Bintrafusp alfa and chemotherapy as first-line treatment in biliary tract cancer: A randomized phase 2/3 trial.

BACKGROUND AND AIMS: We compared the safety and efficacy of bintrafusp alfa (BA) in combination with gemcitabine+cisplatin (GemCis), to those of GemCis alone, in patients with biliary tract cancer. APPROACH AND RESULTS: This randomized, double-blind, placebo-controlled, adaptive design phase 2/3 trial (NCT04066491) included adults who are treatment-naive with locally advanced/metastatic biliary tract cancer. Patients (N = 297) were randomized to receive an IV infusion of BA (2400 mg once/3 wk) plus GemCis (gemcitabine 1000 mg/m 2 +cisplatin 25 mg/m 2 on days 1 and 8/3 wk; 8 cycles) (BA group, n = 148) or placebo+GemCis (placebo group, n = 149). The primary end point was overall survival (OS). For adaptation analysis (phase 2-phase 3; data cutoff: May 20, 2021), efficacy was assessed in the first 150 patients who were antibiotic-naive when 80 progression-free survival events had occurred and ≥ 19 weeks of follow-up had been completed (BA, n = 73; placebo, n = 77). Median OS (95% CI) for the BA (11.5 mo [9.3-not estimable]) and placebo (11.5 mo [10.0-not estimable]) groups was comparable (hazard ration 1.23 [95% CI 0.66-2.28]; p = 0.7394); OS data maturity was 27.2% (41 events/151 patients). The most common grade ≥3 treatment-related adverse event was anemia (BA, 26.0%; placebo, 22.8%). Bleeding adverse events were reported more frequently in the BA group (28.8%) versus the placebo group (7.4%). Deaths within 60 days of the first dose were reported in 7.5% and 1.3% of patients in the BA and placebo groups, respectively. CONCLUSIONS: BA+GemCis did not provide a clinically meaningful benefit compared with GemCis alone as first-line treatment for biliary tract cancer, and the study was discontinued early (terminated: August 20, 2021).

Tasurgratinib in patients with cholangiocarcinoma or gastric cancer: Expansion part of the first-in-human phase I study.

Fibroblast growth factor receptors (FGFRs) are a highly conserved family of transmembrane receptor tyrosine kinases with multiple roles in the regulation of key cellular processes. Specific FGFR mutations have been observed in several types of cancers, including gastric carcinoma and cholangiocarcinoma. Dose escalation data of 24 Japanese patients with solid tumors treated with Tasurgratinib (previously known as E7090), a potent, selective FGFR1-3 inhibitor, was reported in a phase I, first-in-human, single-center study. Based on the safety, pharmacokinetic, and pharmacodynamic profiles observed in this study, the recommended dose of 140 mg once daily was selected for the expansion part (Part 2), a multicenter expansion of the dose-finding study restricted to patients with tumors harboring FGFR gene alterations. Safety and preliminary efficacy were assessed in Part 2. Pharmacodynamic pharmacogenomic markers (serum phosphate, FGF23, and 1,25-(OH)2-vitamin D, circulating tumor DNA) and pharmacokinetic profiles were also evaluated. A total of 16 patients were enrolled in Part 2, six with cholangiocarcinoma and 10 with gastric cancer. The most common treatment-emergent adverse events were hyperphosphatemia, palmar-plantar erythrodysesthesia syndrome, and paronychia. Five partial responses (83.3%) in cholangiocarcinoma patients and one partial response (11.1%) in gastric cancer patients were observed; median progression-free survival was 8.26 months (95% confidence interval [CI] 3.84, not evaluable [NE]) and 3.25 months (95% CI 0.95, 4.86), and overall survival was 22.49 months (95% CI 6.37, NE) and 4.27 months (95% CI 2.23, 7.95), respectively, in the two groups. In conclusion, Tasurgratinib 140 mg has a tolerable safety profile with good clinical efficacy in patients with cholangiocarcinoma harboring FGFR2 gene rearrangements.

Association between treatment-emergent hypertension and survival with lenvatinib treatment for patients with hepatocellular carcinoma in the REFLECT study.

