0000000000213408
AUTHOR
Salah-eddin Al-batran
PaFLO: Pazopanib with 5-fluorouracil, leucovorin, and oxaliplatin (FLO) as first-line treatment in advanced gastric cancer: A randomized phase II study of the Arbeitsgemeinschaft internistische Onkologie (AIO).
TPS4138 Background: VEGF inhibition in gastric cancer shows promising improvement of remission rate and progression-free survival (Ohtsu et al., JCO 2011). Pazopanib is an orally available tyrosine kinase inhibitor (TKI) selectively inhibiting VEGFR-1, -2, -3, c-kit and PDGFR. It is approved for treating renal cell cancer. A phase-I trial showed good tolerability of pazopanib with full-dose FOLFOX in solid tumors (Brady et al., ASCO, 2009). FLO is a widely used combination for advanced gastric cancer recommended in national guidelines. Methods: 75 Patients with HER-2-negative locally advanced or metastatic adenocarcinoma of the stomach or the gastro-esophageal junction will be randomized i…
Zolbetuximab combined with EOX as first-line therapy in advanced CLDN18.2+ gastric (G) and gastroesophageal junction (GEJ) adenocarcinoma : Updated results from the FAST trial.
16 Background: Physiologically, the tight junction protein CLDN18.2 is present only in the gastric mucosa. Upon malignant transformation, CLDN18.2 epitopes are exposed on the cell surface and accessible to targeted therapy. Zolbetuximab (formerly IMAB362) is a chimeric mAb that mediates specific killing of CLDN18.2+ cancer cells through immune effector mechanisms; single-agent activity has been reported in G/GEJ cancer. Methods: Patients (pts) with advanced HER2-negative (HER–) G/GEJ cancer with CLDN18.2 expression of ≥ 2+ staining intensity with the anti-CLDN18 43-14A mAb in ≥ 40% tumor cells were eligible (NCT01630083). Patients were randomized 1:1 to receive first-line EOX ± zolbetuxima…
The “RENAISSANCE” Trial: Effect of chemotherapy alone vs. chemotherapy followed by surgical resection on survival and quality of life in patients with limited-metastatic adenocarcinoma of the stomach or esophagogastric junction—A phase III trial of the German AIO/CAO-V/CAOGI.
TPS4140 Background: Recent data indicates that surgical resection may bring a benefit for select patients with metastatic gastric / esophagogastric junction cancer. However, no data obtained in randomized trials is available up to now. The current RENAISSANCE trial investigates this long-lasting question about the role of surgical intervention in limited-metastatic gastric / esophagogastric junction cancer. Methods: This is a prospective, multicenter, randomized, investigator initiated phase III trial. In this study, previously untreated patients with limited metastatic stage (retroperitoneal lymph node metastases only or a maximum of one incurable organ site that is potentially resectable…
FAST: An international, multicenter, randomized, phase II trial of epirubicin, oxaliplatin, and capecitabine (EOX) with or without IMAB362, a first-in-class anti-CLDN18.2 antibody, as first-line therapy in patients with advanced CLDN18.2+ gastric and gastroesophageal junction (GEJ) adenocarcinoma.
LBA4001 Background: Claudin18.2 (CLDN18.2) is a tight junction protein expressed by several cancers including gastric and GEJ adenocarcinoma. IMAB362 is a chimeric monoclonal antibody that mediates specific killing of CLDN18.2-positive cancer cells by activation of immune effector mechanisms. IMAB362 has demonstrated single-agent activity and was safe and tolerable in patients (pts) with pretreated gastric cancer. Methods: Pts with advanced/recurrent gastric and GEJ cancer were centrally evaluated for CLDN18.2 expression by IHC (validated CLAUDETECT18.2 Kit). Eligible pts had a CLDN18.2 expression of ≥ 2+ in ≥ 40% tumor cells, an ECOG PS of 0–1 and were not eligible for trastuzumab. Pts we…
Treatment until progression: Data of the “on-treatment” population of the FIRE-3 (AIO KRK-0306) study.
