SHIVA Trial: Comparing Molecularly Targeted and Conventional Therapies in Advanced Cancer

Molecularly targeted drugs are effective against tumors in people whose tumors have the exact molecular change. Based on known changes to molecules, these results have led to more off-label use of molecularly targeted medicines. Researchers looked at the effectiveness of several molecularly targeted drugs sold in France. These drugs were picked based on molecular profiling of tumors, but they were used outside of their intended purposes in patients with advanced cancer whose standard treatment had failed. The SHIVA phase 2 open-label, randomized, controlled study was done at eight academic centers in France. Researchers looked at adult patients with any type of solid metastatic tumor not responding to standard care. They had to have an Eastern Cooperative Oncology Group performance level of 0 or 1, a metastatic site that could be biopsied or removed, and at least one lesion that could be measured. A required biopsy of a metastatic tumor and large-scale genomic tests were used to figure out the molecular profile of each patient’s tumor.

Investigators 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). They gave these patients a matched molecularly targeted agent (experimental group) or a treatment chosen by the doctor (control group) by putting them in six-block central randomization. Randomization was done centrally using a web-based response system. It was divided into groups based on the Royal Marsden Hospital prognostic score (0 or 1 vs. 2 or 3) and the changed molecular route. Clinicians and patients knew which medicine was going to be given. In both groups, treatments were given based on each school’s approved product information and standard practice protocols. These treatments were kept up until there was evidence that the disease was getting worse. The main goal was progression-free survival for the people who should be treated. An independent central review did not measure this. Researchers looked at how safe the treatment was for all patients with at least one dose.

From October 4, 2012, to July 11, 2014, researchers checked up on 741 people with any kind of tumor. 293 patients, or 40%, had at least one molecular change that matched one of the 10 known treatment plans. When the data stopped being collected on January 20, 2015, 195 (26%), patients were randomly assigned, with 99 in the experimental group and 96 in the control group. All people in the study group got treatment, and 92 in the control group did the same. Two patients in the control group got a molecularly targeted agent. Both were included in their assigned group for efficacy analyses. The patient who got an agent allowed in the experimental group was kept in the experimental group for safety analyses. In contrast, the other patient, who got both a molecularly targeted agent and chemotherapy, was kept in the control group for safety analyses. At the time of the primary analysis of progression-free survival, the median follow-up time was 1.3 months (IQR: 5.8–11.6) in the experimental group and 1.3 months (IQR: 8.1–11.6) in the control group. The experimental group had a median progression-free survival of 2.3 months (95% CI: 1.7–3.8), while the control group only had a median progression-free survival of 2.0 months (1.8%–2.1) (hazard ratio: 0.88, 95% CI: 0.65–1.19, P=0.41). In the safety group, 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 side effects (P=030).

Source: https://pubmed.ncbi.nlm.nih.gov/26342236/

Clinical Trial: http://clinicaltrials.gov/show/NCT01771458

Le Tourneau C, Delord JP, Gonçalves A, Gavoille C, Dubot C, Isambert N, Campone M, Trédan O, Massiani MA, Mauborgne C, Armanet S, Servant N, Bièche I, Bernard V, Gentien D, Jezequel P, Attignon V, Boyault S, Vincent-Salomon A, Servois V, Sablin MP, Kamal M, Paoletti X; SHIVA investigators. Molecularly targeted therapy based on tumor molecular profiling versus conventional therapy for advanced cancer (SHIVA): a multicentre, open-label, proof-of-concept, randomized, controlled phase 2 trial. Lancet Oncol. 2015 Oct;16(13):1324-34. doi: 10.1016/S1470-2045(15)00188-6. Epub 2015 Sep 3. PMID: 26342236.