Pancreatic cancer Clinical research projects of the German oncology groups (ACO, AIO, and ARO)

Background: The incidence of pancreatic cancer (PC) is increasing. Due to a combination of therapeutic resistance and to advanced disease already at diagnosis, PC remains one of the most fatal malignant solid tumors with a 5-year survival rate of only 8-9%. Objectives: The German oncology study groups offer a broad portfolio of clinical trials. We present the most current projects of Arbeitsgemeinschaft Chirurgische Onkologie (ACO), Arbeitsgemeinschaft Internistische Onkologie (AIO), and Arbeitsgemeinschaft Radiologische Onkologie (ARO) in PC including recruiting studies as well as those envisaged or recently completed. Results: Combination chemotherapy is still the backbone of PC therapy. In localized disease, curatively intended resection followed by adjuvant chemotherapy remains standard in fit patients (e.g., modified FOLFIRINOX, gemcitabine-based). In addition, clinical trial activities focus on the role of perioperative therapy in PC. Recent clinical trials analyze the benefit in the (borderline) resectable (NEONAX), locally advanced (NEOLAP), and oligometastatic (METAPANC, HOLIPANC) setting. In metastatic PC, intensified chemotherapeutic protocols and combined epigenetic and immune targeting concepts are currently being evaluated. Conclusion: Taking into account the relevant therapeutic resistance of PC, new therapeutic concepts are needed to further ameliorate the prognosis. The role of perioperative therapy needs to be further clarified and is the objective of recent studies

MCL1 as putative target in pancreatoblastoma

: Pancreatoblastoma (PB) is a rare tumor of the pancreas. In case of metastases, the treatment options are sparse and targeted approaches are not developed. We here evaluate MCL1 amplification as a putative target in PB.Thirteen samples from adult (10/13) and pediatric patients (3/13) were collected. Three of these samples had been previously subjected to whole-exome sequencing (2 cases) or whole-genome sequencing (1 case) within a precision oncology program (NCT/DKTK MASTER), and this analysis had shown copy number gains of MCL1 gene. We established a fluorescence in situ hybridization (FISH) test to assess the copy number alterations of MCL1 gene in 13 formalin-fixed paraffin-embedded PBs, including the 3 cases assessed by genome sequencing. FISH analysis showed the amplification of MCL1 in 2 cases (both were adult PB), one of which was a case with the highest copy number gain at genomic analysis. In both cases, the average gene copy number per cell was ≥ 5.7 and the MCL1/1p12 ratio was ≥ 2.4. Our data support MCL1 as a putative target in PB. Patients with MCL1-amplified PB might benefit from MCL1 inhibition. Sequencing data is useful to screen for amplification; however, the established FISH for MCL1 can help to determine the level and cellular heterogeneity of MCL1 amplification more accurately

Lasting response by vertical inhibition with cetuximab and trametinib in KRAS\it KRAS-mutated colorectal cancer patient-derived xenografts

Although approximately half of all metastatic colorectal cancers (mCRCs) harbour mutations in $\it KRAS$ or $\it NRAS$, hardly any progress has been made regarding targeted treatment for this group over the last few years. Here, we investigated the efficacy of vertical inhibition of the RAS-pathway by targeting epidermal growth factor receptor (EGFR) and mitogen-activated protein kinase kinase (MEK) in patient-derived xenograft (PDX) tumours with primary $\it KRAS$ mutation. In total, 19 different PDX models comprising 127 tumours were tested. Responses were evaluated according to baseline tumour volume changes and graded as partial response (PR; ≤ − 30%), stable disease (SD; between −30% and +20%) or progressive disease (PD; ≥ + 20%). Vertical inhibition with trametinib and cetuximab induced SD or PR in 74% of analysed models, compared to 24% by monotherapy with trametinib. In cases of PR by vertical inhibition (47%), responses were lasting (as long as day 137), with a low incidence of secondary resistance (SR). Molecular analyses revealed that primary and SR was driven by transcriptional reprogramming activating the RAS pathway in a substantial fraction of tumours. Together, these preclinical data strongly support the translation of this combination therapy into clinical trials for CRC patients

Efficacy of Immune Checkpoint Inhibitors Alone or in Combination With Chemotherapy in NSCLC Harboring ERBB2 Mutations

Introduction: In contrast to other driver mutations, no targeted therapies have yet been approved in ERBB2-mutated NSCLC (HER2mu NSCLC). Nevertheless, several compounds have revealed promising early efficacy data, which need to be evaluated in the context of current standard approaches. Although data on the efficacy of immune checkpoint inhibitors (ICIs) in second or subsequent lines of treatment remain limited and conflicting, there are virtually no data on patient outcome under ICI/platinum-doublet combinations in the first-line setting. Methods: We retrospectively evaluated outcomes of patients with HER2mu NSCLC treated with ICI alone or in combination with chemotherapy within the German National Network Genomic Medicine Lung Cancer consortium by means of overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: ICI either in combination with chemotherapy or as monotherapy was applied as first-line treatment in 27 patients, whereas 34 received single-agent ICI in second or subsequent lines. Patient characteristics were in line with previously published data. In treatment-naive patients receiving ICI in combination with chemotherapy, the ORR, median PFS, and OS rate at 1 year were 52%, 6 months, and 88%, respectively. In second or subsequent lines, ICI monotherapy was associated with an ORR of 16%, a median PFS of 4 months, and a median OS of 10 months. Conclusions: ICIs are effective as monotherapy and in combination with platinum-doublet chemotherapy. Therefore, ICI-based treatments may be found as the current standard of care and benchmark for targeted therapies in HER2mu NSCLC. (C) 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved