. A nomogram to predict 6-, 12-, and 18-month survival probabilities was generated, validated by using the concordance index (C-index), and calibrated by the bootstrapping method. And then, we attempted risk stratification for survival by classifying the patients according to the sum of the scores on the nomogram (total nomogram points; TNP).Results A total of 318 patients were enrolled. A prognostic nomogram was generated using data on the Eastern Cooperative Oncology Group performance status, liver metastasis, serum LDH, serum CRP, and serum CA19-9. The C-indexes of the nomogram were 0.77, 0.72 and 0.70 for 6-, 12-, and 18-month survival, respectively. The calibration plot showed optimal agreement at all points. Risk stratification based on tertiles of the TNP yielded clear separations of the survival curves. The median survival times in the low-, moderate-, and high-risk groups were 15.8, 12.8 and 7.8 months (PConclusions: Our nomogram is a convenient and inexpensive tool to accurately predict survival in patients with unresectable pancreatic cancer undergoing treatment with GnP or FFX, and will help clinicians in selecting appropriate therapeutic strategies for individualized management.

Regorafenib is recognized as a later-line standard treatment in patients with metastatic colorectal cancer (mCRC). In this study, we examined the association of the albumin–bilirubin (ALBI) score in patients with mCRC receiving later-line chemotherapy with regorafenib. We retrospectively analyzed data from patients with mCRC treated with regorafenib in a later line between January 2013 and December 2019. Patients were divided into a Normal-ALBI group (ALBI grade 1) and a High-ALBI group (ALBI grades 2 and 3). Primary endpoint was median overall survival (OS) and secondary endpoints were median time to treatment failure (TTF) and incidence of adverse events (AEs). Data from 60 patients were analyzed (Normal-ALBI group: 32 patients and High-ALBI group: 28 patients). Median OS [10.23 vs. 3.70 months, hazard ratio (HR): 1.79, 95% confidence interval (CI) 1.02–3.13, p = 0.041] and median TTF (2.27 vs. 1.78 months, HR: 1.78, 95%CI 1.02–3.09, p = 0.042) were significantly longer in the Normal-ALBI group than High-ALBI group. On Cox proportional hazard analysis, ALBI score was significantly correlated with OS. The incidence of liver dysfunction (grade ≥ 2) was significantly higher in the High-ALBI than the Normal-ALBI group (42.9% vs. 15.6%, p = 0.041), whereas other AEs were comparable between the two groups. ALBI was strongly associated with the prognosis of patients with mCRC treated with regorafenib and with the occurrence of liver-related adverse events. These findings may imply that patients with a high ALBI score should not be treated with regorafenib.

BACKGROUND/AIM Nivolumab is effective against advanced gastric cancer (AGC) refractory to or in patients intolerant of standard chemotherapy. This study was designed to clarify the impact of cancer cachexia in patients with AGC who received nivolumab. PATIENTS AND METHODS We recruited AGC patients who were treated with nivolumab from October 2017 to December 2019. Clinical outcomes were compared between patients with and without cancer cachexia at the start of nivolumab. Cancer cachexia was defined as weight loss >5%; weight loss >2% and body mass index (BMI)

Background We aimed to assess the safety and efficacy of combination treatment with panitumumab plus trifluridine/tipiracil (FTD/TPI) in patients with wild-type RAS metastatic colorectal cancer (mCRC) who were refractory/intolerant to standard therapies other than anti-epidermal growth factor receptor therapy. Methods APOLLON was an open-label, multicentre, phase 1/2 trial. In the phase 1 part, 3 + 3 de-escalation design was used to investigate the recommended phase 2 dose (RP2D); all patients in the phase 2 part received the RP2D. The primary endpoint was investigator-assessed progression-free survival (PFS) rate at 6 months. Secondary endpoints included PFS, overall survival (OS), overall response rate (ORR), disease control rate (DCR), time to treatment failure (TTF), and safety. Results Fifty-six patients were enrolled (phase 1, n = 7; phase 2, n = 49) at 25 Japanese centres. No dose-limiting toxicities were observed in patients receiving panitumumab (6 mg/kg every 2 weeks) plus FTD/TPI (35 mg/m2 twice daily; days 1–5 and 8–12 in a 28-day cycle), which became RP2D. PFS rate at 6 months was 33.3% (90% confidence interval [CI] 22.8–45.3). Median PFS, OS, ORR, DCR, and TTF were 5.8 months (95% CI 4.5–6.5), 14.1 months (95% CI 12.2–19.3), 37.0% (95% CI 24.3–51.3), 81.5% (95% CI 68.6–90.8), and 5.8 months (95% CI 4.29–6.21), respectively. Neutrophil count decreased (47.3%) was the most common Grade 3/4 treatment-emergent adverse event. No treatment-related deaths occurred. Conclusion Panitumumab plus FTD/TPI exhibited favourable anti-tumour activity with a manageable safety profile and may be a therapeutic option for pre-treated mCRC patients.

