Search

Purpose: To determine whether SD-101, a Toll-like receptor 9 agonist, potentiates the antitumor activity of anti-PD-1 antibodies in patients with anti-PD-1/PD-L1 naïve, recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Patients and Methods: Patients with PD-1 Ab-naïve HNSCC received either 2 mg SD-101 injected in one to four lesions or 8 mg SD-101 injected into a single lesion weekly × 4 doses then every 3 weeks × 7 doses. Pembrolizumab was administered at 200 mg every 3 weeks. Results: A total of 28 patients received 2 mg and 23 received 8 mg per injection, respectively. A total of 76% of patients had received prior systemic therapy. Combined positive score was ≥1 to < 20 in 35 patients (70%) and ≥ 20 in 15 patients (30%) of 50 patients with available data. There were 12 patients with grade ≥3 treatment-related adverse events (24%), and no treatment-related deaths. The objective response rate was 24% including 2 complete and 10 partial responses. The median duration of response was 7.0 [95% confidence interval (CI): 2.1–11.1] months. The response rate was higher in human papillomavirus–positive (HPV+) patients (44%, N = 16). Responses were not associated with PD-L1 expression levels or IFNγ-related gene expression at baseline. Responses were observed both in injected (32%) and in noninjected lesions (29%). Progression-free and overall survival at 9 months were 19.0% (95% CI: 9.1–31.7) and 64.7% (95% CI: 45.3–78.7), respectively. Conclusions: SD-101 combined with pembrolizumab induced objective responses, especially in HPV+ tumors, which were frequently associated with increased intratumoral inflammation and effector immune cell activity.

Purpose:To determine whether SD-101, a Toll-like receptor 9 agonist, potentiates the antitumor activity of anti-PD-1 antibodies in patients with anti-PD-1/PD-L1 naïve, recurrent/metastatic head and neck squamous cell carcinoma (HNSCC).Patients and Methods:Patients with PD-1 Ab-naïve HNSCC received either 2 mg SD-101 injected in one to four lesions or 8 mg SD-101 injected into a single lesion weekly × 4 doses then every 3 weeks × 7 doses. Pembrolizumab was administered at 200 mg every 3 weeks.Results:A total of 28 patients received 2 mg and 23 received 8 mg per injection, respectively. A total of 76% of patients had received prior systemic therapy. Combined positive score was ≥1 to < 20 in 35 patients (70%) and ≥ 20 in 15 patients (30%) of 50 patients with available data. There were 12 patients with grade ≥3 treatment-related adverse events (24%), and no treatment-related deaths. The objective response rate was 24% including 2 complete and 10 partial responses. The median duration of response was 7.0 [95% confidence interval (CI): 2.1–11.1] months. The response rate was higher in human papillomavirus–positive (HPV+) patients (44%, N = 16). Responses were not associated with PD-L1 expression levels or IFNγ-related gene expression at baseline. Responses were observed both in injected (32%) and in noninjected lesions (29%). Progression-free and overall survival at 9 months were 19.0% (95% CI: 9.1–31.7) and 64.7% (95% CI: 45.3–78.7), respectively.Conclusions:SD-101 combined with pembrolizumab induced objective responses, especially in HPV+ tumors, which were frequently associated with increased intratumoral inflammation and effector immune cell activity.

Supplementary Figure from Intralesional SD-101 in Combination with Pembrolizumab in Anti-PD-1 Treatment-Naïve Head and Neck Squamous Cell Carcinoma: Results from a Multicenter, Phase II Trial

Supplement

Purpose:Although PD-(L)1 inhibitors have shown efficacy in advanced/metastatic non–small cell lung cancer (NSCLC), many patients do not respond to this treatment and more effective combinations with acceptable toxicities are needed. To assess the potential benefit of combining localized innate immune stimulation with checkpoint blockade, the TLR9 agonist DV281 was combined with nivolumab in a phase Ib study.Patients and Methods:Patients after one or two prior lines of systemic therapy were enrolled in a dose-escalation study with a 3+3 design. DV281 was administered via inhalation in five dose cohorts at 1 to 25 mg; nivolumab 240 mg was administered intravenously every 2 weeks. Safety, tolerability, pharmacodynamics, and response to treatment were assessed.Results:Twenty-six patients with advanced NSCLC enrolled. Baseline programmed death ligand 1 (PD-L1) expression was present in 16 patients (61.5%); 21 (80.7%) had received previous anti–PD-1/PD-L1. Thirteen patients (50%) had stable disease, nine (34.6%) had progressive disease, and four (15.4%) were not evaluable. Median duration of disease control was 124 days. Adverse events were seen in 16 patients (61.5%), mostly grade 1/2 chills, fatigue, flu-like symptoms, diarrhea, and rash; there was only one grade 3 adverse event (dyspnea). Pharmacodynamic assessment, measured by IFN- inducible gene expression, showed target engagement in all dose cohorts. Systemic pharmacodynamic responses plateaued in the 2 highest dose cohorts.Conclusions:DV281 with nivolumab was well tolerated with target engagement observed at every dose. Pharmacodynamic advantages at doses above 10 mg were unclear. The long duration of disease control in 50% of patients suggests clinically relevant activity in this population of heavily pretreated patients.

The epidermal growth factor receptor (EGFR)-src-signal transducers and activators of transcription 3 (STAT3) oncogenic pathway plays a central role in tumorigenesis and is involved not only in cell transformation but also in tumor escape to genotoxic treatments. Despite its importance, the molecular mechanisms by which this signaling pathway induces resistance to DNA damage remain most of the time to be characterized. In this study, we show that the EGFR-src pathway is activated in response to topoisomerase I inhibition. After treatment, this signaling cascade induced the activation of STAT3 and the binding of the transcription factor to the promoter of the Eme1 gene. Eme1 is an endonuclease involved in the processing of DNA damage after topoisomerase I inhibition. These results suggest a model by which the STAT3-mediated activation of Eme1 prevents DNA damage and enhances cell survival in response to topoisomerase inhibition. This survival pathway was inhibited by a combined treatment with a src inhibitor, SKI, and with cetuximab, a monoclonal antibody directed against the EGFR that is widely used in the treatment of colorectal cancers. We therefore propose that the benefit of anti-EGFR therapy relies on an increase of DNA damage generated by topoisomerase I inhibition. [Cancer Res 2008;68(3):815–25]

Supplementary Figure Legend from The EGFR-STAT3 Oncogenic Pathway Up-regulates the Eme1 Endonuclease to Reduce DNA Damage after Topoisomerase I Inhibition

Supplementary Figure 1 from The EGFR-STAT3 Oncogenic Pathway Up-regulates the Eme1 Endonuclease to Reduce DNA Damage after Topoisomerase I Inhibition

Purpose: Although PD-(L)1 inhibitors have shown efficacy in advanced/metastatic non–small cell lung cancer (NSCLC), many patients do not respond to this treatment and more effective combinations with acceptable toxicities are needed. To assess the potential benefit of combining localized innate immune stimulation with checkpoint blockade, the TLR9 agonist DV281 was combined with nivolumab in a phase Ib study. Patients and Methods: Patients after one or two prior lines of systemic therapy were enrolled in a dose-escalation study with a 3+3 design. DV281 was administered via inhalation in five dose cohorts at 1 to 25 mg; nivolumab 240 mg was administered intravenously every 2 weeks. Safety, tolerability, pharmacodynamics, and response to treatment were assessed. Results: Twenty-six patients with advanced NSCLC enrolled. Baseline programmed death ligand 1 (PD-L1) expression was present in 16 patients (61.5%); 21 (80.7%) had received previous anti–PD-1/PD-L1. Thirteen patients (50%) had stable disease, nine (34.6%) had progressive disease, and four (15.4%) were not evaluable. Median duration of disease control was 124 days. Adverse events were seen in 16 patients (61.5%), mostly grade 1/2 chills, fatigue, flu-like symptoms, diarrhea, and rash; there was only one grade 3 adverse event (dyspnea). Pharmacodynamic assessment, measured by IFN- inducible gene expression, showed target engagement in all dose cohorts. Systemic pharmacodynamic responses plateaued in the 2 highest dose cohorts. Conclusions: DV281 with nivolumab was well tolerated with target engagement observed at every dose. Pharmacodynamic advantages at doses above 10 mg were unclear. The long duration of disease control in 50% of patients suggests clinically relevant activity in this population of heavily pretreated patients.