BACKGROUND: Lenvatinib is approved as a first-line treatment for patients with unresectable and/or recurrent hepatocellular carcinoma (HCC). Lenvatinib achieved promising clinical benefits in REFLECT but was associated with clinically significant treatment-emergent hypertension (CSTE-HTN, a grouped term), a common class effect of tyrosine kinase inhibitors. This post hoc analysis assessed the impact of CSTE-HTN on the efficacy and safety of lenvatinib in HCC. METHODS: Patients from REFLECT who received lenvatinib (n = 476) were stratified according to CSTE-HTN. Tumors were assessed by mRECIST. Overall survival (OS) and progression-free survival (PFS) were evaluated using landmark analyses at 4 and 8 weeks. RESULTS: A total of 212 patients in the lenvatinib arm developed CSTE-HTN, and 264 did not. CSTE-HTN first occurred at 3.7 weeks (median); the worst grade CSTE-HTN occurred at 4.1 weeks (median). No patients had life-threatening CSTE-HTN and/or died due to CSTE-HTN. Median OS was numerically longer in patients with versus without CSTE-HTN (at 4 weeks: 16.3 vs. 11.6 months; hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.621-1.004; at 8 weeks: 13.5 vs. 11.6 months; HR, 0.87; 95% CI, 0.696-1.089). Median PFS was similar between patients with and without CSTE-HTN (at 4 weeks: 6.6 vs. 6.4 months; HR, 0.887; 95% CI, 0.680-1.157; at 8 weeks: 5.7 vs. 6.4 months; HR, 1.09; 95% CI, 0.84-1.41). Objective response rate was numerically higher in patients with (48.6%) versus without CSTE-HTN (34.5%). CONCLUSIONS: In this retrospective analysis, CSTE-HTN was associated with improved OS but not PFS. CSTE-HTN did not impair the outcomes of patients with HCC treated with lenvatinib when detected early and managed appropriately.

Clinical utility of BRCA and ATM mutation status in circulating tumour DNA for treatment selection in advanced pancreatic cancer.

BACKGROUND: Identification of homologous recombination deficiency (HRD) remains a challenge in advanced pancreatic cancer (APC). We investigated the utility of circulating tumour DNA (ctDNA) profiling in the assessment of BRCA1/2 and ATM mutation status and treatment selection in APC. METHODS: We analysed clinical and ctDNA data of 702 patients with APC enroled in GOZILA, a ctDNA profiling study using Guardant360. RESULTS: Inactivating BRCA1/2 and ATM mutations were detected in 4.8% (putative germline, 3.7%) and 4.4% (putative germline, 0.9%) of patients, respectively. Objective response (63.2% vs. 16.2%) and PFS (HR 0.55, 95% CI 0.32-0.93) on platinum-containing chemotherapy were significantly better in patients with putative germline BRCA1/2 (gBRCA) mutation than those without. In contrast, putative gBRCA mutation had no impact on the efficacy of gemcitabine plus nab-paclitaxel. In 2 patients treated with platinum-containing therapy, putative BRCA2 reversion mutations were detected. Three of seven patients with somatic BRCA mutations responded to platinum-containing therapy, while only one of four with putative germline ATM mutations did. One-third of somatic ATM mutations were in genomic loci associated with clonal haematopoiesis. CONCLUSION: Comprehensive ctDNA profiling provides clinically relevant information regarding HRD status. It can be a practical, convenient option for HRD screening in APC.

Adjuvant S-1 compared with observation in resected biliary tract cancer (JCOG1202, ASCOT): a multicentre, open-label, randomised, controlled, phase 3 trial.

BACKGROUND: S-1 has shown promising efficacy with a mild toxicity profile in patients with advanced biliary tract cancer. The aim of this study was to evaluate whether adjuvant S-1 improved overall survival compared with observation for resected biliary tract cancer. METHODS: This open-label, multicentre, randomised phase 3 trial was conducted in 38 Japanese hospitals. Patients aged 20-80 years who had histologically confirmed extrahepatic cholangiocarcinoma, gallbladder carcinoma, ampullary carcinoma, or intrahepatic cholangiocarcinoma in a resected specimen and had undergone no local residual tumour resection or microscopic residual tumour resection were randomly assigned (1:1) to undergo observation or to receive S-1 (ie, 40 mg, 50 mg, or 60 mg according to body surface area, orally administered twice daily for 4 weeks, followed by 2 weeks of rest for four cycles). Randomisation was performed by the minimisation method, using institution, primary tumour site, and lymph node metastasis as adjustment factors. The primary endpoint was overall survival and was assessed for all randomly assigned patients on an intention-to-treat basis. Safety was assessed in all eligible patients. For the S-1 group, all patients who began the protocol treatment were eligible for a safety assessment. This trial is registered with the University hospital Medical Information Network Clinical Trials Registry (UMIN000011688). FINDINGS: Between Sept 9, 2013, and June 22, 2018, 440 patients were enrolled (observation group n=222 and S-1 group n=218). The data cutoff date was June 23, 2021. Median duration of follow-up was 45·4 months. In the primary analysis, the 3-year overall survival was 67·6% (95% CI 61·0-73·3%) in the observation group compared with 77·1% (70·9-82·1%) in the S-1 group (adjusted hazard ratio [HR] 0·69, 95% CI 0·51-0·94; one-sided p=0·0080). The 3-year relapse-free survival was 50·9% (95% CI 44·1-57·2%) in the observation group compared with 62·4% (55·6-68·4%) in the S-1 group (HR 0·80, 95% CI 0·61-1·04; two-sided p=0·088). The main grade 3-4 adverse events in the S-1 group were decreased neutrophil count (29 [14%]) and biliary tract infection (15 [7%]). INTERPRETATION: Although long-term clinical benefit would be needed for a definitive conclusion, a significant improvement in survival suggested adjuvant S-1 could be considered a standard of care for resected biliary tract cancer in Asian patients. FUNDING: The National Cancer Center Research and the Ministry of Health, Labour, and Welfare of Japan.

