First-line chemoimmunotherapy in metastatic breast carcinoma: combination of paclitaxel and IMP321 (LAG-3Ig) enhances immune responses and antitumor activity

<p>Abstract</p> <p>Background</p> <p>IMP321 is a recombinant soluble LAG-3Ig fusion protein that binds to MHC class II with high avidity and mediates APC and then antigen-experienced memory CD8⁺T cell activation. We report clinical and biological results of a phase I/II in patients with metastatic breast carcinoma (MBC) receiving first-line paclitaxel weekly, 3 weeks out of 4.</p> <p>Methods</p> <p>MBC patients were administered one dose of IMP321 s.c. every two weeks for a total of 24 weeks (12 injections). The repeated single doses were administered the day after chemotherapy at D2 and D16 of the 28-day cycles of paclitaxel (80 mg/m²at D1, D8 and D15, for 6 cycles). Blood samples were taken 13 days after the sixth and the twelfth IMP321 injections to determine sustained APC, NK and memory CD8 T cell responses.</p> <p>Results</p> <p>Thirty MBC patients received IMP321 in three cohorts (doses: 0.25, 1.25 and 6.25 mg). IMP321 induced both a sustained increase in the number and activation of APC (monocytes and dendritic cells) and an increase in the percentage of NK and long-lived cytotoxic effector-memory CD8 T cells. Clinical benefit was observed for 90% of patients with only 3 progressors at 6 months. Also, the objective tumor response rate of 50% compared favorably to the 25% rate reported in the historical control group.</p> <p>Conclusions</p> <p>The absence of toxicity and the demonstration of activity strongly support the future development of this agent for clinical use in combined first-line regimens.</p> <p>Trial registration</p> <p>ClinicalTrials.gov NCT00349934</p

Phase II randomised discontinuation trial of brivanib in patients with advanced solid tumours

Background: Brivanib is a selective inhibitor of vascular endothelial growth factor and fibroblast growth factor (FGF) signalling. We performed a phase II randomised discontinuation trial of brivanib in 7 tumour types (soft-tissue sarcomas [STS], ovarian cancer, breast cancer, pancreatic cancer, non-small-cell lung cancer [NSCLC], gastric/esophageal cancer and transitional cell carcinoma [TCC]). Patients and methods: During a 12-week open-label lead-in period, patients received brivanib 800 mg daily and were evaluated for FGF2 status by immunohistochemistry. Patients with stable disease at week 12 were randomised to brivanib or placebo. A study steering committee evaluated week 12 response to determine if enrolment in a tumour type would continue. The primary objective was progression-free survival (PFS) for brivanib versus placebo in patients with FGF2-positive tumours. Results: A total of 595 patients were treated, and stable disease was observed at the week 12 randomisation point in all tumour types. Closure decisions were made for breast cancer, pancreatic cancer, NSCLC, gastric cancer and TCC. Criteria for expansion were met for STS and ovarian cancer. In 53 randomised patients with STS and FGF2-positive tumours, the median PFS was 2.8 months for brivanib and 1.4 months for placebo (hazard ratio [HR]: 0.58, p = 0.08). For all randomised patients with sarcomas, the median PFS was 2.8 months (95% confidence interval [CI]: 1.4–4.0) for those treated with brivanib compared with 1.4 months (95% CI: 1.3–1.6) for placebo (HR = 0.64, 95% CI: 0.38–1.07; p = 0.09). In the 36 randomised patients with ovarian cancer and FGF2-positive tumours, the median PFS was 4.0 (95% CI: 2.6–4.2) months for brivanib and 2.0 months (95% CI: 1.2–2.7) for placebo (HR: 0.56, 95% CI: 0.26–1.22). For all randomised patients with ovarian cancer, the median PFS in those randomised to brivanib was 4.0 months (95% CI: 2.6–4.2) and was 2.0 months (95% CI: 1.2–2.7) in those randomised to placebo (HR = 0.54, 95% CI: 0.25–1.17; p = 0.11). Conclusion: Brivanib demonstrated activity in STS and ovarian cancer with an acceptable safety profile. FGF2 expression, as defined in the protocol, is not a predictive biomarker of the efficacy of brivanib

Thérapeutiques anti-cancéreuses (développement et innovations, du stade préèclinique jusqu'après la mise sur le marché)

