Marie-Paule Sablin

Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (SHIVA): a multicentre, open-label, proof-of-concept, randomised, controlled phase 2 trial.

BACKGROUND Molecularly targeted agents have been reported to have anti-tumour activity for patients whose tumours harbour the matching molecular alteration. These results have led to increased off-label use of molecularly targeted agents on the basis of identified molecular alterations. We assessed the efficacy of several molecularly targeted agents marketed in France, which were chosen on the basis of tumour molecular profiling but used outside their indications, in patients with advanced cancer for whom standard-of-care therapy had failed. METHODS The open-label, randomised, controlled phase 2 SHIVA trial was done at eight French academic centres. We included adult patients with any kind of metastatic solid tumour refractory to standard of care, provided they had an Eastern Cooperative Oncology Group performance status of 0 or 1, disease that was accessible for a biopsy or resection of a metastatic site, and at least one measurable lesion. The molecular profile of each patients tumour was established with a mandatory biopsy of a metastatic tumour and large-scale genomic testing. We only included patients for whom a molecular alteration was identified within one of three molecular pathways (hormone receptor, PI3K/AKT/mTOR, RAF/MEK), which could be matched to one of ten regimens including 11 available molecularly targeted agents (erlotinib, lapatinib plus trastuzumab, sorafenib, imatinib, dasatinib, vemurafenib, everolimus, abiraterone, letrozole, tamoxifen). We randomly assigned these patients (1:1) to receive a matched molecularly targeted agent (experimental group) or treatment at physicians choice (control group) by central block randomisation (blocks of size six). Randomisation was done centrally with a web-based response system and was stratified according to the Royal Marsden Hospital prognostic score (0 or 1 vs 2 or 3) and the altered molecular pathway. Clinicians and patients were not masked to treatment allocation. Treatments in both groups were given in accordance with the approved product information and standard practice protocols at each institution and were continued until evidence of disease progression. The primary endpoint was progression-free survival in the intention-to-treat population, which was not assessed by independent central review. We assessed safety in any patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT01771458. FINDINGS Between Oct 4, 2012, and July 11, 2014, we screened 741 patients with any tumour type. 293 (40%) patients had at least one molecular alteration matching one of the 10 available regimens. At the time of data cutoff, Jan 20, 2015, 195 (26%) patients had been randomly assigned, with 99 in the experimental group and 96 in the control group. All patients in the experimental group started treatment, as did 92 in the control group. Two patients in the control group received a molecularly targeted agent: both were included in their assigned group for efficacy analyses, the patient who received an agent that was allowed in the experimental group was included in the experimental group for the purposes of safety analyses, while the other patient, who received a molecularly targeted agent and chemotherapy, was kept in the control group for safety analyses. Median follow-up was 11·3 months (IQR 5·8-11·6) in the experimental group and 11·3 months (8·1-11·6) in the control group at the time of the primary analysis of progression-free survival. Median progression-free survival was 2·3 months (95% CI 1·7-3·8) in the experimental group versus 2·0 months (1·8-2·1) in the control group (hazard ratio 0·88, 95% CI 0·65-1·19, p=0·41). In the safety population, 43 (43%) of 100 patients treated with a molecularly targeted agent and 32 (35%) of 91 patients treated with cytotoxic chemotherapy had grade 3-4 adverse events (p=0·30). INTERPRETATION The use of molecularly targeted agents outside their indications does not improve progression-free survival compared with treatment at physicians choice in heavily pretreated patients with cancer. Off-label use of molecularly targeted agents should be discouraged, but enrolment in clinical trials should be encouraged to assess predictive biomarkers of efficacy.

Changes in Tumor Density in Patients with Advanced Hepatocellular Carcinoma Treated with Sunitinib

Purpose: Response Evaluation Criteria in Solid Tumors (RECIST) may underestimate the efficacy of targeted therapies. In hepatocellular carcinoma (HCC) studies with sunitinib, RECIST-defined response rates are low, although hypodensity on computed tomography (CT) scans occurs more frequently. This exploratory analysis investigated tumor density as a surrogate endpoint of sunitinib activity in a phase II HCC study. Experimental Design: Patients received sunitinib 50 mg/d (4 weeks on/2 weeks off). Tumor size and density were assessed on CT scans by using RECIST and Choi criteria, the latter of which classify a partial response as a 15% or more reduction in tumor density or a 10% or more reduction in tumor size. The overall percentage volume of tumor necrosis was calculated with volumetric reconstruction. Tumor perfusion parameters were assessed by using perfusion CT scans with specific acquisition. Results: Among the 26 evaluable patients, 1 achieved a partial response and 22 had tumor stabilization by RECIST. In analysis of tumor density, 17 of 26 patients (65.4%) were responders by Choi criteria. Volumetric assessment showed major tumor necrosis (≥30% of tumor volume) in 10 of 21 patients (47.6%). Among four patients evaluated, tumor blood flow was reduced by 58.8% and blood volume by 68.4% after 4 weeks of treatment. The median time to progression (TTP) was 6.4 months. Patients with responses by Choi criteria had a significantly longer TTP (7.5 months) compared with nonresponders (4.8 months; HR = 0.33, two-sided P = 0.0182). Conclusions: Tumor density assessment suggested that radiologic endpoints in addition to RECIST may be considered to capture sunitinib activity in HCC. Clin Cancer Res; 17(13); 4504–12. ©2011 AACR.

