Molecular profiling of advanced pancreatic ductal adenocarcinoma (PDAC): Role of ctDNA.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 425-425
Author(s):  
Angela Lamarca ◽  
Mairead Geraldine McNamara ◽  
Richard Hubner ◽  
Juan W. Valle
Keyword(s):  
Palliative Therapy ◽  
Progression Free Survival ◽  
Patient Characteristics ◽  
Molecular Profiling ◽  
Ductal Adenocarcinoma ◽  
P Value ◽  
Ctdna Analysis ◽  
Chemotherapy Initiation ◽  
The Impact

425 Background: Molecular profiling of tumour samples and circulating tumour DNA (ctDNA) may inform treatment of advanced cancer; the role of ctDNA to predict progression-free-survival (PFS) and overall survival (OS) in advanced PDAC is not fully understood. Methods: Eligible patients: those diagnosed with advanced PDAC undergoing molecular profiling [tumour (Foundation Medicine CDx/Caris) or ctDNA (FoundationMedicine Liquid (72 cancer-related genes))]. Baseline patient characteristics and molecular profiling outcomes, including mutant allele frequency (MAF) for pathological alterations were extracted. The primary aim was to assess the impact of presence of ctDNA at time of systemic chemotherapy initiation on PFS and OS. Results: Total of 26 samples (ctDNA 18 samples and 8 tumour samples) from 25 patients diagnosed with advanced PDAC underwent molecular profiling. When the whole population was analysed, the rate of sample analysis failure seemed to be higher when tumour tissue was tested (37.5%) compared to ctDNA (5.56%); p-value 0.072. The overall rate of identification of pathological findings was 72.73%, with 18.18% of patients having targetable findings [EGFRmut (1 patient), KRAS G12C mut (1 patient), FGFR2 fusion (1 patient), RNF43 mut (1 patient)]; these findings impacted treatment management in one patient only (RNF43 mutation; Wnt inhibitor). Variants of unknown significance were identified in 63.64% of samples. Patients with ctDNA analysis at time of palliative chemotherapy initiation (16 samples; 15 patients) were analysed [6 female (40.00%), median age 69.57 years (range 51.61-81.49), metastatic disease (66.67%), 80% first-line (80%), 20% second-line]. Pathological mutations were identified in 9/15 (60.00%) of these patients (KRAS mutation identified in 6/9). After median follow-up of 8.33 months from sample acquisition, 80% and 53.33% of patients had progressed and died, respectively. Median estimated PFS and OS were 5.65 months (95% CI 1.59-8.17) and 7.80 months (95% CI 4.13-not reached). Presence (vs absence) of pathological alterations in ctDNA showed a trend towards shorter PFS (2.91 vs 6.51 months; HR 1.38 (95% CI 0.40-4.77)) and OS (6.12 vs 9.72 months; HR 2.03 (95% CI 0.60-6.82)). Conclusions: This pilot study demonstrates the feasibility of ctDNA analysis in patients with advanced PDAC prior to initiation of palliative therapy. The presence of pathological alterations in ctDNA may prognosticate for worse PFS and OS. Larger studies are required to confirm these findings.

scholarly journals Molecular Profiling in Daily Clinical Practice: Practicalities in Advanced Cholangiocarcinoma and Other Biliary Tract Cancers

2020 ◽  
Vol 9 (9) ◽  
pp. 2854
Author(s):  
Angela Lamarca ◽  
Zainul Kapacee ◽  
Michael Breeze ◽  
Christopher Bell ◽  
Dean Belcher ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Cox Regression ◽  
Tissue Sample ◽  
Palliative Therapy ◽  
Progression Free Survival ◽  
Molecular Profiling ◽  
P Value ◽  
Extrahepatic Cholangiocarcinoma ◽  
Tissue Samples ◽  
Platinum Based Chemotherapy