Early Tumor Shrinkage and Depth of Response as Predictors of Survival for Advanced Biliary Tract Cancer: An Exploratory Analysis of JCOG1113.

BACKGROUND: Recent studies suggest that early tumor shrinkage (ETS) and depth of response (DpR) reflect outcomes of chemotherapy in various cancers. This study evaluated the association of ETS and DpR with clinical outcomes using data from JCOG1113, which demonstrated the non-inferiority of gemcitabine plus S-1 (GS) to gemcitabine plus cisplatin (GC) for chemotherapy-naïve advanced biliary tract cancer. MATERIAL AND METHODS: In total, 354 (289 with measurable target lesions) patients enrolled in JCOG1113 were divided into ETS-unachieved and ETS-achieved groups (≥20% tumor reduction at week 6) and DpR-low and DpR-high groups (≥40% maximum shrinkage) until 12 weeks after enrollment. The impact of ETS and DpR on survival outcome was evaluated using the multivariable Cox proportional hazard model. RESULTS: The proportions of patients in the ETS-achieved and DpR-high groups were similar between the 2 treatment arms. The hazard ratios (HRs) of progression-free survival (PFS) and overall survival (OS) for the ETS-achieved group were 0.70 (95% confidence interval (CI), 0.52-0.93) and 0.60 (95%CI, 0.44-0.81), respectively. The HRs of PFS and OS for the DpR-high group were 0.67 (95%CI, 0.48-0.94) and 0.64 (95%CI, 0.46-0.90), respectively. In the subpopulation treatment effect pattern plot analysis, most patients in the ETS-achieved group in the GC arm did not experience disease progression after 12 weeks from the landmark. CONCLUSION: As on-treatment markers, ETS and DpR were effective tools. ETS was clinically useful, because it can be used to evaluate the outcomes of treatment early at a specific time.

Efficacy of cisplatin-gemcitabine-durvalumab in patients with advanced biliary tract cancer experiencing early vs late disease relapse after surgery: a large real-life worldwide population.

BACKGROUND: In the TOPAZ-1, patients with biliary tract cancers (BTC) and recurrence within 6 months after surgery were excluded, even if this event is frequently observed in clinical practice. Our study aimed to assess if the efficacy of cisplatin-gemcitabine-durvalumab (CGD) in this population is comparable to that reported in the phase 3 trial. METHODS: The study cohort included patients with BTC who underwent surgery on the primary tumor, experienced disease recurrence occurring ≤6 months or >6 months after surgery or after the end of adjuvant therapy and started CGD. The primary objectives were overall survival (OS) and progression free survival (PFS). RESULTS: A total of 178 patients were enrolled. No significant differences were observed between early and late relapse groups in OS (23.4 months vs not reached; HR 1.26; 95% CI, 0.67-2.37; P = .45) and PFS [7.0 months vs 9.8 months; HR 1.3(95% CI, 0.9-2.1) P = .13]. Overall response rate and disease control rate (P = .33 and P = .62) were comparable between the 2 groups, as the overall safety profile. In addition, we compared survival outcomes between the selected population and a historical cohort of patients with BTC treated with cisplatin-gemcitabine (CG) and found that despite the absence of statistical significance, CGD showed an outcome trend compared with CG regardless of the time of recurrence after surgery or adjuvant chemotherapy [(CG ≤ 6 vs CGD ≤ 6 months: HR 0.59, 95%CI, 0.35-1.01, P = .05; HR 0.70; 95%CI, 0.46-1.06, P = .09, OS and PFS, respectively) and (CG > 6 vs. CGD > 6 months: HR 0.50; 95%CI, 0.29-0.88, P = 0.0165; HR 0.54; 95%CI, 0.35-0.84, P = .0068, OS and PFS, respectively)]. CONCLUSION: Our analysis suggests that CGD retains its efficacy independently of the timing of relapse after surgery or completion of adjuvant treatment in patients with advanced BTC.

