BACKGROUNDThe TOPAZ-1 phase III trial demonstrated a survival advantage with durvalumab, an anti-programmed death cell ligand 1 (anti-PD-L1), when used with gemcitabine and cisplatin for patients with advanced biliary tract cancer. In order to gain a broader understanding of the efficacy and tolerability of this new combination in a real-world setting we performed a worldwide multicenter retrospective analysis to investigate the efficacy and safety of this new first-line standard treatment.METHODSThe analyzed population included patients with unresectable, locally advanced or metastatic adenocarcinoma of the biliary tract treated with durvalumab in combination with gemcitabine and cisplatin at 39 sites from 11 countries in Europe, United States, and Asia. The primary endpoint of the study was overall survival (OS).

Durvalumab

Biliary Tract Cancer

10.2139/ssrn.4821675

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Influence of pretreatment with everolimus or sunitinib on the subacute hematotoxicity of ¹⁷⁷Lu-DOTATATE PRRT

Figshare (2021)

Eva Medaer Chris Verslype Eric Van Cutsem Jeroen Dekervel Paul M. Clément

Background: Peptide receptor radionuclide therapy (PRRT) is a validated treatment for somatostatin receptor overexpressing neuroendocrine tumors (NETs). The NETTER-1 trial demonstrated a pronounced positive effect on progression-free-survival compared to high dose somatostatin analogs (SSAs), with a strong tendency toward overall survival benefit. Our aim was to investigate the influence of pretreatment with everolimus and/or sunitinib on subacute hematotoxicity of PRRT. To assess the influence of prior treatment with everolimus/sunitinib might be of clinical relevance due to the link between short-term hematotoxicity and increased incidence of late hematotoxicity. Material and methods: Our single-center retrospective study enrolled all patients treated with ¹⁷⁷Lu-DOTATATE PRRT (1–4 cycles of 7.4 GBq), between November 2013 and July 2018. Patients were assigned to two groups according to their pretreatment: no targeted agents (N = 41), or targeted agents (everolimus, sunitinib or both; N = 41). The end point was subacute hematotoxicity, defined as the nadir value between the first administration until 3 months after the last administration, using the CTCAE 4.03 classification. The impact of splenectomy was also explored. Results: Eighty percent of patients had a primary gastroenteropancreatic NET. No statistically significant differences in severe subacute hematotoxicity were seen in the pretreated group vs. the naive group for hemoglobin (grade 3/4: 12% vs. 22%), neither for leucocytes (grade 3/4: 10% vs. 7%), neutrophils (grade 3/4: 5% vs. 7%), lymphocytes (grade 3/4: 49% vs. 37%) and platelets (grade 3/4: 15% vs. 15%). Furthermore, we observed significantly lower toxicity for total white blood cells, lymphocytes and platelets in the subgroup that had splenectomy (N = 12). Limitations of this study include the potential bias in lack of use of targeted agents in patients more susceptible to toxicity, and the limited number of patients and events. Conclusions: In a patient cohort with NET pretreated with everolimus and/or sunitinib, we could not demonstrate a significant effect of prior/pretreatment with everolimus and/or sunitinib on the subacute hematotoxicity of ¹⁷⁷Lu-DOTATATE PRRT.

Everolimus

10.6084/m9.figshare.11826969

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Updated data from alloSHRINK phase I first-in-human study evaluating CYAD-101, an innovative non-gene edited allogeneic CAR-T in mCRC.

