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Background BRAF mutations occurring in 1%–5% of patients with non-small-cell lung cancer (NSCLC) are therapeutic targets for these cancers but the impact of the exact mutation on clinical activity is unclear. The French National Cancer Institute (INCA) launched the AcSe vemurafenib trial to assess the efficacy and safety of vemurafenib in cancers with various BRAF mutations. We herein report the results of the NSCLC cohort. Patients and methods Tumour samples were screened for BRAF mutations in INCA-certified molecular genetic centres. Patients with BRAF-mutated tumours progressing after ≥1 line of treatment were proposed vemurafenib 960 mg twice daily. Between October 2014 and July 2018, 118 patients were enrolled in the NSCLC cohort. The primary outcome was the objective response rate (ORR) assessed every 8 weeks (RECIST v1.1). A sequential Bayesian approach was planned with an inefficacy bound of 10% for ORR. If no early stopping occurred, the treatment was of interest if the estimated ORR was ≥30% with a 90% probability. Secondary outcomes were tolerance, response duration, progression-free survival (PFS), and overall survival (OS). Results Of the 118 patients enrolled, 101 presented with a BRAFV600 mutation and 17 with BRAFnonV600 mutations; the median follow-up was 23.9 months. In the BRAFnonV600 cohort, no objective response was observed and this cohort was stopped. In the BRAFV600 cohort, 43/96 patients had objective responses. The mean Bayesian estimated success rate was 44.9% [95% confidence intervals (CI) 35.2%–54.8%]. The ORR had a 99.9% probability of being ≥30%. Median response duration was 6.4 months, median PFS was 5.2 months (95% CI 3.8–6.8), and OS was 10 months (95% CI 6.8–15.7). The vemurafenib safety profile was consistent with previous publications. Conclusion Routine biomarker screening of NSCLC should include BRAFV600 mutations. Vemurafenib monotherapy is effective for treating patients with BRAFV600-mutated NSCLC but not those with BRAFnonV600 mutations. Trial registration ClinicalTrials.gov identifier: NCT02304809.

Background: Bevacizumab is approved in combination with chemotherapy for the treatment of ovarian cancer, either in first-line therapy or for patients with recurrent disease not previously treated with the same drug. We aimed to test the value of continuing bevacizumab beyond progression after first-line treatment with the same drug. Methods: In our open-label, randomised, phase 3 trial done at 82 sites in four countries, we enrolled women (aged ≥18 years) who had previously received first-line platinum-based therapy including bevacizumab, and had recurrent (≥6 months since last platinum dose), International Federation of Gynaecology and Obstetrics stage IIIB–IV ovarian cancer with an Eastern Cooperative Oncology Group performance status 0–2. Patients were randomly assigned (1:1) to receive a carboplatin-based doublet intravenously (carboplatin area under the concentration curve [AUC] 5 on day 1 plus paclitaxel 175 mg/m2 on day 1, every 21 days; carboplatin AUC 4 on day 1 plus gemcitabine 1000 mg/m2 on days 1 and 8, every 21 days; or carboplatin AUC 5 on day 1 plus pegylated liposomal doxorubicin 30 mg/m2 on day 1, every 28 days), or a carboplatin-based doublet plus bevacizumab (10 mg/kg intravenous every 14 days combined with pegylated liposomal doxorubicin–carboplatin, or 15 mg/kg every 21 days combined with gemcitabine–carboplatin or paclitaxel–carboplatin). Evaluable disease according to RECIST 1.1 guidelines was required before randomisation. Randomisation was done through the trial website with a minimisation procedure, stratified by centre, time of recurrence, performance status, and type of second-line chemotherapy. The primary endpoint was investigator-assessed progression-free survival, analysed on an intention-to-treat basis. Safety was assessed in all participants who received at least one dose. This trial is registered with ClinicalTrials.gov, NCT01802749 and EudraCT 2012-004362-17. Findings: Between Dec 6, 2013, and Nov 11, 2016, 406 patients were recruited (203 [50%] assigned to the bevacizumab group and 203 [50%] to the standard chemotherapy group). 130 patients (64%) in the bevacizumab group and 131 (65%) in the standard chemotherapy group had progressed after receiving a last dose of platinum more than 12 months before, and 146 patients (72%) in the bevacizumab group and 147 (72%) in the standard chemotherapy group had progressed after completion of first-line bevacizumab maintenance. 161 participants (79%) progressed in the standard chemotherapy group, as did 143 (70%) in the bevacizumab group. Median progression-free survival was 8·8 months (95% CI 8·4–9·3) in the standard chemotherapy group and 11·8 months (10·8–12·9) in the bevacizumab group (hazard ratio 0·51, 95% CI 0·41–0·65; log-rank p