Background Although the efficacy of trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) against metastatic colorectal cancer (mCRC) has been demonstrated, little is known about its effectiveness upon disease stratification by RAS mutations. In this phase II study, we investigated the efficacy and safety profiles of FTD/TPI in mCRC according to RAS mutation status. Patients and methods Eligible patients were mCRC refractory or intolerant to all standard therapies other than FTD/TPI and regorafenib. Patients received 4-week cycles of treatment with FTD/TPI (35 mg/m2, twice daily, days 1-5 and 8-12) and bevacizumab (5 mg/kg, days 1 and 15). The primary endpoint was disease control rate (DCR). The null hypothesis of DCR in both RAS wild-type (WT) and mutant (MUT) cohorts was 44%, assuming a one-sided significance level of 5.0%. The necessary sample size was estimated to be 49 patients (target sample size: 50 patients) for each cohort. Results Between January and September 2018, 102 patients were enrolled, and 97 patients fulfilled the eligibility criteria (48 in the RAS WT cohort and 49 in the RAS MUT cohort). DCRs in the RAS WT and MUT cohort were 66.7% [90% confidence interval (CI), 53.9%-77.8%, P = 0.0013] and 55.1% (90% CI, 42.4%-67.3%, P = 0.0780), respectively. The median progression-free survival (PFS) and overall survival (OS) were 3.8 and 9.3 months, respectively, in the RAS WT cohort and 3.5 and 8.4 months, respectively, in the RAS MUT cohort. The most common grade 3 or higher adverse event in both cohorts was neutropenia (46% in the RAS WT cohort and 62% in the RAS MUT cohort), without unexpected safety signals. Conclusions FTD/TPI plus bevacizumab showed promising activity with an acceptable safety profile for pretreated mCRC, regardless of RAS mutation status, although the efficacy outcomes tended to be better in RAS WT., Highlights • We investigated the efficacy and safety of FTD/TPI in mCRC according to RAS mutation status. • DCRs in the RAS WT and MUT cohorts were 66.7% and 55.1%, respectively. • PFS and OS did not differ significantly according to RAS mutation status. • The most common adverse event (grade 3 or higher) in both cohorts was neutropenia. • FTD/TPI plus BEV treatment showed promising activity for pretreated mCRC, regardless of RAS mutation status.

