A soluble LAG-3 protein (eftilagimod alpha) and an anti-PD-L1 antibody (avelumab) tested in a phase I trial: a new combination in immuno-oncology.

BACKGROUND: Eftilagimod alpha (efti) is a major histocompatibility complex class II agonist activating antigen-presenting cells which leads to greater systemic type 1 T helper response and more cytotoxic CD8+ T-cell activation. This phase I trial evaluated the administration of efti, a soluble lymphocyte activation gene-3 (LAG-3) protein, combined with the anti-programmed death-ligand 1 (PD-L1) antibody avelumab in advanced solid tumors. PATIENTS AND METHODS: Patients with heavily pretreated metastatic solid tumors received intravenous avelumab (800 mg) combined with subcutaneously administered efti (6 or 30 mg) for up to 12 cycles, followed by avelumab monotherapy. The primary endpoint was the assessment of the recommended phase II dose (RP2D) of efti in combination with avelumab. RESULTS: Twelve patients with different tumor entities were enrolled (six patients in each cohort). During treatment, no dose-limiting toxicities occurred, and the severity of most adverse events was grade 1 or 2. In total, nine serious adverse events were documented, resulting in a fatal outcome in two cases, but none of them were assessed to be treatment related. Five patients (42%) achieved partial response. The median progression-free survival was 1.96 months and the median overall survival was not reached, with a 12-month survival rate of 75%. CONCLUSION: Subcutaneously administered efti plus avelumab was well tolerated, and efti of 30 mg was determined to be RP2D. The activity is promising and warrants further investigation in future phase II trials.

Nal-IRI with 5-fluorouracil (5-FU) and leucovorin or gemcitabine plus cisplatin in advanced biliary tract cancer - the NIFE trial (AIO-YMO HEP-0315) an open label, non-comparative, randomized, multicenter phase II study.

BACKGROUND: Biliary tract cancer (BTC) has a high mortality. Primary diagnosis is frequently delayed due to mostly unspecific symptoms, resulting in a high number of advanced cases at the time of diagnosis. Advanced BTCs are in principle chemotherapy sensitive as determined by improved disease control, survival and quality of life (QoL). However, median OS does not exceed 11.7 months with the current standard of care gemcitabine plus cisplatin. Thereby, novel drug formulations like nanoliposomal-irinotecan (nal-IRI) in combination with 5- fluorouracil (5-FU)/leucovorin may have the potential to improve therapeutic outcomes in this disease. METHODS: NIFE is an interventional, prospective, randomized, controlled, open label, two-sided phase II study. Within the study, 2 × 46 patients with locally advanced, non-resectable or metastatic BTC are to be enrolled by two stage design of Simon. Data analysis will be done unconnected for both arms. Patients are allocated in two arms: Arm A (experimental intervention) nal-IRI mg/m2, 46 h infusion)/5-FU (2400 mg/m2, 46 h infusion)/leucovorin (400 mg/m2, 0.5 h infusion) d1 on 14 day-cycles; Arm B (standard of care) cisplatin (25 mg/m2, 1 h infusion)/gemcitabine (1000 mg/m2, 0.5 h infusion) d1 and d8 on 21 day-cycles. The randomization (1:1) is stratified for tumor site (intrahepatic vs. extrahepatic biliary tract), disease stage (advanced vs. metastatic), age (≤70 vs. > 70 years), sex (male vs. female) and WHO performance score (ECOG 0 vs. ECOG 1). Primary endpoint of the study is the progression free survival (PFS) rate at 4 months after randomization by an intention-to-treat analysis in each of the groups. Secondary endpoints are the overall PFS rate, the 3-year overall survival rate, the disease control rate after 2 months, safety and patient related outcome with quality of life. The initial assessment of tumor resectability for locally advanced BTCs is planned to be reviewed retrospectively by a central surgical board. Exploratory objectives aim at establishing novel biomarkers and molecular signatures to predict response. The study was initiated January 2018 in Germany. DISCUSSION: The NIFE trial evaluates the potential of a nanoliposomal-irinotecan/5-FU/leucovorin combination in the first line therapy of advanced BTCs and additionally offers a unique chance for translational research. TRIAL REGISTRATION: Clinicaltrials.gov NCT03044587. Registration Date February 7th 2017.

[Immediate radical re-resection of incidental T1b  gallbladder cancer and the problem of an adequate extent of resection (results of the German Registry "Incidental Gallbladder Cancer")]. / Die unmittelbare radikale Re-Operation bei inzidentellem T1b-Gallenblasenkarzinom und die Frage der angemessenen Radikalität (CAES / CAMIC-Zentralregister: "Okkultes Gallenblasenkarzinom").