Background: Molecular profiling is becoming increasingly relevant in the management of patients with advanced cancer; to identify targetable aberrations and prognostic markers to enable a precision medicine strategy. Methods: Eligible patients were those diagnosed with advanced biliary tract cancer (BTC) including intrahepatic (iCCA) and extrahepatic cholangiocarcinoma (eCCA), gallbladder cancer (GBC), and ampullary carcinoma (Amp) who underwent molecular profiling between April 2017 and June 2020 based on analysis of either tumour samples (FoundationOne CDx®/Oncomine® platforms) or ctDNA (FoundationOne Liquid® platform (Foundation Medicine, Cambridge, MA, USA)). Baseline patient characteristics and molecular profiling outcomes were extracted. The primary aim was to describe sample failure rate. Secondary aims included description of reason for sample failure, summary of findings derived from molecular profiling, and assessment of concordance between paired tissue and ctDNA samples. Results: A total of 149 samples from 104 individual patients diagnosed with advanced BTC were identified and eligible for this analysis: 68.2% iCCA, 100% advanced stage; 94.2% received palliative therapy. The rate of sample failure was 26.8% for tissue and 15.4% for ctDNA; p-value 0.220, predominantly due to insufficient (defined as <20%) tumour content in the sample (the reason for 91.2% of tissue sample failure). Of the 112 samples successfully analysed, pathological molecular findings were identified in the majority of samples (88.4%) and identification of pathological findings using ctDNA, was possible regardless of whether the patient was on active treatment at time of blood acquisition or not (p-value 1.0). The rate of targetable alterations identified was 40.2% across all successfully-analysed samples (39 iCCA; 6 non-iCCA): IDH1 mutations (19.1% of individual patients), FGFR2 alterations (10.1% and 5.6% of individual patients had FGFR2 fusions and mutations, respectively); 10.6% of all patients (12.4% of patients with successfully analysed samples) entered trials with matched targeted therapies as a consequence. Concordance of findings for paired tissue and paired tissue-ctDNA was high (3/3; 100% and 6/6; 100%, respectively). Twelve ctDNA samples were taken prior to palliative treatment initiation, median maximum mutant allele frequency (MAF) was 0.47 (range 0.21–19.8); no significant association between reported maximum MAF and progression-free survival (PFS) or overall survival (OS) (all Cox regression p-values > 0.273). A total of 15 patients (16.6%) harboured alterations in DNA damage repair (DDR) genes; when treated with platinum-based chemotherapy, there was a trend towards increased partial response rate (21.4% vs. 15.9%; p-value 0.653), radiological benefit rate (64.3% vs. 36.2%; p-value 0.071), and longer OS (median OS 20.4 months (95% CI 7.9–26.7) vs. 13.3 (95 CI 11.0–16.4); Cox Regression HR 0.79 (95% CI 0.39–1.61), p-value 0.527). Conclusions: Molecular profiling is of use for identification of novel therapeutic strategies for patients with advanced BTC (mainly iCCA). One in four archived tissue samples may have insufficient tumour content for molecular profiling; ctDNA-based approaches may overcome these obstacles.

Polymorphisms in the dopamine (DA) signaling to predict outcome in patients (pts) with metastatic colorectal cancer (mCRC): Data from TRIBE, MAVERICC, and FIRE-3 phase III trials.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3048-3048
Author(s):  
Francesca Battaglin ◽  
Shu Cao ◽  
Fotios Loupakis ◽  
Sebastian Stintzing ◽  
Aparna Raj Parikh ◽  
...  
Keyword(s):  
Multiple Testing ◽  
Meta Analysis ◽  
Critical Role ◽  
Progression Free Survival ◽  
Phase Iii ◽  
P Value ◽  
Nucleotide Polymorphisms ◽  
First Line ◽  
The Impact