Journal of Clinical Oncology (2021)

Hans Prenen Jeroen Dekervel Alain Hendlisz Sébastien Anguille Ahmad Awada

74 Background: CYAD-101 is a first-in-class, non-gene edited allogeneic CAR T-cell product that combines the broad breadth of tumor targeting of the NKG2D-based chimeric antigen receptor (CAR) with a peptide-based approach that controls graft versus host disease (GvHD). NKG2D binds eight ligands commonly over-expressed across many tumors while the co-expressed T-cell receptor (TCR) inhibitory (TIM) peptide interferes with signaling by the endogenous TCR. A bank of CYAD-101 cells was produced from a single donor and evaluated in the AlloSHRINK phase 1 study (NCT03692429) in patients with unresectable metastatic colorectal cancer (mCRC). Methods: Three CYAD-101 infusions, each administered following a FOLFOX standard cycle as preconditioning chemotherapy, were tested in a 3+3 dose-escalation study (dose-levels (DL): 10 8 , 3x10 8 and 10 9 T-cells per infusion) in patients with relapsed/refractory mCRC who progressed after previous treatment with oxaliplatin-based chemotherapy, with or without irinotecan-based chemotherapy. Results: Fifteen patients (pts) were enrolled (3 pts at DL-1, 3 pts at DL-2, 9 pts at DL-3). No dose-limiting toxicity (DLT), Grade ≥ 3 related adverse events or GvHD were reported after any of the CYAD-101 infusions, thus confirming the overall good safety profile of CYAD-101 post FOLFOX. Encouraging anti-tumor activity was observed with 2 confirmed partial responses (PR), including one response in a KRAS mutated patient. In addition, 9 pts achieved stable disease (SD), with 7 SD lasting at least 3 months. The median progression-free survival in this heavily pre-treated population was 3.9 months (95% CI). Whilst engraftment of the CYAD-101 cells was observed after each infusion, the relative level of systemic cytokines appeared to be primarily modulated by cell dose with some suggestion that the magnitude of modulation might be associated with clinical response. Interestingly, preliminary analysis of the T-cell repertoire identified some evidence of TCR diversity after therapy in the patient showing the most durable partial response. Conclusions: These clinical results demonstrate the safety and tolerability of a fist-in-human non-gene edited allogeneic CAR T-cell treatment with early promising anti-tumor activity in advanced mCRC pts. Preliminary translational analysis present intriguing observations that the modulation of systemic cytokine levels may be associated with dose which is uncommon in CAR T-cell therapies reported to date while limited T-cell clonal diversification in the best responding patient underscores the likely central role of the adoptively transferred T-cell in driving therapeutic response in this particular patient. Extension cohort evaluating CYAD-101 following other preconditioning chemotherapy is expected to be initiated end 2020. Clinical trial information: NCT03692429.

FOLFOX

NKG2D

10.1200/jco.2021.39.3_suppl.74

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Influence of pretreatment with everolimus or sunitinib on the subacute hematotoxicity of ¹⁷⁷Lu-DOTATATE PRRT

Acta Oncologica (2020)

Eva Medaer Chris Verslype Eric Van Cutsem Jeroen Dekervel Paul M. Clément

Background: Peptide receptor radionuclide therapy (PRRT) is a validated treatment for somatostatin receptor overexpressing neuroendocrine tumors (NETs). The NETTER-1 trial demonstrated a pronounced positive effect on progression-free-survival compared to high dose somatostatin analogs (SSAs), with a strong tendency toward overall survival benefit. Our aim was to investigate the influence of pretreatment with everolimus and/or sunitinib on subacute hematotoxicity of PRRT. To assess the influence of prior treatment with everolimus/sunitinib might be of clinical relevance due to the link between short-term hematotoxicity and increased incidence of late hematotoxicity.Material and methods: Our single-center retrospective study enrolled all patients treated with 177Lu-DOTATATE PRRT (1–4 cycles of 7.4 GBq), between November 2013 and July 2018. Patients were assigned to two groups according to their pretreatment: no targeted agents (N = 41), or targeted agents (everolimus, sunitinib or both; N = 41). The end point was subacute hematotoxicity, defined as the nadir value between the first administration until 3 months after the last administration, using the CTCAE 4.03 classification. The impact of splenectomy was also explored.Results: Eighty percent of patients had a primary gastroenteropancreatic NET. No statistically significant differences in severe subacute hematotoxicity were seen in the pretreated group vs. the naive group for hemoglobin (grade 3/4: 12% vs. 22%), neither for leucocytes (grade 3/4: 10% vs. 7%), neutrophils (grade 3/4: 5% vs. 7%), lymphocytes (grade 3/4: 49% vs. 37%) and platelets (grade 3/4: 15% vs. 15%). Furthermore, we observed significantly lower toxicity for total white blood cells, lymphocytes and platelets in the subgroup that had splenectomy (N = 12). Limitations of this study include the potential bias in lack of use of targeted agents in patients more susceptible to toxicity, and the limited number of patients and events.Conclusions: In a patient cohort with NET pretreated with everolimus and/or sunitinib, we could not demonstrate a significant effect of prior/pretreatment with everolimus and/or sunitinib on the subacute hematotoxicity of 177Lu-DOTATATE PRRT.

