Publications by authors named "Masafumi Ikeda"

243 Publications

A phase II study of FOLFIRINOX with primary prophylactic pegfilgrastim for chemotherapy-naïve Japanese patients with metastatic pancreatic cancer.

Int J Clin Oncol 2021 Aug 8. Epub 2021 Aug 8.

Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan.

Background: Although FOLFIRINOX is currently one of the standard therapies for chemotherapy-naïve patients with metastatic pancreatic cancer (MPC), the high rate of febrile neutropenia (FN) presents a clinical problem. This study aimed to evaluate the safety and efficacy of primary prophylactic pegfilgrastim with FOLFIRINOX in Japanese MPC patients.

Methods: FOLFIRINOX (intravenous oxaliplatin 85 mg/m, irinotecan 180 mg/m, levofolinate 200 mg/m, 5-fluorouracil (5-FU) bolus 400 mg/m and 5-FU 46 h infusion 2400 mg/m) and pegfilgrastim 3.6 mg on day 4 or 5, every 2 weeks was administered to previously untreated MPC patients. The primary endpoint was the incidence of FN during the first 3 cycles. The planned sample size was 35 patients, but the trial was predefined to discontinue enrollment for safety if 4 patients developed FN.

Results: At the enrollment of 22 patients, 4 patients developed FN in the first cycle, resulting in an incidence of FN of 18% {95% confidence interval [CI], 0.5-40.3%}, and enrollment was discontinued early. The incidence of grade 3 or higher neutropenia was 36.4%. Median relative dose intensities during the initial 3 cycles of oxaliplatin, irinotecan, bolus 5-FU, infusional 5-FU, and levofolinate maintained high (100%, 89.0%, 100%, 66.0%, and 100%, respectively). Response rate and median overall survival were 54.5% (95% CI 32.7-74.9) and 15.7 months (95% CI 7.9-18.8), respectively.

Conclusions: This phase II study could not demonstrate any reduction in the incidence of FN, nevertheless some patients experience benefits for efficacy by maintaining dose intensity using prophylactic pegfilgrastim.

Trial Registration: http://www.umin.ac.jp/ctr/index-j.htm , UMIN000017538. Date of registration: May/13/2015.
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http://dx.doi.org/10.1007/s10147-021-02001-yDOI Listing
August 2021

Safety, Efficacy, and Pharmacodynamics of Tremelimumab Plus Durvalumab for Patients With Unresectable Hepatocellular Carcinoma: Randomized Expansion of a Phase I/II Study.

J Clin Oncol 2021 Sep 22;39(27):2991-3001. Epub 2021 Jul 22.

Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: This phase I/II study evaluated tremelimumab (anticytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody) and durvalumab (antiprogrammed death ligand-1 monoclonal antibody) as monotherapies and in combination for patients with unresectable hepatocellular carcinoma (HCC), including a novel regimen featuring a single, priming dose of tremelimumab (ClinicalTrials.gov identifier: NCT02519348).

Patients And Methods: Patients with HCC who had progressed on, were intolerant to, or refused sorafenib were randomly assigned to receive T300 + D (tremelimumab 300 mg plus durvalumab 1,500 mg [one dose each during the first cycle] followed by durvalumab 1,500 mg once every 4 weeks), durvalumab monotherapy (1,500 mg once every 4 weeks), tremelimumab monotherapy (750 mg once every 4 weeks [seven doses] and then once every 12 weeks), or T75 + D (tremelimumab 75 mg once every 4 weeks plus durvalumab 1,500 mg once every 4 weeks [four doses] followed by durvalumab 1,500 mg once every 4 weeks). Safety was the primary end point. Secondary end points included objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors v1.1 and overall survival; exploratory end points included circulating lymphocyte profiles.

Results: A total of 332 patients were enrolled (T300 + D, n = 75; durvalumab, n = 104; tremelimumab, n = 69; and T75 + D, n = 84). Tolerability was acceptable across arms, with grade ≥ 3 treatment-related adverse events occurring in 37.8%, 20.8%, 43.5%, and 24.4%, respectively. Confirmed ORRs (95% CI) were 24.0% (14.9 to 35.3), 10.6% (5.4 to 18.1), 7.2% (2.4 to 16.1), and 9.5% (4.2 to 17.9), respectively. An early expansion of CD8+ lymphocytes was associated with response across arms, with highest proliferating CD8+ lymphocyte levels occurring in the T300 + D arm. The median (95% CI) overall survival was 18.7 (10.8 to 27.3), 13.6 (8.7 to 17.6), 15.1 (11.3 to 20.5), and 11.3 (8.4 to 15.0) months in the T300 + D, durvalumab, tremelimumab, and T75 + D arms, respectively.

Conclusion: All regimens were found to be tolerable and clinically active; however, the T300 + D regimen demonstrated the most encouraging benefit-risk profile. The unique pharmacodynamic activity and association with ORR of the T300 + D regimen further support its continued evaluation in HCC.
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http://dx.doi.org/10.1200/JCO.20.03555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8445563PMC
September 2021

Systemic therapy for hepatocellular carcinoma: current status and future perspectives.

Jpn J Clin Oncol 2021 Aug;51(9):1363-1371

Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan.

Since sorafenib was established as the standard of care for patients with advanced hepatocellular carcinoma, various tyrosine kinase inhibitors, targeting vascular endothelial growth factor receptor and other molecular growth factors, have been developed. Lenvatinib demonstrated non-inferiority to sorafenib in terms of the overall survival, and it has also become confirmed as another standard of care for patients with advanced hepatocellular carcinoma. Recently, various immune checkpoint inhibitors have been investigated, either as monotherapy or in combination with another agent, and superiority of the combination of atezolizumab plus bevacizumab, in terms of the overall survival and progression-free survival, has been demonstrated over sorafenib, which is recognized as the treatment regimen of first choice for first-line systemic therapy of advanced hepatocellular carcinoma. Regorafenib, cabozantinib and ramucirumab have been demonstrated to show survival benefits as second-line treatment agents for progressive disease after first-line sorafenib treatment. There are still various medical requirements in systemic therapy for hepatocellular carcinoma. To date, no evidence has been established for the selection of sequential treatment after immune checkpoint inhibitor-containing treatments, especially atezolizumab plus bevacizumab. A promising treatment for Child-Pugh class B hepatocellular carcinoma patients is also an urgent medical need that has not yet been met. Although there are some difficulties in establishing the needed evidence, well-designed clinical trials are warranted.
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http://dx.doi.org/10.1093/jjco/hyab108DOI Listing
August 2021

Management of Hepatocellular Carcinoma in Japan: JSH Consensus Statements and Recommendations 2021 Update.

Liver Cancer 2021 Jun 19;10(3):181-223. Epub 2021 May 19.

Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan.