339 Background: Hypoxia inducible factor-2 alpha (HIF2a) is a transcription factor and key tumorigenic driver of clear cell renal cell carcinoma (ccRCC). Normally, HIF2a is expressed at low levels and targeted for degradation by the von Hippel-Lindau ( VHL) tumor suppressor protein. VHL inactivation, the causative event of ccRCC, induces tumorigenesis through uncontrolled accumulation of HIF2a and constitutive expression of downstream target genes implicated in cell survival, cell proliferation and angiogenesis. ARO-HIF2 is a synthetic double-stranded RNAi trigger with an alpha-v beta3 targeting ligand, designed to silence HIF2a expression. Herein, we present initial results from a phase 1 clinical trial of ARO-HIF2 in advanced ccRCC (NCT04169711). Methods: Advanced ccRCC patients (pts) (ECOG ≤ 1), with progressive disease on prior anti-VEGF and checkpoint inhibitor therapy, were enrolled into three escalating dose cohorts (up to 10 per cohort) to receive 225, 525 or 1,050 mg i.v. weekly of ARO-HIF2 until progression or unacceptable toxicity. The primary endpoint was incidence and severity of AEs. Secondary endpoints included tumor response based on RECIST. All pts underwent tumor biopsy at baseline and post-dose for analysis of changes in HIF2a mRNA (qPCR) and protein expression (IHC). Results: At the time of data cut, twenty-three pts (median age 66.5) were enrolled across 3 cohorts. Seventy four percent of pts received ≥ 3 prior lines of therapy. The most common treatment emergent AE was fatigue (39%). Three SAEs in 3 pts were reported by investigators as possibly drug related including, myocarditis (in a pt with a history of TKI induced cardiomyopathy and NSTEMI requiring stent placement), demyelinating neuropathy (in a pt with autoimmune sequelae secondary to checkpoint inhibitors), and hypoxia (in a pt with a pulmonary infiltrate treated with antibiotics). No cases of drug related anemia were reported. Among pts with adequate biopsy for qPCR (n=7), mean (max) reductions in HIF2a mRNA were 38% (47%), 25% (30%) and 28% (28%) in cohorts 1, 2, and 3, respectively. Among pts with adequate biopsy for IHC (n = 12), 8 showed reductions in HIF2a protein with mean (max) reductions of 45% (82%), 57% (90%) and 63% (63%) in cohorts 1, 2, 3, respectively. Across all 3 cohorts, disease control (CR+PR+SD) was seen in 7 (30%) of pts. One pt (cohort 2, with prior sunitinib, nivolumab, axitinib) experienced a partial response with 66% reduction in sum of longest diameters. Six pts had a best response of stable disease. Three pts remain on drug with stable disease and treatment durations between 20 and 32 weeks. Conclusions: HIF2a is a clinically validated driver of ccRCC which can be targeted with a RNAi therapeutic. This ongoing phase 1 study provides initial proof of target engagement based on reductions in HIF2a expression as well as a favorable safety profile in response to escalating doses of ARO-HIF2. Clinical trial information: NCT04169711.

Aurora kinases are involved in the pathophysiology of several cancers including acute myeloid leukemia (AML). In this phase 1 study, we investigated the safety and efficacy of AMG 900, an orally administered, highly potent, selective, small-molecule inhibitor of both Aurora kinase A and B, in patients with AML. Patients with pathologically documented AML who either declined standard treatments or had relapsed from or were refractory to previous therapies were enrolled. Two every-2-week dose-escalation schedules using a modified 3 + 3+3 design were used: AMG 900 given daily for 4 days with 10 days off (4/10 schedule), and AMG 900 given daily for 7 days with 7 days off (7/7 schedule). Thirty-five patients were enrolled at 9 different dose levels: 22 patients on the 4/10 schedule (doses from 15 to 100 mg daily), and 13 patients on the 7/7 schedule (doses from 30 to 50 mg daily). Both schedules were tolerated; nausea (31%), diarrhea (29%), febrile neutropenia (29%), and fatigue (23%) were the most common treatment-related adverse events. Three patients (9%) achieved complete response with incomplete count recovery. Patients with higher baseline expression of a set of specific pathway-related genes (BIRC5, AURKA, TTK, CDC2, and CCNB1) were more likely to respond in an exploratory biomarker analysis. AMG 900 was tolerated in a general AML population, and pathway-specific biomarkers identified a potential target population. Future research efforts will be directed toward further exploration of biomarkers of response and combination of AMG 900 with other anticancer agents. This article is protected by copyright. All rights reserved.

5-Fluorouracil (5-FU)–based treatments can lead to early-onset severe (4%–5%) even fatal (0.3%) toxicities in patients with dihydropyrimidine dehydrogenase (DPD) deficiency. This multicenter prospective cohort study aimed to assess the clinical benefit of pretherapeutic screening for DPD deficiency using a multiparametric approach. Two parallel cohorts of patients treated with 5-FU–based chemotherapy for colorectal carcinoma were compared in a prospective nonrandomized study. In arm A, patients had DPD deficiency screening before treatment, whereas in arm B no pretherapy screening was performed. Dosing was based on 5-FU administration guidelines of each institution. DPD deficiency screening was performed using a combined multiparametric approach (5-FUODPM Tox). The frequency of early grade 4–5 toxic events potentially induced by 5-FU was compared in the two groups. At total of 1,142 patients (n = 1,116 evaluable) were enrolled. In arm A, out of 718 evaluable patients, nine grade 4 early toxicities potentially related to 5-FU were reported in nine patients (1.2%) with no toxic death despite one complete DPD deficiency and 24 partial deficiencies. The 24 patients with partial deficiency had safe pharmacokinetics (PK)-monitored 5-FU. In arm B, among 398 evaluable patients, 17 grade 4–5 toxic early events potentially related to 5-FU were reported in 12 patients (4.2%). The incidence of early severe toxicity was significantly higher in arm B (P = .0019), confirming the positive impact of pretherapeutic DPD assessment. The percent of patients with a toxicity grade 3 or higher observed in arm A was 10.8% (n = 78) compared to 17.55% (n = 69) in arm B (P = .0497). The percentage of death was reduced from 2.5/1,000 in arm B to 0 in arm A. The time to occurrence of all grade ≥3 toxicities was determined in both arms and the difference between the two arms was significant (P = .047). Overall, one patient with complete DPD deficiency confirmed retrospectively died within 13 days from grade 5 multivisceral toxicity. Enrollment was prematurely closed after external experts’ decision. In conclusion, multiparametric pretherapeutic DPD deficiency screening significantly lowered the risk of early severe toxicity and avoided an early toxic death. This approach should be used for safe administration of 5-FU–based treatments.

Purpose: Although controversial, assessment of epidermal growth factor receptor (EGFR) expression is required for the approved indications of Cetuximab in metastatic colorectal cancer (mCRC). With the objective of improving patient selection, “ERBITUX-OUEST” study aimed at analyzing EGFR status in a large cohort of mCRC patients who received cetuximab without preliminary EGFR screening, and assessing the correlation between EGFR status and response to treatment retrospectively. Patients and methods: 332 patients treated with Irinotecan Cetuximab based regimen after progression on irinotecan or oxaliplatin therapy were included. EGFR status was assessed using three available immunohistochemistry (IHC) tests and in situ hybridization in case of negativity. Clinical outcomes of EGFR-positive and EGFR-non-detected (or considered as negative with at least one test) patients were compared. Results: Of the 332 samples centrally screened, 194 were classified as full-positive (i.e., EGFR-positive for all three tests), 86 as full-negative, and 52 as discordant. One third of the 131 negative samples with FDA approved test should be reclassified as positive with at least one of the two others tests. Regarding results from FDA approved test only, neither objective response rate (ORR), progression-free survival (PFS) nor overall survival (OS) differed significantly between EGFR-negative and EGFR-positive patients (P = 0.788, 0.326 and 0.888, respectively). Similarly, comparison of full-negative to other groups did not show any significant difference in terms of ORR (P = 0.507), PFS (P = 0.222) or OS (P = 0.686). Conclusion: These data strongly argue against mCRC patients selection for Cetuximab treatment based on EGFR expression as measured by currently available IHC technics.