3048 Background: Strong evidence supports the critical role of the gut-brain axis in modulating gastrointestinal function and homeostasis. Available data suggest an involvement of the dopaminergic pathway in CRC dynamics. DA could inhibit proliferation and migration of tumor endothelial cells and enhanced 5-fluorouracil efficacy in CRC preclinical models. Hence, we hypothesized that genetic variants in DA signaling may predict treatment outcomes in mCRC pts. Methods: The impact on outcome of 22 selected single nucleotide polymorphisms (SNPs) in 9 genes of the DA signaling pathway ( DRD1, DRD2, DRD3, DRD4, DRD5, TAAR1, SLC6A3, SLC18A2, PPP1R1B) was analyzed on a total of 884 pts enrolled in three independent randomized first-line trials: TRIBE (n = 324), MAVERICC (n = 324), and FIRE-3 (n = 236). Genomic DNA from blood samples of pts was genotyped through the OncoArray, a custom array manufactured by Illumina. A meta-analysis approach using the METASOFT software was used to quantify SNPs prognostic effects and heterogeneities across treatment arms. P values were adjusted for multiple testing using the false discovery rate (FDR) method. Results: Overall, DRD3 rs3732790, rs9817063 and rs2134655 showed a significant nominal p value ( P) in association with tumor response (TR) across trials ( P= 0.032, P= 0.021, P= 0.027, respectively). TAAR1 rs8192620 showed an association with both progression free survival (PFS) ( P= 0.01) and overall survival (OS) ( P= 0.033), similar to DA transporter SLC6A3 rs6347 ( P= 0.016 and P= 0.002, respectively). SLC6A3 rs6347 association with OS remained significant after FDR ( PFDR= 0.045). Subgroup analyses showed a significant association with PFS for DRD1 rs267410 and SLC6A3 rs2652510 in females ( PFDR= 0.056), and between SLC6A3 rs6347 and OS ( PFDR= 0.041) and SLC6A3 rs6876890 and TR ( PFDR= 0.05) in KRAS wild type. Conclusions: Our results suggest that SNPs in DA signaling may have a prognostic value in mCRC pts receiving first-line treatment. Upon validation, these findings may provide novel insight on the role of DA signaling in CRC and possibly contribute to open novel therapeutic perspectives.

Role of ctDNA to predict risk of recurrence following potentially curative resection of biliary tract and pancreatic malignancies.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 336-336
Author(s):  
Angela Lamarca ◽  
Mairead Geraldine McNamara ◽  
Richard Hubner ◽  
Juan W. Valle
Keyword(s):  
Relapse Rate ◽  
Curative Resection ◽  
Cox Regression ◽  
Statistical Significance ◽  
Molecular Profiling ◽  
P Value ◽  
Relapse Risk ◽  
Baseline Characteristics

336 Background: The potential role of ctDNA to identify residual disease after potentially curative resection has been suggested in some malignancies; its role in resected pancreatico(P)-biliary(B) malignancies is unknown. Methods: Patients diagnosed with PB malignancies underwent molecular profiling (ctDNA) using FoundationMedicine Liquid (72 cancer-related genes) following potentially curative resection. Baseline patient characteristics and molecular profiling outcomes, including mutant allele frequency (MAF) for pathological alterations were extracted. Primary objective: prevalence of ctDNA identification and its correlation with recurrence (relapse-free survival (RFS) and relapse rate). Results: Total of 11 individuals had ctDNA analysed following potentially curative resection for PB malignancies: 8 B (4 extra-hepatic cholangiocarcinoma (eCCA), 2 ampulla, 1 intrahepatic cholangiocarcinoma (iCCA), 1 gallbladder cancer (GBC)) and 3 P. Baseline characteristics: 6 female (54.55%), median age 71.59 years (range 39.98-81.19). Most were pT2 (45.45%), pN0 (54.55%) and R0 (63.64%). Following surgery, 6 patients were started on adjuvant chemotherapy; at the end of follow-up (data cut-off 25/6/2020; median follow-up 11.15 months (range 5.45-13.52); 5 relapsed (45.45%) and 2 died (18.18%). Estimated median RFS was 11.43 months (95% CI 2.28-not reached); median overall survival was not reached. No sample failed ctDNA analysis; presence of ctDNA was identified in 3/11 (27.27%) of the samples; 2 and 1 samples had 2 and 1 pathological alterations identified, respectively: ALK fusion (1 sample; GBC), TP53 mutation (2 samples; eCCA and GBC), CHEK2 mutation (1 sample; pancreas), IDH2 mutation (1 sample; eCCA). Mean maximum MAF was 1.47 (2 in biliary; 0.43 in pancreas). Variants of unknown significance were identified in 72.73% of the samples (87.5% in B; 33.33% in P; p-value 0.152). None of the baseline characteristics explored correlated with presence of ctDNA. There was a trend towards increased relapse risk in the patients with ctDNA present following potentially curative surgery; Cox regression for RFS [HR 2.64 (95% CI 0.36-19.31); median RFS 11.44 months (95% CI 2.28-not reached) vs 10.87 (95% CI 2.21-not reached)]; relapse rate 37.5% (ctDNA absent) vs 66.67% (ctDNA present); statistical significance was not reached (p-value 0.340 and p-value 0.545, respectively). Conclusions: This pilot study demonstrates the feasibility of testing for ctDNA following potentially curative resection in PB malignancies. Presence of ctDNA may be associated with increased relapse risk; further studies are required to increase sample size and assess clinical implications.