Ramucirumab for advanced hepatocellular carcinoma in the current real world: a Japanese single-arm study post-REACH-2 (The R-evolution study).

This study aimed to complement the results of the REACH-2 study by prospectively evaluating the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma (HCC) in a real-world setting. This was an open-label, nonrandomized, multicenter, prospective study conducted at 13 institutions in Japan (jRCTs031190236). The study included Child-Pugh Class A patients with advanced HCC who had received pretreatment with atezolizumab plus bevacizumab (Atez/Bev) or lenvatinib. Ramucirumab was introduced as a second-line treatment after Atez/Bev or lenvatinib and as a third-line treatment after Atez/Bev and lenvatinib. Between May 2020 and July 2022, we enrolled 19 patients, including 17 who received ramucirumab. Additionally, seven patients received lenvatinib, another seven patients received Atez/Bev, and three patients received Atez/Bev followed by lenvatinib as prior treatment. The primary endpoint was a 6-month progression-free survival (PFS) rate, which was 14.3%. The median PFS and overall survival were 3.7 and 12.0 months, respectively. The most common grade ≥ 3 adverse events (AEs) were hypertension (23.5%), proteinuria (17.6%), and neutropenia (11.8%). The discontinuation rate due to AEs was 29.4%. Six patients progressed from Child-Pugh A to B after treatment with ramucirumab. Thirteen patients were eligible for post-ramucirumab treatment, including systemic therapy. Despite the limited number of patients, the efficacy of ramucirumab was comparable to that observed in the REACH-2 study when used after lenvatinib and Atez/Bev. However, the incidence of AEs was higher than that in the REACH-2 study.

Treatment outcomes of gemcitabine plus nab-paclitaxel in pancreatic cancer patients with malignant ascites.

BACKGROUND: Gemcitabine plus nab-paclitaxel (GnP) therapy has been shown to improve the prognosis in patients with metastatic pancreatic cancer (PC); however, the efficacy and safety of GnP in PC patients with malignant ascites (MA) remains unknown. METHODS: We retrospectively investigated PC patients with peritoneal dissemination who had received GnP as first-line chemotherapy at our institution between March 2015 and August 2021. The following patient data were reviewed: patient characteristics, overall survival (OS), progression-free survival (PFS), objective response rate (ORR), adverse events (AEs), and relative dose intensity (RDI). The severity of MA was categorized based on the CT findings as grade 1 (small), grade 2 (moderate), or grade 3 (massive). RESULTS: A total of 189 patients were included; the study endpoints were compared between patients with each ascites grade and 41 patients without MA. The MA was classified as grade 1 in 85 patients, grade 2 in 41 patients, and grade 3 in 22 patients. In the patients with MA, the median OS, PFS and ORR were 11.2 months, 5.7 months and 24.3%, respectively. The OS and PFS decreased with increasing the severity of MA; in particular, patients with grade 2 and 3 showed a poorer prognosis. There were no differences in AEs, except for anorexia, or the RDI according to the severity of MA. CONCLUSION: GnP showed moderate efficacy with manageable safety profile in PC patients with MA. However, PC patients with moderate to massive ascites still have a dismal prognosis, and further development of effective treatments is needed.

Early tumor shrinkage as a prognostic predictor in chemotherapy-naïve patients with locally advanced pancreatic cancer treated with modified FOLFIRINOX or gemcitabine plus nab-paclitaxel combination therapy: An exploratory analysis of JCOG1407.

BACKGROUND: Early tumor shrinkage (ETS) is a prognostic predictor for patients treated with chemotherapy in colorectal cancer, although scarce studies evaluated its potential in locally advanced pancreatic cancer (LAPC). In this exploratory analysis of JCOG1407, a randomized phase II study comparing modified 5-fluorouracil, levofolinate, irinotecan, and oxaliplatin (mFOLFIRINOX) and gemcitabine plus nab-paclitaxel (GnP), we evaluated whether ETS can predict prognosis of patients with LAPC. METHODS: Of the 126 patients enrolled in JCOG1407, 112 with measurable lesions were included in this study. ETS was defined as a ≥20 % reduction in tumor diameter compared with baseline at the initial imaging assessment 6-10 weeks after initiating chemotherapy. Patients were divided into the ETS (achieved ETS) and non-ETS (failed to achieve ETS) groups based on their ETS status. The impact of ETS on overall survival (OS) was compared using multivariable Cox regression analysis. RESULTS: Fourteen of 55 (25.5 %) and 24 of 57 (42.1 %) patients in the mFOLFIRINOX and GnP arms, respectively, achieved ETS. In the overall population, mFOLFIRINOX arm, and GnP arm, the median OS in the ETS and non-ETS groups was 27.1 and 20.4, 29.8 and 20.6, and 24.1 and 20.4, months, respectively. The adjusted hazard ratios of OS for the ETS group in the overall population, mFOLFIRINOX arm, and GnP arm were 0.451 (95 % confidence interval [CI]: 0.270-0.754), 0.371 (95 % CI: 0.149-0.926), and 0.508 (95 % CI: 0.255-1.004), respectively. CONCLUSIONS: ETS may be a prognostic predictor in chemotherapy-naïve patients with LAPC treated with mFOLFIRINOX or GnP.