Background Aurora kinase overexpression or amplifications are associated with high proliferation, poor prognosis, and therapeutic resistance in human tumors. AMG 900 is an investigational, oral, selective pan-Aurora kinase inhibitor. Methods This first-in-human trial included dose-escalation and dose-expansion phases ( ClinicalTrials.gov : NCT00858377). Dose escalation evaluated the safety, tolerability, and pharmacokinetics of AMG 900 in advanced solid tumors and determined the maximum tolerated dose (MTD) with/without granulocyte colony-stimulating factor (G-CSF) prophylaxis. Dose expansion evaluated clinical activity in three tumor types: taxane- and platinum-resistant ovarian cancer, taxane-resistant triple-negative breast cancer (TNBC), and castration-resistant and taxane- or cisplatin/etoposide–resistant prostate cancer (CRPC). AMG 900 was administered 4 days on/10 days off at 1–50 mg/day during escalation and at the MTD with G-CSF during expansion. Results AMG 900 showed rapid absorption with fast clearance, supporting once-daily dosing. The MTD was 25 mg/day, increasing to 40 mg/day with G-CSF. Grade ≥ 3 treatment-related adverse events included neutropenia (37%), anemia (23%), leukopenia (14%), and thrombocytopenia (12%). During dose expansion, 3/29 (10.3%, 95% CI: 2.0%–28.0%) evaluable patients with ovarian cancer experienced partial response by central imaging per RECIST 1.1; median duration of response was 24.1 weeks (95% CI: 16.1–34.1). Seven patients (24.1%, 95% CI: 10.3%–43.5%) experienced partial response per Gynecologic Cancer InterGroup criteria; 5/9 patients positive for p53 expression responded to treatment. No objective responses were observed in patients with TNBC or CRPC per RECIST 1.1. Conclusions AMG 900 40 mg/day with G-CSF had manageable toxicity and demonstrated single-agent activity in patients with heavily pretreated, chemotherapy-resistant ovarian cancer.

Background Trebananib is an anti-angiogenic peptibody under investigation in patients with advanced cancer. This study evaluated the pharmacokinetic (PK) drug-drug interaction of paclitaxel and trebananib. Patients and methods Patients with advanced solid tumors received weekly 80 mg/m2 intravenous (IV) paclitaxel (3 weeks on/1 week off) with weekly 15 mg/kg IV trebananib starting at Week 2. Blood samples for PK analysis were collected at Week 1 (paclitaxel alone), Week 6 (paclitaxel and trebananib), and Week 8 (trebananib alone). An absence of interaction was to be concluded if the 90 % confidence intervals (CI) for the differences in paclitaxel exposure fell within the 0.80–1.25 interval. Results The primary study was conducted between 7/2012 and 10/2013. Thirty-five patients were enrolled and 34 received both treatments. Most patients were white (91 %) and female (59 %); mean age was 61 years. The most common tumor types were ovarian (32 %) and bladder (27 %), 71 % of patients had stage IV disease, and all had Eastern Cooperative Oncology Group (ECOG) scores of 0 or 1. PK parameter analysis was done on patients with evaluable PK data at both assessments (with and without concomitant therapy; n = 28). The geometric least squares mean (GLSM) ratio (90 % CI) of paclitaxel AUCinf with and without trebananib was 1.17 (1.10, 1.25). The GLSM ratio (90 % CI) of trebananib AUCtau,ss with and without paclitaxel was 0.92 (0.87, 0.97). The most common adverse events were fatigue, local edema, peripheral edema, and nausea. Conclusions This study showed no evidence of clinically meaningful PK interaction between paclitaxel and trebananib.

International audience; We conducted a multicenter proof of concept phase II trial in patients with advanced colorectal cancer receiving FOLFIRI-cetuximab regimens to explore individual drug tailoring using pharmacogenetics and pharmacokinetics (PK) monitoring. Patients were stratified by their pharmacogenetic/phenotypic status: the irinotecan dose was adjusted according to the number of TA tandem repeats in the UGT1A1 promoter, while the 5-fluorouracil (5-FU) dose was initially adjusted according to dihydropyrimidine dehydrogenase (DPD) activity at initial screening (5-FU[ODPM Tox]) followed by PK-guided dose optimization (5-FU[ODPM Protocol]). An advanced cetuximab PK/pharmacodynamics (PD) study was performed but dosage remained unchanged. Eighty-five patients receiving second-line chemotherapy were enrolled. Mean irinotecan doses at 3 months were 247 ± 50, 210 ± 53 and 140 ± 21 mg/m[2] for those with 6/6 (33), 6/7 (26), and 7/7 (7) TATA repeats in the UGT1A1 promoter region, respectively. The 5-FU dose was initially reduced in four patients with DPD deficiency, but mean 5-FU dose at 3 months was 2,412 ± 364 mg/m2 (1,615-3,170 mg/m[2]). Grade 4 toxicities were not encountered and grade 4 neutropenia occurred in 6.8%, 5.9%, and 0% of patients with 6/6, 6/7, and 7/7 UGT1A1 genotypes. The objective response rate was 25.8% among the 85 patients, 57.3% in patients with tumors wild type (WT) for KRAS, and 25% in those whose tumor harbored a mutant-KRAS. Secondary resection of hepatic metastases was performed in 31.7% of patients. Median progression-free survival (PFS) for all 85 patients was 181 days and 200, 132, and 121 days for patients with 6/6, 6/7, and 7/7 UGT1A1 genotypes, respectively; these differences were not statistically different. In parallel, a strong relationship was shown between cetuximab AUC and regimen efficacy. We conclude that personalized drug tailoring when administering in FOLFIRI + cetuximab allows for safe and efficient individual dose intensification.

Aurora kinases are involved in the pathophysiology of several cancers including acute myeloid leukemia (AML). In this phase 1 study, we investigated the safety and efficacy of AMG 900, an orally administered, highly potent, selective, small-molecule inhibitor of both Aurora kinase A and B, in patients with AML . Patients with pathologically documented AML who either declined standard treatments or had relapsed from or were refractory to previous therapies were enrolled. Two every-2-week dose-escalation schedules using a modified 3 + 3 + 3 design were evaluated AMG 900 given daily for 4 days with 10 days off (4/10 schedule), and AMG 900 given daily for 7 days with 7 days off (7/7 schedule). Thirty-five patients were enrolled at 9 different dose levels: 22 patients on the 4/10 schedule (doses from 15 to 100 mg daily), and 13 patients on the 7/7 schedule (doses from 30 to 50 mg daily). Both schedules were tolerated; nausea (31%), diarrhea (29%), febrile neutropenia (29%), and fatigue (23%) were the most common treatment-related adverse events. Three patients (9%) achieved complete response with incomplete count recovery. Patients with higher baseline expression of a set of specific pathway-related genes (BIRC5, AURKA, TTK, CDC2, and CCNB1) were more likely to respond in an exploratory biomarker analysis. AMG 900 was tolerated in a general AML population, and pathway-specific biomarkers identified a potential target population. Future research efforts will be directed toward further exploration of biomarkers of response and combination of AMG 900 with other anticancer agents.

En 2006, bevacizumab-FOLFIRI represente la therapie ciblee administrable des la premiere ligne chez les patients porteurs d’un cancer colorectal metastatique non operable. Une serie homogene de 111 patients colliges en region Bretagne et Pays de la Loire ayant recu du bevacizumab- FOLFIRI en premiere ligne en 2006 revele les resultats suivants: 51 reponses, 29 stabilites, 21 progressions et 10 toxicites avant evaluation. La mediane de survie globale (OS) est de 25,1 mois et la mediane de survie sans progression (PFS) de 10,2 mois. Dans le cas d’une chirurgie secondaire, l’OS median triple de 18,8 mois chez les patients non reseques versus 59,2 mois ceux reseques. En comparant les sujets âges de plus et de moins de 70 ans, aucune difference n’a ete mise en evidence en termes de benefice ou de risque. Bevacizumab-FOLFIRI pourrait etre administre en pratique courante chez les personnes âgees sous couvert d’une evaluation geriatrique et d’une approche multidisciplinaire.