The Clinical Practice Manual for Hepatocellular Carcinoma was published based on evidence confirmed by the Evidence-based Clinical Practice Guidelines for Hepatocellular Carcinoma along with consensus opinion among a Japan Society of Hepatology (JSH) expert panel on hepatocellular carcinoma (HCC). Since the JSH Clinical Practice Guidelines are based on original articles with extremely high levels of evidence, expert opinions on HCC management in clinical practice or consensus on newly developed treatments are not included. However, the practice manual incorporates the literature based on clinical data, expert opinion, and real-world clinical practice currently conducted in Japan to facilitate its use by clinicians. Alongside each revision of the JSH Guidelines, we issued an update to the manual, with the first edition of the manual published in 2007, the second edition in 2010, the third edition in 2015, and the fourth edition in 2020, which includes the 2017 edition of the JSH Guideline. This article is an excerpt from the fourth edition of the HCC Clinical Practice Manual focusing on pathology, diagnosis, and treatment of HCC. It is designed as a practical manual different from the latest version of the JSH Clinical Practice Guidelines. This practice manual was written by an expert panel from the JSH, with emphasis on the consensus statements and recommendations for the management of HCC proposed by the JSH expert panel. In this article, we included newly developed clinical practices that are relatively common among Japanese experts in this field, although all of their statements are not associated with a high level of evidence, but these practices are likely to be incorporated into guidelines in the future. To write this article, coauthors from different institutions drafted the content and then critically reviewed each other's work. The revised content was then critically reviewed by the Board of Directors and the Planning and Public Relations Committee of JSH before publication to confirm the consensus statements and recommendations. The consensus statements and recommendations presented in this report represent measures actually being conducted at the highest-level HCC treatment centers in Japan. We hope this article provides insight into the actual situation of HCC practice in Japan, thereby affecting the global practice pattern in the management of HCC.
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http://dx.doi.org/10.1159/000514174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237791PMC
June 2021

Impact of Endoscopic Ultrasound-Guided Tissue Acquisition on Decision-Making in Precision Medicine for Pancreatic Cancer: Beyond Diagnosis.

Diagnostics (Basel) 2021 Jun 30;11(7). Epub 2021 Jun 30.

Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa 277-8577, Chiba, Japan.

Precision medicine in cancer treatment refers to targeted therapy based on the evaluation of biomarkers. Although precision medicine for pancreatic cancer (PC) remains challenging, novel biomarker-based therapies, such as pembrolizumab, olaparib, and entrectinib, have been emerging. Most commonly, endoscopic ultrasound-guided tissue acquisition (EUS-TA) had been used for the diagnosis of PC until now. However, advances in EUS-TA devices and biomarker testing, especially next-generation sequencing, have opened up the possibility of sequencing of various genes even in limited amounts of tissue samples obtained by EUS-TA, and identifying potential genetic alterations as therapeutic targets. Precision medicine benefits only a small population of patients with PC, but biomarker-based therapy has shown promising results in patients who once had no treatment options. Now, the role of EUS-TA has extended beyond diagnosis into decision-making regarding the treatment of PC. In this review, we mainly discuss tissue sampling by EUS-TA for biomarker testing and the current status of precision medicine for PC.
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http://dx.doi.org/10.3390/diagnostics11071195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8307595PMC
June 2021

Safety, pharmacokinetics, and preliminary efficacy of the PARP inhibitor talazoparib in Japanese patients with advanced solid tumors: phase 1 study.

Invest New Drugs 2021 Jun 23. Epub 2021 Jun 23.

National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.

Background: Talazoparib is a poly(ADP-ribose) polymerase enzyme inhibitor. This open-label, non-randomized, phase 1 study of talazoparib investigated the safety, pharmacokinetics, and preliminary antitumor activity in Japanese patients with locally advanced or metastatic solid tumors, regardless of mutations in DNA damage repair-related genes, who are resistant to/ineligible for standard therapies.

Methods: Patients received talazoparib dosed orally at 0.75 or 1 mg once daily using a modified 3 + 3 dose-escalation scheme. Primary endpoint was dose-limiting toxicities during the first cycle of talazoparib.

Results: Nine patients (median age 62.0 years) were included: 3 and 6 patients at the 0.75 and 1.0 mg once-daily dose levels, respectively. No dose-limiting toxicities were reported. The most commonly reported treatment-emergent adverse events (≥2 patients) were anemia, stomatitis, maculopapular rash, platelet count decreased, neutrophil count decreased, and alanine aminotransferase increased. Three patients had grade ≥ 3 treatment-emergent adverse events (anemia, brain metastases [1 patient each], and neutrophil and white blood cell count decreased [same patient]). Two patients temporarily discontinued treatment due to a treatment-emergent adverse event, and 1 patient required a dose reduction for neutrophil count decreased (all at 1 mg once daily). Talazoparib exposure (C and AUC) after single and multiple dosing was slightly higher proportionally with talazoparib 1 mg than talazoparib 0.75 mg. The overall disease control rate was 44.4%, including 2 patients with stable disease. The recommended phase 2 dose of talazoparib was established as 1 mg once daily.

Conclusions: Single-agent talazoparib was well tolerated and had preliminary antitumor activity in Japanese patients with advanced solid tumors. ClinicalTrials.gov identifier: NCT03343054 (November 17, 2017).
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http://dx.doi.org/10.1007/s10637-021-01120-7DOI Listing
June 2021

Comparison of gemcitabine-based chemotherapies for advanced biliary tract cancers by renal function: an exploratory analysis of JCOG1113.

Sci Rep 2021 Jun 18;11(1):12885. Epub 2021 Jun 18.

Department of Gastroenterological Surgery, Osaka International Cancer Institute, Osaka, Japan.

JCOG1113 is a randomized phase III trial in patients with advanced biliary tract cancers (BTCs) (UMIN000001685), and gemcitabine plus S-1 (GS) was not inferior to gemcitabine plus cisplatin (GC). However, poor renal function often results in high toxicity of S-1. Therefore, we examined whether GS can be recommended for patients with low creatinine clearance (CCr). Renal function was classified by CCr as calculated by the Cockcroft-Gault formula: high CCr (CCr ≥ 80 ml/min) and low CCr (80 > CCr ≥ 50 ml/min). Of 354 patients, 87 patients on GC and 91 on GS were included in the low CCr group, while there were 88 patients on GC and 88 patients on GS in the high CCr group. The HR of overall survival for GS compared with GC was 0.687 (95% CI 0.504-0.937) in the low CCr group. Although the total number of incidences of all Grade 3-4 non-haematological adverse reactions was higher (36.0% vs. 11.8%, p = 0.0002), the number of patients who discontinued treatment was not different (14.1% vs. 16.9%, p = 0.679) for GS compared with GC in the low CCr group. This study suggests that GS should be selected for the treatment of advanced BTC patients with reduced renal function.
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http://dx.doi.org/10.1038/s41598-021-92166-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213853PMC
June 2021

Pharmacodynamic Biomarkers Predictive of Survival Benefit with Lenvatinib in Unresectable Hepatocellular Carcinoma: From the Phase III REFLECT Study.

Clin Cancer Res 2021 Sep 9;27(17):4848-4858. Epub 2021 Jun 9.

Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow, UK.

Purpose: In REFLECT, lenvatinib demonstrated an effect on overall survival (OS) by confirmation of noninferiority to sorafenib in unresectable hepatocellular carcinoma. This analysis assessed correlations between serum or tissue biomarkers and efficacy outcomes from REFLECT.

Experimental Design: Serum biomarkers (VEGF, ANG2, FGF19, FGF21, and FGF23) were measured by ELISA. Gene expression in tumor tissues was measured by the nCounter PanCancer Pathways Panel. Pharmacodynamic changes in serum biomarker levels from baseline, and associations of clinical outcomes with baseline biomarker levels, were evaluated.