Oxaliplatin-based adjuvant chemotherapy may be associated with debilitating peripheral sensory neuropathy (PSN) in patients with high-risk stage II colon cancer. This open-label, multicenter, randomized phase III trial was conducted as a prospective pooled analysis to investigate the non-inferiority of 3 versus 6 months of adjuvant oxaliplatin-based chemotherapy.From 12 February 2014 to 31 January 2017, 525 Asian patients with high-risk stage II colon cancer were randomly assigned to 3- and 6-month treatment arms. The treatment consisted of either modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or capecitabine combined with oxaliplatin (CAPOX). The primary end point was disease-free survival (DFS). The secondary end points were treatment compliance and safety.Of the 525 randomized patients, 11 were not treated. Among the 514 participating patients (255 in the 3-month arm; 259 in the 6-month arm), 432 (84%) received CAPOX, and 184 (36%) presented with T4 as a high-risk factor for recurrence. The 3-year DFS rate was 88.2% in the 3-month arm and 87.9% in the 6-month arm [hazard ratio (HR), 1.12; 95% confidence interval (CI), 0.67-1.87]. With CAPOX, the 3-year DFS rate was 88.2% in the 3-month arm and 88.4% in the 6-month arm (HR, 1.13; 95% CI, 0.65-1.96). The discontinuation rate in the 3- and 6-month arms was 10% and 31% for mFOLFOX6 (P = 0.0193), and 15% and 35% for CAPOX (P0.0001), respectively. The incidence of grade ≥2 PSN was significantly lower in the 3-month arm than in the 6-month arm (16% and 43%, respectively, P0.0001).Three months of combination therapy presented significantly less grade ≥2 PSN than the respective 6-month regimen. The shortened therapy duration did not affect the 3-year DFS rate, suggesting that a 3-month course of CAPOX can be an effective treatment option.UMIN Clinical Trials Registry, UMIN000013036 and Japan Registry of Clinical Trials, jRCTs031180128.

Background FOLFOXIRI plus bevacizumab is used as a first-line therapy for patients with unresectable or metastatic colorectal cancer. However, there are no clear recommendations for second-line therapy after FOLFOXIRI plus bevacizumab combination. Here, we describe our planning for the EFFORT study to investigate whether FOLFIRI plus aflibercept has efficacy following FOLFOXIRI plus bevacizumab for mCRC. Methods EFFORT is an open-label, multicenter, single arm phase II study to evaluate whether a FOLFIRI plus aflibercept has efficacy following FOLFOXIRI plus bevacizumab for mCRC. Patients with unresectable or metastatic colorectal cancer who received FOLFOXIRI plus bevacizumab as a first-line therapy will receive aflibercept and FOLFIRI (aflibercept 4 mg/kg, irinotecan 150 mg/m2 IV over 90 min, with levofolinate 200 mg/m2 IV over 2 h, followed by fluorouracil 400 mg/m2 bolus and fluorouracil 2400 mg/m2 continuous infusion over 46 h) every 2 weeks on day 1 of each cycle. The primary endpoint is progression-free survival (PFS). To achieve 80% power to show a significant response benefit with a one-sided alpha level of 0.10, assuming a threshold progression-free survival of 3 months and an expected value of at least 5.4 months, we estimated that 32 patients are necessary. Secondary endpoints include overall survival, overall response rate, safety, and exploratory biomarker analysis for differentiating anti-VEGF drug in 2nd-line chemotherapy for unresectable or metastatic colorectal cancer. Discussion This is the first study to investigate whether FOLFIRI plus aflibercept has efficacy following FOLFOXIRI plus bevacizumab for unresectable or metastatic colorectal cancer. Switching to a different type of anti-VEGF drug in second-line therapy after FOLFOXIRI plus bevacizumab appears to be an attractive treatment strategy when considering survival benefit. It is expected that this phase II study will prove the efficacy of this strategy and that a biomarker for drug selection will be discovered. Trial registration Japan Registry of Clinical Trials jRCTs071190003. Registered April 18, 2019.

OBJECTIVE The aim of this study is to identify biomarkers that predict efficacy of preoperative therapy and survival for esophageal squamous cell carcinoma (ESCC). BACKGROUND It is essential to improve the accuracy of preoperative molecular diagnostics to identify specific patients who will benefit from the treatment; thus, this issue should be resolved with a large-cohort, retrospective observational study. METHODS A total of 656 patients with ESCC who received surgery after preoperative CDDP + 5-FU therapy, docetaxel + CDDP + 5-FU therapy or chemoradiotherapy (CRT) were enrolled. Immunohistochemical analysis of TP53, CDKN1A, RAD51, MutT-homolog 1, and programmed death-ligand 1 was performed with biopsy samples obtained before preoperative therapy, and expression was measured by immunohistochemistry. RESULTS In all therapy groups, overall survival was statistically separated by pathological effect (grade 3 > grade 2 > grade 0, 1, P < 0.0001). There was no correlation between TP53, CDKN1A, MutT-homolog 1, programmed death-ligand 1 expression, and pathological effect, whereas the proportion of positive RAD51 expression (≥50%) in cases with grade 3 was lower than that with grade 0, 1, and 2 (P = 0.022). In the CRT group, the survival of patients with RAD51-positive tumor was significantly worse than RAD51-negative expressors (P = 0.0119). Subgroup analysis of overall survival with respect to positive RAD51 expression indicated preoperative chemotherapy (CDDP + 5-FU or docetaxel + CDDP + 5-FU) was superior to CRT. CONCLUSIONS In ESCC, positive RAD51 expression was identified as a useful biomarker to predict resistance to preoperative therapy and poor prognosis in patients who received preoperative CRT. Administration of preoperative chemotherapy may be warranted for patients with positive RAD51 expression.