New inhibitors of the mammalian target of rapamycin signaling pathway for cancer

Importance of the field: Contrasting with the broad activation of the PI3K/AKT/mammalian target of rapamycin (mTOR) survival pathway in most cancer, activity of rapalogues appears to be restricted to a few tumor types. Areas covered in this review: The analysis of molecular activity of the PI3K/AKT/mTOR pathway and resistance mechanisms of rapamycin and rapalogues led to the development of several inhibitory molecules. What the reader will gain: New anticancer agents including PI3K inhibitors, dual PI3K/mTOR inhibitors, specific mTOR inhibitors, and AKT inhibitors may have direct inhibitory effects on targets by competing with ATP or may be non-ATP-competitive allosteric modulators of protein functions. In addition, another way of blocking the abnormal activation of the PI3K/AKT/mTOR pathway may be achieved by using HSP90 inhibitors. In this paper we review novel drugs inhibiting the mTOR signaling pathway. Take home message: Several trials are ongoing with novel drugs targeting key kinases involved in the mTOR pathway. Benchmarking those agents with rapalogues in rationally designed preclinical models and conceiving clinical trials in everolimus/temsirolimus-sensitive tumor types may help to identify drugs with a real clinical potential. Understanding mechanisms associated with primary and acquired resistance to rapalogues may help to enlarge indications and provide a rationale for designing combinations that will minimize the risk of developing resistance to rapalogues.

Predictive biomarkers for the activity of mammalian target of rapamycin (mTOR) inhibitors

In the quest for personalized medicine, only a few biological parameters are routinely used to select patients prior to the initiation of anticancer targeted therapies, including mTOR inhibitors. Identifying biological factors that may predict efficacy or resistance to mTOR inhibitors represents an important challenge since rapalogs may exert antitumor effects through multiple mechanisms of action. Despite the fact that no such a factor is currently available, several molecular patterns are emerging, correlating with sensitivity and/or resistance to rapalogs. While activation of the phosphatidylinositol 3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, overexpression of cyclin D1, and functional apoptosis seem to sensitize tumor cells to rapalogs, Bcl2 overexpression or KRAS mutations are reported to be associated with resistance to mTOR inhibitors in several preclinical models. Translational research aimed at validating those parameters in clinical trials is ongoing.

Novel anticancer agents in clinical trials for well-differentiated neuroendocrine tumors.

Neuroendocrine tumors (NETs) are rare malignancies that arise from endocrine cells located in various anatomic locations, with a dramatic increase in incidence during the last 30 years. Limited therapeutic options are currently available for patients with advanced well-differentiated NETs, including carcinoids and pancreatic NETs. Streptozotocin-based chemotherapy and somatostatin analogues are drugs that are currently used for the treatment of progressive metastatic NETs. Recently, sunitinib demonstrating efficacy in pancreatic islet cell carcinomas has opened a new avenue for the treatment of NETs, and further trials shall be considered in NET types such as carcinoids, poorly differentiated neuroendocrine carcinomas, and several other endocrine tumors that depend on vascular endothelial growth factor (VEGF)/VEGF receptor for angiogenesis. In addition, drugs with distinct mechanisms of action, such as mammalian target of rapamycin inhibitors, currently investigated in phase 3 trials, may also supply novel options to control tumor growth and metastasis. Although acknowledged as rare tumors, recent data demonstrated the feasibility of large randomized trials in this disease. Furthermore, data from large trials also showed the importance of selecting an appropriate patient population when designing randomized studies. This review focuses on novel therapeutic approaches in the treatment of well-differentiated NETs. Based on recent data, novel strategies may now be designed using those anticancer agents to optimize the current treatment of patients with NETs.

Ocular adverse events of molecularly targeted agents approved in solid tumours: a systematic review.

When using molecularly targeted agents (MTAs), oncologists and patients face new and sometimes unexpected toxicities. Though ocular adverse events (OAEs) are not uncommon with chemotherapy, they are rarely severe or dose limiting. Ocular toxicity profile may differ with MTAs, indeed severe and dose limiting toxicities have been described with targeted therapies currently under investigation. Our study aimed to review OAEs experienced with MTAs approved in solid tumours. This review revealed that many OAEs, frequent and potentially severe, exist and concern most MTAs. The suggestion is prompt referral of patients with severe pain and/or visual impairment to the ophthalmologist since these symptoms can be associated with potentially severe OAE and need ophthalmic assessment. Oncologists must be aware of such events and their potential severity for better treatment and better diagnosis in daily practice as well as in clinical trials.