Results: Four hundred and seven patients were included in the serum analysis set (lenvatinib = 279, sorafenib = 128); 58 patients were included in the gene-expression analysis set (lenvatinib = 34, sorafenib = 24). Both treatments were associated with increases in VEGF; only lenvatinib was associated with increases in FGF19 and FGF23 at all time points. Lenvatinib-treated responders had greater increases in FGF19 and FGF23 versus nonresponders at cycle 4, day 1 (FGF19: 55.2% vs. 18.3%, = 0.014; FGF23: 48.4% vs. 16.4%, = 0.0022, respectively). Higher baseline VEGF, ANG2, and FGF21 correlated with shorter OS in both treatment groups. OS was longer for lenvatinib than sorafenib [median, 10.9 vs. 6.8 months, respectively; HR, 0.53; 95% confidence interval (CI), 0.33-0.85; interaction = 0.0397] with higher baseline FGF21. In tumor tissue biomarker analysis, VEGF/FGF-enriched groups showed improved OS with lenvatinib versus the intermediate VEGF/FGF group (HR, 0.39; 95% CI, 0.16-0.91; = 0.0253).

Conclusions: Higher baseline levels of VEGF, FGF21, and ANG2 may be prognostic for shorter OS. Higher baseline FGF21 may be predictive for longer OS with lenvatinib compared with sorafenib, but this needs confirmation.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4219DOI Listing
September 2021

Patient-reported outcomes with atezolizumab plus bevacizumab versus sorafenib in patients with unresectable hepatocellular carcinoma (IMbrave150): an open-label, randomised, phase 3 trial.

Lancet Oncol 2021 07 27;22(7):991-1001. Epub 2021 May 27.

Department of Medical Oncology, Gustave Roussy, Villejuif, France.

Background: Understanding patients' experience of cancer treatment is important. We aimed to evaluate patient-reported outcomes (PROs) with atezolizumab plus bevacizumab versus sorafenib in patients with advanced hepatocellular carcinoma in the IMbrave150 trial, which has already shown significant overall survival and progression-free survival benefits with this combination therapy.

Methods: We did an open-label, randomised, phase 3 trial in 111 hospitals and cancer centres across 17 countries or regions. We included patients aged 18 years or older with systemic, treatment-naive, histologically, cytologically, or clinically confirmed unresectable hepatocellular carcinoma and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, with disease that was not amenable to curative surgical or locoregional therapies, or progressive disease after surgical or locoregional therapies. Participants were randomly assigned (2:1; using permuted block randomisation [blocks of six], stratified by geographical region; macrovascular invasion, extrahepatic spread, or both; baseline alpha-fetoprotein concentration; and ECOG performance status) to receive 1200 mg atezolizumab plus 15 mg/kg bevacizumab intravenously once every 3 weeks or 400 mg sorafenib orally twice a day, until loss of clinical benefit or unacceptable toxicity. The independent review facility for tumour assessment was masked to the treatment allocation. Previously reported coprimary endpoints were overall survival and independently assessed progression-free survival per Response Evaluation Criteria in Solid Tumors 1.1. Prespecified secondary and exploratory analyses descriptively evaluated treatment effects on patient-reported quality of life, functioning, and disease symptoms per the European Organisation for Research and Treatment of Cancer (EORTC) quality-of-life questionnaire for cancer (QLQ-C30) and quality-of-life questionnaire for hepatocellular carcinoma (QLQ-HCC18). Time to confirmed deterioration of PROs was analysed in the intention-to-treat population; all other analyses were done in the PRO-evaluable population (patients who had a baseline PRO assessment and at least one assessment after baseline). The trial is ongoing; enrolment is closed. This trial is registered with ClinicalTrials.gov, NCT03434379.

Findings: Between March 15, 2018, and Jan 30, 2019, 725 patients were screened and 501 patients were enrolled and randomly assigned to atezolizumab plus bevacizumab (n=336) or sorafenib (n=165). 309 patients in the atezolizumab plus bevacizumab group and 145 patients in the sorafenib group were included in the PRO-evaluable population. At data cutoff (Aug 29, 2019) the median follow-up was 8·6 months (IQR 6·2-10·8). EORTC QLQ-C30 completion rates were 90% or greater for 23 of 24 treatment cycles in both groups (range 88-100% in the atezolizumab plus bevacizumab group and 80-100% in the sorafenib group). EORTC QLQ-HCC18 completion rates were 90% or greater for 20 of 24 cycles in the atezolizumab plus bevacizumab group (range 88-100%) and 21 of 24 cycles in the sorafenib group (range 89-100%). Compared with sorafenib, atezolizumab plus bevacizumab reduced the risk of deterioration on all EORTC QLQ-C30 generic cancer symptom scales that were prespecified for analysis (appetite loss [hazard ratio (HR) 0·57, 95% CI 0·40-0·81], diarrhoea [0·23, 0·16-0·34], fatigue [0·61, 0·46-0·81], pain [0·46, 0·34-0·62]), and two of three EORTC QLQ-HCC18 disease-specific symptom scales that were prespecified for analysis (fatigue [0·60, 0·45-0·80] and pain [0·65, 0·46-0·92], but not jaundice [0·76, 0·55-1·07]). At day 1 of treatment cycle five (after which attrition in the sorafenib group was more than 50%), the mean EORTC QLQ-C30 score changes from baseline in the atezolizumab plus bevacizumab versus sorafenib groups were: -3·29 (SD 17·56) versus -5·83 (20·63) for quality of life, -4·02 (19·42) versus -9·76 (21·33) for role functioning, and -3·77 (12·82) versus -7·60 (15·54) for physical functioning.

Interpretation: Prespecified analyses of PRO data showed clinically meaningful benefits in terms of patient-reported quality of life, functioning, and disease symptoms with atezolizumab plus bevacizumab compared with sorafenib, strengthening the combination therapy's positive benefit-risk profile versus that of sorafenib in patients with unresectable hepatocellular carcinoma.

Funding: F Hoffmann-La Roche and Genentech.
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http://dx.doi.org/10.1016/S1470-2045(21)00151-0DOI Listing
July 2021

Current status of medical treatment for gastroenteropancreatic neuroendocrine neoplasms and future perspectives.

Jpn J Clin Oncol 2021 Aug;51(8):1185-1196

Department of Medical Oncology, Kyorin University Faculty of Medicine, Tokyo, Japan.

Neuroendocrine neoplasms (NENs) constitute a heterogeneous group of tumors. In this review, we summarize the results of various clinical trials that have been conducted to investigate the efficacy and safety of various therapeutic options for NENs. Based on the encouraging results obtained from these trials, various therapeutic options have been established for the treatment of NENs, including somatostatin analogs (SSAs), molecularly targeted drugs and cytotoxic agents. In addition, peptide receptor radionucleotide therapy has recently been evaluated for the treatment of various NENs. We also discuss the approach for selecting the appropriate drugs and sequence of treatment with the various drug classes, as recommended by different treatment guidelines. Finally, we discuss the scope for future research in this field, especially into the merits of combination therapy with molecularly targeted drugs plus SSAs, along with ongoing studies.
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http://dx.doi.org/10.1093/jjco/hyab076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8326384PMC
August 2021

A Low Tumor Mutational Burden and Mutations Are Predictors of a Negative Response to PD-1 Blockade in MSI-H/dMMR Gastrointestinal Tumors.

