Friederike Nollmann, Freiburg i. Br., D
Introduction: Clinical responses of pancreatic ductal adenocarcinoma (PDAC) to the available combination chemotherapy regimens are highly heterogenous. Molecular profiling uncovers predictive biomarkers in only a small fraction of cases. Patient-derived pancreatic cancer organoids (PDAC-PDOs) are therefore under investigation as functional precision oncology tool, allowing to test an individual tumor`s drug sensitivities in a co-clinical time-relevant setting. So far, most reports extrapolate from in vitro responses to single drugs (oxaliplatin) to clinical responses to combination regimens (FOLFIRINOX), often omitting the necessary validation steps.
Methods: For this study, we employed a fully characterized cohort of PDAC-PDOs (n=20), derived from patients undergoing resection or surgical biopsy of pancreatic adenocarcinoma at our institution. We studied in vitro drug sensitivity following rigorously standardized and quality-controlled protocols. We went on to assemble combination chemotherapy protocols form in vitro testing mimicking clinically applied regimens (FOLFIRINOX, gemcitabine/nab-paclitaxel). We assessed responses to single drugs versus combination regimens for correlation, cross-compared sensitivities between the distinct chemo- protocols and finally integrated in vitro testing results with clinically observed responses and molecular profiles of individual tumors (DNA and RNA sequencing data).
Results: Ex vivo responses of PDAC-PDOs to individual chemotherapeutic drugs showed considerable variation (IC50, AUC), in line with previous reports. Responses of individual PDAC-PDOs were highly reproducible and consistent across assay conditions. FOLFIRINOX was modelled in vitro in several distinct ways, altogether producing highly consistent results. Notably, there was no correlation between responses to individual drugs and chemo-combinations observed. PDAC-PDOs showed highly heterogenous responses to FOLFIRINOX and gemcitabine/nab-paclitaxel in vitro. We will present further data regarding correlation of in vitro responses to clinical data and molecular profiles at the meeting.
Summary: Ex vivo chemotherapy sensitivity testing in PDAC-PDOs is technically feasible, generating robust results. Notably, single drug sensitivities show no correlation with response to clinically established chemotherapy combination regimens, which has significant implications for data interpretation and trial design.
V470 Charakterisierung des NFκB-Signalwegs in ARID1A-defizienten Pankreaskarzinom-Subtypen
Lena Aperdannier, Göttingen, D
Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive, fast proliferating disease with an overall 5-year survival rate of less than 8%.
Although therapeutic options have increased within the last years, the extreme molecular heterogeneity remains a major problem. In order to target the genetic background of the different tumor subtypes, patient individualized and subtype-specific therapies are an important opportunity.
The tumor suppressor gene ARID1A, a member of the SWI/SNF chromatin remodeling complex, is often mutated in different tumor entities. Its loss of function correlates with inflammatory phenotypes. In 20% of PDAC specimen a mutation along with a loss of function of ARID1A could be shown. Therefore, targeting inflammatory pathways such as the NFκB-signaling or the JAK-STAT pathway may be a potential therapeutic strategy in ARID1A-deficient tumor subtypes.
Methods: To investigate the role of ARID1A loss in controlling the inflammatory environment, IHC staining was performed comparing PDACs in mice with or without conditional ARID1A mutation. Different TFs in ARID1A wildtype and knockout (CRISPR/CAS9) cells were analyzed using Western blot and immunofluorescence. QRT-PCR and cytokine ELISA demonstrated the upregulated expression of inflammatory cytokines. Luciferase assays were used to analyze the transactivation of a NFκB- responsive Promoter. The functional effects of blocking inflammatory signaling pathways were investigated by Annexin/PI- and BrdU-based flow cytometry.
Results: Cytokine expression and secretion were upregulated in the context of ARID1A loss. The analysis of the JAK-STAT and the NFκB-signaling pathways showed an increased activation in different signaling specific subunits and an enhanced transcription of target genes. Additionally, Annexin/PI staining revealed an ARID1A-dependent induction of apoptosis.