Background We raise the hypothesis that a STOP and GO strategy with induction by double immunotherapy Nivolumab + Ipilimumab combination during 6 months, followed by observation in patients with disease control (DC) at 6 months, would not be inferior to immunotherapy combination continuation until progression or unacceptable toxicity, in terms of progression-free survival, allowing lower toxicities cumulative rates, better quality of life and lower costs. Such strategy should not penalize overall survival, provided resuming immunotherapy at disease progression before second-line platinum-based chemotherapy. Trial design This is an open-label, randomized, phase III study in adult (≥18 years) patients, with stage IV non-small cell lung cancer, PD-L1 positive tumors, previously untreated for advanced disease. Subjects will first be locally assessed for PD-L1 expression, using 1% cut-off. Patients with enough tumor samples for central PD-L1 expression assessment, will be given first-line Nivolumab+Ipilumumab combination as followed: Nivolumab administered IV over 30 minutes at 3 mg/kg every 2 weeks combined with Ipilimumab administered IV over 30 minutes at 1 mg/kg every 6 weeks. Only patients with DC (objective response or stable disease), confirmed at 6 months, after a 1rst tumor evaluation at 3 months or beyond in case of pseudo-progression needing tumor reassessment, and without drug-related toxicity commanding treatment discontinuation will be randomized 1:1 either to continuation of Nivolumab+Ipilumumab combination until disease progression or unacceptable toxicity, or to clinical and radiological observation from week 24. Subjects receiving Nivolumab+Ipilimumab beyond investigator assessed progression must also continue tumor assessments until treatment discontinuation. Enrollment will end after approximately 868 subjects have been randomized (25/months). The primary endpoint of the study is Progression-Free Survival. Clinical trial identification NCT03469960. Legal entity responsible for the study IFCT (French Cooperative Thoracic Intergroup). Funding Bristol-Myers Squibb. Disclosure All authors have declared no conflicts of interest.

Background: Triple-negative (TN) and HER2-positive (HER2+) breast cancers have usually a worse prognosis than the luminal subtypes despite an initial chemosensitivity. The aim of this single-center study was to compare pathologic complete response (pCR) rates, disease-free (DFS) and overall (OS) survivals rates after neoadjuvant therapy according to both HER2 and hormonal status. Patients and Methods: Between 1978 and 2008, 461 patients were treated with neoadjuvant therapy at Georges-François Leclerc Cancer Center. Patients were classified in 3 groups: TN (defined by both estrogen/progesterone receptor negative and HER2 negative), HER2+ (3+ in immunohistochemistry or 2+ with amplification in fluorescence in situ hybridization) and HR+ (estrogen and/or progesterone receptor positive without HER2 overexpression or amplification). Median follow-up lasted 7.1 years [range: 0.49-29.8]. Number of events was 213 for DFS calculation and number of deaths was 150 for OS calculation. Response rates were compared using Chi2-tests. Survivals were calculated according to Kaplan-Meier and compared using log-rank tests. Univariate and multivariate Cox proportional hazards models were performed. The multivariate models were internally validated using bootstrapping (400 replications). Results: 86 of 461 were TN (19%), 125 were HER2+ (27%) and 250 were HR+ (54%). Patients with TN and HER2+ breast cancer were younger (p=0.032), had more inflammatory cancer (p=0.033) and aggressive tumors (SBR 3, P Median DFS was 4.4years for TN, 7.8y for HER2+ and 9y for HR+ (p=0.003, logrank test). In HER2+ patients, neoadjuvant trastuzumab was associated with a higher DFS (8.65 vs. 3.24y, p=0.002). Patients who achieved a pCR had a higher DFS (p=0.015) than those with only partial pathologic response (median=6.9y vs. 12.7y). In multivariate analysis, pCR remained significant (HR (bootstrapping) = 0.5 [IC95%, 0.28-0.91], p=0.023). Median OS was 6.4y for TN, 15.1y for HER2+ and 13.1y for HR+ (P50years (HR (bootstrapping)=1.79 [IC95%, 1.23-2.60], p=0.002), in TN subgroup (HR=2.46 [IC95%, 1.5-4.03], p=0.001) and when pCR was not achieved (HR=0.28, [IC95%, 0.12-0.66], p=0.003). Conclusion: After neoadjuvant therapy, TN breast cancers have a worse prognosis despite their initial chemosensitivity with a high pCR rate. HER2+ have a lower DFS than HR+/HER2- breast cancers but a better OS, mainly due to anti-HER2 targeted therapies. Pathologic complete response is a strong independent prognostic factor after neoadjuvant therapy for breast cancer. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-11-02.