Clin Cancer Res 2021 Jul 29;27(13):3714-3724. Epub 2021 Apr 29.

National Cancer Center Hospital East, Kashiwa, Chiba, Japan.

Purpose: This study performed a comprehensive molecular characterization of microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) gastrointestinal (GI) tumors to elucidate predictors of response to PD-1 blockade.

Experimental Design: Forty-five patients with MSI-H/dMMR GI tumors, including gastric cancer, colorectal cancer, cholangiocarcinoma, small intestine cancer, pancreatic cancer, and duodenal cancer, receiving PD-1 blockade were analyzed. We conducted the genomic profiling of GI tumors by whole-exome sequencing or targeted next-generation sequencing. The tumor microenvironment was evaluated by transcriptomic analysis and multiplex fluorescence IHC.

Results: Patients with low tumor mutational burdens (TMBs) had lower objective response rates (ORRs; 0% vs. 48.8%) and a significantly shorter progression-free survival (PFS; 2.3 vs. 15.6 months; HR, 6.20; = 0.002) than those with high TMBs. Among common gene alterations in GI tumors, only mutations, which were mutually exclusive with a low TMB, were significantly associated with a lower ORRs than wild-type (21.4 vs. 54.8%; odds, 4.45; = 0.045). Compared with wild-type mutations in the phosphatase domain were associated with significantly lower ORRs (12.5 vs. 54.8%; = 0.049), shorter PFS (2.6 vs. 15.6 months; HR, 5.04; < 0.001), lower intratumoral CD8 T-cell levels, higher intratumoral CD204 macrophage levels, and PI3K/AKT/mTOR pathway enrichment, whereas mutations in the C2 domain were not.

Conclusions: Low TMBs and mutations, especially mutations in the phosphatase domain associated with an immunosuppressive environment, were mutually exclusive and might be negative predictors of PD-1 blockade responses in patients with MSI-H/dMMR GI tumors.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0401DOI Listing
July 2021

Ramucirumab in patients with advanced hepatocellular carcinoma and elevated α-fetoprotein: Outcomes by treatment-emergent ascites.

Hepatol Res 2021 Jun 4;51(6):715-721. Epub 2021 May 4.

Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.

Aim: The REACH and REACH-2 trials investigated ramucirumab versus placebo in patients with advanced hepatocellular carcinoma (HCC). Ascites is common in HCC and is associated with poorer outcomes. This exploratory, pooled meta-analysis of patients with baseline α-fetoprotein (AFP) ≥400 ng/ml investigated outcomes by treatment-emergent (TE) ascites in REACH and REACH-2.

Methods: A pooled meta-analysis of independent patient data for participants (N = 542) with baseline AFP ≥400 ng/ml (stratified by study) from REACH and REACH-2 was carried out. Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier estimator, and OS further assessed by Cox models. The effect of TE ascites on OS was evaluated by multivariate Cox models.

Results: Treatment-emergent ascites developed in 66 patients (20.9%) in the ramucirumab group and 33 patients (14.8%) in the placebo group. When adjusted for treatment duration, the incidence rates per 100 patient-years of any grade TE ascites were 59.1 and 71.9 for the ramucirumab and placebo groups, respectively, and the incidence of grade ≥3 TE ascites were 13.4 and 19.6, respectively. Treatment-emergent ascites was associated with TE hypoalbuminemia (odds ratio 4.9; 95% confidence interval 2.5-9.3), but not TE proteinuria or hypertension. One patient discontinued ramucirumab treatment due to TE ascites. Ramucirumab treatment improved OS and PFS compared with placebo, irrespective of TE ascites.

Conclusions: When adjusted for treatment duration, the incidence of TE ascites was no higher in patients who received ramucirumab than in those who received placebo. Ramucirumab was well tolerated and provided a survival benefit irrespective of the development of TE ascites.
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http://dx.doi.org/10.1111/hepr.13638DOI Listing
June 2021

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.

Cancer Med 2021 03 26;10(6):2088-2099. Epub 2021 Feb 26.

Department of Medical Oncology, Faculty of Medicine, Kyorin University, Tokyo, Japan.

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).
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http://dx.doi.org/10.1002/cam4.3813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957161PMC
March 2021

Phase I Assessment of Safety and Therapeutic Activity of BAY1436032 in Patients with IDH1-Mutant Solid Tumors.

Clin Cancer Res 2021 May 23;27(10):2723-2733. Epub 2021 Feb 23.

Pharmaceuticals Division, Bayer HealthCare Pharmaceuticals, Inc., Whippany, New Jersey.

Purpose: BAY1436032, an inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), was active against multiple IDH1-R132X solid tumors in preclinical models. This first-in-human study was designed to determine the safety and pharmacokinetics of BAY1436032, and to evaluate its potential pharmacodynamics and antitumor effects.

Patients And Methods: The study comprised of dose escalation and dose expansion cohorts. BAY1436032 tablets were orally administered twice daily on a continuous basis in subjects with m solid tumors.

Results: In dose escalation, 29 subjects with various tumor types were administered BAY1436032 across five doses (150-1,500 mg twice daily). BAY1432032 exhibited a relatively short half-life. Most evaluable subjects experienced target inhibition as indicated by a median maximal reduction of plasma R-2-hydroxyglutarate levels of 76%. BAY1436032 was well tolerated and an MTD was not identified. A dose of 1,500 mg twice daily was selected for dose expansion, where 52 subjects were treated in cohorts representing four different tumor types [lower grade glioma (LGG), glioblastoma, intrahepatic cholangiocarcinoma, and a basket cohort of other tumor types]. The best clinical outcomes were in subjects with LGG ( = 35), with an objective response rate of 11% (one complete response and three partial responses) and stable disease in 43%. As of August 2020, four of these subjects were in treatment for >2 years and still ongoing. Objective responses were observed only in LGG.

Conclusions: BAY1436032 was well tolerated and showed evidence of target inhibition and durable objective responses in a small subset of subjects with LGG.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4256DOI Listing
May 2021

Risk stratification and prognostic factors in patients with unresectable undifferentiated carcinoma of the pancreas.

Pancreatology 2021 Jun 14;21(4):738-745. Epub 2021 Feb 14.

Department of Medical Oncology, Kyorin University Faculty of Medicine, Tokyo, Japan.

Background: Undifferentiated carcinoma (UC) of the pancreas has been considered a highly aggressive malignancy. However, only a few studies have systematically described the clinical course of UC patients. The aim of this study was to clarify the prognosis and construct a prognostic model for patients with unresectable UC.

Methods: This study was conducted at 17 institutions in Japan, and a total of 55 patients were analyzed.

Results: The median overall survival (OS) of patients with unresectable UC was 3.95 months. In the multivariate Cox proportional hazards (CPH) model, age ≥65 years, Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2, and C-reactive protein (CRP) >10 mg/L were independent prognostic factors for OS (age ≥65 years: hazard ratio [HR], 2.732; 95% confidence interval [CI], 1.353-5.515; ECOG PS ≥ 2: HR, 7.866; 95% CI, 1.981-31.241; CRP >10 mg/L: HR, 1.956; 95% CI, 1.013-3.775). Based on the β coefficients from the CPH model, the prognostic scores were defined as follows: age ≥65 years (3 points), ECOG PS ≥ 2 (6 points), and CRP >10 ml/L (2 points). The final prognostic model was the sum of the points. The derived prognostic model stratified patients into high-risk (score ≥4) and low-risk (score 0-3) groups, with significant differences in OS (1.45 vs. 8.19 months, respectively; p < 0.001).