Phase II trial of niraparib for BRCA-mutated biliary tract, pancreatic and other gastrointestinal cancers: NIR-B.

Due to the widespread use of cancer genetic testing in gastrointestinal cancer, the BRCA1/2 genetic mutation has been identified in biliary tract cancer as well as pancreatic cancer. Niraparib is a poly(ADP-ribose) polymerase (PARP) inhibitor, and PARP inhibitors exert their cytotoxicity against cancer cells in the context of homologous recombination deficiency, such as BRCA mutations, via the mechanism of synthetic lethality. The aim of this phase II NIR-B trial is to evaluate the efficacy and safety of niraparib for patients with unresectable advanced or recurrent biliary tract cancer, pancreatic cancer or other gastrointestinal cancers with germline or somatic BRCA1/2 mutations revealed by genetic testing. The primary end point is an investigator-assessed objective response rate in each cohort.Clinical Trial Registration: jRCT2011200023 (ClinicalTrials.gov).

A clinical study to confirm the efficacy and safety of niraparib for people with advanced biliary tract, pancreatic and other abdominal cancers with the BRCA genetic mutation: the NIR-B trial.BRCA gene is involved in repairing DNA injury and plays an important role in cancer growth. Cells with a mutation in the BRCA gene cannot repair DNA using a method called homologous recombination repair. Niraparib is part of a class of drugs called 'PARP inhibitors' that inhibit enzymes called 'PARP' involved in repairing DNA injury, and has shown efficacy against cancers with BRCA gene mutations. BRCA gene mutations are infrequent but have been found in a variety of cancers. The NIR-B trial is a clinical trial to evaluate the efficacy and safety of niraparib for people with advanced biliary tract, pancreatic and other abdominal cancers with BRCA gene mutations.

Multicenter validation study of a treatment selection MAP for pancreatic neuroendocrine tumors.

BACKGROUND: Somatostatin analogs, molecular-targeted agents and cytotoxic anticancer agents are available as therapeutic agents for the systemic treatment of pancreatic neuroendocrine tumors, and we have developed a first-line treatment selection MAP to enable selection of the optimal treatment strategy for pancreatic neuroendocrine tumors. The purpose of this study was to validate the usefulness of the treatment selection MAP. METHODS: Patients who had received systemic therapy for a pancreatic neuroendocrine tumor between January 2017 and December 2020 were compared according to whether they had been treated as recommended by the MAP (matched patients) or not (unmatched patients) to determine whether better outcomes were achieved by the matched patients. The primary endpoint was progression-free survival of the matched group and unmatched groups in the somatostatin analog, molecular-targeted agent and cytotoxic anticancer agents areas of the MAP. RESULTS: There were 41 (55%) MAP-matched patients in all areas among the 74 patients registered at seven hospitals. The MAP-matched rates were 100, 77 and 38% in the somatostatin analog area, molecular-targeted agent area and cytotoxic anticancer agents area, respectively. All of the unmatched patients had been selected for less intensive treatment. The median progression-free survival in the matched group and unmatched group in the molecular-targeted agent area of the MAP were 46.6 and 15.4 months, respectively, and a multivariate analysis identified MAP-matched (hazard ratio 0.18 [95% confidence interval: 0.04-0.87], P = 0.032) as the only significant independent favorable predictive factor. CONCLUSION: The usefulness of the MAP for treatment selection was validated in the molecular-targeted agent area of the MAP.

Current status of the cost burden of first-line systemic treatment for patients with advanced hepatocellular carcinoma in Japan, 2021-22.