3589 Background: The FIRE-3 study (AIO KRK-0306) was designed as a randomized multicenter trial to compare the efficacy of FOLFIRI plus cetuximab (cet) to FOLFIRI plus bevacizumab (bev) as first-line treatment in KRAS WT mCRC patients. FOLFIRI plus cet as first-line treatment of KRAS WT mCRC patients resulted in comparable overall response rates (ORR) and progression free survival (PFS) when compared to FOLFIRI plus bev. Overall survival (OS) was significantly longer in the FOLFIRI plus cet arm. Methods: In this exploratory analysis outcome parameters were calculated in dependence of progression during antibody treatment. As reported before by Saltz et al. (ASCO GI 2007) an “on study treatm…
Relation of early tumor shrinkage (ETS) observed in first‐line treatment to efficacy parameters of subsequent treatment in FIRE‐3 (AIOKRK0306)
We explored the association of early tumor shrinkage (ETS) and non-ETS with efficacy of first-line and consecutive second-line treatment in patients with KRAS wild-type metastatic colorectal cancer treated in FIRE-3. Assessment of tumor shrinkage was based on the sum of longest diameters of target lesions, evaluated after 6 weeks of treatment. Shrinkage was classified as ETS (shrinkage by ≥ 20%), mETS (shrinkage by 0 to20%), mPD (minor progression0 to20%) and PD (progression ≥20%). Overall survival (OS) was 33.2 (95% CI 28.0-38.4) months in ETS patients, while non-ETS was associated with less favorable outcome (mETS 24.0 (95% CI 21.2-26.9) months, mPD 19.0 (95% CI 13.0-25.0) months, PD 12.8…
VEGFR-3 and CXCR4 as predictive markers for treatment with fluorouracil, leucovorin plus either oxaliplatin or cisplatin in patients with advanced esophagogastric cancer: a comparative study of the Arbeitsgemeinschaft Internistische Onkologie (AIO)
Abstract Background Combination of fluoropyrimidines and a platinum derivative are currently standards for systemic chemotherapy in advanced adenocarcinoma of the stomach and gastroesophageal junction (GEJ). Nevertheless, individual likelihood for response to these therapeutic regimes remains uncertain. Even more, no predictive markers are available to determine which patients may benefit more from oxaliplatin versus cisplatin or vice versa. The new invasion and stem cell markers VEGFR-3 and CXCR4 have been linked prognostically with more aggressive esophagogastric cancer types. Thus, we aimed to assess correlations of VEGFR-3 and CXCR4 expression levels with clinical outcome in a randomize…
Time-course evaluation of survival and treatment in FIRE-3 trial (AIO KRK0306).
3528Background: To investigate overall survival (OS) differences in FIRE-3 in context of exposure to treatments (i.e. first-, second-, third-line) in time course. Methods: We compared OS in FIRE-3 ...
Expression of Claudin 18.2 and HER2 in gastric, gastroesophageal junction, and esophageal cancers : Results from the FAST study
4038 Background: Claudin 18.2 (CLDN18.2), a gastric mucosa tight junction protein, is aberrantly expressed in various cancers. In the FAST Phase 2 trial (NCT01630083), IMAB362, an anti-CLDN18.2 monoclonal antibody, administered in combination with EOX chemotherapy, prolonged survival compared to EOX alone in patients with advanced/recurrent gastric, gastroesophageal junction (GEJ), and esophageal cancers ineligible for trastuzumab. The aim of the present analysis was to assess tumor CLDN18.2 expression and co-expression with HER2 in the FAST population. Methods: Tumor tissue samples from patients screened for inclusion into the FAST trial were analyzed for CLDN18.2 expression using a CE-ma…
A Phase II Study of the Histone Deacetylase Inhibitor Panobinostat (LBH589) in Pretreated Patients with Small-Cell Lung Cancer
Background: In vitro data suggest that panobinostat (LBH589), a pan-deacetylase inhibitor, may add therapeutic benefit in the treatment of small-cell lung cancer (SCLC) with regression of tumors. Methods: This multicenter, nonrandomized phase 2 trial was designed to evaluate antitumor activity of LBH589 in patients with previously treated SCLC. Patients received LBH589 administered intravenously at a dose of 20 mg/mq (days 1–8) every 21 days. Results: A total of 21 patients with extensive- or limited-stage SCLC were enrolled. Patients received a median of two cycles (range, 1–6). LBH589 was well tolerated, and the most common toxicities were grade 1 to 2 gastrointestinal disorders (nausea 3…
Geriatric assessment and biomarkers in patients with metastatic breast cancer receiving first-line mono-chemotherapy: Results from the randomized phase III PELICAN trial.