Conclusions: The prognostic model stratified patients into high-risk and low-risk groups. These findings suggest that this model can serve as a tool for patient information and decision-making with regard to the therapeutic strategy for UC.
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http://dx.doi.org/10.1016/j.pan.2021.02.008DOI Listing
June 2021

Phase I studies of peptide vaccine cocktails derived from GPC3, WDRPUH and NEIL3 for advanced hepatocellular carcinoma.

Immunotherapy 2021 Apr 2;13(5):371-385. Epub 2021 Feb 2.

Department of Medical Oncology, Kyorin University Faculty of Medicine, Tokyo, Japan.

Two peptide cocktail vaccines using glypican-3, WD-repeat-containing protein up-regulated in hepatocellular carcinoma (HCC) and nei endonuclease VIII-like three epitopes were evaluated in advanced HCC in two Phase I studies. Study 1 evaluated dose-limiting toxicities (DLTs) of peptides 1-3 (HLA-A24-restricted) and study 2 evaluated DLTs of peptides 1-6 (HLA-A24 or A02-restricted). Overall, 18 and 14 patients were enrolled in studies 1 and 2, respectively. No DLTs were observed up to 7.1 mg of the vaccine cocktail. No complete response/partial response was observed. Stable disease was reported in nine and five patients with a disease control rate of 52.9% and 35.7% in studies 1 and 2, respectively. Both vaccines showed good tolerability and potential usefulness against HCC. Clinical trial registration: JapicCTI-121933; JapicCTI-142477.
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http://dx.doi.org/10.2217/imt-2020-0278DOI Listing
April 2021

Cabozantinib in Japanese patients with advanced hepatocellular carcinoma: a phase 2 multicenter study.

J Gastroenterol 2021 02 3;56(2):181-190. Epub 2021 Jan 3.

Oncology Clinical Research Department, Oncology Therapeutic Area Unit for Japan and Asia, Takeda Pharmaceutical Company Limited, Osaka, Japan.

Background: To evaluate the efficacy and safety of cabozantinib in Japanese patients with advanced hepatocellular carcinoma (HCC) who had progressed following one or two lines of systemic therapy including sorafenib. An exploratory evaluation in sorafenib-naïve patients was performed.

Methods: In this open-label, single-arm, phase 2 trial, patients received oral cabozantinib 60 mg once daily. The primary endpoint was progression-free survival (PFS) rate at Week 24. Secondary endpoints included PFS, overall survival (OS), objective response rate (ORR, best response of complete/partial response), disease control rate (DCR, objective response or stable disease) and safety.

Results: Thirty-four patients received cabozantinib across 17 centers (prior sorafenib cohort, n = 20; sorafenib-naïve cohort, n = 14). PFS rate at 24 weeks was 59.8% [90% confidence interval (CI) 36.1-77.2%] in the prior sorafenib cohort, 16.7% (90% CI 4.0-36.8%) in the sorafenib-naïve cohort and 40.1% (90% CI 24.8-55.0%) overall. Median PFS was 7.4 months for the prior sorafenib cohort, 3.6 months for the sorafenib-naïve cohort, and 5.6 months overall. OS rate at 6 months was 100.0%, 78.6% and 91.1%, respectively; DCR was 85.0%, 64.3% and 76.5%, respectively. The ORR was 0.0% for both cohorts. All patients required dose modifications due to adverse events, the most common of these were palmar-plantar erythrodysesthesia syndrome and diarrhea. Three patients (8.8%) discontinued due to adverse events other than disease progression.

Conclusions: Cabozantinib 60 mg/day has a favorable benefit/risk profile for Japanese patients with advanced HCC who have previously received one or two lines of systemic anticancer therapy including sorafenib. (Clinical trial registration: NCT03586973).
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http://dx.doi.org/10.1007/s00535-020-01753-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862203PMC
February 2021

Effect of ramucirumab on ALBI grade in patients with advanced HCC: Results from REACH and REACH-2.

JHEP Rep 2021 Apr 13;3(2):100215. Epub 2020 Nov 13.

Massachusetts General Hospital Cancer Center, Harvard Medical Center, Boston, MA, USA.

Background & Aims: The albumin-bilirubin (ALBI) grade/score is derived from a validated nomogram to objectively assess prognosis and liver function in patients with hepatocellular carcinoma (HCC). In this analysis, we assessed prognosis in terms of survival by baseline ALBI grade and monitored liver function during treatment with ramucirumab or placebo using the ALBI score in patients with advanced HCC.

Methods: Patients with advanced HCC, Child-Pugh class A with prior sorafenib treatment were randomised in REACH trials to receive ramucirumab 8 mg/kg or placebo every 2 weeks. Data were analysed by trial and as a meta-analysis of individual patient-level data (pooled population) from REACH (alpha-fetoprotein ≥400 ng/ml) and REACH-2. Patients from REACH with Child-Pugh class B were analysed as a separate cohort. The ALBI grades and scores were calculated at baseline and before each treatment cycle.

Results: Baseline characteristics by ALBI grade were balanced between treatment arms among patients in the pooled population (ALBI-1, n = 231; ALBI-2, n = 296; ALBI-3, n = 7). Baseline ALBI grade was prognostic for overall survival (OS; ALBI grade 2 1; hazard ratio [HR]: 1.38 [1.13-1.69]), after adjusting for other significant prognostic factors. Mean ALBI scores remained stable in both treatment arms compared with baseline and were unaffected by baseline ALBI grade, macrovascular invasion, tumour response, geographical region, or prior locoregional therapy. Baseline ALBI grades 2 and 3 were associated with increased incidence of liver-specific adverse events and discontinuation rates in both treatments. Ramucirumab improved OS in patients with baseline ALBI grade 1 (HR 0.605 [0.445-0.824]) and ALBI grade 2 (HR 0.814 [0.630-1.051]).

Conclusions: Compared with placebo, ramucirumab did not negatively impact liver function and improved survival irrespective of baseline ALBI grade.

Lay Summary: Hepatocellular carcinoma is the third leading cause of cancer-related death worldwide. Prognosis is affected by many clinical factors including liver function both before and during anticancer treatment. Here we have used a validated approach to assess liver function using 2 laboratory parameters, serum albumin and bilirubin (ALBI), both before and during treatment with ramucirumab in 2 phase III placebo-controlled studies. We confirm the practicality of using this more simplistic approach in assessing liver function prior to and during anticancer therapy, and demonstrate ramucirumab did not impair liver function when compared with placebo.
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http://dx.doi.org/10.1016/j.jhepr.2020.100215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772786PMC
April 2021

FOLFIRINOX in advanced pancreatic cancer patients with the double-variant type of UGT1A1 *28 and *6 polymorphism: a multicenter, retrospective study.

Cancer Chemother Pharmacol 2021 03 2;87(3):397-404. Epub 2021 Jan 2.

Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.