scholarly journals No Correlation between KRAS Status and Advanced Pancreatic Adenocarcinoma Survival

2017 ◽  
Vol 6 (2) ◽  
pp. 45 ◽  
Author(s):  
Misato Ogata ◽  
Hironaga Satake ◽  
Takatsugu Ogata ◽  
Yukihiro Imai ◽  
Yukimasa Hatachi ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Growth Factor Receptor ◽  
Gene Mutations ◽  
Progression Free Survival ◽  
Patient Characteristics ◽  
Predictive Biomarker ◽  
First Line ◽  
Kras Mutations ◽  
Kras Status ◽  
The Impact

Erlotinib plus gemcitabine is one of the standard chemotherapies for unresectable pancreatic cancer. Pancreatic cancer has the highest frequency of KRAS gene mutations among human cancers, and some studies suggest that KRAS status might be a predictive biomarker for anti-epidermal growth factor receptor treatment. However, the reliability of this biomarker has not been confirmed. Here, we evaluated the impact of KRAS mutations in pancreatic cancer patients treated with first line gemcitabine-based chemotherapy. 23 patients treated with gemcitabine-based chemotherapy whose KRAS status could be examined from primary or metastatic lesions were enrolled. KRAS mutations were analyzed by sequencing codons 12 and 13. We retrospectively evaluated the correlation between KRAS status, and prognosis and treatment efficacy. Patient characteristics were as follows: median age 68 years, male/female=6/17, PS 0/1=9/14, TNM stage III/IV=1/22, and gemcitabine alone/erlotinib plus gemcitabine=13/10. Among the 23 patients, KRAS codon 12 was mutated in 15, one of whom also had mutation on codon 13. Median progression-free survival (PFS) and overall survival (OS) of all patients were 4.3 months (95% confidence interval (CI): 3.1 to 5.4) and 8.1 months (95% CI: 5.9 to 10.0; events in 96%), respectively. KRAS status showed no association with PFS (p=0.310), OS (p=0.934), or the efficacy of treatment with (p=0.833) or without erlotinib (p=0.478). Thus, in this study, there was no correlation between KRAS status and the efficacy of first line chemotherapy with gemcitabine with or without erlotinib. Identification of a rationale for personalized medicine in pancreatic cancer will require further exploratory prospective studies.

scholarly journals The Emerging Role of Microbiota and Microbiome in Pancreatic Ductal Adenocarcinoma

Biomedicines ◽  
2020 ◽  
Vol 8 (12) ◽  
pp. 565
Author(s):  
Sona Ciernikova ◽  
Maria Novisedlakova ◽  
Danka Cholujova ◽  
Viola Stevurkova ◽  
Michal Mego
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Malignant Tumors ◽  
Current Knowledge ◽  
Early Stage ◽  
Poor Response ◽  
Response To Therapy ◽  
Oral Microbiome ◽  
Ductal Adenocarcinoma ◽  
The Impact

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignant tumors due to the absence of biomarkers for early-stage detection and poor response to therapy. Since mounting evidence supports the role of microbiota composition in tumorigenesis and cancer treatment, the link between microbiome and PDAC has been described. In this review, we summarize the current knowledge regarding the impact of the gut and oral microbiome on the risk of PDAC development. Microenvironment-driven therapy and immune system interactions are also discussed. More importantly, we provide an overview of the clinical trials evaluating the microbiota role in the risk, prognosis, and treatment of patients suffering from PDAC and solid tumors. According to the research findings, immune tolerance might result from the microbiota-derived remodeling of pancreatic tumor microenvironment. Thus, microbiome profiling and targeting represent the potential trend to enhance antitumor immunity and improve the efficacy of PDAC treatment.