Conclusion: Loss of ARID1A expression leads to an upregulation of inflammation, a trigger of carcinogenesis. A change in the transcription of cytokines resulted in increased secretion of inflammatory cytokines in the context of ARID1A-deficiency. Therefore, targeting inflammatory signaling pathways such as the NFκB or the JAK-STAT pathway could be a promising therapeutic option in ARID1A-deficient PDAC.
V139 JADE: Die prospektive, nationale, intersektorale Registerplattform zur Untersuchung von Behandlungsrealität, Wirksamkeit und Erkrankungsverlauf von Patienten mit Hepatozellulärem oder Cholangiozellulärem Karzinom in Deutschland
Karin Potthoff, Freiburg, D
Introduction: Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCC) are the most frequent types of primary liver cancer and currently the fastest rising causes of cancer-related deaths worldwide. Comprehensive, prospective, multicenter real-world evidence of patients (pts) with liver cancer, however, is still scarce. Here we present JADE, the clinical research platform on pts with primary liver cancer and malignancies of the biliary tract treated in real-world in Germany.
Patients and methods: JADE is a prospective, national, multicenter, intersectoral, longitudinal cohort study designed to collect data on pts with HCC or CCC (intra- or extrahepatic disease such as primary gall bladder or bile duct carcinoma) from approximately 100 sites, i.e. university and community hospitals and office-based medical oncologists and gastroenterologists, in Germany. Between 2020 and 2023, about 1,000 pts with early, intermediate or advanced/metastatic stage HCC or CCC will be enrolled at start of their first locoregional or systemic treatment. Data will be collected in electronic case report forms; plausibility checks and random monitoring will be performed to ensure data quality. Patient and tumor characteristics, treatment and outcome data will be documented. Patient-reported outcomes will be assessed using the EORTC QLQ-C30 and -HCC18 or -BIL21 questionnaires, respectively, at the time of enrollment and every 3 months for a maximum of 3 years. In addition, pts will be asked to give informed consent to use their routinely collected tumor samples for future translational research.
The JADE registry study was approved by local ethics committees and is registered at clinicaltrials.gov (NCT04510740).
Results: The first patient was recruited in August 2020. At the time of abstract submission (April 2021), 165 pts had been recruited at 54 sites, and further 39 sites had already agreed to participate. Data cut for the first planned interim analysis will be April 30th, 2021. First results on patient and disease characteristics and treatments will be presented.
Conclusion: The prospective registry study JADE will, for the first time, present real-world data on patient and tumor characteristics, treatment and outcomes of pts with liver and biliary tract cancer across all health care sectors in Germany. In the future, JADE will shed light on the treatment landscape in real-world and will help to identify unmet medical needs for future clinical research.
V394 Lenvatinib plus Pembrolizumab für Patienten mit zuvor behandeltem Gallengangskrebs in der Phase 2 Mehrkohortenstudie LEAP-005
Daniel Heudobler, Regensburg, D
Introduction: Second-line treatment options for patients (pts) with biliary tract cancers (BTC) are limited. Anti-angiogenic multikinase inhibitor lenvatinib (LEN) in combination with the programmed death-1 immune checkpoint inhibitor pembrolizumab (pembro), has demonstrated promising antitumor activity and manageable safety in pts with select advanced solid tumors. LEAP-005 (NCT03797326) is evaluating the efficacy and safety of LEN plus pembro in pts with previously treated advanced solid tumors; we present results from the BTC cohort.
Methods: In this nonrandomized, open-label, phase 2 study, eligible pts were aged ≥18 years with histologically or cytologically documented advanced (metastatic and/or unresectable) BTC with disease progression after 1 prior line of therapy, measurable disease per RECIST v1.1, ECOG PS of 0‒1, and tissue sample evaluable for PD-L1 expression. Pts received LEN 20 mg once daily plus pembro 200 mg Q3W for up to 35 cycles (2 years) or until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. Treatment with LEN could continue beyond 2 years in pts experiencing clinical benefit. Primary endpoints were ORR (per RECIST v1.1 by blinded independent central review) and safety. Secondary endpoints were disease control rate (DCR; comprising CR, PR, and SD), duration of response (DOR), PFS, and OS. Tumor imaging was performed Q9W from treatment initiation for 54 wks, then Q12W to wk 102, and Q24W thereafter.
