Timorshah Habibzada

Krankenhaus Nordwest

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Thorsten Oliver Goetze

Krankenhaus Nordwest

Disorn Sookthai

Krankenhaus Nordwest

Claudia Pauligk

Krankenhaus Nordwest

Kristina Ihrig

Heidelberg University

Maria A. González-Carmona

University Hospital Bonn

S-E. Al-Batran

Institute of Clinical Cancer Research

Eray Goekkurt

Eppendorf (Germany)

Sylvie Lorenzen

Klinikum rechts der Isar

Thomas Jens Ettrich

University Hospital Ulm

Peter Herhaus

Technical University of Munich

Cooperative Institutions

University of Tübingen

German Cancer Research Center

Krankenhaus Nordwest

Deutschen Konsortium für Translationale Krebsforschung

University Children's Hospital Tübingen

Institute of Clinical Cancer Research

Heidelberg University

University Hospital Frankfurt

Goethe University Frankfurt

Institute of Immunology

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107P Comprehensive genomic profiling of “The German-registry of incidental gallbladder carcinoma” cases

Annals of Oncology (2023)

Nihat Buğra Ağaoğlu Lisa Kochen David W.M. Muller Doerthe Vortmeyer Timorshah Habibzada

Gallbladder Cancer

ARID1A

10.1016/j.annonc.2023.09.1400

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Ramucirumab beyond progression plus TAS‐102 in patients with advanced or metastatic esophagogastric adenocarcinoma, after treatment failure on a ramucirumab‐based therapy

International Journal of Cancer (2023)

Thorsten Oliver Goetze Alexander Stein Sylvie Lorenzen Timorshah Habibzada Eray Goekkurt

Abstract Based on results of prior trials (TAGS, REGARD, RAINBOW), the combination of ramucirumab beyond progression with TAS‐102 (trifluridine/tipiracil) seems to be promising in advanced esophagogastric adenocarcinoma (EGA). In this multicenter, non‐randomized, open‐label, investigator‐initiated pilot trial, ramucirumab‐pretreated patients with metastatic EGA received a maximum of 4 cycles of ramucirumab (8 mg/kg i.v. on day 1 and 15, Q2W) plus TAS‐102 (35 mg/m 2 p.o. bid on day 1‐5 and day 8‐12; Q2W). Primary endpoint was tolerability and toxicity, defining a positive trial if the SAE rate according to CTCAE 5.0 will increase <30% (up to 55%) compared to historical results from TAGS trial (SAE rate 43%). Secondary endpoints were further evaluation of safety and assessment of efficacy according to tumor response and overall and progression‐free survival (OS/PFS). Twenty patients, 20% gastric and 80% GEJ cancers and 55% with ECOG 0 were enrolled. In total, nine SAEs were reported in 25% [95% CI: 8.7‐49.1] of the patients, all without relationship to the systemic therapy. The median OS and PFS were 9.1 months [5.4‐10.1] and 2.9 months [1.7‐4.8], respectively. In addition, a disease control rate of 45% was obtained. The trial showed a favorable safety profile with a numerically lower incidence of SAEs for the combination of ramucirumab with TAS‐102 compared to historical TAGS trial. Furthermore, the combination demonstrated efficacy in the beyond progression setting and therefore warrants further evaluation in a randomized trial compared to TAS‐102 alone.

Ramucirumab

Tolerability

Clinical endpoint

Progression-free survival

10.1002/ijc.34652

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Citations (2)

Ramucirumab beyond progression plus TAS 102 in patients with advanced or metastatic adenocarcinoma of the stomach or the gastroesophageal junction, after treatment failure on a ramucirumab-based therapy: Final results of the phase II RE-ExPEL study.

Journal of Clinical Oncology (2023)

Thorsten Oliver Goetze Alexander Stein Sylvie Lorenzen Timorshah Habibzada Eray Goekkurt

359 Background: Based on results of prior trials (TAGS, REGARD, RAINBOW), it seems promising to combine Ramucirumab (Ram) beyond progression (PD) with TAS-102 (trifluridine/tipiracil). The purpose of RE-ExPEL is to investigate the tolerability, safety and benefit of Ram beyond PD in combination with TAS-102 in advanced esophagogastric adenocarcinoma (EGA). Methods: This is a multicenter, non-randomized, open-label investigator initiated pilot trial. 20 ram-pretreated patients (pts) with advanced EGA were enrolled to a maximum of 4 cycles of ramucirumab 8mg/kg every two weeks (days 1, 15; qd28) plus TAS-102 35 mg/m 2 /p.o. bid (d1-5 and d8-12; qd28). Primary endpoint (EP) was tolerability and toxicity, defining a positive trial if SAE rate according (acc.) to CTCAE 5.0 will increase less than 30% (up to 55%) compared with results from TAGS (SAE-rate 43%). Secondary EPs are further safety data and efficacy data, OS, PFS and ORR. Results: 20 pts (20% female) were enrolled between Oct 2020 and Aug 2021, 20% gastric and 80% GEJ- cancers, 55% of pts with ECOG 0. Results of the final analysis showed that only 25% of pts had at least one SAE and the total no. of SAEs was 9, one with fatal outcome, all without relationship to systemic therapy and no SUSAR reported. RE-ExPEL was able to show a median OS of 9.07 mo (95% CI 5.42-10.09) and a DCR of 45%. 90% of pts got study medication in 3 rd line whereas 10% were even further line pts. Conclusions: The safety data showed a favorable safety profile with a low rate of severe toxicity for ram+TAS-102, maybe due to the long disease stabilization and therefore less tumor associated symptoms. Regarding the primary safety endpoint, the trial was positive with even a numerically lower SAE rate compared with TAGS. Furthermore, RE-ExPEL was able to show very promising efficacy data for the combination ram plus TAS-102 with median OS of 9.07 mo. Ram+TAS-102 seems to be more effective than TAS-102 alone acc. to TAGS-trial respecting the limitation of the RE-ExPEL one arm study design with only 20pts. The combination needs further evaluation in a randomized phase III trial. Clinical trial information: NCT04517747 .

