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Results from this histology-independent, biomarker-selected, early phase 2 basket study show modest antitumor activity in cancers that sporadically express the BRAF V600 mutation. A growing number of agents have been approved for use in biomarker-positive cancers, including human epidermal growth factor receptor 2–positive breast cancer 26 and gastric cancer, 27 EGFR-mutated lung cancer, 28 ALK-translocated lung cancer, 29 and KIT (CD117)–positive gastrointestinal stromal tumor. 30 Systematic profiling efforts have shown that many approved and investigational biomarkers are present in various tumor types, although often at low frequencies. 4 Basket studies may permit the detection of early signals of activity across multiple tumor types simultaneously while also allowing for the possibility that tumor lineage might influence drug sensitivity. The flexible biostatistical design of this study, including the addition of a cohort of patients with any tumor types that were not prespecified, facilitated identification of modest activity in certain orphan cancers. With the expectation of sufficient enrollment among all indications, basket trials may be effectively designed for independent evaluations. In the presence of limited or imbalanced enrollment, however, one may wish to combine subpopulations or use statistical methods to facilitate information sharing among patient subpopulations. 5, 30 Guidelines for evaluating the operating characteristics of subpopulation analyses are needed for both confirmatory and nonconfirmatory settings. 33, 34

Fossella FV, DeVore R, Kerr RN, et al. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. J Clin Oncol 2000;18: 2354- 2362 Lopez-Chavez A, Thomas A, Rajan A, et al: Molecular profiling and targeted therapy for advanced thoracic malignancies: A biomarker-derived, multiarm, multihistology phase II basket trial. J Clin Oncol 33: 1000- 1007, 2015 Link, Google Scholar Hainsworth JD, Meric-Bernstam F, Swanton C, Hurwitz H, Spigel DR, Sweeney C, et al. Targeted Therapy for Advanced Solid Tumors on the Basis of Molecular Profiles: Results From MyPathway, an Open-Label, Phase IIa Multiple Basket Study. J Clin Oncol. 2018;36:536–42. Heinrich MC, Joensuu H, Demetri GD, Corless CL, Apperley J, Fletcher JA, et al. Phase II, open-label study evaluating the activity of imatinib in treating life-threatening malignancies known to be associated with imatinib-sensitive tyrosine kinases. Clin Cancer Res. 2008;14:2717–25.Hobbs BP, Barata PC, Kanjanapan Y, et al: Seamless designs: Current practice and considerations for early-phase drug development in oncology. J Natl Cancer Inst 111:118-128, 2019 Google Scholar Chen C, Li X, Yuan S, et al: Statistical design and considerations of a phase 3 basket trial for simultaneous investigation of multiple tumor types in one study. Stat Biopharm Res 8: 248- 257, 2016 Crossref, Google Scholar An In‐Basket Test is a device for learning about an individual's ability to perform certain management tasks. In the In‐Basket Test the person taking the test is confronted with a miniature sample of the job in the form of the contents of a manager's “in‐basket” – i.e., his incoming mail. These documents, including notes, letters, reports, papers for signature, memoranda, etc., are to be handled as they would be handled on the job, with the additional requirement that all actions, plans, decisions, agenda for meetings, etc., must be put in writing. These written records of the person's administrative behavior are then scored or evaluated to yield measures of performance.

Slosberg ED, Kang BP, Peguero J, et al: Signature program: A platform of basket trials. Oncotarget 9:21383-21395, 2018 Google Scholar De Benedetti F, Anton J, Gattorno M, Lachmann H, Kone-Paut I, Ozen S, et al. Pharmacokinetics and pharmacodynamics of canakinumab in patients with periodic fever syndromes (colchicine-resistant FMF, HIDS/MKD and TRAPS): Results from a phase III pivotal umbrella trial. Pediatr Rheumatol. 2017;15(Suppl 1):P20. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5461530/. Diamond EL, Dagna L, Hyman DM, et al. Consensus guidelines for the diagnosis and clinical management of Erdheim-Chester disease. Blood 2014;124: 483- 492 BRAF V600 mutations occur in various nonmelanoma cancers. We undertook a histology-independent phase 2 “basket” study of vemurafenib in BRAF V600 mutation–positive nonmelanoma cancers. MethodsHaroche J, Charlotte F, Arnaud L, et al. High prevalence of BRAF V600E mutations in Erdheim-Chester disease but not in other non-Langerhans cell histiocytoses. Blood 2012;120: 2700- 2703 Sydes MR, Spears MR, Mason MD, Clarke NW, Dearnaley DP, de Bono JS, et al. Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: Directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol. Ann Oncol. 2018;29:1235–48. In conclusion, we found that the BRAF V600 mutation is a targetable oncogene in some, but not all, cancer types. Histology-independent, biomarker-selected basket studies are feasible and can serve as a tool for developing molecularly targeted cancer therapy. Confirmation of promising activity identified in basket studies will often necessitate additional studies. Progress in the areas of genomics, disease pathways, and drug discovery has advanced into clinical cancer research. The latest innovations in clinical trials have followed with master protocols, which are defined by inclusive eligibility criteria and devised to interrogate multiple therapies for a given tumor histology and/or multiple histologies for a given therapy under one protocol. 1, 2 The use of master protocols for oncology has become more common with the desire to improve the efficiency of clinical research and accelerate overall drug development. The LUNG-MAP study, for example, used a master protocol for a phase II/III comparative trial designed to evaluate biomarker-matched therapies in patients with previously treated advanced squamous non–small-cell lung cancer. 3 Shortly after initiation, the US Food and Drug Administration approved a new immunotherapy for the same population. The design’s flexibility facilitated subsequent modification of the standard of care, which preserved the relevance of the study. 1 A second example includes the CREATE study master protocol, which evaluated the efficacy of crizotinib in patients with ALK or MET mutations among six different tumor histologies, where each histology constituted a subtrial of ALK/MET-positive or ALK/MET-negative tumors. 2 Concise summaries and expert physician commentary that busy clinicians need to enhance patient care.