La dihydropyrimidine deshydrogenase (DPD) est l’enzyme cle du catabolisme de la famille des fluoropyrimidines. Son activite dans la population generale suit une courbe de Gauss, et elle est soumise a un polymorphisme genetique qui peut avoir des repercussions fonctionnelles, c’est-a-dire entrainer des deficits majeurs a l’origine de toxicite grave chez 2 a 5 % des patients traites. La severite de ces toxicites aigues fait de leur prevention une priorite medicale et de sante publique. Differentes approches ont ete evaluees, et la combinaison de deux techniques complementaires, de genotypage et de phenotypage, nous apparait indispensable pour la detection fiable d’un deficit en DPD en pratique courante et la prevention de toxicites severes liees aux fluoropyrimidines.

Background and Objectives: DV281 is a synthetic CpG-ODN agonist of TLR9 that stimulates dendritic cells to release IFN-alpha and mature into antigen presenting cells to activate T cell anti-tumor responses. Nivolumab is a PD-1 inhibitor that has demonstrated activity in advanced/metastatic NSCLC. Study DV9- NSC-01 (NCT03326752) is a phase 1b/2 study to assess safety and pharmacodynamic activity of DV281 in combination with nivolumab in patients with advanced or metastatic NSCLC and to determine the recommended dose for expansion. Methods: Anti-PD-1/L1 experienced or naïve patients were enrolled in 2L or 3L NSCLC in the escalation phase, 3+3 design: 5 dose cohorts, with intra-patient dose escalation between the first 2 monotherapy doses: cohort 1: 1 mg; cohort 2: 1 to 3 mg; cohort 3: 3 to 10 mg; cohort 4: 10 to 15 mg; cohort 5: 15 to 25 mg. Nivolumab was administered at 240 mg Q2w. Safety was primary objective and pharmacodynamic effects including IFN-inducible gene expression were key secondary objective. DV281 is administered via inhalation, first alone, weekly for 2 doses, then 6 doses weekly with nivolumab, followed by a 5 week off period of DV281, while continuing nivolumab, then DV281 with intravenous nivolumab Q2w for an additional 24 weeks. Preliminary Results from the Escalation phase: 22 patients have been enrolled to date: Cohort (C) 1: 4 patients; C 2: 3 pts; C3: 7 pts; C 4: 7 pts; C 5: 1pt, ongoing. Median age 67 y/o; male 50%; all ECOG PS0-1 (27.3/72.7%); non squamous 15 (68%), squamous 7 (32%); locally advanced 4 (18%), metastatic 18 (82%); PD-L1 expression: positive 12 pts (52%), negative 10 pts (48%); prior lines of therapy - 1 line: 10 pts (45.5%), 2 lines:12 (54.5%). Previous treatment with PD-1/PD-L1 inhibitors: 18 pts (9 as single agent, 9 in combination). Median treatment duration 11.5 weeks (1 to 38). Eighteen patients discontinued DV281: adverse event 2, PD 14, other 2. Safety profile of DV281 alone and combined with nivolumab with a median number of 5 doses (1.0 to 18.0): grade 1/ 2 chills (18%), fatigue (13.6%), flu-like symptoms (4.5%), diarrhea (13.6%) and rash (13.6%); no grade ≥3 DV281/nivolumab treatment related AE; no immune-related AEs. Pharmacodynamic (PD) assessment (IFN-induced genes) shows target engagement in all dose cohorts, with every patient showing evidence of target engagement in cohorts 3 and 4. A dose dependent increase in PD activity appears to begin to plateau at the 15 mg dose. Conclusions: In this population of heavily pretreated patients, DV281 in monotherapy and in combination with nivolumab was well tolerated. Target engagement was observed at all dose levels. The expansion phase will use a modified dosing schedule, evaluating several groups of patients: non squamous resistant to PD-1/PD-L1 or to EGFR inhibitors; squamous experienced or naïve to anti PD-1/PD-L1. Citation Format: Edward Garon, Alexander I. Spira, Melissa Johnson, Lyudmila Bazhenova, Joseph Leach, Albert Candia, Robert Coffman, Mary Janatpour, Erick Gamelin, Robert Janssen, Laura Q. Chow. Phase Ib/II, open label, multicenter study of inhaled DV281, a Toll-like receptor 9 agonist, in combination with nivolumab in patients with advanced or metastatic non small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT224.

9534 Background: SD-101 is a synthetic CpG TLR9 agonist. Pembrolizumab is a PD-1 inhibitor. SYNERGY-001/KEYNOTE-184 assesses the safety and preliminary efficacy of the combination of SD-101 and pembrolizumab in patients naïve to anti-PD-1/L1 therapy with unresectable stage IIIC-IV melanoma. Methods: SD-101 was evaluated as 2 mg/lesion injected into 1 to 4 lesions and 8 mg/lesion in 1 lesion as 4 weekly doses followed by 7 doses Q3W. Pembrolizumab was administered as 200 mg IV Q3W. CT scans were performed every 9 weeks. Responses were assessed per investigator using RECIST v1.1. Responses and post-hoc Kaplan-Meier analyses of PFS in the ITT population were compared for patients who received 2 mg/lesion with 8 mg/lesion. Results: 86 patients (2 mg: N = 45; 8 mg: N = 41) have been enrolled with similar baseline characteristics: median age = 66 years; male = 67%; ECOG stage 0 = 67%; disease stage: IIIC = 21%; IVM1a/b = 50%; IVM1c = 28%; LDH ≤ ULN = 71%; treatment naïve = 73%. Median follow up to date is 8.1 months in 2 mg group and 8.3 months in 8 mg group. SD-101 safety profile comprises flu-like symptoms with most frequent grade ≥3 SD-101-related AEs of headache (7%), fatigue (7%), malaise (5%), myalgia (4%), and chills (4%). Immune-related AEs were reported in 19%. ORR in 2 mg group = 71% (95% CI: 57, 82) (CR: 13%) and in 8 mg group = 49% (95% CI: 33, 65) (CR: 7%) with responses in both injected and non-injected lesions, including visceral. DOR = not reached (NR) in either group. ORR by baseline PD-L1 expression in 62 patients, 53% of whom were PD-L1 positive: 2 mg = 80%/79% (PD-L1 positive/negative); 8 mg = 62%/40% (PD-L1 positive/negative). PFS was higher in 2 mg group with median PFS in 2 mg = NR (95% CI: Not estimable [NE], NE) and in 8 mg = 10.4 months (95% CI: 4.2, NE), HR = 0.45 (95% CI: 0.21, 0.98), p = 0.036. 6 month PFS rate in 2 mg = 81% and in 8 mg = 60%. 6 month OS rate in 2 mg = 98% and in 8 mg = 92%. Conclusions: The TLR9 innate immune stimulant, SD-101, in combination with pembrolizumab has been well-tolerated, and is showing promising high response rates and PFS, regardless of PD-L1 expression, particularly in patients who received 2 mg SD-101. Clinical trial information: NCT02521870.

9555 Background: SD-101 is a synthetic CpG-ODN agonist of TLR9 that stimulates dendritic cells to release IFN-alpha and mature into antigen presenting cells - activating T cell anti-tumor responses. Pembrolizumab has demonstrated activity in melanoma. SYNERGY-001/KEYNOTE-184 study assesses the safety and preliminary efficacy of the combination of intratumoral SD-101 and intravenous pembrolizumab in PD1/PDL 1 resistant unresectable stage IIIC- IV melanoma. A prior phase 2 study with SD-101 at 8 mg per injection resulted in a 21.4% ORR in this population (Abstract 3781, ESMO 2018). We report preliminary data in this ongoing phase 2 trial evaluating efficacy at a lower SD-101 dose of 2 mg per injection. Methods: PD1/PDL 1 resistant melanoma patients received 2 mg of SD-101 intratumorally per lesion in 1-4 lesions (weekly x 4 doses followed by Q3W x 7). Pembrolizumab was administered at a dose of 200 mg intravenously Q3W. Scans were performed Q9W. Responses were assessed per RECIST v1.1. Results: 23 patients have been enrolled with baseline characteristics: median age 65 years; male: 77%; stage at screening: IIIC = 26%; IV = 57%, unknown = 17%; LDH > ULN: 36%. Lines of prior therapy: 1: 52%; 2: 22%; > 2: 26%. Prior anti CTL-A4 therapy: 39%. Best overall response on prior antiPD-1/PD-L1: PD: 88%, PR/CR: 8%, SD: 4%. Safety: Grade ≥3 treatment-related AEs: pneumonia and constipation (8%). No immune-related AEs reported. 2 non-treatment related SAEs reported from 2 patients: pneumonia and intussusception. 4 patients discontinued treatment early: 1 post SAE, per patient’s request, 3 due to PD. 1 patient died due to malignant pleural effusion after 1 dose of SD 101 and Pembrolizumab. No treatment related deaths. Efficacy: Mean duration on treatment: 39 days (1 - 169). mITT population: six patients at time of first CT scan at day 64: PR: 1, SD: 1, PD:3; non-evaluable: 1. 17 patients on study have not yet had first CT scan. Conclusions: The TLR9 innate immune stimulant, SD-101, in combination with pembrolizumab is well tolerated. Mature efficacy data, with additional first and second follow-up CT scans, will be presented at the meeting. Clinical trial information: NCT02521870.