Lessons Learned A biweekly TAS-102 plus BEV schedule in patients with heavily pretreated mCRC showed equivalent efficacy with less toxicity compared with the current schedule of TAS-102 plus BEV combination. Biweekly TAS-102 plus BEV combination could reduce unnecessary dose reduction of TAS-102, maintain higher doses, and possibly be effective even in cases without chemotherapy-induced neutropenia (CIN). The prespecified subgroup analysis of this study showed an obvious association between CIN within the first two cycles and prognosis of biweekly TAS-102 plus BEV. Background TAS-102 (trifluridine/tipiracil) plus bevacizumab (BEV) combination therapy has shown promising activity in patients with metastatic colorectal cancer (mCRC). However, the previously reported dose and schedule for the TAS-102 (70 mg/m2/day on days 1–5 and 8–12, every 4 weeks) plus BEV (5 mg/kg on day 1, every 2 weeks) regimen is complicated by severe hematological toxicities and difficult administration schedules. Here, we evaluated the efficacy and safety of a more convenient biweekly TAS-102 plus BEV combination. Methods Patients with mCRC who were refractory or intolerant to standard chemotherapies were enrolled. Patients received biweekly TAS-102 (twice daily on days 1–5, every 2 weeks) with BEV (5mg/kg on day 1, every 2 weeks). The primary endpoint was progression-free survival rate at 16 weeks (16-w PFS rate). Results From October 2017 to January 2018, 46 patients were enrolled. The recommended phase II dose was determined to be TAS-102 (70 mg/m2/day). Of the 44 eligible patients, the 16-w PFS rate was 40.9% (95% confidence interval, 26.3%–56.8%), and the null hypothesis was rejected (p < .0001). Median progression-free survival (PFS) and overall survival were 4.29 months and 10.86 months, respectively. Disease control rate was 59.1%. Common grade 3 or higher adverse events were hypertension (40.9%), neutropenia (15.9%), and leucopenia (15.9%). Conclusion Biweekly TAS-102 plus BEV showed promising antitumor activity with safety.

This study was designed to assess the tolerability, efficacy, and safety of tri-weekly irinotecan plus S-1 (IRIS) and weekly cetuximab in patients with metastatic colorectal cancer (mCRC). The main eligibility criteria were RAS wild-type mCRC with no prior chemotherapy. S-1 was given orally at a dose of 40 mg/m2 (40–60 mg) twice for 2 weeks, followed by a 1-week rest. Irinotecan was given on day 1 of each cycle at a dose of 150 mg/m2. Cetuximab was administered on days 1 (400 mg/m2), 8 (250 mg/m2), and 15 (250 mg/m2), and then once weekly (250 mg/m2) thereafter. A standard 3 + 3 phase I dose de-escalation design was used to determine the maximum tolerated dose and the recommended dose (RD) of irinotecan. The primary end point of the Phase II study was overall response rate (ORR). Between December 2014 and September 2017, 4 and 54 patients were enrolled in phase I and phase II studies, respectively. No dose-limiting toxicity was observed in the phase I study, and the RD of irinotecan was 150 mg/m2. In the phase II study, the ORR was 56.9% (90% confidence interval 44.4%–68.7%). The safety profile revealed that the most common grade 3/4 adverse events were neutropenia (31.4%), appetite loss (27.5%), hypokalemia (11.8%), and diarrhea (11.8%). Grade 3/4 hand–foot skin syndrome occurred in nine patients (9.8%). This study showed that the efficacy and safety of IRIS combined with cetuximab were comparable to those for other first-line treatments. This regimen is a good candidate for first-line treatment of RAS wild-type mCRC.