BACKGROUND: Although recent advances in systemic therapies for hepatocellular carcinoma (HCC) have led to prolonged patient survival, the high costs of the drugs place a heavy burden on both patients and society. The objectives of this study were to examine the treatment regimens used as first-line systemic treatment for patients with advanced HCC in Japan and to estimate the treatment costs per regimen. METHODS: For this study, we aggregated the data of patients who had received first-line systemic treatment for advanced HCC between July 2021 and June 2022. The treatment cost per month of each regimen was estimated based on standard usage, assuming an average weight of 60 kg for male patients. The data were categorized by the treatment regimen, and the treatments were categorized based on the cost into very high-cost (≥1 000 000 Japanese yen [JPY]/month), high-cost (≥500 000 JPY/month) and other (<500 000 JPY/month) treatments. RESULTS: Of the total of 552 patients from 24 institutions whose data were analyzed in this study, 439 (79.5%) received atezolizumab plus bevacizumab, 98 (17.8%) received lenvatinib and 15 (2.7%) received sorafenib as the first-line treatment. The treatment cost per month for each of the above regimens was as follows: atezolizumab plus bevacizumab, 1 176 284 JPY; lenvatinib, 362 295 JPY and sorafenib, 571 644 JPY. In total, 82.2% of patients received high-cost regimens, and the majority of these patients received a very high-cost regimen of atezolizumab plus bevacizumab. CONCLUSIONS: Advances in systemic therapies for HCC have led to prolonged patient survival. However, the treatment costs are also increasing, imposing a burden on both the patients and society.

Influence of major hepatectomy on gemcitabine-based chemotherapy for recurrent biliary tract cancer after surgery: a subgroup analysis of JCOG1113.

BACKGROUND: Major hepatectomy (MH) can increase the risk of adverse events (AEs) owing to impaired drug metabolism due to decreased liver volume and surgical injury. Thus, we performed this subgroup analysis using data from JCOG1113, a phase III trial comparing gemcitabine plus S-1 (GS) and gemcitabine plus cisplatin (GC) in patients with advanced and recurrent biliary tract cancer (BTC), to evaluate the effect of MH on the safety and efficacy of GC and GS regimens in patients with recurrent BTC. METHODS: Of the 354 patients with advanced BTC enrolled in JCOG1113, 76 patients with postoperative recurrence (30 in the MH group and 46 in the non-MH group) were analyzed. RESULTS: Grade ≥ 3 platelet count decreased in both arms was more frequent in the MH group than in non-MH group (GC, 0.0 vs. 17.6%; GS, 3.9 vs. 15.4%). However, in the MH group, the white blood cell decreased (GC, 55.0 vs. 38.5%; GS, 23.1 vs. 7.7%) and anemia (GC, 15.0 vs. 11.8%; GS, 23.1 vs. 7.7%) were less common than in the non-MH group. The MH and non-MH groups showed no significant difference in overall survival (OS) in both GC [median OS, 23.0 in MH vs. 16.9 months in non-MH (hazard ratio, 0.857; 95% CI 0.387-1.899)], and GS [median OS, 21.5 vs. 14.9 months (hazard ratio, 0.670; 95% CI 0.310-1.447)] arms. CONCLUSIONS: The safety and efficacy of gemcitabine-based chemotherapy were comparable between patients who underwent MH and those who underwent other surgeries.

Lenvatinib plus pembrolizumab versus lenvatinib plus placebo for advanced hepatocellular carcinoma (LEAP-002): a randomised, double-blind, phase 3 trial.