6039 Background: SD-101, a synthetic CpG-ODN agonist of TLR9, stimulates dendritic cells to release IFN-alpha and mature into antigen presenting cells - activating T cell anti-tumor responses. Pembrolizumab has demonstrated activity in HNSCC. Study DV3-MEL-01 (NCT02521870) assesses safety and efficacy of SD-101 in combination with pembrolizumab in patients with recurrent/metastatic HNSCC. We have previously reported a 27.3% ORR in 22 patients receiving 8 mg SD-101/injection in the modified ITT after at least 2 CT scans due to late responses (Abstract 3560, ESMO 2018). Higher efficacy at a lower SD-101 dose, 2 mg/injection, has been reported in advanced melanoma patients (LBA 45, ESMO 2018). Consequently, this dose is now being assessed in HNSCC. We report preliminary data with the 2 mg/injection dose in 23 patients in mITT at the first CT scan. Methods: Anti-PD-1/PD-L1 naïve patients received 2 mg SD-101 intratumorally in 1 - 4 lesions (weekly x 4 doses then Q3W x 7 doses). Pembrolizumab is was administered IV at 200 mg Q3W. Responses were assessed per RECIST v1.1. Results: 28 patients enrolled: median age 63 y/o, male 68%; ECOG PS 0-1 (18%/82%); mean prior lines of systemic therapy 1 (0-3); mean treatment duration 70 days (1-253). Primary tumors: 19 (68%) oropharyngeal; 3 (10%) laryngeal; 2 (7%) hypopharyngeal; 4 (14%) unknown. Mean number of target lesions: 1.82 (1 to 5). HPV status: 7 (25%) +, 9 (32%) -, 12 (43%) unknown. 18 (64 %) discontinued treatment: 12 (42%) due to PD, 4 (16%) deaths, 1 (3%) consent withdrawn, 1 (3%) went to hospice. Mean follow up 2.70 months. Safety: 16 non-treatment-related SAEs in 9 patients. 2 treatment-related Grade ≥3 AEs: sepsis (4%) and lymphopenia (4% ). No treatment-related deaths. Efficacy: 23 patients in the mITT population with first CT scan at day 64: ORR: CR: 2, PR: 3 (22%); SD: 6 (26%), PD: 7 (30%), non-evaluable: 5 (22%). Disease control rate (48%). 5 patients on study have not had a CT scan. Conclusions: SD-101 with Pembrolizumab shows early promising data and is well tolerated. Additional follow-up scans from both dose cohorts are being evaluated and will be presented. Clinical trial information: NCT02521870.

SUMMARY 5-fluorouracil (5-FU) is widely used in chemotherapeutic treatments of solid tumors. However, adverse events after its administration occur in about 30% of patients. Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme in the 5-FU catabolic pathway: several studies have focused on its genetics and/or pharmacokinetics in order to explain the wide interpatient variability in the DPD activity, including the rare event of its complete absence of activity. The pretreatment screening for DPD activity with a multiparametric approach (genotyping, phenotyping, clinico–pathological characteristics) shows the greatest specificity and sensitivity to avoid severe early-onset toxicity to fluoropyrimidines. In addition, using the pharmacokinetics of 5-FU, the dose adaptation can be used to properly dose each cycle for optimal efficacy and reduction of early-onset toxicities.

International audience; The neonatal Fc receptor (FcRn) encoded by FCGRT is known to be involved in the pharmacokinetics (PK) of therapeutic monoclonal antibodies (mAbs). Variability in the expression of FCGRT gene and consequently in the FcRn protein level could explain differences in PK observed between patients treated with mAbs. We studied whether the previously described variable number tandem repeat (VNTR) or copy number variation (CNV) of FCGRT are associated with individual variations of PK parameters of cetuximab. VNTR and CNV were assessed on genomic DNA of 198 healthy individuals and of 94 patients treated with the therapeutic mAb. VNTR and CNV were analyzed by allele-specific PCR and duplex real-time PCR with Taqman (®) technology, respectively. The relationship between FCGRT polymorphisms (VNTR and CNV) and PK parameters of patients treated with cetuximab was studied. VNTR3 homozygote patients had a lower cetuximab distribution clearance than VNTR2/VNTR3 and VNTR3/VNTR4 patients (p = 0.021). We observed no affects of VNTR genotype on elimination clearance. One healthy person (0.5%) and 1 patient (1.1%) had 3 copies of FCGRT. The PK parameters of this patient did not differ from those of patients with 2 copies. The FCGRT promoter VNTR may influence mAbs' distribution in the body. CNV of FCGRT cannot be used as a relevant pharmacogenetic marker because of its low frequency.

Clearance of trebananib (AMG 386), a 64-kD antiangiogenic peptibody, has been associated with estimated glomerular filtration rate (eGFR). We prospectively evaluated trebananib pharmacokinetics and safety/tolerability in advanced solid tumor patients with varying degrees of renal function. Patients were assigned to normal renal function, mild, moderate, or severe renal dysfunction cohorts based on eGFR, received trebananib 15 mg/kg i.v. weekly, and underwent week 1 and week 5 pharmacokinetic and weekly safety assessments. For 28 patients, trebananib clearance decreased from normal renal function (1.52 mL/hr/kg), to mild (1.20 mL/hr/kg), moderate (0.79 mL/hr/kg), and severe (0.53 mL/hr/kg) renal dysfunction (P ≤ 0.001). Treatment-related adverse events showed no association with clearance. Trebananib clearance was proportional to eGFR and unrelated to pretreatment protein excretion. These data confirm a role for renal clearance of a recombinant peptibody with molecular weight

Panitumumab monotherapy is approved for KRAS wild-type (WT) metastatic colorectal cancer (mCRC) progressing after standard chemotherapy. This study evaluated first-line panitumumab plus FOLFIRI in patients with mCRC.In this phase II, single-arm study, panitumumab (6 mg/kg) and FOLFIRI [irinotecan (180 mg/m(2)) and leucovorin (400 mg/m(2)) followed by a 5-fluorouracil 400 mg/m(2) bolus and a 2,400-3,000 mg/m(2) continuous infusion] were administered every 14 days until progression. Data were analysed descriptively overall and by tumour KRAS status.KRAS data were available for 145/154 (94%) patients: 59% KRAS WT and 41% mutant (MT); mean follow-up was 39.5 versus 35.8 weeks, respectively. Objective responses occurred in 49% of patients: 56% versus 38% in the KRAS WT versus MT groups [(18% difference (95% CI 1-35%); odds ratio 2.1 (95% CI 1.0-4.4)]; median duration of response was 13.0 versus 7.4 months. More patients in the WT group underwent R0 resection (8% vs. 5%); median progression-free survival also favoured this group (8.9 vs. 7.2 months). The most common adverse events (any grade) were integument toxicities (98%), diarrhoea (79%) and stomatitis/oral mucositis (51%).As expected, consistently favourable efficacy was observed in patients with KRAS WT versus MT tumours receiving first-line panitumumab plus FOLFIRI treatment.

