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We enrolled patients in six prespecified cancer cohorts; patients with all other tumor types were enrolled in a seventh cohort. A total of 122 patients with BRAF V600 mutation–positive cancer were treated, including 27 patients with colorectal cancer who received vemurafenib and cetuximab. The primary end point was the response rate; secondary end points included progression-free and overall survival. Results

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 Concise summaries and expert physician commentary that busy clinicians need to enhance patient care. One challenge in interpreting the results of basket studies is drawing inferences from small numbers of patients. Although partial responses and tumor regression were observed in patients with anaplastic thyroid cancer, cholangiocarcinoma, anaplastic pleomorphic xanthoastrocytoma, high-grade gliomas, salivary-duct cancer, low-grade serous ovarian cancer, clear-cell sarcoma, carcinoma of unknown primary type, and pancreatic cancer, the largest of these subgroups consisted of only eight patients. In several cases, only a single patient with the tumor type was treated. Although these responses are noteworthy because of the limited therapeutic options available for many of these cancers, they must be interpreted with caution. In the absence of more definitive data, which might not be forthcoming for many diseases owing to logistical impediments, these data present a challenge to clinicians who want to make treatment decisions on the basis of tumor genomic profiling. De Benedetti F, Anton J, Gattorno M, Lachmann H, Kone-Paut I, Ozen S, et al. Efficacy and safety of Canakinumab in patients with periodic fever syndromes (colchicine-resistant fmf, hids/mkd and traps): Results from a phase 3, pivotal, umbrella trial. Pediatr Rheumatol. 2017;15(Suppl 1):O1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5461530/.

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LoRusso PM, Boerner SA, Pilat MJ, Forman KM, Zuccaro CY, Kiefer JA, et al. Pilot Trial of Selecting Molecularly Guided Therapy for Patients with Non-V600 BRAF-Mutant Metastatic Melanoma: Experience of the SU2C/MRA Melanoma Dream Team. Mol Cancer Ther. 2015;14:1962–71.

In the cohort with non–small-cell lung cancer, the response rate was 42% (95% confidence interval [CI], 20 to 67) and median progression-free survival was 7.3 months (95% CI, 3.5 to 10.8). In the cohort with Erdheim–Chester disease or Langerhans’-cell histiocytosis, the response rate was 43% (95% CI, 18 to 71); the median treatment duration was 5.9 months (range, 0.6 to 18.6), and no patients had disease progression during therapy. There were anecdotal responses among patients with pleomorphic xanthoastrocytoma, anaplastic thyroid cancer, cholangiocarcinoma, salivary-duct cancer, ovarian cancer, and clear-cell sarcoma and among patients with colorectal cancer who received vemurafenib and cetuximab. Safety was similar to that in prior studies of vemurafenib for melanoma. Conclusions Renfro L, Sargent D: Statistical controversies in clinical research: Basket trials, umbrella trials, and other master protocols: A review and examples. Ann Oncol 28:34-43, 2017 Google Scholar Papadimitrakopoulou V, Lee JJ, Wistuba II, Tsao AS, Fossella FV, Kalhor N, et al. The BATTLE-2 Study: A Biomarker-Integrated Targeted Therapy Study in Previously Treated Patients With Advanced Non-Small-Cell Lung Cancer. J Clin Oncol. 2016;34:3638–47.

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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. Hirakawa A, Asano J, Sato H, Teramukai S. Master protocol trials in oncology: Review and new trial designs. Contemp Clin Trials Commun. 2018;12:1–8.

Nakamura Y, Komatsu Y, Kato K, et al: bTMB-High Basket trial: A multicenter phase II trial of nivolumab monotherapy in patients with advanced gastrointestinal cancers with high blood tumor mutational burden (bTMB). J Clin Oncol 37, 2019 (suppl; abstr TPS179) Google Scholar The design of Thall et al. [ 10] is more applicable but requires accepting hierarchical modeling and Badalian-Very G, Vergilio JA, Degar BA, et al. Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood 2010;116: 1919- 1923 Master protocols, classified as basket trials, umbrella trials, and platform trials, are novel designs that investigate multiple hypotheses through concurrent sub-studies (e.g., multiple treatments or populations or that allow adding/removing arms during the trial), offering enhanced efficiency and a more ethical approach to trial evaluation. Despite the many advantages of these designs, they are infrequently used. Methods 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

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Sydes MR, Parmar MKB, James ND, Clarke NW, Dearnaley DP, Mason MD, et al. Issues in applying multi-arm multi-stage methodology to a clinical trial in prostate cancer: the MRC STAMPEDE trial. Trials. 2009;10:39. Schöffski P, Wozniak A, Escudier B, et al: Crizotinib achieves long-lasting disease control in advanced papillary renal-cell carcinoma type 1 patients with MET mutations or amplification. EORTC 90101 CREATE trial. Eur J Cancer 87: 147- 163, 2017 Crossref, Medline, Google Scholar