PURPOSE This study evaluated the continuous use of trastuzumab beyond progression (TBP) in human epidermal growth factor receptor 2 (HER2)-positive advanced gastric or gastroesophageal junction (G/GEJ) cancer. PATIENTS AND METHODS Patients with HER2-positive advanced G/GEJ cancer refractory to first-line chemotherapy with trastuzumab in combination with fluoropyrimidine and platinum were eligible. Patients were randomly assigned to the paclitaxel (80 mg/m2, days 1, 8, and 15, every 4 weeks) or paclitaxel with trastuzumab (PT; initially 8 mg/kg followed by 6 mg/kg, every 3 weeks) arms. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), response rate, and safety. Biomarkers such as HER2 expression status in tumor tissue after first-line treatment, HER2 amplification evaluated in serum cell-free DNA, and soluble HER2 levels were analyzed. RESULTS Overall, 91 patients were allocated to the paclitaxel (n = 46) and PT (n = 45) arms. The median PFS in the paclitaxel and PT arms was 3.2 and 3.7 months, respectively (hazard ratio [HR], 0.91; 80% CI, 0.67 to 1.22; P = .33), and the median OS in both arms was 10 months (HR, 1.2; 95% CI, 0.75 to 2.0; P = .20). The overall response rates in the paclitaxel and PT arms were 32% and 33%, respectively ( P = 1.00), and safety was comparable between the 2 arms. On exploratory analyses, HER2 positivity of tumor tissues was lost after first-line chemotherapy in 11 (69%) of 16 patients whose tumor tissues were available, and circulating HER2 DNA amplification was detected in 41 (60%) of 68 patients. However, no biomarkers associated with efficacy of TBP were found. CONCLUSION The TBP strategy failed to improve PFS in patients with HER2-positive advanced G/GEJ cancer, and no beneficial biomarkers were found.

Background: Molecular targeted drugs having angiogenesis-inhibiting properties allow the induction of necrosis inside tumors. We retrospectively investigated the relationship between changes on imaging associated with regorafenib (REGO) and treatment outcomes using real-world data. Patients and Methods: The eligibility criteria included an ECOG PS of 0–1, a starting dose of 120 or 160 mg/day of REGO, and a duration of treatment of at least 35 days. Regarding changes on imaging, cavitation in lung lesions (CLL), morphologic response of liver lesions (MRL), and change of liver metastasis density (CLD) were evaluated. Results: We finally screened 671 cases, and 226 cases were eligible. In total, 172 and 145 patients had lung and liver metastases, respectively. Among the patients with lung metastasis, CLL was found in 69 patients (40.0%). The median progression-free survival (PFS) of the patients with and those without CLL was 3.2 and 2.4 months, respectively (hazard ratio [HR] = 0.758; 95% confidence interval [CI]: 0.529–1.087), and the median overall survival (OS) of these groups was 10.5 and 8.9 months, respectively (HR = 0.862; 95% CI: 0.579–1.285). MRL and CLD of liver metastasis were analyzed in 145 and 90 patients, respectively. The median OS with and without MRL was 8.9 and 8.2 months, respectively, whereas the median OS with and without CLD was 11.6 and 7.7 months, respectively (HR = 0.523; 95% CI: 0.275–0.992). Conclusion: CLL may predict PFS but not OS among patients with lung metastasis. CLD was predictive of favorable outcomes for REGO in patients with liver metastasis.