Results: 31 pts were enrolled in the BTC cohort (55% ECOG PS 1; 84% ex-US). Median time from first dose to data cutoff (DCO; April 10, 2020) was 9.5 months (range, 3.1‒11.9), with 8 pts on treatment at DCO. There were 3 (10%) PRs and 18 (58%) SDs. ORR was 10% (95% CI, 2‒26), and DCR was 68% (95% CI, 49‒83). Median DOR was 5.3 months (range, 2.1+ to 6.2). Median (95% CI) PFS and OS were 6.1 mo (2.1‒6.4) and 8.6 mo (5.6 to NR), respectively. 30 pts (97%) had treatment-related AEs; 15 (48%) had grade 3 AEs (no grade 4-5). 2 (6%) discontinued treatment due to treatment-related AEs (myocarditis, pyrexia). The most common treatment-related AEs were hypertension (42%), dysphonia (39%), diarrhea, fatigue, and nausea (32% each). 14 pts (45%) had immune-mediated AEs; 1 pt (3%) had an infusion reaction.
Conclusions: LEN plus pembro demonstrated encouraging efficacy and manageable toxicity in pts with advanced BTC who had received 1 line of prior therapy. Based on these data, BTC cohort enrollment was expanded to 100 pts.
V3 IMbrave150: aktualisierte Überlebensdaten (OS) einer globalen, randomisierten open-label Phase III Studie von Atezolizumab (atezo) + Bevacizumab (bev) vs Sorafenib (sor) bei Patienten (pts) mit nicht-resektablem hepatozellulären Karzinom (HCC)
Peter Galle, Mainz, D
Background: Atezo+bev has been approved globally for pts with unresectable HCC without prior systemic therapy based on IMbrave150 (NCT03434379). We report an updated OS analysis for IMbrave150.
Methods: The global, multicenter, randomized, open-label, Ph III study IMbrave150 enrolled 501 systemic treatment-naive pts with unresectable HCC, ≥1 measurable untreated lesion (RECIST 1.1), Child-Pugh class A liver function and ECOG PS 0/1. Pts were randomized 2:1 to atezo 1200 mg IV q3w + bev 15 mg/kg IV q3w or sor 400 mg bid until unacceptable toxicity or loss of clinical benefit per investigator. This post hoc descriptive OS analysis included 12 mo of additional follow-up from the primary analysis.
Results: 501 pts were enrolled (atezo+bev:336; sor:165). At the clinical cutoff of August 31, 2020, median follow-up was 15.6 mo and 280 OS events were observed. Median OS was 19.2 mo with atezo+bev vs 13.4 mo with sor (HR, 0.66 [95% CI, 0.52-0.85]; P=0.0009). Survival at 18 mo was 52% with atezo+bev and 40% with sor. Survival benefit with atezo+bev vs sor was generally consistent across subgroups and with the primary analysis. The updated objective response rate (ORR; 29.8% per RECIST 1.1) with atezo+bev was in line with the primary analysis, with more pts achieving complete response (CR; 7.7%) than previously reported. Additional response data are in Table 1. Safety was consistent with the primary analysis, with no new signals identified.
Conclusion: IMbrave150 showed consistent clinically meaningful treatment benefit and safety with an additional 12 mo of follow-up. The combination provides the longest survival seen in a front-line Ph III study in advanced HCC, confirming atezo+bev as a standard of care for previously untreated, unresectable HCC.
© 2021 ASCO, Inc. Reused with permission. This abstract was accepted and previously presented at the 2021 GI Cancers Symposium. All rights reserved.