beta-Cyclodextrin (beta-CD) is a bile acid and sterol sequestrant produced by enzymatic modification of starch; this product has the potential to decrease plasma cholesterol. In contrast to the sequestrants having resin- or saponin-like properties, beta-CD is rapidly broken down by the large intestine microflora. beta-CD effects on cecal fermentations and lipid metabolism were thus investigated in rats adapted to semipurified diets containing 0%, 2.5%, or 5% beta-CD. In rats fed beta-CD diets, there was an enlargement of the cecum together with a dramatic increase in the cecal concentration of propionic acid (even with the 2.5% level, in moderately acidic pH conditions). Propionic acid produced in the cecum was readily absorbed and entirely taken up by the liver, whereas there was no significant acetic acid uptake. Dietary beta-CD was highly effective in enhancing bile acid entry into to the cecum: the cecal bile acids pool was 2.2 and 3.6-fold enlarged in rats fed the 2.5% and 5% beta-CD diets, respectively. The solubility percentage of bile acids decreased to approximately 25% in rats fed the beta-CD diets (v 51% in controls); the cecal concentration of soluble bile acids was thus relatively low in these animals. The fecal excretion of steroids was strongly enhanced by beta-CD, and bile acids excretion was practically proportional to the dietary beta-CD level. There was a net lipid-lowering effect of beta-CD, even at the 2.5% level. The effect was more pronounced on triglycerides than on cholesterol.(ABSTRACT TRUNCATED AT 250 WORDS)

Background: Triple negative breast cancer (TNBC) accounts for 15 to 20% of breast cancers. Despite initial chemosensitivity, patients with TNBC had a poor outcome with worse disease-free and overall survivals than others with non-triple-negative breast cancer. The aim of this single-center study was to describe clinical characteristics, pathologic complete response rate, disease-free survival and overall survival rates after neoadjuvant chemotherapy in TNBC.Methods: Forty six consecutive patients with TNBC were treated with neoadjuvant chemotherapy at Georges-François Leclerc Cancer Center. Median follow-up lasted 6.3 years [4.4-10.5y]. Descriptive statistics were performed in this population. Survival rates were calculated according to Kaplan-Meier.Results: Clinical characteristics of patients were the followings: median age was 46 years [24-80y]; 24% had a breast neoplastic hereditary. Initial characteristics of tumors were: 4 T1 (9%), 25 T2 (54%), 17 T3 (37%), 18 N0 (39%), 25 N1 (54%), 3 N2 (7%); 12 grades II (26%), 31 grades III (68%) and 3 (6%) unknown. All the tumors were invasive ductal carcinomas. After neoadjuvant chemotherapy, tumors were classified as pT0 (33%), pT1 (35%), pT2 (30%), pT3 (2%), pN0 (67%) and pN+ (33%). Forty patients (87%) were treated with anthracyclines-based neoadjuvant therapy, 4 (9%) with taxanes and 2 (4%) with another regimen. Pathologic complete response rate was 28.2% according to Chevallier's classification. Forty-five patients (98%) had adjuvant radiotherapy and 20 (43%) had adjuvant chemotherapy. Median disease-free survival was 9.7years [4.4-ND]. The disease-free survival rate was 82.4% [66.6%-91.2%] and 44.8% [23.7%-64%] at 2 and 10 years respectively. Median overall survival was 10.2years [6.4-ND]. The overall survival rate was 97.4% [86.2%-99.6%] and 53.7% [31.8%-71.5%] at 2 and 10 years respectively.Conclusion: The pathologic complete response rate is consistent with that reported in other studies involving neoadjuvant chemotherapy of TNBC and higher than that observed in the other subgroups of breast cancer. However, disease-free and overall survivals are lower than in non triple-negative breast cancers, thereby confirming the worse prognosis of TNBC Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1103.