ABSTRACT:Relapse after remission remains the primary cause of treatment failure in acute myeloid leukemia (AML), underscoring the need for strategies to eliminate residual leukemic cells. The bone marrow (BM) microenvironment, largely orchestrated by the CXC chemokine receptor 4 (CXCR4)-CXC motif chemokine 12 axis (CXCL12), enables leukemia cell survival and chemoresistance by anchoring blasts in their protective BM niche. Motixafortide, a selective CXCR4 antagonist, mobilizes leukemic cells and disrupts tumor microenvironment interactions in preclinical models. In this randomized, double-blind, placebo-controlled phase 2 trial, 128 patients in first remission received high-dose cytarabine plus motixafortide or placebo. Median relapse-free survival did not substantially differ between groups: 10.3 months (95% confidence interval [CI], 8.0-12.0) for motixafortide and 11.5 months (95% CI, 8.6-24.1) for placebo (log-rank P = .98). But single-cell measurable residual disease (scMRD) analysis, performed before consolidation, demonstrated heterogeneity of CXCR4 inhibition benefit; in the placebo group, higher CXCR4 expression was associated with increased relapse risk (P = .02), whereas in the motixafortide group, higher CXCR4 expression was linked to a reduced relapse rate (P = .047). Exploratory analyses identified scMRD levels at which higher MRD burden was associated with inferior overall survival. Taken together, combining functional MRD profiling with biomarker-driven patient selection, such as CXCR4 expression, may enable more precise and effective postremission interventions in AML. This trial was registered at www.clinicaltrials.gov as NCT02502968 and at EudraCT as 2014-002702-21.

Precision oncology is a multi-step process including patient selection, tumor profiling, molecular tumor board discussion and personalized cancer management. So far, it remains largely unstandardized. The implementation of precision oncology can be beneficial for patients but implementation differs widely between tumor types and local practices. A working group was established by the Austrian, German and Swiss societies for Hematology and Medical Oncology to establish an expert consensus on evidence-based standards and implementation of precision oncology. Herein, we present a summary of this guideline. The full documents are available at www.onkopedia-guidelines.info.

PURPOSE:Epidermal growth factor receptor (EGFR) mutations are a main actionable driver in non-small cell lung cancer (NSCLC). However, the clinical significance of catenin beta-1 (CTNNB1) comutations remains unclear. This study evaluated outcomes of patients with EGFR/CTNNB1 comutated NSCLC in a dual-center cohort. METHODS:A retrospective analysis of 1,804 patients with NSCLC undergoing next-generation sequencing (NGS) in 2019-2024 at University Hospital Würzburg (single-center cohort, including 15 patients with EGFR/CTNNB1 comutations) was complemented with patients with EGFR/CTNNB1 comutated NSCLC receiving first-line osimertinib at the Thoraxklinik Heidelberg (n = 11) to extend and validate initial findings. We assessed clinical outcomes after first-line osimertinib therapy in 90 EGFR-mutated patients with CTNNB1 wild-type (wt) status and 23 with CTNNB1 comutation. RESULTS:CTNNB1 mutations were identified in 2.0% (36/1,804) of all patients with NSCLC from the single-center cohort, with 41.7% of these also harboring EGFR mutations. Among EGFR-mutant tumors, 7.7% (15/195) exhibited concurrent CTNNB1 mutations. In the dual-center cohort, the objective response rate with first-line osimertinib was 74.4% in CTNNB1-wt (n = 90) and 65.0% in CTNNB1-mutant patients (n = 23; P = .38). Notably, CTNNB1 mutations were associated with significantly longer progression-free survival (PFS; hazard ratio [HR], 0.32; P < .001) and overall survival (OS; HR, 0.33; P = .003). Multivariate analysis confirmed CTNNB1 comutation as an independent prognostic factor for improved PFS (HR, 0.31 [95% CI, 0.14 to 0.69]; P = .004) and OS (HR, 0.26 [95% CI, 0.10 to 0.65]; P = .004). Additionally, CTNNB1 mutations correlated with lower PD-L1 expression (P = .001) and TP53-wt status (P < .001). CONCLUSION:CTNNB1 comutations are associated with lower PD-L1 expression and TP53-wt status, correlating with improved outcomes in patients with EGFR-mutant NSCLC undergoing osimertinib therapy. These results suggest that CTNNB1 comutations may serve as a favorable prognostic biomarker in patients with EGFR-mutant NSCLC. Additional prospective studies are warranted to validate these results.