Background: The randomized phase II WJOG6510G study demonstrated the non-inferiority of panitumumab to cetuximab in terms of progression-free survival (PFS) in patients with wild-type KRAS exon 2 metastatic colorectal cancer. In this study, we performed exploratory analyses of updated survival data using the KRAS exon 2 and RAS/BRAF statuses. Methods: Patients with wild-type KRAS exon 2 metastatic colorectal cancer who experienced progression after the failure of fluoropyrimidine, oxaliplatin, and irinotecan were randomized to receive panitumumab or cetuximab in combination with irinotecan. An independent central laboratory performed RAS/BRAF testing using a PCR-reverse sequence-specific oligonucleotide method. Results: In the updated analysis of 121 enrolled patients after a median follow-up of 31.3 months, the median PFS was 5.4 months in the panitumumab arm, versus 4.3 months in the cetuximab arm (hazard ratio [HR]=0.68). The median overall survival (OS) times were 14.9 and 12.5 months in the panitumumab and cetuximab arms, respectively (HR=0.68). In 83 analyzed patients, RAS/BRAF testing identified 19 (23%) and 4 patients (5%) with RAS and BRAF mutations, respectively. In the wild-type RAS and BRAF population, trends of better PFS (6.5 months versus 4.6 months; HR=0.57) and OS (15.3 months versus 11.8 months; HR=0.77) were observed for panitumumab. Conclusions: In this updated analysis, panitumumab was associated with a modest survival benefit versus cetuximab in patients with centrally confirmed wild-type KRAS exon 2 metastatic colorectal cancer as well as in the wild-type RAS and BRAF population.

43 Background: Three antiangiogenic (AA) drugs, bevacizumab (BEV), ramucirumab (RAM) and aflibercept (AFL) are recommended as the second-line (2L) treatment for metastatic colorectal cancer (mCRC) in the CRC treatment guidelines of multiple countries and regions including the US, EU and Japan. However, little evidence of 2L RAM and AFL after anti-EGFR antibodies (EGFRab) in first- line (1L) has been reported. This study assessed treatment sequence for mCRC patients who received 2L irinotecan-based chemotherapy with AA drug after FOLFOX + EGFRab in 1L, treatment duration from the start of 2L to the end of last treatment line (treatment duration from 2L) and factors associated with the treatment duration from 2L. Methods: This is a real-world observational study using a hospital-based claims database of 393 hospitals in Japan. The mCRC patients who started 1L treatment with FOLFOX + EGFRab between May 2016 and Sep 2019 (identification period) and further treated with irinotecan-based chemotherapy + AA drug were enrolled. The key outcomes were the treatment sequence, treatment duration from 2L by AA drug, and factors associated with the treatment duration from 2L. Survival curves were estimated using the Kaplan–Meier method. Associated factors were investigated using Cox regression analysis. Results: Among 2,453 patients with 1L FOLFOX + EGFRab during the identification period, 506 patients who received the intended 2L therapies were enrolled in this study (mean age 63.5 years, male 66.6%). Number (%) of patients who used BEV, RAM and AFL in 2L was 345 (68.2), 120 (23.7) and 41 (8.1), respectively. Patient characteristics involving tumor location, metastatic site and prior anti-tumor therapy before starting 2L were similar among BEV, RAM and AFL. The treatment duration from 2L (median month and its 95%CI) was 11.1 (10.2-12.5) in the overall population and was similar among the patients who received BEV (10.8 [9.9-13.1]), RAM (11.2 [10.0-14.2]) and AFL (12.8 [6.9-NA]) in 2L. The treatment duration from 2L (median month and its 95%CI) for the patients who took or didn’t take proteinuria tests during 2L was 12.5 (11.1-15.2) and 8.5 (6.5-11.2), respectively. Factors positively associated with treatment duration from 2L were left-sided CRC (HR [95%CI] = 0.71 [0.53-0.96]) and ≥6 months of 1L duration (0.72 [0.56-0.93]); having renal disease (1.92 [1.28-2.88]) or received NSAIDs (1.63 [1.25-2.13]) within 60 days before starting 2L were associated negatively. Conclusions: The real-world data revealed that treatment duration were similar among BEV, RAM and AFL in 2L after EGFRab. Tumor location and 1L duration were associated with the treatment duration from 2L positively, while negative association was observed with renal disease and received NSAIDs. Treatment management was important for treatment continuation.