BACKGROUND: Systemic therapies have improved the management of hepatocellular carcinoma, but there is still a need to further enhance overall survival in first-line advanced stages. This study aimed to evaluate the addition of pembrolizumab to lenvatinib versus lenvatinib plus placebo in the first-line setting for unresectable hepatocellular carcinoma. METHODS: In this global, randomised, double-blind, phase 3 study (LEAP-002), patients aged 18 years or older with unresectable hepatocellular carcinoma, Child Pugh class A liver disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no previous systemic treatment were enrolled at 172 global sites. Patients were randomly assigned (1:1) with a central interactive voice-response system (block size of 4) to receive lenvatinib (bodyweight <60 kg, 8 mg/day; bodyweight ≥60 kg, 12 mg/day) plus pembrolizumab (200 mg every 3 weeks) or lenvatinib plus placebo. Randomisation was stratified by geographical region, macrovascular portal vein invasion or extrahepatic spread or both, α-fetoprotein concentration, and Eastern Cooperative Oncology Group performance status. Dual primary endpoints were overall survival (superiority threshold at final overall survival analysis, one-sided p=0·019; final analysis to occur after 532 events) and progression-free survival (superiority threshold one-sided p=0·002; final analysis to occur after 571 events) in the intention-to-treat population. Results from the final analysis are reported. This study is registered with ClinicalTrials.gov, NCT03713593, and is active but not recruiting. FINDINGS: Between Jan 17, 2019, and April 28, 2020, of 1309 patients assessed, 794 were randomly assigned to lenvatinib plus pembrolizumab (n=395) or lenvatinib plus placebo (n=399). Median age was 66·0 years (IQR 57·0-72·0), 644 (81%) of 794 were male, 150 (19%) were female, 345 (43%) were Asian, 345 (43%) were White, 22 (3%) were multiple races, 21 (3%) were American Indian or Alaska Native, 21 (3%) were Native Hawaiian or other Pacific Islander, 13 (2%) were Black or African American, and 46 (6%) did not have available race data. Median follow up as of data cutoff for the final analysis (June 21, 2022) was 32·1 months (IQR 29·4-35·3). Median overall survival was 21·2 months (95% CI 19·0-23·6; 252 [64%] of 395 died) with lenvatinib plus pembrolizumab versus 19·0 months (17·2-21·7; 282 [71%] of 399 died) with lenvatinib plus placebo (hazard ratio [HR] 0·84; 95% CI 0·71-1·00; stratified log-rank p=0·023). As of data cutoff for the progression-free survival final analysis (April 5, 2021), median progression-free survival was 8·2 months (95% CI 6·4-8·4; 270 events occurred [42 deaths; 228 progressions]) with lenvatinib plus pembrolizumab versus 8·0 months (6·3-8·2; 301 events occurred [36 deaths; 265 progressions]) with lenvatinib plus placebo (HR 0·87; 95% CI 0·73-1·02; stratified log-rank p=0·047). The most common treatment-related grade 3-4 adverse events were hypertension (69 [17%] of 395 patients in the lenvatinib plus pembrolizumab group vs 68 [17%] of 395 patients) in the lenvatinib plus placebo group), increased aspartate aminotransferase (27 [7%] vs 17 [4%]), and diarrhoea (25 [6%] vs 15 [4%]). Treatment-related deaths occurred in four (1%) patients in the lenvatinib plus pembrolizumab group (due to gastrointestinal haemorrhage and hepatorenal syndrome [n=1 each] and hepatic encephalopathy [n=2]) and in three (1%) patients in the lenvatinib plus placebo group (due to gastrointestinal haemorrhage, hepatorenal syndrome, and cerebrovascular accident [n=1 each]). INTERPRETATION: In earlier studies, the addition of pembrolizumab to lenvatinib as first-line therapy for advanced hepatocellular carcinoma has shown promising clinical activity; however, lenvatinib plus pembrolizumab did not meet prespecified significance for improved overall survival and progression-free survival versus lenvatinib plus placebo. Our findings do not support a change in clinical practice. FUNDING: Eisai US, and Merck Sharp & Dohme, a subsidiary of Merck.

Fibroblast inhibition by tocilizumab enabled gemcitabine/nab-paclitaxel rechallenge for pancreatic cancer.

Interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) pathway inhibition may overcome chemoresistance of metastatic pancreatic cancer (MPC). We sought to determine the safety and recommended dose of tocilizumab (TCZ), an IL-6 receptor monoclonal antibody, and biological correlates of tumor shrinkage in patients with gemcitabine (GEM)/nanoparticle albumin-bound paclitaxel (nab-PTX)-refractory MPC. This phase 1 study enrolled 10 patients with MPC who had progressed after GEM/nab-PTX. Patients initially received TCZ 8 mg/kg on Day 1 and nab-PTX 100 mg/m2 + GEM 750 mg/m2 on Days 2, 9, and 16. Before and at the end of Cycle 1, biopsy of liver metastases was performed 3-5 h after levofloxacin (LVFX) administration to measure LVFX infiltration into tumor tissue. No dose-limited toxicities occurred, and the recommended dosage of TCZ was determined to be 8 mg/kg. Treatment-emergent adverse events occurred in 80% of patients, of which decreased neutrophil count was the most common. Tumor reduction during Cycle 1 was observed in four patients, who were defined as responders. In paired-biopsy samples, responder-related biological activities were an increase of cleaved PARP expression of tumor nuclei (p = 0.01), a decrease of proliferative cancer-associated fibroblasts (CAFs) (p = 0.08), and an increase of LVFX infiltration in the tumor (p = 0.04). A decrease of phosphorylated STAT3 expression (p = 0.02) favored an increase in LVFX infiltration. In conclusion, TCZ + GEM/nab-PTX-rechallenge had a manageable safety profile and showed preliminary activity via inhibition of CAF and improved intratumoral drug infiltration in MPC.

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

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

Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma.