Abstract Objectives To determine predictive/prognostic factors for patients with metastatic breast cancer (MBC) receiving first-line monochemotherapy using biomarker analysis and geriatric assessment (GA). Materials and Methods Karnofsky Performance Status (KPS) and GA as clinical parameters, and prognostic inflammatory and nutritional index (PINI), and Glasgow prognostic score (GPS) as biomarkers were analyzed for association with clinical outcome within the randomized phase III PEg-LIposomal Doxorubicin vs. CApecitabin iN MBC (PELICAN) trial of first-line pegylated liposomal doxorubicin (PLD) or capecitabine. Results Of 210 patients, 38% were > 65 years old. GA (n = 152) classified 74% as…
POWER: An open-label, randomized phase III trial of cisplatin and 5-FU with or without panitumumab (P) for patients (pts) with nonresectable, advanced, or metastatic esophageal squamous cell cancer (ESCC).
TPS4158 Background: More than 50% of pts with esophageal cancer have locally advanced or metastatic disease at the time of initial diagnosis. For this group chemotherapy is increasingly used intending local and distant tumor control, improvement of quality of life (QoL) and longer survival. Previous data suggested that EGFR-targeting antibodies may be safely combined with cisplatin and 5-FU, and in addition may increase the efficacy of the standard cisplatin/5-FU regimen [Lorenzen et al, Ann Oncol2009; 20(10): 1667-1673]. Methods: In this open-label, randomized (1:1), multicenter, multinational phase III trial pts with nonresectable, advanced or metastatic ESCC, not eligible for definitive…
A prospective trial for defining a subset of patients with limited metastatic gastric cancer who may be candidates for bimodal treatment strategies: FLOT3.
4090 Background: The utility of surgery for metastatic gastric cancer is debated. A prospective trial was performed to evaluate a prognostic model for selecting patients (pts) treated with systemic chemotherapy (ct) who may also be candidates for surgical intervention. Methods: Using a predefined algorithm pts with untreated gastric cancer were prospectively stratified into 3 groups: operable (OD), limited metastatic (LD), or extensive metastatic (ED) disease and treated with 5-FU, oxaliplatin, leucovorin and docetaxel (FLOT). LD was defined as: distant intra-abdominal lymph node metastases only or/and a maximum of 1 organ involved, normal serum alkaline phosphatase, < 5 liver lesions, …
Cisplatin and 5-Fluorouracil with or Without Epidermal Growth Factor Receptor Inhibition Panitumumab for Patients with Non-Resectable, Advanced or Metastatic Esophageal Squamous Cell Cancer: A Prospective, Open-Label, Randomised Phase 3 AIO/EORTC Trial (Power)
Background: Advanced unresectable esophageal squamous cell cancer (ESCC) is treated with palliative chemotherapy of cisplatin and 5-fluorouracil (CF). Targeting epidermal growth factor receptor (EGFR) with antibodies panitumumab (P) or cetuximab with chemotherapy enhanced overall survival (OS) in metastatic colorectal cancer or squamous cell cancer of head and neck. With prospective serum and tumour biomarkers, we tested if P added to CF (CFP) improved OS in confirmed advanced ESCC. Methods: 146 patients, not curatively resectable and not qualified for definitive radio-chemotherapy were randomised 1:1 to CF (cisplatin [100 mg/m² i.v., day 1] and 5-fluorouracil [1000 mg/m²/day i.v., days 1-4…
FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial
Summary Background Cetuximab and bevacizumab have both been shown to improve outcomes in patients with metastatic colorectal cancer when added to chemotherapy regimens; however, their comparative effectiveness when partnered with first-line fluorouracil, folinic acid, and irinotecan (FOLFIRI) is unknown. We aimed to compare these agents in patients with KRAS (exon 2) codon 12/13 wild-type metastatic colorectal cancer. Methods In this open-label, randomised, phase 3 trial, we recruited patients aged 18–75 years with stage IV, histologically confirmed colorectal cancer, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, an estimated life expectancy of greater than 3 month…
FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer (FIRE-3): a post-hoc analysis of tumour dynamics in the final RAS wild-type subgroup of this randomised open-label phase 3 trial.