Ramucirumab

Tolerability

Clinical endpoint

10.1200/jco.2023.41.4_suppl.359

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Citations (1)

Phase I/II trial of a peptide-based COVID-19 T-cell activator in patients with B-cell deficiency

Nature Communications (2023)

Jonas S. Heitmann Claudia Tandler Maddalena Marconato Annika Nelde Timorshah Habibzada

T-cell immunity is central for control of COVID-19, particularly in patients incapable of mounting antibody responses. CoVac-1 is a peptide-based T-cell activator composed of SARS-CoV-2 epitopes with documented favorable safety profile and efficacy in terms of SARS-CoV-2-specific T-cell response. We here report a Phase I/II open-label trial (NCT04954469) in 54 patients with congenital or acquired B-cell deficiency receiving one subcutaneous CoVac-1 dose. Immunogenicity in terms of CoVac-1-induced T-cell responses and safety are the primary and secondary endpoints, respectively. No serious or grade 4 CoVac-1-related adverse events have been observed. Expected local granuloma formation has been observed in 94% of study subjects, whereas systemic reactogenicity has been mild or absent. SARS-CoV-2-specific T-cell responses have been induced in 86% of patients and are directed to multiple CoVac-1 peptides, not affected by any current Omicron variants and mediated by multifunctional T-helper 1 CD4+ T cells. CoVac-1-induced T-cell responses have exceeded those directed to the spike protein after mRNA-based vaccination of B-cell deficient patients and immunocompetent COVID-19 convalescents with and without seroconversion. Overall, our data show that CoVac-1 induces broad and potent T-cell responses in patients with B-cell/antibody deficiency with a favorable safety profile, which warrants advancement to pivotal Phase III safety and efficacy evaluation. ClinicalTrials.gov identifier NCT04954469.

Reactogenicity

10.1038/s41467-023-40758-0

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Citations (17)

Chemotherapy with or without surgery for locally advanced or borderline resectable pancreatic ductal adenocarcinoma: A retrospective multicenter international study.

Journal of Clinical Oncology (2024)

Marino Venerito Danmei Zhang Selina Becht Juliane Schütz Christoph Steup

e16352 Background: Current clinical guidelines recommend surgery for patients with locally advanced (LA)/borderline resectable (BR) pancreatic ductal adenocarcinoma (PDAC) who achieve disease control after induction therapy. However, the additional survival benefit of surgery in these patients is unknown. Methods: In this multicenter international retrospective cohort study, consecutive patients with BR/LA PDAC who achieved disease control after three to six months of induction therapy (combination chemotherapy or chemoradiotherapy) between January 2014 and July 2021 were retrospectively identified at 8 centers in Germany and Italy. Resectability status was determined by consensus in a multidisciplinary tumor board based on imaging findings, serum CA19-9, performance status and clinical response. Patient characteristics, progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Cox regression analysis was used to compare survival data. Results: A total of 138 patients who achieved disease control with induction therapy were analyzed. The median age at diagnosis was 66 years (range 45-82) and 43% of patients were female. 73 patients underwent surgery and 65 patients did not (median age 64 and 69 years, respectively, p = 0.02). Median OS was 20.0 months (95%CI 16.1-23.8) in the surgery group and 18.0 months (95%CI 13.6-22.4) in the nonsurgery group (hazard ratio for death, 0.90; 95%CI, 0.63 to 1.29, p = 0.57). Median PFS was 14.0 months (95%CI 8.9-19.1) in the surgery group and 15.0 months (95%CI 11.7-18.3) in the nonsurgery group (hazard ratio for disease progression, 1.04; 95%CI, 73 to 1,47, p = 0.83). The 2-year survival rates in the surgery and nonsurgery groups were 32.9% and 40.0%, respectively, with an overall odds ratio of 0.74 (95% CI: 0.37-1.47). Conclusions: In our multicenter international retrospective analysis, additional surgery did not confer a survival advantage to patients with BR/LA PDAC who achieved disease control with induction therapy.