Patient-Specific Circulating Tumor DNA Detection during Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer.

BACKGROUND In nonmetastatic triple-negative breast cancer (TNBC) patients, we investigated whether circulating tumor DNA (ctDNA) detection can reflect the tumor response to neoadjuvant chemotherapy (NCT) and detect minimal residual disease after surgery. METHODS Ten milliliters of plasma were collected at 4 time points: before NCT; after 1 cycle; before surgery; after surgery. Customized droplet digital PCR (ddPCR) assays were used to track tumor protein p53 (TP53) mutations previously characterized in tumor tissue by massively parallel sequencing (MPS). RESULTS Forty-six patients with nonmetastatic TNBC were enrolled. TP53 mutations were identified in 40 of them. Customized ddPCR probes were validated for 38 patients, with excellent correlation with MPS (r = 0.99), specificity (≥2 droplets/assay), and sensitivity (at least 0.1%). At baseline, ctDNA was detected in 27/36 patients (75%). Its detection was associated with mitotic index (P = 0.003), tumor grade (P = 0.003), and stage (P = 0.03). During treatment, we observed a drop of ctDNA levels in all patients but 1. No patient had detectable ctDNA after surgery. The patient with rising ctDNA levels experienced tumor progression during NCT. Pathological complete response (16/38 patients) was not correlated with ctDNA detection at any time point. ctDNA positivity after 1 cycle of NCT was correlated with shorter disease-free (P < 0.001) and overall (P = 0.006) survival. CONCLUSIONS Customized ctDNA detection by ddPCR achieved a 75% detection rate at baseline. During NCT, ctDNA levels decreased quickly and minimal residual disease was not detected after surgery. However, a slow decrease of ctDNA level during NCT was strongly associated with shorter survival.

Rôle de la voie PI3K-AKT-mTOR dans le cancer et les thérapeutiques antitumorales

PI3K/AKT/mTOR pathway is an intracellular signalling pathway composed of different kinases. Many protein mutations are described in that pathway, and are responsible of dysregulation of cell growth, proliferation, survival and angiogenesis. Rapamycin is an antibiotic inhibiting mTOR. Different analogs of rapamycin are developed or being developed in antitumoral therapy, in which temsirolimus, everolimus and deforolimus, demonstrated antitumoral activity in renal cancer and mantle cell lymphoma, and many clinical trials are in progress in other tumors. In the future, predictive factors of response need to be identified; patient selection and associations with chemotherapy or with other targeted therapies should be explored.

Critical Evaluation of Disease Stabilization As a Measure of Activity of Systemic Therapy: Lessons From Trials With Arms in Which Patients Do Not Receive Active Treatment

analysis and by the results of the Radiotherapy With Cisplatin Versus Radiotherapy With Cetuximab After Induction Chemotherapy for Larynx Preservation (TREMPLIN) randomized trial that failed to show a difference between cisplatin and cetuximab concomitant to radiotherapy after induction chemotherapy. In our experience, the absence of parallelism between clinical and statistical heterogeneity is frequent. Regarding the editorial by Forastiere et al, we agree that knowing the sources of financial support are important to interpret the results of a study. However, in the present case, we would like to specify that this project was only modestly supported by an unrestricted grant by sanofi-aventis. sanofi-aventis had no role in the design of the metaanalysis, the analysis and interpretation of the data, nor the publication of this meta-analysis. For instance, they received the manuscript after its publication. We would like to take this opportunity to thank Forastiere et al, and fully agree with them that the role of taxane-based chemotherapy in the treatment of head and neck squamous cell carcinomas is not fully answered by this article and needs to be clarified, although it should be considered as one of the standards of care for laryngeal preservation.

Benefits from pharmacological and pharmacokinetic properties of sunitinib for clinical development

Importance of the field: In the last 10 years, oncology has been greatly modified by the introduction of new drugs especially designed for molecular targets. Sunitinib belongs to the category of new drugs that inhibit multityrosine kinase receptors involved in the key steps of tumorigenesis and angiogenesis. Areas covered in this review: This article reviews the pharmacological and clinical aspects of sunitinib. Literature search was conducted in PubMed, and articles selected for relevance to pharmacology or clinical efficacy up to March 2010. What the reader will gain: Pharmacology of sunitinib, data regarding clinical efficacy, and challenges to overcome resistance and improve outcomes of patients. Take home message: Sunitinib is an oral small molecule that displays mainly antiangiogenic properties and also direct antitumoral effects. Being well tolerated, this small molecule is now an essential treatment of advanced renal cell carcinoma and gastrointestinal stromal tumors refractory or intolerant to imatinib, two localizations associated with a poor prognosis. Future developments include the extension of the indications of sunitinib in pancreatic neuroendocrine tumors, the evaluation of combinations with conventional cytotoxic and other targeted drugs and the development of strategy to overcome resistance to sunitinib.