Summary Background FIRE-3 compared first-line 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus cetuximab with FOLFIRI plus bevacizumab in patients with KRAS exon 2 wild-type metastatic colorectal cancer. The same study also reported an exploratory analysis of a subgroup of patients with tumours that were wild-type at other RAS genes ( KRAS and NRAS exons 2–4). We report here efficacy results for the FIRE-3 final RAS ( KRAS/NRAS , exons 2–4) wild-type subgroup. Moreover, new metrics of tumour dynamics were explored during a centralised radiological review to investigate how FOLFIRI plus cetuximab conferred overall survival benefit in the absence of differences in investigator-assess…
Cytokeratin-18 fragments predict treatment response and overall survival in gastric cancer in a randomized controlled trial
Background:Gastric cancer is common malignancy and exhibits a poor prognosis. At the time of diagnosis, the majority of patients present with metastatic disease which precludes curative treatment. Non-invasive biomarkers which discriminate early from advanced stages or predict the response to treatment are urgently required. This study explored the cytokeratin-18 fragment M30 and full-length cytokeratin-18 M65 in predicting treatment response and survival in a randomized, placebo-controlled trial of advanced gastric cancer.Methods:Patients enrolled in the SUN-CASE study received sunitinib or placebo as an adjunct to standard therapy with leucovorin (Ca-folinate), 5-fluorouracil, and irinote…
FOLFIRI plus sunitinib versus FOLFIRI alone in advanced chemorefractory esophagogastric cancer patients: A randomized placebo-controlled multicentric AIO phase II trial
4086 Background: Sunitinib is an receptor tyrosine kinase (RTK) inhibitor of VEGFR1-3, PDGFR-α-β, and other RTK. After we established Sunitinib (Sun) alone associated with limited response rate (RR) and good tolerability in refractory advanced esophagogastric cancer patients (Moehler et al. EUR J Cancer. 2011, 47: 1511), this double-blinded placebo-controlled phase II evaluated safety and efficacy of SUN as add-on in second-line or third-line FOLFIRI (ClinicalTrials.gov NCT01020630). Methods: Patients with failure of any prior docetaxel and/or platinum-based chemotherapy were randomized to receive 6-week cycles including FOLFIRI two weekly and SUN (25 mg) versus (vs) placebo (PLA) daily fo…
Exploring the effect of primary tumor sidedness on therapeutic efficacy across treatment lines in patients with metastatic colorectal cancer: analysis of FIRE-3 (AIOKRK0306).
// Dominik Paul Modest 1, 2 , Sebastian Stintzing 1, 2 , Ludwig Fischer von Weikersthal 3 , Thomas Decker 4 , Alexander Kiani 5 , Ursula Vehling-Kaiser 6 , Salah-Eddin Al-Batran 7 , Tobias Heintges 8 , Christoph Kahl 9 , Gernot Seipelt 10 , Frank Kullmann 11 , Werner Scheithauer 12 , Markus Moehler 13, 14 , Julian Walter Holch 1, 2 , Jobst Christian von Einem 1, 2 , Swantje Held 15 and Volker Heinemann 1, 2 1 Department of Medicine III, University Hospital, LMU Munich, Munich, Germany 2 German Cancer Consortium (DKTK), German Cancer Research Centre (DKFZ), Heidelberg, Germany 3 Gesundheitszentrum St. Marien, Amberg, Germany 4 Oncological Practice, Ravensburg, Germany 5 Medizinische Klinik I…
Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial
Background Docetaxel-based chemotherapy is effective in metastatic gastric and gastro-oesophageal junction adenocarcinoma. This study reports on the safety and efficacy of the docetaxel-based triplet FLOT (fluorouracil plus leucovorin, oxaliplatin and docetaxel) as a perioperative therapy for patients with locally advanced, resectable tumours. Methods In this controlled, open-label, phase 2/3 trial, we randomly assigned 716 patients with histologically-confirmed advanced clinical stage cT2 or higher or nodal positive stage (cN+), or both, resectable tumours, with no evidence of distant metastases, via central interactive web-based-response system, to receive either three pre-operative and t…