BACKGROUND: The combination of atezolizumab and bevacizumab showed encouraging antitumor activity and safety in a phase 1b trial involving patients with unresectable hepatocellular carcinoma. METHODS: In a global, open-label, phase 3 trial, patients with unresectable hepatocellular carcinoma who had not previously received systemic treatment were randomly assigned in a 2:1 ratio to receive either atezolizumab plus bevacizumab or sorafenib until unacceptable toxic effects occurred or there was a loss of clinical benefit. The coprimary end points were overall survival and progression-free survival in the intention-to-treat population, as assessed at an independent review facility according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1). RESULTS: The intention-to-treat population included 336 patients in the atezolizumab-bevacizumab group and 165 patients in the sorafenib group. At the time of the primary analysis (August 29, 2019), the hazard ratio for death with atezolizumab-bevacizumab as compared with sorafenib was 0.58 (95% confidence interval [CI], 0.42 to 0.79; P<0.001). Overall survival at 12 months was 67.2% (95% CI, 61.3 to 73.1) with atezolizumab-bevacizumab and 54.6% (95% CI, 45.2 to 64.0) with sorafenib. Median progression-free survival was 6.8 months (95% CI, 5.7 to 8.3) and 4.3 months (95% CI, 4.0 to 5.6) in the respective groups (hazard ratio for disease progression or death, 0.59; 95% CI, 0.47 to 0.76; P<0.001). Grade 3 or 4 adverse events occurred in 56.5% of 329 patients who received at least one dose of atezolizumab-bevacizumab and in 55.1% of 156 patients who received at least one dose of sorafenib. Grade 3 or 4 hypertension occurred in 15.2% of patients in the atezolizumab-bevacizumab group; however, other high-grade toxic effects were infrequent. CONCLUSIONS: In patients with unresectable hepatocellular carcinoma, atezolizumab combined with bevacizumab resulted in better overall and progression-free survival outcomes than sorafenib. (Funded by F. Hoffmann-La Roche/Genentech; ClinicalTrials.gov number, NCT03434379.).

A Multicenter Survey on Eligibility for a Randomized Phase III Trial of Adjuvant Chemotherapy for Resected Biliary Tract Cancer (JCOG1202, ASCOT).

BACKGROUND: The Adjuvant S-1 for Cholangiocarcinoma Trial (JCOG1202, [ASCOT]) was a multicenter, randomized controlled trial aimed at investigating the efficacy and safety of adjuvant chemotherapy (AC) with S-1 for resected biliary tract cancer (BTC). This trial reported that overall survival was prolonged with AC compared with observation. METHODS: With the aim of increasing enrollment, the present survey biannually recorded the number of patients eligible for enrollment into ASCOT and reasons for ineligibility among patients who had undergone surgery for BTC from April 2015 to September 2017 at 36 institutions participating in ASCOT. RESULTS: Of 2039 patients who underwent surgery for BTC, 211 (10.3%) were already enrolled, 166 (8.1%) were eligible but had not been enrolled, and 1662 (81.5%) were ineligible. Among ineligible patients, the predominant reasons for ineligibility were patient refusal (n = 332, 20.0%), pathologic stage (pT1N0; n = 248, 14.9%), age (≥ 81 years; n = 196, 11.8%), and prolonged postoperative complications (n = 176, 10.6%). CONCLUSIONS: Patients undergoing surgery for BTC are a heterogeneous cohort comprising patients with earlier pathologic stage, advanced age, and prolonged postoperative complications. These factors should be considered during the design of future clinical trials of perioperative treatments for resectable BTC.

Optimal first-line treatment strategies of systemic therapy for unresectable gastrointestinal neuroendocrine tumors based on the opinions of Japanese experts.

There are several options for systemic therapy of gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN), including somatostatin analogues (SSA), molecular-targeted agents, cytotoxic agents, and peptide receptor radionuclide therapy. However, the effectiveness of each agent varies according to the primary site. Although SSA and everolimus are key drugs used for systemic therapy of neuroendocrine tumors arising from the gastrointestinal tract (GI-NET), the optimal strategy for selecting among these modalities remains unexplored. Japanese experts on GI-NET discussed and determined optimal first-line treatment strategies based on the results of previously reported pivotal trials. The consensus was reached that tumor aggressiveness and prognosis can be predicted using hepatic tumor load and Ki-67 labeling index, which are thought to be clinically important factors when selecting systemic therapy for unresectable GI-NET. SSA therapy is considered appropriate for patients with a low hepatic tumor load and low Ki-67 value and everolimus for those with contraindications to SSA therapy. There was also agreement that the treatment strategy should be determined according to whether the origin is in the midgut, considering the biological differences. Based on this strategy, the experts have tentatively created treatment maps and applied them in representative cases of unresectable GI-NET. Japanese experts proposed tentative maps for optimal first-line treatment in patients with unresectable GI-NET. Further investigation is warranted to validate the usefulness of these maps.