Everolimus

Radionuclide therapy

Clinical endpoint

10.1080/0284186x.2020.1723161

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OS-112-YI Outcome and management of patients with hepatocellular carcinoma who achieved complete response to immunotherapybased systemic therapy

Journal of Hepatology (2024)

Bernhard Scheiner Beodeul Kang Lorenz Balcar Pompilia Radu Florian P. Reiter

Systemic therapy

Complete response

10.1016/s0168-8278(24)00553-1

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A phase 1b study of the MET inhibitor capmatinib combined with cetuximab in patients with MET-positive colorectal cancer who had progressed following anti-EGFR monoclonal antibody treatment

Investigational New Drugs (2020)

Jean–Pierre Delord Guillem Argilés Jérôme Fayette Lori J. Wirth Stefan Kasper

Pharmacodynamics

EGFR Inhibitors

10.1007/s10637-020-00928-z

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Citations (18)

International real-world study of TOTAL neoadjuvant therapy (TNT) for locally advanced rectal cancer (LARC).

Journal of Clinical Oncology (2024)

Alessandro Audisio Vaneja Velenik Hélène Meillat Érika Ruiz-García María Carmen Riesco Martínez

40 Background: TNT has recently emerged as a standard treatment for LARC. However, use and outcome of the different TNT regimens in real-world practice are largely unknown. Methods: This is an international, multicentre, retrospective study sponsored by the Institut Jules Bordet, Brussels. Eligibility was limited to newly diagnosed LARC patients treated with TNT between March 2013 and May 2023 and outside the context of a clinical trial. The primary objective was to describe real-word practice across international centres. Secondary objectives included treatment safety and efficacy. Data were collected into a central electronic database, and remotely monitored. Descriptive statistics were used, and survival outcomes were estimated with Kaplan-Meier curves. Results: 1,272 eligible patients were included from 47 centres across four continents (Europe, Asia, North America and South America). Baseline characteristics were as follows: 63% males, median age 60 years (range 21-88), 47% low rectum, 26% cT4, 47% cN2, 49% EMVI+, 59% CRM+. In the overall population, 21% of the resected patients had a pathological complete response (pCR), while 11.3% were managed according to a watch-&-wait (w&w) strategy. Median follow-up was 24.1 months (IQR 23.7). Local and distant recurrences after curative-intent surgery occurred in 5.5% and 16.2% of patients, respectively. 3-year event-free survival (EFS) was 68.3%, while 3-year overall survival (OS) was 89%. Serious adverse events were reported in 4.3% of patients during radiotherapy, and in 14.7% during chemotherapy. Patient distribution according to the TNT sequence/regimen, and respective efficacy outcomes are reported in the table. Conclusions: This is the largest real-world study of TNT for LARC. Our findings show substantial variation in the choice of TNT sequence and regimen. Efficacy and safety results are overall in line with those reported in clinical trials, and confirm feasibility of TNT in a real-world setting. Patient recruitment is ongoing, and updated results with propensity score matching analyses will be reported at the meeting. [Table: see text]

10.1200/jco.2024.42.3_suppl.40

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Citations (2)