Background: UGT1A1 *28 and *6 polymorphism is associated with reduced enzyme activity and severe toxicities of irinotecan, especially in patients with homozygous or heterozygous for UGT1A1*28 or *6 polymorphism for both UGT1A1*28 and *6 (double-variant-type of UGT1A1 polymorphism, UGT1A1-DV). FOLFIRINOX is one of the standard treatments for metastatic pancreatic cancer (PC). The optimal dose of irinotecan as a component of the FOLFIRINOX has not been established yet for patients with UGT1A1-DV.

Patients And Methods: Advanced PC patients with UGT1A1-DV who had received at least one cycle of FOLFIRINOX from December 2013 to March 2016 were collected retrospectively conducted at multicenter in Japan. We evaluated the patient characteristics, efficacy and safety of FOLFIRINOX and investigate the optimal initial dose of irinotecan in Japanese advanced PC patients with UGT1A1-DV.

Results: A total of 31 patients were enrolled. Grade 4 neutropenia was seen more frequently (67%; 4/6) in patients who had received irinotecan at an initial dose of  ≥ 150 mg/m than in those who had received the drug at an initial dose of  ≤ 120 mg/m (20%; 5/24). The response rate (RR) and progression-free survival (PFS) in patients given irinotecan of  ≤ 120 mg/m were 21.4% and 8.1 months, respectively, which were consistent with previous report for patients without UGT1A1-DV.

Conclusion: Based on our findings, we recommend that in Japanese advanced PC patients with UGT1A1- DV treated with FOLFIRINOX, irinotecan be administered at an initial dose of  ≤ 120 mg/m.
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http://dx.doi.org/10.1007/s00280-020-04206-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889544PMC
March 2021

Multicenter Retrospective Analysis of Chemotherapy for Advanced Pancreatic Acinar Cell Carcinoma: Potential Efficacy of Platinum- and Irinotecan-Containing Regimens.

Pancreas 2021 01;50(1):77-82

Department of Medical Oncology, Kyorin University Faculty of Medicine, Tokyo.

Objectives: The aim of this multicenter retrospective study was to identify the optimal chemotherapeutic regimen for advanced pancreatic acinar cell carcinoma (PACC).

Methods: Fifty-eight patients with histopathologically confirmed advanced PACC who had received chemotherapy between 1996 and 2013 were enrolled. The clinical characteristics of the patients and the treatment efficacy data were collected from the medical records at 16 Japanese institutions, using standardized data collection instrument.

Results: The most commonly selected treatment regimens were gemcitabine-, fluoropyrimidine-, platinum-, and irinotecan-containing regimens. The overall response rate in the patients who received first-line chemotherapy were 7% and 38%, respectively, and the median overall survival was 13.2 months. When the data for all the treatment lines were aggregated, the response rates to gemcitabine-, fluoropyrimidine-, platinum-, and irinotecan-containing regimens were 7%, 18%, 40%, and 29%, respectively. The overall survival tended to be better in patients who had received a platinum-containing regimen (hazard ratio, 0.50; 95% confidence interval, 0.23-1.11; P = 0.08) or irinotecan-containing regimen (hazard ratio, 0.42; 95% confidence interval, 0.15-1.19; P = 0.09) at least once in the treatment course as compared with those who had not.

Conclusions: Our findings suggested that platinum- and irinotecan-containing regimens exhibited some potential efficacy in patients with advanced PACC.
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http://dx.doi.org/10.1097/MPA.0000000000001718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748047PMC
January 2021

Relationship between surgical R0 resectability and findings of peripancreatic vascular invasion on CT imaging after neoadjuvant S-1 and concurrent radiotherapy in patients with borderline resectable pancreatic cancer.

BMC Cancer 2020 Dec 2;20(1):1184. Epub 2020 Dec 2.

Department of Hepato-Biliary-Pancreatic Surgery, Chiba Cancer Center, Chiba, Japan.

Background: Borderline resectable pancreatic cancer (BRPC) is frequently associated with positive surgical margins and a poor prognosis because the tumor is in contact with major vessels. This study evaluated the relationship between the margin-negative (R0) resection rate and findings indicating peripancreatic vascular invasion on multidetector computed tomography (MDCT) imaging after neoadjuvant chemoradiotherapy (NACRT) in patients with BRPC.

Methods: Twenty-nine BRPC patients who underwent laparotomy after neoadjuvant S-1 with concurrent radiotherapy were studied retrospectively. Peripancreatic major vessel invasion was evaluated based on the length of tumor-vessel contact on MDCT. The R0 resection rates were compared between the progression of vascular invasion (PVI) group and the non-progression of vascular invasion (NVI) group.

Results: There were 3 patients with partial responses (10%), 25 with stable disease (86%), and 1 with progressive disease (3%) according to the RECISTv1.1 criteria. Regarding vascular invasion, 9 patients (31%) were classified as having PVI, and 20 patients (69%) were classified as having NVI. Of the 29 patients, 27 (93%) received an R0 resection, and all the PVI patients received an R0 resection (9/9; R0 resection rate = 100%) while 90% (18/20) of the NVI patients underwent an R0 resection. The exact 95% confidence interval of risk difference between those R0 resection rates was - 10.0% [- 31.7-20.4%].

Conclusions: Patients with BRPC after NACRT achieved high R0 resection rates regardless of the vascular invasion status. BRPC patients can undergo R0 resections unless progressive disease is observed after NACRT.

Trial Registration: UMIN-CTR, UMIN000009172 . Registered 23 October 2012.
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http://dx.doi.org/10.1186/s12885-020-07698-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709301PMC
December 2020

Phase 2 study of lenvatinib monotherapy as second-line treatment in unresectable biliary tract cancer: primary analysis results.

BMC Cancer 2020 Nov 16;20(1):1105. Epub 2020 Nov 16.

National Cancer Centre Hospital, Tokyo, Japan.

Background: Biliary tract cancer (BTC) has a poor prognosis and lacks a standardized second-line therapy. Vascular endothelial growth factor (VEGF), fibroblast growth factor receptor (FGFR) 4, and platelet-derived growth factor receptor (PDGFR) are highly expressed in BTC. Therefore, lenvatinib (a known inhibitor of VEGF receptors 1-3, FGFRs 1-4, and PDGFR-α) was evaluated for second-line treatment of BTC.

Methods: In this single-arm, multicenter, open-label, phase 2 study, patients with BTC received lenvatinib 24 mg orally once daily in 28-day cycles. The primary endpoint was objective response rate (ORR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), PFS rate at 12 weeks, disease control rate, clinical benefit rate, safety and pharmacokinetic profiles.

Results: Twenty-six Japanese patients were enrolled and treated; 3 had a confirmed partial response per investigator assessment and per independent imaging review (IIR); ORR was 11.5% (90% confidence interval [CI]: 3.2-27.2). Median PFS was 3.19 months (95% CI: 2.79-7.23) per investigator assessment and 1.64 months (95% CI: 1.41-3.19) per IIR. Median OS was 7.35 months (95% CI: 4.50-11.27). Grade ≥ 3 treatment-emergent adverse events (TEAEs) occurred in 21 patients (80.8%) and included hypertension (n = 10 [38.5%]), proteinuria (n = 3 [11.5%]), palmar-plantar erythrodysesthesia (n = 3 [11.5%]), decreased appetite (n = 3 [11.5%]), and anemia (n = 3 [11.5%]). Two deaths occurred due to TEAEs between treatment initiation and 30 days after last dose, but neither were considered treatment related.