L’Observatoire des medicaments et des innovations therapeutiques (OMIT) Bretagne et Pays de la Loire a ete cree en 2003 par lesAgences regionales de l’hospitalisation (ARH) respectives. Il est specialise en cancerologie, assure le suivi qualitatif de medicaments en continu et federe les etablissements publics et prives des deux regions sur des objectifs communs. Les prescriptions de trastuzumab (Herceptin®) ont fait l’objet d’une analyse dans tous les etablissements recenses par l’OMIT. Suite aux resultats positifs des essais HERA, NSABP B31 et NCCTG N9831 presentes en seance pleniere au Congres de l’ASCO (American Society of Clinical Oncology) en mai 2005, et publies depuis, les praticiens du comite de pilotage OMIT ont decide de colliger toutes les donnees des patientes traitees dans ces situations afin de connaitre les schemas therapeutiques employes, l’incidence des dysfonctionnements cardiaques en pratique courante ainsi que leurs facteurs de risque.

5-Fluorouracil (5-FU)-based chemotherapy has been widely used for almost 50 years in the treatment of solid malignancies, especially in digestive cancers. Its main effect consists in the inhibition, via its active metabolite, of thymidylate synthase, a major enzyme involved in DNA synthesis. In normal conditions, less than 20% of the administered 5-FU is used in this anabolic pathway while more than 80% is catabolized via dihydropyrimidine dehydrogenase (DPD) [1]. This is the initial and rate-limiting enzyme in the catabolic pathway and therefore a partial or complete DPD deficiency is associated with different degrees of 5-FU toxicity whose most frequent manifestations include neutropenia, mucositis and diarrhoea [2].

Background:5-Fluorouracil (5-FU) is the most widely used chemotherapy drug, primarily against gastrointestinal, head and neck, and breast cancers. 5-FU has large pharmacokinetic variability resulting in unexpected toxicity or ineffective treatment. Therapeutic drug management of 5-FU minimizes toxic

De la biologie devenue strategique en clinique aux nouveaux outils d’evaluation diagnostique, des nouvelles therapeutiques ciblees couplees a une chimiotherapie aux effets secondaires controles a la radiotherapie toujours plus precise associee a une chirurgie de plus en plus optimisee, la recherche clinique en cancerologie digestive est devenue clairement multidisciplinaire. Son challenge va etre de developper ces avancees ensemble et avec un souci d’evaluation constant, d’essayer d’etendre les progres connus dans le cancer colorectal metastatique aux autres localisations digestives au pronostic beaucoup plus defavorable. Dans ce cadre, la prevention et l’optimisation des traitements par l’aide de facteurs predictifs, le developpement de l’oncogeriatrie et la dimension medicoeconomique seront parmi les grands challenges a relever ensemble.

This study aims at establishing relationships between genetic and non-genetic factors of variation of the pharmacokinetics of irinotecan and its metabolites; and also at establishing relationships between the pharmacokinetic or metabolic parameters and the efficacy and toxicity of irinotecan. We included 49 patients treated for metastatic colorectal cancer with a combination of 5-fluorouracil and irinotecan; a polymorphism in the UGT1A1 gene (TA repeat in the TATA box) and one in the CES2 gene promoter (830CG) were studied as potential markers for SN-38 glucuronidation and irinotecan activation, respectively; and the potential activity of CYP3A4 was estimated from cortisol biotransformation into 6beta-hydroxycortisol. No pharmacokinetic parameter was directly predictive of clinical outcome or toxicity. The AUCs of three important metabolites of irinotecan, SN-38, SN-38 glucuronide and APC, were tentatively correlated with patients' pretreatment biological parameters related to drug metabolism (plasma creatinine, bilirubin and liver enzymes, and blood leukocytes). SN-38 AUC was significantly correlated with blood leukocytes number and SN-38G AUC was significantly correlated with plasma creatinine, whereas APC AUC was significantly correlated with plasma liver enzymes. The relative extent of irinotecan activation was inversely correlated with SN-38 glucuronidation. The TATA box polymorphism of UGT1A1 was significantly associated with plasma bilirubin levels and behaved as a significant predictor for neutropoenia. The level of cortisol 6beta-hydroxylation predicted for the occurrence of diarrhoea. All these observations may improve the routine use of irinotecan in colorectal cancer patients. UGT1A1 genotyping plus cortisol 6beta-hydroxylation determination could help to determine the optimal dose of irinotecan.

Purpose A phase III, multicenter, randomized study compared conventional dosing of fluorouracil (FU) plus folinic acid with pharmacokinetically guided FU dose adjustment in terms of response, tolerability, and survival. Patients and Methods Two hundred eight patients with measurable metastatic colorectal cancer were randomly assigned to one of two arms: arm A (104 patients; 96 assessable), in which the FU dose was calculated based on body-surface area; and arm B (104 patients; 90 assessable), in which the FU dose was individually determined using pharmacokinetically guided adjustments. The initial regimen was 1,500 mg/m2 FU plus 200 mg/m2 folinic acid infusion during a continuous 8-hour period administered once weekly. FU doses were adjusted weekly in arm B based on a single-point measurement of FU plasma concentrations at steady state until the therapeutic range (targeted area under the curve 20-25 mg·h·L−1) previously established in other studies was reached. Results An intent-to-treat analysis of the 208 patients showed the objective response rate was 18.3% in arm A and 33.7% in arm B (P = .004). Median overall survival was 16 months in arm A and 22 months in arm B (P = .08). The mean FU dose throughout treatment was 1,500 mg/m2/wk in arm A and 1,790 ± 386 mg/m2/wk (range, 900 to 3,300 mg/m2/wk) in arm B. Toxic adverse effects were significantly more frequent and severe in arm A compared with arm B (P = .003). Conclusion Individual FU dose adjustment based on pharmacokinetic monitoring resulted in significantly improved objective response rate, a trend to higher survival rate, and fewer grade 3/4 toxicities. These results support the value of pharmacokinetically guided management of FU dose in the treatment of metastatic colorectal patients.

Resume Des unites de pharmacogenetique moleculaire se sont mises en place au sein de laboratoires hospitaliers francais. L’impact clinique de ces nouvelles structures est encore limite et de nombreuses questions d’ordre organisationnel, ethique, juridique, technique, social et economique les concernant restent a resoudre. Leur multiplication ainsi que l’accroissement de leur activite et de leur champ d’application sont cependant previsibles. A terme, ces unites devraient contribuer a limiter le probleme de sante publique que posent actuellement dans notre pays les variations interindividuelles de reponse aux medicaments. Devant ces perspectives d’evolution, il semble indispensable que cette activite hospitaliere soit rapidement reconnue par les pouvoirs publics et les differents acteurs de la sante en France. Il semble aussi indispensable que les problemes qu’elle pose soient pris en consideration et qu’elle puisse beneficier comme les autres activites de genetique moleculaire, d’une structuration en un reseau national de prise en charge et de garanties de financements.

The purpose of this study was to determine simple genetic factors helpful to tailor 5-FU administration and determine strategy in first-line chemotherapy of advanced colorectal cancer. In 76 patients initially treated by 5-FU, thymidylate synthase, dihydropyrimidine dehydrogenase and methylene tetrahydrofolate reductase germinal polymorphisms, dihydrouracil/uracil plasma ratio and 5-FU plasma clearance were investigated and correlated for tolerance (10.5% grade 3 and 4 toxicity) and efficacy (32.9% objective response rate and 20 months median overall survival time). Toxicity was linked to performance status >2 (P=0.004), low UH2/U ratio, 2846 A>T, IVS 14+1G>A for DPD (P=0.031), and homozygoty C/C for MTHFR 1298 A>C (P=0.0018). The overall survival of the patients with a 3R/3R TS genotype associated with C/C for 677 C>T or A/A for 1298 A>C was statistically shorter (log-rank test P=0.0065). Genetic factors permit the tailoring of 5-FU treatment. They should occupy center stage in future clinical trials for specifically designing treatment for patients with a given biologic feature.