Une revue de la littérature des étapes du développement de thérapeutiques en cancérologie s'intéressant aux méthodes, à la planification, aux informations apportées et à la façon dont sont rapportés les résultats a été réalisée. Les différences entre les traitements cytotoxiques et ciblés sont montrées. Des travaux personnels innovants proposent des approches cherchant à optimiser les données disponibles par la modélisation. Au stade pré-clinique, de nouveaux critères pour l évaluation de la réponse à des agents testés sur des xénogreffes ont été développés : ils permettent de mieux décrire les courbes de croissance et de réaliser des tests statistiques plus puissants. Puis, dans les essais de phase II, une étude comparative de deux planifications multi-étapes, la méthode de Fleming et le test triangulaire a été effectuée, afin de mieux sélectionner des agents anti-cancéreux. Enfin, dans les essais de phase III, à partir de données sur des traitements préventifs des cancers, une méthode pour étudier la variation au cours du temps des risques relatifs de survenue d un événement est présentée. Ses potentiels en thérapeutique sont montrés sur des exemples.PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Benefits of homeopathic complementary treatment in breast cancer patients. A retrospective cohort.

International audienceIntroduction: There is a growing use of complementary therapy in oncology and homeopathy features prominently. Their purpose is to help patients better cope with the illness and the side effects (SEs) of cancer treatments that particularly affect quality of life (HRQOL). However, there are few comparative studies. The objective of this study is to assess the benefits of homeopathy treatment on the HRQOL for patients with non-metastatic breast cancer (BC), prescribed in post-surgical complementary therapy, compared to treatment without homeopathy.Methods: An extraction from the French nationwide healthcare database targeted all patients who underwent mastectomy for newly diagnosed BC during 2012-2013. HRQOL was assessed through proxies, primarily the use of medication palliating the SEs of cancer treatments. Exposure to homeopathy and use of SEs medication were measured by the number of dispensing. The association was assessed using a Random Effect Poisson Count Model, with adjustment for co-factors.Results: 98,009 patients were included (mean age 61.1). Patients taking homeopathy appeared to have less cardiovascular and diabetes comorbidities. Usage of homeopathy was observed in 11% of patients 7-12 months before surgery, 26% during the 6 months before surgery, 22% during the 6 months after, 18% 7-12 months after, then stable at 15% for 4 years. During the six months after surgery, there was a significant overall decrease (RR=0.88, CI95=[0.87; 0.89]) in the dispensing of SEs medication for patients with ?3 homeopathy dispensing vs. none. Decrease appeared to be greater for immunostimulants (RR=0.79, CI95=[0.74; 0.84]), corticosteroids (RR=0.82, CI95=[0.79; 0.85]), antidiarrheals (RR=0.83, CI95=[0.77; 0.88]), systemic antifungals (RR=0.86, CI95=[0.8; 0.92]), and antiemetics (RR=0.9, CI955=[0.87; 0.93]).Conclusion: The study showed a rising use of homeopathy by patients with BC, starting with diagnosis. This use was sustained after surgery and seemed to play an important role in helping to better tolerate SEs of cancer treatments

Apports de la prise en charge homéopathique en soins de support dans le cancer du sein : Impact sur la consommation des traitements palliant les effets indésirables liés à la prise en charge du cancer du sein - Étude d’après les données du Système National des Données de Santé (SNDS)