BackgroundDedifferentiated liposarcoma (DDLPS) is a rare mesenchymal cancer originating from the adipose tissue, with poor survival rates for most patients, highlighting the critical need for novel treatment options.Case descriptionThis report examines the efficacy and safety of sequential pre-treatment with the marine-derived alkaloid trabectedin followed by checkpoint inhibition using the anti-PD-1 antibody nivolumab in a 63-year-old male patient with unresectable retroperitoneal DDLPS. Treatment was initiated at the time of the seventh relapse as part of the NitraSarc phase 2 multicenter trial for inoperable soft tissue sarcoma conducted by the German Interdisciplinary Sarcoma Group (GISG-15, NCT03590210). The patient demonstrated an immediate tumor response, and in combination with minor surgery, achieved R0 resection status, which was subsequently maintained without the need for further therapy for the past 52 months. Correlative molecular analyses revealed a sustained DNA damage repair machinery and downregulation of PD-1 protein expression in post-treatment tumor samples.ConclusionThis report provides exemplary insight on the feasibility and efficacy of sequential pre-treatment with trabectedin as a priming strategy for PD-1 inhibition in advanced DDLPS. Full trial results from NitraSarc are pending for publication.

4193 Background: Perioperative chemotherapy (CTX) in resectable pancreatic ductal adenocarcinoma (rPDAC) is still not considered standard of care and data are limited. NEONAX examined gemcitabine (Gem)/nab-paclitaxel (nab-P), in the perioperative or adjuvant therapy of resectable PDAC (NCCN criteria). Methods: NEONAX is a prospective, randomized phase II trial with two independent arms (127 patients, 22 German centers) and randomization 1:1 to perioperative (2 pre- and 4 postoperative cycles, po-arm A) or adjuvant (6 cycles, ad-arm B) of gem (1000mg/m2 BSA, d1, 8, 15) and nab-P (125mg/m2 BSA, d1, 8, 15), q4w. Results: As we previously reported were R0- and N0-resection rates high (po-R0 88%, ad-R0 67%, po-N0 33%, ad-N0 29%) in the ITT-population (all randomized pts.). The primary endpoint DFS rate of 55% @ 18 months in the mITT population (defined as R0/R1 resected pts. that either started perioperative (A) or adjuvant (B) CTX), was not reached in both arms (arm A: 32%, arm B 41%). Whereas 91.5% of pts. in po-arm A started and 84.7% completed neoadjuvant CTX, only 42.4% of pts. in ad-arm B started and 25% completed adj. CTX, so the CTX dose intensity was higher in the po-arm A. (Seufferlein et al., Ann Onc 2023) Here we report long-time 5-year outcomes according to PFS and OS and present a preplanned subgroup analysis of potential prognostic factors. The mOS in the ITT population (all randomized pts.) was 25.5 mo. in the po-arm and 16.8 mo. in the ad- arm. This corresponds to an mDFS of 11.4 mo. in the po-arm and 5.1 mo. in the ad-arm, respectively. The mOS in the mITT population (all randomized pts. that started po-ctx (po-arm) or started ad-ctx (ad-arm)) was 27.9 mo. in the po-arm and 26.8 mo. in the ad-arm. This corresponds to an mDFS of 14.1 mo. in the po-arm and 16.1 mo. in the ad-arm, respectively. In the preplanned analysis of subgroup factors impacting outcome, the benefit of po-treatment was independent of tumor size, N-status and baseline Ca19-9 level. This benefit was not visible in the mITT population where only patients in the ad-arm were included who had started adjuvant treatment postoperatively. Conclusions: These 5 year data confirm the outcome of patients receiving gem/nab in the po-setting in the ITT population. DFS and OS effect were numerically better compared to the ad-arm although the trial was not powered for direct comparison of the arms. This difference disappeared in the mITT population when patients received more CTX in the ad arm. We conclude that the difference between ITT and mITT is likely because more CTX could administered in the po-arm when the ITT population was considered and may constitute one of the major effects of neoadjuvant chemotherapy in resectable PDAC, particularly when a high rate of patients as in our multicenter trial could get neoadjuvant, but not adjuvant treatment. Clinical trial information: NCT02047513 .