The impact of adjuvant chemotherapy for patients with localized colon adenocarcinoma is obvious for stage III and high-risk stage II patients but remains somewhat controversial for low-risk stage II. Until now, the decision of an adjuvant chemotherapy is based on pathologic and clinical data. However, some important questions remain. In stage III, how can we improve the results? In low-risk stage II patients, who will benefit from adjuvant chemotherapy? In the event that an adjuvant therapy is decided, which drugs will be chosen, and is the patient at high risk of toxicity because of metabolic deficiency? Different approaches have been developed: 1) genetics to detect DNA mutations or variants in the primary tumor or the patient himself, 2) RNA expression quantification either based on microarray or with real-time quantitative reverse transcriptase-polymerase chain reaction, and 3) protein expression by immunohistochemistry. Despite promising results from retrospective or prospective studies, the available data remain insufficient to draw guidelines. Genetics with the detection of microsatellite instability status and loss of heterozygoty is investigated for validation in large international prospective ongoing clinical trials. Some genes, such as excision repair cross complementing 1, thymidylate synthase, mismatch repair seem to be very good candidates to predict sensitivity to certain drugs. Clearly, the major potential interest of biologic markers highlights the need of multicentric prospective clinical trials to answer crucial questions about adjuvant therapy.

5-Fluorouracil (5-FU)-related early toxicity, due to a metabolic deficiency, is rare but is potentially severe and even lethal (0.1%). It is due to dihydropyrimidine dehydrogenase (DPYD) gene polymorphism or some epigenetic factors. The detection of metabolic change could prevent severe toxicity, but until now it has not been carried out in clinical practice. Purpose To find the simplest and most accurate pretherapeutic test to predict DPD deficiency in patients treated with 5-FU by comparing different approaches. Results Two hundred and fifty two French Caucasian patients treated by 5-FU infusion were studied. A two-step strategy, combining firstly SNP detection and uracil plasma measurement, followed, in cases where metabolic deficiency was suspected, by dihydrouracil/uracil ratio determination to confirm deficiency and to determine the optimum 5-FU dosage, appeared the best approach, with 83% and 82% sensitivity and specificity, respectively. Conclusion These data support the future use of this approach, suitable to clinical practice, as screening test to identify DPD deficiency before 5-FU-based therapy.

In the year of its fiftieth anniversary, 5-fluorouracil (5-FU) continues to be a cornerstone in the treatment of many cancers, including colorectal, head and neck, stomach, and breast carcinomas. The introduction of new targeted therapies represents a promising generation of treatment approaches, but 5-FU remains at the center of all validated protocols. Originally, 5-FU alone was administered as a bolus, but more recently, it is being used with biomodulating agents and/or a change in the schedule of administration of 5-FU to infusion. Because of the preclinical evidence that increased duration of 5-FU exposure improves cytotoxic activity and the fact that 5-FU has a short plasma half-life, continuous infusion schedules were further developed as a strategy to increase the percentage of tumor cells exposed to 5-FU. These regimens have resulted in up to a 2-fold improvement of response rates (RRs) with an improved safety profile when compared with bolus schedules. Capecitabine, an oral fluoropyrimidine, is a 5-FU prodrug drug that closely simulates infusional administration of the drug, delivering 5-FU at the target itself rather than providing systemic 5-FU exposure. Phase III studies incorporating capecitabine (such as the XELOX [capecitabine/oxaliplatin] regimen) demonstrate that XELOX is noninferior to the FOLFOX4 (oxaliplatin/leucovorin [LV]/5-FU) in terms of progression-free survival (PFS), and that adding bevacizumab to FOLFOX4/XELOX improves PFS significantly. It is now well established that infusional 5-FU schedules, as well as delivery of fluoropyrimidines via oral route, serve as the critical backbone for combination regimens and are widely used for the treatment of advanced disease, as well as for the adjuvant therapy of earlystage colorectal cancer (CRC). 5-fluorouracil pharmacokinetics are characterized by a wide interpatient and intrapatient variability and clearance values when equal doses calculated by body surface area are administered to different patients, leading to marked differences in systemic exposures. There is a substantial body of data for colorectal and head and neck cancer (HNC) showing significant relationships between systemic exposure, area under the curve (AUC) concentration at steady state, and pharmacodynamics (toxicity, response, and survival). Several groups reported reduced 5-FU clearance in elderly patients, resulting in an increased rate and degree of toxicity. Some of this risk can be predicted by the MAX2 index, which takes into account the mean percentage of occurrence of the most frequent grade 4 hematologic toxicity and grade 3/4 nonhematologic toxicity. This index might allow for an adjustment factor (on a group basis) for toxicity, when several agents are used in a 5-FU–based regimen. There is a need to individualize 5-FU dosing, and the shift from bolus to continuous infusion administration has created better conditions for dose management. Different approaches are available. A number of studies have demonstrated that the target AUC for 5-FU is the same regardless of tumor type, administration schedule, and drug combination. Also, there have been many successful strategies to monitor 5-FU blood concentrations and adjust individual doses based upon systemic exposure. The clinical utility of this approach has Highlights from: 5-Fluorouracil Drug Management Pharmacokinetics and Pharmacogenomics Workshop Orlando, Florida; January 2007

Numerous toxic side-effects, sometimes severe, are regularly reported in patients treated with 5-fluorouracil, and oral fluoropyrimidines, UFT and capecitabine, in metastatic and adjuvant setting. These toxic effects are due to a large interindividual variability of the metabolism, mainly depending on dihydropyrimidine dehydrogenase activity (DPD), the major enzyme of the catabolism of fluoropyrimidines. Thus, the patients with a DPD deficiency are at high risk of early severe acute toxicity, with this kind of drug. These toxic side-effects are potentially lethal. DPD deficiency frequencies, partial or complete, are about 3-5% and 0.2% respectively. They are most often due to a gene polymorphism. Different techniques for the detection of DPD deficiency before treatment have been reported: phenotypic, such as the plasma ratio of dihydrouracil/uracil, or genotypic, such as the detection of DPD gene variants, deleterious for enzyme activity. The pretherapeutic detection of DPD deficiency would permit to avoid almost every early acute toxic side-effects. We must emphasize that it is not merely a genetic result, since the detection of a deficiency most often does not contra-indicate the use of a fluoropyrimidine, but it must be combined with therapeutic advice.

Constitutive activation of STAT3 (signal transducer and activator of transcription) has been reported in several primary cancers and tumor cell lines where it induces cell transformation through a combined inhibition of apoptosis and cell-cycle activation. Several studies have suggested that STAT3 prevents cell-cycle arrest and cell death through upregulation of survival proteins and downregulation of tumor suppressors. As a consequence of anti-apoptotic and proliferative lesions, we propose that this oncogenic pathway is also involved in intrinsic drug resistance and that STAT3-expressing tumors are resistant to chemotherapeutic agents. If this hypothesis is correct, the detection of the activated form of this protein should help to define subsets of tumors that fail to respond to chemotherapy. Furthermore, interfering with the STAT3 oncogenic pathway might restore the sensitivity to anticancer drugs.

International audience; Aim: The efficacy of a cetuximab-based regimen used to treat metastatic colorectal cancer (mCRC) could be influenced by VEGFA polymorphisms. Materials & methods: We studied the effects of five polymorphisms in the VEGFA gene (-2549D/I, -1154G/A, -460T/C, +405G/C and +936C/T) on the outcome of 98 mCRC patients treated with FOLFIRI plus cetuximab. Results: Patients homozygous for the -2549D, -1154G and -460T alleles did exhibit higher response rates to treatment and longer progression-free survival compared with others. In addition, the DGTGC and IGCGC haplotypes were significantly associated with a lower risk of disease progression. Conclusion: These findings suggest that VEGFA genetic variations might influence response/resistance of FOLFIRI plus cetuximab treatment in mCRC patients.

International audience; Induction of senescence by chemotherapy was initially characterized as a suppressive response that prevents tumor cell proliferation. However, in response to treatment, it is not really known how cells can survive senescence and how irreversible this pathway is. In this study, we analyzed cell escape in response to irinotecan, a first line treatment used in colorectal cancer that induced senescence. We detected subpopulations of cells that adapted to chemotherapy and resumed proliferation. Survival led to the emergence of more transformed cells that induced tumor formation in mice and grew in low adhesion conditions. A significant amount of viable polyploid cells was also generated following irinotecan failure. Markers such as lgr5, CD44, CD133 and ALDH were downregulated in persistent clones, indicating that survival was not associated with an increase in cancer initiating cells. Importantly, malignant cells which resisted senescence relied on survival pathways induced by Mcl-1 signaling and to a lesser extent by Bcl-xL. Depletion of Mcl-1 increased irinotecan efficiency, induced the death of polyploid cells, prevented cell emergence and inhibited growth in low-adhesion conditions. We therefore propose that Mcl-1 targeting should be considered in the future to reduce senescence escape and to improve the treatment of irinotecan-refractory colorectal cancers.