scholarly journals Routine intraoperative jejunostomy placement and minimally invasive oesophagectomy: an unnecessary step?†

2019 ◽  
Vol 56 (4) ◽  
pp. 746-753 ◽  
Author(s):  
Tiuri E Kroese ◽  
Leonidas Tapias ◽  
Jacqueline K Olive ◽  
Lena E Trager ◽  
Christopher R Morse
Keyword(s):  
Weight Loss ◽  
Minimally Invasive ◽  
Relative Weight ◽  
Patient Characteristics ◽  
Perioperative Outcomes ◽  
P Value ◽  
Oral Nutrition ◽  
Significant Difference ◽  
Minimally Invasive Oesophagectomy ◽  
The Impact

Abstract OBJECTIVES: Adequate nutrition is challenging after oesophagectomy. A jejunostomy is commonly placed during oesophagectomy for nutritional support. However, some patients develop jejunostomy-related complications and the benefit over oral nutrition alone is unclear. This study aims to assess jejunostomy-related complications and the impact of intraoperative jejunostomy placement on weight loss and perioperative outcomes in patients with oesophageal cancer treated with minimally invasive Ivor Lewis oesophagectomy (MIE). METHODS: From a prospectively maintained database, patients were identified who underwent MIE with gastric reconstruction. Between 2007 and 2016, a jejunostomy was routinely placed during MIE. After 2016, a jejunostomy was not utilized. Postoperative feeding was performed according to a standardized protocol and similar for both groups. The primary outcomes were jejunostomy-related complications, relative weight loss at 3 and 6 months postoperative and perioperative outcomes, including anastomotic leak, pneumonia and length of stay, respectively. RESULTS: A total of 188 patients were included, of whom 135 patients (72%) received a jejunostomy. Ten patients (7.4%) developed jejunostomy-related complications, of whom 30% developed more than 1 complication. There was no significant difference in weight loss between groups at 3 months (P = 0.73) and 6 months postoperatively (P = 0.68) and in perioperative outcomes (P-value >0.999, P = 0.591 and P = 0.513, respectively). CONCLUSIONS: The use of a routine intraoperative jejunostomy appears to be an unnecessary step in patients undergoing MIE. Intraoperative jejunostomy placement is associated with complications without improving weight loss or perioperative outcomes. Its use should be tailored to individual patient characteristics. Early oral nutrition allows patients to maintain an adequate nutritional status.

scholarly journals The Hepatic Microenvironment and TRAIL-R2 Impact Outgrowth of Liver Metastases in Pancreatic Cancer after Surgical Resection

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 745 ◽  
Author(s):  
Lauritz Miarka ◽  
Charlotte Hauser ◽  
Ole Helm ◽  
Dörthe Holdhof ◽  
Silje Beckinger ◽  
...  
Keyword(s):  
Liver Metastases ◽  
Surgical Resection ◽  
Tumor Resection ◽  
Ductal Adenocarcinoma ◽  
Vascular Endothelial ◽  
Liver Inflammation ◽  
Tumor Growth And Metastasis ◽  
Endothelial Growth Factor ◽  
The Impact

Most patients with pancreatic ductal adenocarcinoma (PDAC) undergoing curative resection relapse within months, often with liver metastases. The hepatic microenvironment determines induction and reversal of dormancy during metastasis. Both tumor growth and metastasis depend on the Tumor necrosis factor (TNF)-related apoptosis-inducing ligand-receptor 2 (TRAIL-R2). This study investigated the interplay of TRAIL-R2 and the hepatic microenvironment in liver metastases formation and the impact of surgical resection. Although TRAIL-R2-knockdown (PancTu-I shTR2) decreased local relapses and number of macroscopic liver metastases after primary tumor resection in an orthotopic PDAC model, the number of micrometastases was increased. Moreover, abdominal surgery induced liver inflammation involving activation of hepatic stellate cells (HSCs) into hepatic myofibroblasts (HMFs). In coculture with HSCs, proliferation of PancTu-I shTR2 cells was significantly lower compared to PancTu-I shCtrl cells, an effect still observed after switching coculture from HSC to HMF, mimicking surgery-mediated liver inflammation and enhancing cell proliferation. CXCL-8/IL-8 blockade diminished HSC-mediated growth inhibition in PancTu-I shTR2 cells, while Vascular Endothelial Growth Factor (VEGF) neutralization decreased HMF-mediated proliferation. Overall, this study points to an important role of TRAIL-R2 in PDAC cells in the interplay with the hepatic microenvironment during metastasis. Resection of primary PDAC seems to induce liver inflammation, which might contribute to outgrowth of liver metastases.

scholarly journals Molecular profiling of advanced solid tumours. The impact of experimental molecular-matched therapies on cancer patient outcomes in early-phase trials: the MAST study

2021 ◽  
Author(s):  
Valentina Gambardella ◽  
Pasquale Lombardi ◽  
Juan Antonio Carbonell-Asins ◽  
Noelia Tarazona ◽  
Juan Miguel Cejalvo ◽  
...  
Keyword(s):  
Early Phase ◽  
Progression Free Survival ◽  
Tumor Board ◽  
Prior Therapy ◽  
Early Phase Trials ◽  
Molecular Tumor Board ◽  
Early Phase Clinical Trials ◽  
The Impact ◽  
To Receive

Abstract Introduction Molecular-matched therapies have revolutionized cancer treatment. We evaluated the improvement in clinical outcomes of applying an in-house customized Next Generation Sequencing panel in a single institution. Methods Patients with advanced solid tumors were molecularly selected to receive a molecular-matched treatment into early phase clinical trials versus best investigators choice, according to the evaluation of a multidisciplinary molecular tumor board. The primary endpoint was progression-free survival (PFS) assessed by the ratio of patients presenting 1.3-fold longer PFS on matched therapy (PFS2) than with prior therapy (PFS1). Results Of a total of 231 molecularly screened patients, 87 were eligible for analysis. Patients who received matched therapy had a higher median PFS2 (6.47 months; 95% CI, 2.24–14.43) compared to those who received standard therapy (2.76 months; 95% CI, 2.14–3.91, Log-rank p = 0.022). The proportion of patients with a PFS2/PFS1 ratio over 1.3 was significantly higher in the experimental arm (0.33 vs 0.08; p = 0.008). Discussion We demonstrate the pivotal role of the institutional molecular tumor board in evaluating the results of a customized NGS panel. This process optimizes the selection of available therapies, improving disease control. Prospective randomized trials are needed to confirm this approach and open the door to expanded drug access.

Alemtuzumab Reduces Chronic Graft Versus Host Disease (cGVHD) and Treatment Related Mortality (TRM) after Reduced Intensity Conditioning for AML and MDS.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1076-1076 ◽  
Author(s):  
Koen van Besien ◽  
Marcos de Lima ◽  
Andrew Artz ◽  
Betul Oran ◽  
Wendy Stock ◽  
...  
Keyword(s):  
Chronic Gvhd ◽  
Progression Free Survival ◽  
Patient Characteristics ◽  
Cancer Center ◽  
P Value ◽  
Unrelated Donor ◽  
Post Transplant ◽  
Md Anderson

