Master protocol trials are more complex, but can replace multiple traditional single drug/single disease trials.

“The main challenge of these basket trials is that by nature, they [focus on] molecular aberrations regardless of tumor type,” Dr Subbiah said. “These are very rare aberrations, so the trial needs to be open in a ton of sites for accrual.”

Cancer center departments and oncologists traditionally specialize on the diagnosis and treatment of cancer based on anatomic tumor type (for example, lung cancer or breast cancer), he added.

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“So, one question is: where would these tissue-agnostic trials be housed?” he asked. “You need a cancer center and a cancer doctor who treats all kinds of tumor types regardless of the site of origin. Major cancer centers like MD Anderson Cancer Center and Memorial Sloan Kettering Cancer Center have tissue-agnostic departments, whereas smaller cancer hospitals may not. So, the key question in smaller centers is where to house these trials and how to get these trials accrued.”

Dr Subbiah has been involved in several basket trials that led to new therapeutic indications for rare diseases.

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“Vemurafenib was FDA-approved for Erdheim-Chester disease [histiocytic neoplasm] and Langerhans cell histiocytosis based on an arm of one of the first-ever histology-independent clinical trials, the VE-BASKET study,” he said.4,5

Another was the Rare Oncology Agnostic Research (ROAR) basket study, a phase 2, open-label study in patients with BRAF V600E–mutated rare cancers that assessed the efficacy and safety of combination dabrafenib BRAF inhibition plus trametinib MEK inhibition ( Identifier: NCT02034110).6 That study showed promising results for patients with anaplastic thyroid cancer, a rare and highly aggressive malignancy.

“This is a rare, highly lethal malignancy with poor patient outcomes and no systemic therapies with clinical benefit,” Dr Subbiah said. “The confirmed overall response rate was 69%. The FDA granted priority review and a breakthrough therapy designation for this indication. Orphan drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases, was also granted for this regimen and indication. Based on the study results, it received FDA approval. This was the first agent to be approved for this horrible disease.”

But when patients are assigned to basket study groups based on tumor mutation or biomarker status rather than the primary tumor’s anatomic location, small numbers of patients with any given anatomic cancer type might sometimes preclude meaningful subgroup analyses — and differences in outcomes between patients with different cancer types could be missed.

“One of the weaknesses of basket studies [is] that they may have small sample sizes because we are looking for rare genetic aberrations across multiple cancers,” Dr Subbiah reiterated.

Basket studies also often lack a comparator arm, Dr Subbiah noted.

“It is very hard to think about [a] comparator arm, as different cancers may have different comparators,” he explained. “So, it can be difficult to interpret efficacy in a particular tumor type.”

Patient-Reported Outcome Measures Could Enrich Basket Trial Findings

Dr Subbiah hopes to see wider use of patient-reported outcomes (PROs) in basket trials to assess quality-of-life impacts, acute adverse events, and long-term toxicities that might not otherwise be detected using standard clinical trial measures, he said.

“I strongly feel PROs should be analyzed and interpreted with basket trials,” Dr Subbiah said. “PROs may help capture the full picture that may not be caught in the tumor shrinkage measurements in the waterfall plots.”  

“Many times, the RECIST measurements showing tumor shrinkage may not capture the full story,” he said. “Patients may start to feel well even with stable disease not amounting to response under RECIST criteria, and conversely, even if there is a partial response with tumor shrinkage, a patient may clinically feel worse.”


  1. US Food and Drug Administration. FDA in Brief: FDA modernizes clinical trial designs and approaches for drug development, proposing new guidance on the use of adaptive designs and master protocols. Updated September 28, 2018. Accessed April 22, 2019.
  2. American Society of Clinical Oncology. Clinical trial design and methodology. Accessed April 3, 2019.
  3. Woodcock J, LaVange LM. Master protocols to study multiple therapies, multiple diseases, or both. New Engl J Med. 2017;377(1):62-70.
  4. Diamond EL, Subbiah V, Lockhart AC, et al. Vemurafenib for BRAF V600-mutant Erdheim-Chester disease and Langerhans cell histiocytosis: analysis of data from the histology-independent, phase 2, open-label VE-BASKET study. JAMA Oncol. 2018;4(3):384-388.
  5. Hyman DM, Blay JY, Chau I, et al. VE-BASKET, a first-in-kind, phase II, histology-independent “basket” study of vemurafenib (VEM) in nonmelanoma solid tumors harboring BRAF V600 mutations (V600m). J Clin Oncol. 201;32(15_suppl):2533. Subbiah V, Kreitman RJ, Wainberg ZA, et al. Dabrafenib and trametinib treatment in patients with locally advanced or metastatic BRAF V600-mutant anaplastic thyroid cancer. J Clin Oncol. 2018;36(1):7-13.