In addition to its function as a cyclin-dependent kinase (cdk) inhibitor, p21waf1 fulfills additional roles involved in DNA replication and transcriptional regulation that could also contribute to cell cycle arrest. In this study, we have shown that p21waf1 functions as a transcriptional repressor of the myc and cdc25A genes. Ectopic expression of the cell cycle inhibitor down-modulates myc and cdc25A transcription but has no effect on cdk4 levels. Using chromatin immunoprecipitation, we found that p21waf1 is recruited to the promoters of these two genes together with the STAT3 and E2F1 transcription factors. Its presence on DNA is associated with an inhibition of the recruitment of the p300 histone acetylase and with a down-regulation of histone H4 acetylation. The same effect was also observed following DNA damage because topoisomerase inhibitors such as sn38 or doxorubicin also induce the association of p21waf1 with DNA. Following transcriptional repression of the myc and cdc25A genes, cells were arrested in the fraction with 4 N DNA content. By contrast, the expression of these two genes remains elevated in the absence of the cell cycle inhibitor, and p21waf1-/- cells re-replicate their DNA and become polyploid. In light of these results, we propose that p21waf1 simultaneously targets cdk and transcriptional regulators to prevent the expression of oncogenic pathways upon DNA damage.

Purpose: Although single nucleotide polymorphisms (SNP) of the dihydropyrimidine dehydrogenase gene (DPYD) have been reported, which affect enzyme activity and the severity of 5-fluorouracil (5-FU) toxicity, no pretherapeutic detection has thus far been developed. We investigated 22 DPYD gene SNPs, their respective incidence, their link with grade 3 to 4 toxic side effects, and their management in practice: 9 were looked for in 487 patients, whereas 13 others were investigated in 171 patients. Patients and Methods: SNPs were detected before 5-FU-based treatment in WBC using a Pyrosequencing method. Close clinical and biological follow-up was done. Results: Five different SNPs were found in 187 patients (IVS14 + 1G>A, 2846A>T, 1679T>G, 85T>C, −1590T>C). Three hundred patients had no SNP. Forty-four patients had grade 3 to 4 toxic side effects in either the first or second cycle. Sixty percent of patients with either IVS14 + 1G>A or 2846A>T SNPs and the only patient with 1679T>G SNP experienced early grade 3 to 4 toxicity, compared with 0%, 5.5%, and 15% of those with either −1590T>C, 85T>C SNP, or no SNP, respectively. In cases with grade 3 to 4 toxicity, treatment either had to be quickly stopped, or could be safely continued with an individual dose adjustment. Sensitivity, specificity, and positive and negative predictive values of the detection of these three major SNPs as toxicity predictive factors were 0.31, 0.98, and 0.62 and 0.94, respectively. Conclusion: Pretreatment detection of three DPYD SNPs could help to avoid severe toxic side effects. This approach is suitable for clinical practice and should be compared or combined with pharmacologic approaches. In the case of dihydropyrimidine dehydrogenase deficiency, 5-FU administration often can be safely continued with an individual dose adjustment. [Mol Cancer Ther 2006;5(11):2895–904]

Les cancerologues se heurtent toujours aux deux ecueils majeurs de la chimiotherapie, la resistance tumorale, en grande partie liee au fait que les traitements sont decides sur des criteres statistiques d’efficacite, et la toxicite, souvent severe, due a l’index therapeutique etroit de tous les medicaments anticancereux. De nouvelles approches sont necessaires pour individualiser les traitements. La pharmacogenomique, basee sur l’etude du genome tumoral et sur des profils d’expression genique est tres prometteuse dans le cadre de la prediction d’efficacite, mais les resultats sont souvent encore trop parcellaires pour des applications en clinique. Des donnees disponibles sur des genes particuliers d’interet, tels que TS, MTHFR, permettent d’esperer un transfert prochain a la clinique. La pharmacogenetique beneficie de la simplicite d’acces au genome de l’hote, de la connaissance acquise de genes d’interet, cibles de la chimiotherapie ou enzymes de catabolisme porteurs de polymorphismes. Actuellement beaucoup tournee vers la prevention des effets toxiques, elle apporte des donnees deja suffisamment solides pour des applications en pratique courante, telles que la recherche de deficits en dihydropyrimidine dehydrogenase ou du genotype 7/7 de l’UGT1A1, caracteristique du syndrome de Gilbert, a l’origine de toxicites severes, respectivement avec le 5-FU et l’irinotecan. Il ne s’agit pas alors d’un simple rendu de resultats mais d’un veritable conseil therapeutique, la decouverte d’un deficit metabolique ne contre-indiquant que rarement l’utilisation du medicament. Parallelement aux grands essais cliniques indispensables aux progres therapeutiques, il faut developper la recherche de transfert, pas seulement dans des etudes ancillaires optionnelles, mais dans des essais d’envergure, permettant d’evaluer l’impact des parametres biologiques de la tumeur et de l’hote, sur l’efficacite et la tolerance des traitements et de poursuivre dans la voie de l’individualisation des traitements.

Purpose Isolated hepatic metastases of colorectal cancer constitute a frequent and serious therapeutic problem that has led to the evaluation of hepatic arterial infusion (HAI) of different drugs. Oxaliplatin combined with fluorouracil (FU) and leucovorin is effective in the treatment of colorectal cancer. In this context, a phase II study was conducted to evaluate concomitant administration of oxaliplatin by HAI and intravenous (IV) FU plus leucovorin according to the LV5FU2 protocol (leucovorin 200 mg/m2, FU 400 mg/m2 IV bolus, FU 600 mg/m2 22-hour continuous infusion on days 1 and 2 every 2 weeks). Patients and Methods Patients had metastatic colorectal cancer that was restricted to the liver and inoperable. The patients were not to have previously received oxaliplatin. After surgical insertion of a catheter in the hepatic artery, patients were treated with oxaliplatin 100 mg/m2 HAI combined with FU + leucovorin IV according to the LV5FU2 protocol. Treatment was continued until disease progression or toxicity. Response was evaluated every 2 months. Results Twenty-eight patients were included, and 26 patients were treated. Two hundred courses of therapy were administered, and the median number of courses received was eight courses (range, zero to 20 courses). The most frequent toxicity consisted of neutropenia. The main toxicity related to HAI was pain. The intent-to-treat objective response rate was 64% (95% CI, 44% to 81%; 18 of 28 patients). With a median follow-up of 23 months, the median overall and disease-free survival times were 27 and 27 months, respectively. Conclusion The combination of oxaliplatin HAI and FU + leucovorin according to the LV5FU2 protocol is feasible and effective in patients presenting with isolated hepatic metastases of colorectal cancer.

Purpose: We wanted to assess polymorphisms in the uridine diphosphoglucuronosyl transferase 1A1 (UGT 1A1) gene: the TATA box polymorphism and UGT 1A1 G71R and Y486D mutations in the coding sequence, the main mutations characterizing Gilbert’s syndrome, as predictors of severe toxic event occurrence after irinotecan (CPT-11) administration. Therefore, we set up a rapid, sensitive, and reliable technique in routine practice to detect before CPT-11 treatment, the at-risk patients. Experimental Design: Seventy-five patients with advanced colorectal cancer and treated with CPT-11 and 5-fluorouracil, entered the study. We used the Pyrosequencing technology a real-time sequencing method, to detect the UGT 1A1 TATA box polymorphisms and mutations in the coding regions. Patients were also assessed for both biochemical and clinical evaluation and tolerance to treatment. Results: No G71R and Y486D mutations were found in our population. Frequencies for UGT 1A1 TATA box polymorphisms were 41, 47, and 9% for wild-type 6/6, heterozygous 6/7, and Gilbert’s syndrome 7/7, respectively. Tolerance to treatment decreased with increased number of TA repeat with 71% of the patients in 7/7 group who experienced grade 3/4 toxicity. Conclusions: The method we set up is suitable for the detection of UGT 1A1 polymorphism in routine practice before irinotecan treatment. It could help to detect the patients homozygous or heterozygous for Gilbert’s syndrome, at-risk of CPT 11-induced toxicity, and thus could help to individualize the dose to optimize efficacy and limit toxicity.