10.1200/jco.2024.42.16_suppl.e16352

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1042P INSIGHT 003 evaluating feasibility of eftilagimod alpha (soluble LAG-3) combined with first-line chemo-immunotherapy in metastatic non-small cell lung cancer (NSCLC) adenocarcinomas

Annals of Oncology (2023)

Akin Atmaca David W.M. Muller Timorshah Habibzada Marina Schaaf Jorge Klagges

Pemetrexed

Tolerability

10.1016/j.annonc.2023.09.2181

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Citations (3)

P-30 Ramucirumab beyond progression plus TAS-102 in patients with advanced or metastatic esophagogastric adenocarcinoma, after treatment failure on a ramucirumab-based therapy – final results of the phase II RE-ExPEL study

Annals of Oncology (2023)

Thorsten Oliver Goetze Alexander Stein Sylvie Lorenzen Timorshah Habibzada Eray Goekkurt

Ramucirumab

Tolerability

Clinical endpoint

Progression-free survival

10.1016/j.annonc.2023.04.086

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Citations (0)

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

ESMO Open (2023)

S-E. Al-Batran Daniel Mueller M.-R. Rafiyan Dragan Kiselicki Akin Atmaca

Avelumab

10.1016/j.esmoop.2023.101623

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ADJUBIL: Phase II Study of Adjuvant Immunotherapy with STRIDE Regimen With/Without Capecitabine in Biliary Tract Cancers

Future Oncology (2024)

Thorsten Oliver Goetze Maria A. González-Carmona Lisa Kochen Nihat Buğra Ağaoğlu Salah‐Eddin Al‐Batran

Biliary tract cancer is a highly heterogeneous group of gastrointestinal cancers, and the only curative treatment is surgery, which is only applicable at early stages of the malignancy. ADJUBIL, a phase II trial (NCT05239169), aims to evaluate immunotherapy with durvalumab and tremelimumab with or without capecitabine in adjuvant situations for biliary tract cancers. A total of 40 prospective patients will be randomly assigned following surgery, consisting of a two-arm feasibility pilot part with a pick-the-winner design with durvalumab and tremelimumab in combination with or without capecitabine.

Tremelimumab

Durvalumab

Regimen

10.2217/fon-2023-0961

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ADJUBIL: A phase II study of immunotherapy with durvalumab and tremelimumab in combination with capecitabine or without capecitabine in adjuvant situation for biliary tract cancer.

Journal of Clinical Oncology (2023)

Thorsten Oliver Goetze Lisa Kochen Doerthe Vortmeyer Salah‐Eddin Al‐Batran Timorshah Habibzada

TPS4187 Background: Despite improvements in multidisciplinary management, patients with biliary tract cancer (BTC) have a poor outcome. Only 20% of patients are eligible for surgical resection with curative intent, with 5-year overall survival of less than 10% for all patients. Data regarding pure adjuvant chemotherapy in BTC’s are conflicting and the SOC of the western world is currently capecitabine according to the British BILCAP- trial, even though BILCAP was formally negative. Based on the positive data for durvalumab in the TOPAZ- 1 – trial in BTC and for STRIDE- regimen in HCC according to the Himalaya- data, evaluation of IO- combination in the adjuvant setting seems to be promising. Preclinical studies indicate that the antibody combination results in stronger and more durable anti-tumor effects than single therapies by synergistically modulating the immunosuppressive tumor microenvironment which is particularly rich in cholangiocarcinoma. The aim of this study is the assessment of the clinical activity of the anti-PD-L1 (programmed- death 1-ligand) antibody durvalumab and the anti-CTLA-4 (cytotoxic T- lymphocyte-associated antigen 4) antibody tremelimumab in combination with or without capecitabine in patients with respectable BTC in the adjuvant situation. This is a randomized phase II study as a proof-of-concept for a potentially larger research program. Methods: The ADJUBIL trial is an open-label, multicenter phase II study, including patients with BTC after curative surgery with no previous systemic treatment. Patients are randomly assigned to receive tremelimumab (300mg, one dose) plus durvalumab (1500mg every 4 weeks; STRIDE, for a maximum of 12 months), with or without capecitabine (for 8 cycles). Forty evaluable patients will be enrolled in the study (1:1) to receive anticancer treatment until disease recurrence or intolerable toxicities. Primary objective is to assess the anti-tumor activity of the treatment in both arms by the recurrence-free survival rate after 12 months (RFS@12). Secondary endpoints are recurrence-free survival, overall survival, toxicity, and quality of life. Exploratory endpoints: Explore predictive biomarkers for recurrence-free survival and overall survival. Study start of the ADJUBIL trial was in June 2021. By January 2023, 12 centers across Germany have been initiated and a total of 8 out of 40 planned patients (1:1) have been enrolled. The study is currently ongoing. Clinical trial information: EUCTR2021-002389-41 .

Tremelimumab

Durvalumab

Regimen

10.1200/jco.2023.41.16_suppl.tps4187

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Citations (2)