Introduction Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. The use of sequential polychemotherapies has improved the survival of patients with advanced metastatic disease. However, the survival rates achieved are low, and chemotherapy-related side effects are significant. Therefore, new, efficient, and tolerable therapies are urgently needed. In this study, we investigate the efficacy of pharmacological cyclin D-dependent kinase (CDK) 4/6 inhibition and explore the relevance of p16 as predictors of susceptibility to CDK 4/6 therapy. Materials and methods CDK 4/6 inhibitors were evaluated in native and FOLFOX- or ribociclib-resistant CRC, hepatocellular carcinoma (HCC), and breast cancer (BC) cell lines using viability, colony formation, and flow cytometry (FC)-based assays. Western blotting was employed to assess the expression of Rb and members of the INK4 family. SiRNA-based knockdown of CDK4/6 was utilized to gain insights into mechanisms of action or resistance. Tissue from 185 CRC patients was examined for the expression of p16 and its relevance for progression-free and overall survival. The prognostic relevance of cyclin-dependent kinase inhibitor 2 A ( CDKN2A ) mRNA expression data was derived from The Cancer Genome Atlas (TCGA) data. Results Ribociclib demonstrates significant antitumoral effects in various CRC, HCC, and BC cell lines, similar to two other approved CDK4/6 inhibitors (palbociclib and abemaciclib). Ribociclib-resistant cell lines (Hep-3B, HCC-1937, and BT-549) exhibited higher p16 expression compared to ribociclib-sensitive cell lines. In ribociclib-sensitive cell lines, CDK4/6 inhibition led to G1 phase arrest, whereas resistant cells did not exhibit such effects. A similar phenotype could be observed upon dual siRNA based CDK4/6 knockdown in ribociclib-sensitive HuH-7 and ribociclib-resistant Hep-3B cell lines. All CRC cell lines tested showed sensitivity to ribociclib, including the FOLFOX-resistant SW620 cell line. Low mRNA expression of CDKN2A (p16) was associated with favorable prognosis in CRC patients. No prognostic significance was found for p16 protein expression in an early-stage CRC cohort ( n = 185). Conclusion Ribociclib demonstrates significant antitumoral effects across a large panel of cancer cell lines and chemoresistant models, especially in CRC. Resistance towards ribociclib is associated with high p16 expression, which is a negative prognostic marker for patients with CRC. Our findings underscore p16 as a promising biomarker for predicting ribociclib responsiveness and emphasize the need for further mechanistic studies and combination therapy approaches to overcome resistance in p16 high patients.