International audienceIntroductionOn observe un recours croissant aux soins de support associés aux traitements conventionnels du cancer, (plus de 40 % des patients), et l’homéopathie occupe une place prépondérante (> 60 %). Le but est d’aider les patients à mieux supporter la maladie et les effets indésirables (EI) des traitements anticancéreux qui affectent particulièrement la qualité de vie (QDV). Cependant, il n’existe que peu d’études comparatives à ce sujet.ObjectifL’objectif est d’évaluer, en France, les bénéfices sur la QDV pour les patientes atteintes d’un cancer du sein non métastatique, d’une prise en charge homéopathique, prescrite en soins oncologiques de support post-chirurgie, comparativement à une prise en charge sans homéopathie.MéthodeUne extraction du SNDS a ciblé sur la période 2012-2013 l’ensemble des patientes françaises ayant eu recours à une mastectomie pour un cancer du sein nouvellement diagnostiqué. Les données analysées portent sur 2 ans avant la chirurgie et 5 ans après. L’évaluation de la QDV est réalisée à l’aide d’indicateurs indirects et en premier lieu la consommation des médicaments palliant les EI des traitements du cancer.L’exposition à l’homéopathie et la consommation des traitements palliant les EI sont déterminées selon le nombre de délivrances. L’évaluation de leur association est réalisée à l’aide d’un modèle de Poisson mixte ajusté avec effet aléatoire sur le patient, par périodes successives de 180 jours, avec facteurs d’ajustement (chimiothérapies et radiothérapie, comorbidités, continuité des soins, pratique homéopathique du médecin le plus consulté).RésultatsUn total de 98 009 patientes a été inclus (97,8 % de stade I-II), 21 % avec une mastectomie totale. L’âge moyen est de 61 ans (± 13). Les patientes consommant de l’homéopathie semblent moins défavorisées, présentent moins d’antécédents cardiovasculaires (8 % vs 10 %), sont moins traitées par antidiabétiques (6 % vs 8 %) et par antihypertenseurs ou hypolipémiants (39 % vs 44 %). Il n’y a pas de différence concernant les autres comorbidités. Par ailleurs, la consommation de produits homéopathiques semble associée à davantage d’arrêts de travail.La consommation de produits homéopathiques, observée chez 11 % des patientes de 7 à 12 mois avant chirurgie (avant le diagnostic), progresse à 26 % durant les 6 mois avant chirurgie, puis 22 % durant les 6 mois après, 18 % de 7 à 12 mois après et demeure ensuite stable à 15 % durant les 4 ans qui suivent. Au cours du premier semestre après chirurgie, on observe une diminution globale significative (RR = 0,88, IC95= [0,87 ; 0,89]) des délivrances des médicaments palliant les EI pour les patientes ayant 3 délivrances ou plus d’homéopathie vs aucune. Cette diminution apparait plus importante pour les immunostimulants (RR = 0,79, IC95= [0,74 ; 0,84]), les corticoïdes (RR = 0,82, IC95= [0,79 ; 0,85]), les antidiarrhéiques (RR = 0,83, IC95= [0,77 ; 0,88]), les antifongiques à usage systémique (RR = 0,86, IC95= [0,8 ; 0,92]), et les antémétiques (RR = 0,9, IC95= [0,87 ; 0,93]).ConclusionL’étude révèle une augmentation du recours à l’homéopathie par les patientes atteintes d’un cancer du sein dès l’annonce du diagnostic. Cet usage se poursuit après chirurgie et semble jouer un rôle important en aidant à mieux supporter les EI des traitements. Cette étude est l’une des premières à notre connaissance à mettre en lumière l’exploitation possible des données du SNDS dans le but d’évaluer les bénéfices attendus sur la QDV des patients

Innovative anticancer agents reserved to hospital use and not involved in the hospital budget: Creation and evolution

International audienc

Prostate-specific antigen doubling-time (PSA DT) before onset of chemotherapy as survival predictor for hormone refractory prostate cancer (HRPC) patients

International audienceBackground: PSA DT has been reported as a prognostic factor in prostate cancer patients (pts) who relapse after radical prostatectomy, radiation or hormonal therapy. The rate at which the PSA is rising is known to correlate with cancer aggressiveness. We evaluated the interest of the initial PSA DT value, before start of chemotherapy (CT), as a surrogate end point for survival of metastatic HRPC pts. Methods: PSA DT was calculated as log x 2 divided by the slope of the log PSA line (the difference in the 2 log PSA values divided by the time between). A minimum of three PSA measurements were required, maximum three months before start of CT. The primary outcome measure was overall survival. Differences in survival rates and PSA DT were calculated using the log-rank and Cox hazard regression methods, stratified according to CT regimen. All statistical tests were two-sided. Hazard ratio (HR) and relative risk reduction were also estimated with 95% confidence interval (CI). Results: A retrospective analysis was performed on 202 metastatic HRPC pts, registered from June 1999 to July 2004 in a single institution. Pts received as first-line CT: docetaxel- (77%) or mitoxantrone (23%) based regimen. The median PSA DT value was 44 days (range 5-1028 days) and median interval between two consecutive PSA determinations before CT (used tu estimate the PSA DT) was 21 days. Overall, there were 124 deaths (61%). Median survival was 14.3 months (95% CI, 10.5 to 18 months) for pts with PSA DT 44 days. There were significant differences between survival distributions of PSA DT categories (log-rank, p=0.006), independently of CT regimen. The stratified HR was 0.61 (95% CI, 0.43 to 0.87) with a relative risk reduction of 39% (95% CI, 13% to 57%). Conclusions: A low PSA DT before onset of CT in HRPC pts was associated with an increased risk of death. This parameter could be a potential auxiliary end point in the evaluation of new cytotoxic drugs in metastatic HRPC setting. These data may be also useful in the design of clinical trials and the identification of men for enrolment into experimental protocols