Abstract In vivo T-cell depletion with alemtuzumab has been used to reduce acute and chronic GVHD. In order to evaluate its overall effect on transplant outcomes in AML and MDS we compared 90 pts who received fludarabine/melphalan/alemtuzumab (FMA) conditioning and post-transplant tacrolimus at the University of Chicago, with 112 who received fludarabine/melphalan (FM) and post-transplant tacrolimus/methotrexate at MD Anderson Cancer Center. Pt and transplant characteristics were well balanced except for a higher proportion of MDS in the FM group. Median age, proportion unrelated donor tx and proportion high/intermediate and low risk by ASBMT criteria were balanced between the groups. With median follow up of 28 months in both groups, one year progression free survival and overall survival are identical. TRM is significantly higher after FM, but relapse is higher in FMA. 19/103 d 28 survivors after FM vs 7/84 after FMA developed gr III–IV acute GVHD (p=0.04). 46/77 d100 survivors after FM developed ext cGVHD vs 7/63 after FMA (p=0.0000). 43 patients remain alive after FM and 27 have ext cGVHD. 41 remain alive after FMA and 1 has ext cGVHD. Alemtuzumab results in a considerable reduction in acute and particularly chronic GVHD. TRM is reduced compared with standard GVHD prophylaxis. Low incidence of chronic GVHD and reduced TRM may be the major benefit of this strategy. Relapse rates are increased, because of reduced GVL effects or because of improved early survival of high risk patients. Other approaches are necessary for improving long term outcomes. Patient Characteristics and Outcome FMA FM P-value N 90 102 Age (range) 54 (22–74) 51 (17–77) 0.6 AML/MDS 13/77 29/83 0.04 MUD/related 42/48 59/63 0.5 High./Intermediate/LowRisk 48/13/28 76/10/26 0.12 Median Follow up mths (range) 28 (3–89) 28 (1–66) 0.07 TRM@ 100 days 13% + 7% 24% + 8% 0.04 TRM@ 1 year 30% + 12% 42% + 10% 0.04 Relapse @ 1 year 40% + 12% 26% + 10% 0.01 PFS @ 2 years 33% + 11% 37% + 9% 0.9 OS @ 2 year 42% + 11% 44% + 9% 0.5 AGVD gr III–IV 7/84 19/103 0.04 Ext cGVHD 7/63 46/77 0.0000 Ext cGVHD in survivors 1/41 27/43 0.0000

Regorafenib (REG) in progressive metastatic colorectal cancer (mCRC): Analysis of age subgroups in the phase III CORRECT trial.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3636-3636 ◽  
Author(s):  
Eric van Cutsem ◽  
Alberto Sobrero ◽  
Salvatore Siena ◽  
Alfredo Falcone ◽  
Marc Ychou ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Phase Iii ◽  
P Value ◽  
Correct Trial ◽  
Multikinase Inhibitor ◽  
Once Daily ◽  
Grade 3 ◽  
Dose Modifications ◽  
The Impact ◽  
To Receive

3636 Background: In the CORRECT phase III trial, the multikinase inhibitor REG demonstrated significant improvement in overall survival (OS) and progression-free survival vs placebo (Pla) in patients (pts) with mCRC whose disease progressed on other standard therapies. The most frequent REG-related grade ≥3 adverse events (AEs) of interest were hand–foot skin reaction (HFSR), fatigue, diarrhea, hypertension, and rash/desquamation. We explored whether the impact of REG in pts aged ≥65 years differed from that in younger patients. Methods: Pts with mCRC progressing following all other available therapies were randomized 2:1 to receive REG 160 mg once daily (n=505) or Pla (n=255) for the first 3 weeks of each 4-week cycle. The dose could be modified to manage AEs. The primary endpoint was OS. We report efficacy, safety, and dosing data from REG recipients by age. Results: The REG treatment group included 309 pts <65 years (307 evaluable for safety) and 196 pts ≥65 years (193 evaluable for safety). The OS hazard ratio (REG/Pla) was 0.72 (95% confidence interval [CI] 0.56–0.91) in pts <65 years and 0.86 (95% CI 0.61–1.19) in pts ≥65 years (interaction p-value = 0.405). Median OS was 6.7 vs 5 months for REG vs Pla in pts <65 years, and 6.0 vs 5.6 months, respectively, in pts ≥65 years. Most pts experienced drug-related AEs (<65 years: 93.8%; ≥65 years: 91.7%). The rates of grade ≥3 REG-related AEs of interest and dose modifications are shown in the Table. In pts <65 years vs ≥65 years, median (interquartile range [IQR]) duration of REG was 7.6 weeks (6.6–15.4) vs 7.1 weeks (5.1–17.2), median (IQR) daily REG dose was 160.0 mg (134.6–160.0) vs 160.0 mg (137.5–160.0), and median (IQR) proportion of planned REG dose was 83.3% (65.7–100.0) vs 78.6% (66.7–100.0), respectively. Conclusions: In the CORRECT trial, REG demonstrated an OS benefit in pts <65 years and ≥65 years. Safety and tolerability of REG appeared to be similar in both age subgroups. Clinical trial information: NCT01103323. [Table: see text]

Sign in / Sign up

Export Citation Format

Share Document