605 Background: The aim of the ALPACA study was to investigate whether improved overall tolerability accompanied by prolonged treatment duration and increased efficacy can be achieved by alternating treatment cycles of Gem/nab-Pac and Gem monotherapy compared to standard continuous Gem/nab-Pac after a 3-month induction phase in patients with mPC. Methods: The randomized, multicenter phase 2 ALPACA trial of the German AIO study group enrolled patients with confirmed mPC in the first-line setting. After an induction phase with 3 cycles of standard dose Gem/nab-Pac (Gem 1000 mg/m 2 and nab-Pac 125 mg/m 2 on d1, 8, 15 of each 28-day cycle), patients were randomized (1:1) either to continue treatment with standard Gem/nab-Pac, or to receive alternating cycles of standard dose Gem/nab-Pac combination therapy and Gem monotherapy (Gem 1000 mg/m 2 on d1, 8, 15 of each 28-day cycle). Primary study endpoint was overall survival (OS) after randomization. The trial was registered with ClinicalTrials.gov, NCT02564146. Results: Between May 2016 and May 2021, 325 patients were enrolled from 29 German centers. 6 of the enrolled patients did not start treatment within the study. Following 3 cycles of induction treatment, 174 patients (53.5%) could be randomized. Main reasons for premature dropout were death (24.8%), progression of disease (22.8%), and adverse events (15.9%). Median OS after randomization in the alternating treatment arm was comparable to the standard treatment arm (10.5 vs. 10.4 months; HR 0.903, 80% CI 0.723-1.128, p=0.5551). Likewise, median progression-free survival was comparable in both arms (5.5 vs. 5.3 months; HR 0.767, 95% CI 0.556-1.056, p=0.1017). Tolerability was improved for mPC patients treated with alternating cycles compared to standard therapy, especially regarding peripheral neuropathy (all grades, 44.7% vs. 52.5%), and occurrence of infections (all grades, 29.4% vs. 47.5%). Treatment duration after randomization was similar in both arms (3.25 vs. 3.02 months). Fewer patients receiving alternating treatment cycles dropped out of the study due to adverse events compared to patients treated with continuous Gem/nab-Pac (14.9% vs 27.5%). In return, these patients terminated the study slightly more often due to progression of disease (48.3% vs 42.5%). Conclusions: The ALPACA trial suggests that a dose-reduced regimen with alternating cycles of Gem/nab-Pac and Gem monotherapy after 3 induction cycles of standard Gem/nab-Pac is feasible and associated with an OS comparable to standard treatment while resulting in improved tolerability. Clinical trial information: NCT02564146 .

This case report describes the efficacy of selpercatinib, a selective RET inhibitor, in an unusual case of large-cell neuroendocrine pancreatic carcinoma (LCNEPAC) harboring a CCDC6::RET fusion. A 56-year-old male with a history of multiple lines of systemic therapies exhibited marked clinical amelioration shortly after initiating selpercatinib within the LOXO-RET-17001 study (ClinicalTrials.gov ID: NCT03157128, first posted: 2017-05-17). Data from the patient's smartwatch suggested early efficacy before conventional methods, such as serum tumor markers and CT imaging confirmed the antitumor activity. This case not only underscores the efficacy of selpercatinib in treating RET fusion-positive rare tumors but also highlights the potential of wearable technology in cancer care. In conclusion, the standard readings from commercially available wearable devices can be useful for the monitoring of treatment response to targeted therapy and may serve as digital biomarkers in clinical trials. This approach marks a significant advancement in patient-centric healthcare, leveraging technology to enhance the effectiveness and precision of treatment evaluation.

Background Pancreatic ductal adenocarcinoma (PDAC) comprises two clinically relevant subtypes. Currently, determining the tumor subtype relies on tissue biopsies. Unfortunately, these biopsies are spatially biased, highly invasive, difficult to obtain, and unsuitable for monitoring tumor dynamics. Methods We employed whole transcriptome sequencing (WTS) on circulating cell-free (cf) RNA in plasma samples from patients with well-characterized tumor subtypes. Additionally, quantitative protein mass spectrometry was utilized to identify minimally invasive markers for tumor subtypes. We validated our findings using independent liquid and tissue samples from large clinical trials and investigated treatment-induced subtype dynamics and responses. Results An exploratory analysis of 10 patients (four basal-like and six classical) was conducted using whole transcriptome sequencing (WTS). Following differential transcript abundance analysis and integration with expression data from tumor and non-tumor samples (N > 200), we identified 32 protein-coding subtype-specific cfRNA-defined transcripts. The subtype specificity of these transcripts was validated in two independent tissue cohorts comprising 195 and 250 cases, respectively. Three disease-relevant cfRNA-defined subtype markers ( DEGS1, KDELC1 , and RPL23AP7 ) consistently associated with basal-like tumors across all cohorts and were validated using machine learning. Further analysis of these markers using RT-ddPCR in over 160 patient sera and 24 samples from healthy donors revealed their predictive and prognostic value, as well as subtype specificity and therapy-induced dynamics. In both tumor and liquid biopsies, the overexpression of these markers was associated with poor overall and progression-free survival. Moreover, elevated tissue/liquid levels of the identified markers were linked to a poor response to systemic therapy and rapid disease recurrence in resected patients. Conclusion Our data provide support for the clinical significance of cfRNA markers in determining tumor subtypes and monitoring disease recurrence and therapy-induced subtype switches in pancreatic ductal adenocarcinoma (PDAC). Consequently, further validation studies in larger independent cohorts are warranted to confirm the robustness and generalizability of these findings.