Conclusions: Lenvatinib demonstrated antitumor activity in BTC, with a tolerable safety profile, and should be further evaluated as potential second-line therapy for this difficult to treat population.

Trial Registration: ClinicalTrials.gov NCT02579616 . Date of registration: October 19, 2015.
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http://dx.doi.org/10.1186/s12885-020-07365-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667859PMC
November 2020

Randomized phase II study of chemoradiotherapy with versus without induction chemotherapy for locally advanced pancreatic cancer: Japan Clinical Oncology Group trial, JCOG1106.

Jpn J Clin Oncol 2021 Feb;51(2):235-243

Clinical Research Center, Chiba Cancer Center, Chiba.

Background: Chemoradiotherapy is a treatment option for locally advanced pancreatic cancer. However, the efficacy of induction chemotherapy prior to chemoradiotherapy is uncertain. The aim of this randomized, multicentre phase II study is to evaluate the efficacy and safety of chemoradiotherapy with and without induction chemotherapy to determine the significance of induction chemotherapy.

Methods: Patients with locally advanced pancreatic cancer were randomly assigned to the chemoradiotherapy arm (Arm A) or induction chemotherapy followed by the chemoradiotherapy arm (Arm B). Patients in Arm A underwent radiotherapy with concurrent S-1. Patients in Arm B received induction gemcitabine for 12 weeks, and thereafter, only patients with controlled disease underwent the same chemoradiotherapy as Arm A. After chemoradiotherapy, gemcitabine was continued until disease progression or unacceptable toxicity in both arms. The primary endpoint was overall survival.

Results: Amongst 102 patients enrolled, 100 were eligible for efficacy assessment. The probability of survival was greater in Arm B in the first 12 months, but the trend was reversed in the following periods (1-year survival 66.7 vs. 69.3%, 2-year survival 36.9 vs. 18.9%). The hazard ratio was 1.255 (95% confidence interval 0.816-1.930) in favour of Arm A. Gastrointestinal toxicity was slightly more frequent and three treatment-related deaths occurred in Arm A.

Conclusions: This study suggested that the chemoradiotherapy using S-1 alone had more promising efficacy with longer-term survival, compared with induction gemcitabine followed by chemoradiotherapy for locally advanced pancreatic cancer.

Clinical Trial Registration: The study was registered at the UMIN Clinical Trials Registry as UMIN000006811.
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http://dx.doi.org/10.1093/jjco/hyaa198DOI Listing
February 2021

Molecular detection and clinicopathological characteristics of advanced/recurrent biliary tract carcinomas harboring the FGFR2 rearrangements: a prospective observational study (PRELUDE Study).

J Gastroenterol 2021 03 26;56(3):250-260. Epub 2020 Oct 26.

Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Background: Fibroblast growth factor receptor 2 (FGFR2) rearrangement is expected to be a novel therapeutic target in advanced/recurrent biliary tract cancer (BTC). However, efficient detection and the exact frequency of FGFR2 rearrangements among patients with advanced/recurrent BTC have not been determined, and the clinical characteristics of FGFR2 rearrangement-positive patients have not been fully elucidated. We aimed to determine the frequency of FGFR2 rearrangement-positive patients among those with advanced/recurrent BTC and elucidate their clinicopathological characteristics.

Methods: Paraffin-embedded tumor samples from formalin-fixed surgical or biopsy specimens of patients with advanced/recurrent BTC were analyzed for positivity of FGFR2 rearrangement by fluorescent in situ hybridization (FISH). RNA sequencing was performed on samples from all FISH-positive and part of FISH-negative patients.

Results: A total of 445 patients were enrolled. FISH was performed on 423 patients (272 patients with intrahepatic cholangiocarcinoma (ICC), 83 patients with perihilar cholangiocarcinoma (PCC), and 68 patients with other BTC). Twenty-one patients with ICC and four patients with PCC were diagnosed as FGFR2-FISH positive. Twenty-three of the 25 FISH-positive patients (20 ICC and 3 PCC) were recognized as FGFR2 rearrangement positive by targeted RNA sequencing. Younger age (≤ 65 years; p = 0.018) and HCV Ab- and/or HBs Ag-positivity (p = 0.037) were significantly associated with the presence of FGFR2 rearrangement (logistic regression).

Conclusions: FGFR2 rearrangement was identified in ICC and PCC patients, and was associated with younger age and history of hepatitis viral infection.
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http://dx.doi.org/10.1007/s00535-020-01735-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7932978PMC
March 2021

nal-IRI+5-FU/LV versus 5-FU/LV in post-gemcitabine metastatic pancreatic cancer: Randomized phase 2 trial in Japanese patients.

Cancer Med 2020 12 25;9(24):9396-9408. Epub 2020 Oct 25.

Department of Cancer Survey and Gastrointestinal Oncology, Osaka International Cancer Institute, Osaka, Japan.

Background: In the NAPOLI-1 phase 3 trial, liposomal irinotecan (nal-IRI) +5-fluorouracil/leucovorin (5-FU/LV) significantly increased mPFS versus 5-FU/LV (3.1 vs. 1.5 months [unstratified HR = 0.56, p = 0.0001]) in patients with mPAC that progressed on prior gemcitabine-based therapy. This randomized phase 2 trial evaluated nal-IRI+5-FU/LV tolerability (Part 1), safety, and efficacy (Part 2; outcomes reported here) in Japanese patients with mPAC that progressed on gemcitabine-based therapy.

Methods: Patients were randomized 1:1 and stratified by KPS (70 and 80 vs. ≥90) and baseline albumin (≥4.0 g/dl vs. <4.0 g/dl). Primary endpoint was PFS; secondary endpoints were ORR, DCR, OS, TTF, CA19-9 response, and QoL. The ITT population comprised all randomized patients.

Results: Patient characteristics differed between nal-IRI+5-FU/LV (n = 40) and 5-FU/LV (n = 39) arms, including baseline hepatic lesions (63% vs. 51%), stage IV disease at diagnosis (78% vs. 51%), and post-study anticancer therapy (55% vs. 72%). Investigator-assessed mPFS increase with nal-IRI+5-FU/LV was clinically meaningful and statistically significant versus 5-FU/LV (2.7 vs. 1.5 months, HR = 0.60). Independently assessed mPFS showed similar trends (1.7 vs. 1.6 months, HR = 0.79). mOS was 6.3 months with nal-IRI+5-FU/LV and not reached with 5-FU/LV. ORR increased significantly with nal-IRI+5-FU/LV versus 5-FU/LV (18% vs. 0, rate difference 17.5). Commonly reported grade ≥3 treatment-emergent AEs were decreased neutrophil count (37% vs. 3%), decreased white blood cell count (20% vs. 0), and diarrhea (17% vs. 3%).

Conclusions: In conclusion, clinically meaningful and statistically significant gains in investigator-assessed PFS and ORR were observed with nal-IRI+5-FU/LV versus 5-FU/LV in Japanese patients, with no new or unexpected safety signals. (Clinicaltrials.gov ID: NCT02697058).
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http://dx.doi.org/10.1002/cam4.3558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774735PMC
December 2020

Hepatic Arterial Infusion Chemotherapy versus Sorafenib in Patients with Advanced Hepatocellular Carcinoma.