INTRODUCTION: Gallbladder cancer is suspected preoperatively in only 30 % of all patients, while the other 70 % of cases are discovered incidentally by the pathologist (incidental or occult gallbladder cancer or IGBC). If gallbladder cancer is suspected preoperatively, an open cholecystectomy must be performed. The increasing rate of cholecystectomies via laparoscopy has lad to the detection of more gallbladder cancers in an early stage. Extended resection with regional lymph node dissection for T2 carcinomas and for more advanced cancer has been suggested. If IGBC is detected postoperatively by the pathologist after simple cholecystectomy, radical re-resection in cases of T2 tumours and more advanced stages is recommended. However, it has been argued that T1b cancers may have spread regionally or systemically at presentation and, thus, it remains debatable whether T1b cancers should be treated by simple cholecystectomy or by radical resection. PATIENTS / MATERIAL AND METHOD: This investigation was based on the German Registry of "Incidental Gallbladder Cancer" of the German Society of Surgery. In the present study, we evaluated whether T1 carcinoma patients do profit from a radical re-resection and if the different techniques of liver resection have comparable results in T1 carcinomas. RESULTS: We analysed 684 cases of IGBC including 124 patients with T1 cancer with a 5-year survival of 48 %. An extended re-resection increased the 5-year survival up to 68 % for T1-IGBC. The analysis shows no advantage for re-resection of T1a cancer. In contrast, the current analysis shows a statistically significant survival benefit for re-resection of T1b cancers from 34 % to 75 %. The Registry data show a trend of better survival for the patients treated with the wedge resection technique compared to other resection techniques. CONCLUSION: For T1a cancer a simple cholecystectomy is sufficient. An immediate re-resection is highly recommended for patients with IGBC in T1b stage. The wedge resection technique combined with a locoregional lymphadenectomy of the hepatoduodenal ligament seems to be the strategy of choice for T1b cancer. An extended re-resection is necessary to determine the nodal status exactly, and to determine an exact definite staging for patients with T1b cancer.

[Incidental T1b-T3 gallbladder carcinoma. Extended cholecystectomy as an underestimated prognostic factor-results of the German registry]. / Inzidentelle T1b- bis T3-Gallenblasenkarzinome. Die radikale Cholezystektomie als unterschätzter Prognosefaktor - Ergebnisse des CAES/CAMIC-Zentralregisters.

BACKGROUND: The immediate radical re-resection (IRR) after simple cholecystectomy in incidental gallbladder carcinoma (IGBC) is debated in the literature. The German S3 guidelines recommend IRR in T2 and more advanced stages. Current literature recommends more extensive surgery even in T1b tumors. METHODS: The German registry database was used for this study. RESULTS: To date 883 cases of IGBC have been analyzed. In 8 out of 39 patients with a T1a tumor IRR was carried out as well as in 43 out of 109 patients with a T1b tumor. There was a significant survival benefit for re-resected T1b patients. There was also a significant survival benefit for the 215 T2 tumors and the 75 T3 patients with IRR compared to the 441 T2 tumors and 207 T3 tumors without IRR. Comparison of liver resection techniques showed good results for the wedge resection technique in T1b and T2 carcinomas. For T3 carcinomas more radical techniques showed better results. Less than 50 % of T2-3 tumors in the registry have been re-resection. CONCLUSIONS: The IRR should be highly recommended in patients with T1b and more advanced IGBC. The wedge resection technique is an attractive procedure for T1b and T2 IGBC due to the lower invasiveness in spite of oncological adequacy.

Immediate re-resection of T1 incidental gallbladder carcinomas: a survival analysis of the German Registry.

BACKGROUND: Incidental gallbladder carcinoma (IGBC) is a carcinoma first detected by the pathologist. The indication for cholecystectomy is a benign disease. The indication for immediate re-resection (IRR) in the case of T1b incidental gallbladder carcinoma (IGBC) is debated in the literature, and different recommendations often are drawn on the basis of data collected from only small groups. However, the management of IGBC is difficult because no guidelines have been established. This study aimed to determine whether T1b IGBC actually benefits from an IRR. METHODS: A registry was founded in 1997 for prospective recording of all IGBCs in Germany. All the patients who had a re-resection in this study were treated according to the effective guidelines in Germany. This study analyzes 502 cases of IGBC. Kaplan-Meier curves were used to determine whether an IRR improves the survival of patients with T1 and T1b IGBC. RESULTS: No benefit was found for 5 of the 21 T1a patients who had an IRR, but 23 of the 72 T1b patients who had an IRR experienced a significant benefit. The rate of tumor recurrence was three times lower in the T1b group that underwent IRR. CONCLUSION: An IRR should be highly recommended for patients with IGBC in the T1b stage.