Pancreatic ductal adenocarcinoma (PDAC) comprises two clinically relevant molecular subtypes that are currently determined using tissue biopsies, which are spatially biased and highly invasive. We used whole transcriptome sequencing of 10 plasma samples with tumor-informed subtypes, complemented by proteomic analysis for minimally invasive identification of PDAC subtype markers. Data were validated in independent large cohorts and correlated with treatment response and patient outcome. Differential transcript abundance analyses revealed 32 subtype-specific, protein-coding cell-free RNA (cfRNA) transcripts. The subtype specificity of these transcripts was validated in two independent tissue cohorts comprising 195 and 250 cases, respectively. Three disease-relevant cfRNA-defined subtype markers (DEGS1, KDELC1, and RPL23AP7) that consistently associated with basal-like tumors across all cohorts were identified. In both tumor and liquid biopsies, the overexpression of these markers correlated with poor survival. Moreover, elevated levels of the identified markers were linked to a poor response to systemic therapy and early relapse in resected patients. Our data indicate clinical applicability of cfRNA markers in determining tumor subtypes and monitoring disease recurrence.

Background A standardised dose-reduction strategy has not been established for the widely used gemcitabine plus nab-paclitaxel regimen in patients with metastatic pancreatic ductal adenocarcinoma. We aimed to investigate the efficacy and tolerability of alternating treatment cycles of nab-paclitaxel-gemcitabine combination therapy and gemcitabine alone versus continuous treatment with the nab-paclitaxel-gemcitabine combination. Methods ALPACA was a randomised, open-label, phase 2 trial conducted at 29 study centres across Germany. Patients aged 18 years or older with a histologically or cytologically confirmed diagnosis of metastatic pancreatic ductal adenocarcinoma who had not been previously treated for advanced disease were enrolled. After an induction phase with three cycles of nab-paclitaxel-gemcitabine combination therapy (nab-paclitaxel 125 mg/m2 2 and gemcitabine 1000 mg/m2 2 administered intravenously on days 1, 8, and 15 of each 28-day cycle), patients were randomly assigned (1:1) by stratified permuted block randomisation either to continue treatment with standard nab-paclitaxel-gemcitabine or to receive alternating cycles of nab-paclitaxel-gemcitabine and gemcitabine alone. Patients and investigators were not masked to treatment allocation. Randomisation was done centrally by the study statistician using a computer- generated randomisation list, and was stratified by Karnofsky Performance Status and presence of liver metastases. The primary endpoint was the derivation of an unbiased point estimate and an associated confidence interval with a confidence coefficient of 80% for the hazard ratio (HR) for overall survival after randomisation, without testing a specific hypothesis, analysed by intention to treat in all patients who started randomised treatment. Safety was analysed according to treatment received. This trial is registered with ClinicalTrials.gov, NCT02564146, and is completed. Findings Between May 27, 2016, and May 27, 2021, 325 patients were enrolled. Following three cycles of induction treatment, 174 patients were randomly assigned: 85 to continue receiving standard nab-paclitaxel-gemcitabine, of whom 79 started treatment, and 89 to the alternating treatment schedule, of whom 88 started treatment. Of the 167 patients who started randomised treatment, 88 (53%) were female and 79 (47%) were male. Median overall survival after randomisation was 104 months (80% CI 92-120) in the group that received standard treatment and 105 months (102-111) in the group that received alternating treatment (HR 090, 80% CI 072-113; p=056). The most common adverse events of any grade were peripheral neuropathy (59 [74%] of 80 patients in the continuous treatment group vs 53 [62%] of 85 patients in the alternating treatment group) and fatigue (43 [54%] vs 44 [52%]). Treatment-emergent serious adverse events after randomisation occurred in 40 (50%) patients in the continuous treatment group and in 28 (33%) in the alternating treatment group. Fewer treatment-emergent adverse events of grade 3 or higher occurred in patients treated with alternating cycles compared with those receiving standard therapy, especially for peripheral neuropathy (17 [21%] patients in the continuous treatment group vs 12 [14%] in the alternating treatment group) and infections (16 [20%] vs nine [11%]). There were two treatment-related deaths after randomisation, both in the continuous treatment group (one multiple organ dysfunction syndrome, not treated after randomisation, and one interstitial lung disease). Interpretation Our findings suggest that a dose-reduced regimen with alternating cycles of nab-paclitaxel-gemcitabine and gemcitabine alone after three induction cycles is associated with similar overall survival to that for standard treatment with nab-paclitaxel-gemcitabine, but with improved tolerability. We therefore propose that a switch to the alternating schedule could be considered in a clinical setting for patients with metastatic pancreatic cancer who have at least stable disease after three cycles of nab-paclitaxel-gemcitabine treatment. Funding Celgene/Bristol Myers Squibb. Copyright (c) 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.

In patients with metastatic pancreatic cancer, after failure of gemcitabine/nab-paclitaxel, this trial compares the efficacy of second-line therapy with FOLFIRI vs. OFF (1:1 randomisation) with cross-over to the vice-versa regimen as third-line therapy. The primary endpoint was PFS (progression-free survival: time from randomization until progression or death) of second-line therapy. The trial aimed to demonstrate non-inferiority of FOLFIRI vs OFF (non-inferiority margin of a hazard ratio (HR) of 1.5, power of 80

ABSTRACTPurposeOffering equal Patient Access to Precision Oncology (PO) is a major challenge of clinical oncologists and cancer center representatives. Here, we provide an easily transferable model adopted from strategic management science to assess the geographic impact of a cancer center – in terms of general cancer care and PO participation.MethodsAs members of the German WERA alliance, the cancer centers Würzburg, Erlangen, Regensburg and Augsburg merged care data regarding their geographical impact. Specifically, we examined the provenance of patients from WERA’s molecular tumor boards (MTBs) between 2020 and 2022 (n = 2243). As second dimension, we added the provenance of patients receiving general cancer care (termed Total Cancer Care, TCC) by WERA. Clustering our outreach along these two dimensions allowed us to set up a four-quadrant matrix consisting of postal code areas with referrals towards WERA. These areas were re-identified on a map of the Federal State of Bavaria and surrounding regions.ResultsIn terms of positive MTB and general cancer care referrals, the WERA Matrix overlooked an active screening area of n = 821 postal code areas – representing about 50% of Bavaria’s spatial expansion and more than six million inhabitants. The WERA Matrix identified regions successfully connected to our outreach structures in terms of subsidiarity – with general cancer care mainly performed locally but PO performed in cooperation with WERA. At the same time, we detected postal code areas with a potential PO backlog – characterized by high levels of cancer care performed by WERA and low levels or no MTB representation.ConclusionsThe WERA Matrix provided a transparent portfolio of postal code areas, which helped assessing the geographical impact of our PO program. We believe that its intuitive principle can easily be transferred to other cancer centers.