| General information |
| Database: | DB00676 |
| Objective: | They 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 standardofcare therapy had failed. |
| Authors: | Le Tourneau C, et al |
| Title: | Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (SHIVA): a multicentre, openlabel, proofofconcept, randomised, controlledphase 2 trial. |
| Journal: | Lancet Oncol. |
| Year: | 2015 |
| PMID: | 26342236 |
| Trial Design |
| Clinical Trial Id: | NCT01771458 |
| Agent: | erlotinib, lapatinib plus trastuzumab, sorafenib, imatinib, dasatinib, vemurafenib, everolimus, abiraterone, letrozole, tamoxifen
|
| Target: | NA
|
| Cancer Type: | advanced solid tumors |
| Cancer Subtype: | advanced solid tunors |
| Therapy Type: | com |
| Therapeutic Combination Type: | 7 |
| Therapeutic Combination Content: | erlotinib, lapatinib + trastuzumab, sorafenib, imatinib, dasatinib, vemurafenib, everolimus, abiraterone, letrozole, tamoxifen |
| Study Type: | a proofofconcept, multicentre, openlabel, randomised, controlledphase II trial |
| Key Patients Feature: | Patients older than 18 years with any kind of recurrentor metastatic solid tumour for whom standard of care therapy had failed were eligible for the study, providedtheir disease was accessible for a biopsy or resection of ametastatic site. atients needed to have an EasternCooperative Oncology Group (ECOG) performancestatus of 0 or 1; measurable disease in accordance withResponse Evaluation Criteria in Solid Tumors (RECIST)version 1.1; and values within the prespecified range forabsolute neutrophil count (more than and equal to 1 ¡Á 10 platelets per L), platelets (more than and equal to 1 ¡Á 1011 cells per L), haemoglobin (more than and equal to 90 g/L), serum creatinine (less than and equal to 1.5 times upper limit of normal[ULN]), serum total bilirubin (less than and equal to 1.5 times ULN), andaspartate and alanine aminotransferases (less than and equal to 3 times ULNor less than and equal to 5 times ULN for patients with liver metastases).Patients with brain metastases that had been controlledfor at least 3 months were eligible. they excluded patientstreated with antivitamin K anti coagulation. To beeligible for randomisation, patients needed a leftventricular ejection fraction more than 50%, a QTcinterval less than 480 ms, and preserved ECOGperformance status and renal, hepatic, and bone marrowfunction. |
| Biomarker: | molecular alteration was identified within one of three molecular pathways (hormone receptor, PI3K/AKT/mTOR, RAF/MEK) |
| Biomark Analysis: | NA |
| Control Group Info: | a matched molecularly targeted agent (experimental group) VS treatment at physician's choice (control group) |
| Treatment Info: | They randomly assigned these patients (1:1) to receive a matched molecularly targeted agent (experimental group) or treatment at physician's choice (control group) by central block randomisation (blocks of size six). Randomisation was done centrally with a theybbased 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. |
| Primary End Point: | progression free survival in the intentiontotreat population |
| Secondary End Point: | safety |
| Patients Number: | 741 |
| Trial Results |
| DLT_MTD: | NA |
| Objective Response Rate: | NA |
| Disease Control Rate: | NA |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | 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). |
| Median OS A vs. C: | NA |
| Adverse Event(agent arm): | 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). |
| Conclusions: | The use of molecularly targeted agents outside their indications does not improve progression free survival compared with treatment at physician's choice in heavily pretreated patients with cancer. Offlabel use of molecularly targeted agents should be discouraged, but enrolment in clinical trials should be encouraged to assess predictive biomarkers of efficacy. |