Editors' ChoiceCancer

Basket trials: Making sense of context

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Science Translational Medicine  16 Sep 2015:
Vol. 7, Issue 305, pp. 305ec159
DOI: 10.1126/scitranslmed.aad3616

With the increased understanding of their molecular basis, even cancers that arise from the same organ and share similar histologic appearances are now known to consist of distinct molecular subsets. In cases where these molecular subsets are rare, it is a formidable challenge to assess targeted therapies in traditional clinical trials, which are usually organ-specific in their design.

Hyman and colleagues now report a histology-independent, biomarker-selected approach towards patient enrolment—a so-called “basket” clinical trial design—to address this issue. They focused on the BRAF V600E mutation, which is found in over 50% of cutaneous melanomas but in less than 5% of nonmelanoma cancers. Vemurafenib, a selective oral inhibitor of the V600E mutant form of the BRAF kinase, produces tumor shrinkage and prolongs survival of V600E-mutant melanoma patients, but its effect on V600E-mutant nonmelanoma cancers is not known. The trial enrolled 122 patients with V600E-mutant nonmelanoma cancers, regardless of histology, and treated them with vemurafenib. The primary objective was to assess the efficacy of vemurafenib in shrinking nonmelanoma cancers harboring a BRAF V600E mutation. Whereas tumor responses were observed in V600E-mutant non–small cell lung cancer, Langerhans cell histiocytosis, and a few other rare cancers, none were observed in V600E-mutant colon cancer. These results underscore the context dependency of molecular alterations: BRAF V600 mutation can be targeted with vemurafenib in some, but not all, cancers.

Additional studies are needed to confirm these observations. Nevertheless, basket trials may permit the rapid detection of early signals of clinical activity of targeted drugs across multiple tumor types simultaneously while also allowing for the possibility that tumor lineage might influence drug sensitivity.

D. M. Hyman et al., Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N. Engl. J. Med. 373, 726–736 (2015). [Abstract]

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