Liver Cancer 2020 Sep 24;9(5):583-595. Epub 2020 Jul 24.

Yamanashi Prefectural Central Hospital, Kofu, Japan.

Background: Prior to the approval of sorafenib, hepatic arterial infusion chemotherapy (HAIC) was offered to patients with advanced hepatocellular carcinoma (HCC) in East Asia, particularly Japan. According to the Japanese guidelines, HAIC is recommended as one of the treatment options in patients without extrahepatic metastasis (EHM).

Methods: The present cohort study compared the use of HAIC and sorafenib on outcomes of patients with advanced HCC. Consecutive patients with advanced HCC who received HAIC or sorafenib as a first-line systemic therapy were enrolled from 10 Japanese institutions. The primary outcomes were overall survival (OS) in patients with macrovascular invasion (MVI), but without EHM, and OS in patients without both MVI and EHM.

Results: Between 2009 and 2016, 2,006 patients were enrolled (541 HAIC patients, 1,465 sorafenib patients). After propensity score matching, the OS of patients with MVI but without EHM was significantly longer in the HAIC group compared with the sorafenib group (10.1 vs. 9.1 months for the HAIC and sorafenib groups, respectively; = 170 for each group; hazard ratio [HR] 0.668; 95% confidence interval [95% CI] 0.475-0.935; = 0.018). There was no significant difference in OS between patients without both MVI and EHM (12.2 vs. 15.4 months for the HAIC and sorafenib groups, respectively; = 76 in each cohort after propensity score matching; HR 1.227; 95% CI 0.699-2.155; = 0.475).

Conclusion: HAIC is a potential front-line treatment choice in a subpopulation of patients with advanced HCC with MVI but without EHM.
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http://dx.doi.org/10.1159/000508724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548914PMC
September 2020

Neoadjuvant S-1 With Concurrent Radiotherapy Followed by Surgery for Borderline Resectable Pancreatic Cancer: A Phase II Open-Label Multicenter Prospective Trial (JASPAC05).

Ann Surg 2020 Oct 15. Epub 2020 Oct 15.

Department of Hepato-biliary Pancreatic Surgery, Shizuoka Cancer Center Hospital, Shizuoka, Japan.

Objective: This study assessed whether neoadjuvant chemoradiotherapy (CRT) with S-1 increases the R0 resection rate in borderline resectable pancreatic cancer (BRPC).

Summary Background Data: Although a multidisciplinary approach that includes neoadjuvant treatment has been shown to be a better strategy for BRPC than upfront resection, a standard treatment for BRPC has not been established.

Methods: A multicenter, single-arm, phase II study was performed. Patients who fulfilled the criteria for BRPC received S-1 (40 mg/m bid) and concurrent radiotherapy (50.4 Gy in 28 fractions) before surgery. The primary endpoint was the R0 resection rate. At least 40 patients were required, with a one-sided α = 0.05 and β = 0.05 and expected and threshold values for the primary endpoint of 30% and 10%, respectively.

Results: Fifty-two patients were eligible, and 41 were confirmed to have definitive BRPC by a central review. CRT was completed in 50 (96%) patients and was well tolerated. The rate of grade 3/4 toxicity with CRT was 43%. The R0 resection rate was 52% among the 52 eligible patients and 63% among the 41 patients who were centrally confirmed to have BRPC. Postoperative grade III/IV adverse events according to the Clavien-Dindo classification were observed in 7.5%. Among the 41 centrally confirmed BRPC patients, the 2-year overall survival rate and median overall survival duration were 58% and 30.8 months, respectively.

Conclusions: S-1 and concurrent radiotherapy appear to be feasible and effective at increasing the R0 resection rate and improving survival in patients with BRPC.

Trial Registration: UMIN000009172.
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http://dx.doi.org/10.1097/SLA.0000000000004535DOI Listing
October 2020

Clinical utility of circulating tumor DNA sequencing in advanced gastrointestinal cancer: SCRUM-Japan GI-SCREEN and GOZILA studies.

Nat Med 2020 12 5;26(12):1859-1864. Epub 2020 Oct 5.

Translational Research Support Section, National Cancer Center Hospital East, Kashiwa, Japan.

Comprehensive genomic profiling enables genomic biomarker detection in advanced solid tumors. Here, to evaluate the utility of circulating tumor DNA (ctDNA) genotyping, we compare trial enrollment using ctDNA sequencing in 1,687 patients with advanced gastrointestinal (GI) cancer in SCRUM-Japan GOZILA (no. UMIN000016343), an observational ctDNA-based screening study, to enrollment using tumor tissue sequencing in the same centers and network (GI-SCREEN, 5,621 patients). ctDNA genotyping significantly shortened the screening duration (11 versus 33 days, P < 0.0001) and improved the trial enrollment rate (9.5 versus 4.1%, P < 0.0001) without compromising treatment efficacy compared to tissue genotyping. We also describe the clonal architecture of ctDNA profiles in ~2,000 patients with advanced GI cancer, which reinforces the relevance of many targetable oncogenic drivers and highlights multiple new drivers as candidates for clinical development. ctDNA genotyping has the potential to accelerate innovation in precision medicine and its delivery to individual patients.
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http://dx.doi.org/10.1038/s41591-020-1063-5DOI Listing
December 2020

Multicenter Phase II Trial of Axitinib Monotherapy for Gemcitabine-Based Chemotherapy Refractory Advanced Biliary Tract Cancer (AX-BC Study).

Oncologist 2021 02 17;26(2):97-e201. Epub 2020 Oct 17.

Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan.

Lessons Learned: Axitinib exhibited marginal activity against gemcitabine-refractory unselected biliary tract cancer. Pretreated soluble vascular endothelial growth factor receptor-2 may be a useful biomarker for axitinib treatment outcome. Ascites should be carefully monitored in patients receiving anti-vascular endothelial growth factor receptor therapy including axitinib in advanced biliary tract cancer.

Background: There are no clear options for second-line treatment in patients with gemcitabine (GEM)-refractory biliary tract cancer (BTC). We conducted a multicenter, single-arm, phase II trial to confirm the efficacy and safety of axitinib, a potent selective inhibitor of vascular endothelial growth factor receptor (VEGFR)-1/2/3, in patients with GEM-refractory BTC.

Methods: Patients refractory or intolerant to GEM-based chemotherapy were enrolled. Axitinib was administered orally at an initial dose of 5 mg twice daily. The primary endpoint was progression-free survival (PFS), and the threshold and expected values were set at 2 and 3 months, respectively. The target sample size was 32 patients.

Results: Nineteen patients were enrolled. The trial was interrupted for a total of 13 months for the evaluation of adverse events. Thirteen patients were previously treated with ≥2 regimens. The median PFS was 2.8 months (95% confidence interval [CI]: 2.1-4.1). The median overall survival was 5.8 months (95% CI: 3.3-9.7). The response rate was 5.3% (95% CI: 0.0-15.3). Grade 3 ascites occurred in two patients. Baseline soluble VEGFR-2 levels were significantly associated with PFS.

Conclusion: Axitinib exhibited marginal activity against GEM-refractory BTC. Ascites should be carefully monitored in axitinib-treated patients with advanced BTC.
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http://dx.doi.org/10.1002/onco.13547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873316PMC
February 2021
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