The trial, conducted in France, was a proof-of-concept study to evaluate the efficacy of targeted agents in patients, based on their tumor's molecular profile.
Bioinformatics has opened up multiple avenues for researchers. Next generation clinical trials are moving away from histology-based tumor classification and directing their attention to the genetic and proteomic profile of the tumor. The results of one such proof-of-concept trial, conducted at academic centers in France, have now been published in The Lancet Oncology. The SHIVA trial, which assessed the clinical efficacy of molecularly targeted agents being marketed in the country outside of their indications, failed to improve progression-free survival (PFS) with off-label use compared with treatment per physician’s choice.
The trial was designed as an open-label, randomized, controlled phase 2, with participants that included adult patients with metastatic solid tumor refractory to standard of care. The primary criteria for inclusion were:
Of the 741 patients screened, only those with alterations in the hormone receptor pathway, PI3K/AKT/mTOR pathway, or the RAF/MEK pathway were included in the trial. The patients could be matched to 1 of 10 regimens (erlotinib, lapatinib plus trastuzumab, sorafenib, imatinib, dasatinib, vemurafenib, everolimus, abiraterone, letrozole, tamoxifen). Eligible patients (195) were randomly assigned to an experimental group, to receive a matched molecularly targeted agent (99) and a control group that received treatment at physician’s choice (96). Median follow-up was 11.3 months (range, 5.8 to 11.6 months) in the experimental group and 11.3 months (range 8.1 months to 11.6 months) in the control group.
The median PFS observed was 2.3 months (95% confidence interval (CI), 1.7-3.8) in the experimental group versus 2 months in the control group (95% CI, 0.65-1.19; P = .41). In the safety studies, 43% of patients in the experimental group and 35% of patients in the control group (administered cytotoxic chemotherapy) had grade 3 to 4 adverse events. Based on their results, the authors conclude that off-label indications for molecularly targeted agents should be discouraged.
However, Richard Schilsky, MD, chief medical officer of the American Society of Clinical Oncology, said in an interview that results of the SHIVA study are important because it tells us “that we need to continue doing research in this area of personalized medicine.” He thinks that at this early stage though, such studies should be conducted under the umbrella of a clinical trial.
A similar trial was recently launched in the United States. The National Cancer Institute’s MATCH trial will evaluate between 10 and 15 molecularly targeted agents in patients grouped based on tumor type or genetic abnormality.