Exceptional Responders Initiative: Questions and Answers

1.  What is the purpose of the Exceptional Responders Initiative?

The National Cancer Institute (NCI) embarked on the Exceptional Responders Initiative (ERI) to understand the molecular underpinnings of exceptional responses to treatment, primarily via chemotherapy, in cancer patients. Exceptional responders are patients who have a unique response to treatments that are not effective for most other patients.

For this initiative, exceptional responders were identified among patients enrolled in early-phase clinical trials in which fewer than 10% of the patients responded to the treatments being studied; patients who were treated with drugs not found to be generally effective for their disease; patients who were treated in later-phase clinical trials of single agents or combinations; and even patients who were treated with established therapies.

In this study, malignant tissue (and normal tissue, when possible) and clinical data were obtained from a group of exceptional responders for detailed analysis. The goal is to determine whether certain molecular features of the malignant tissue can predict responses to the same or similar drugs. The study also has an optional survey of complementary and alternative medicines, lifestyle changes, and additional medical conditions and their medications that may help to clarify the exceptional response.

2.  Can researchers and physicians submit cases for review or consideration?

No. As of November 21, 2017, the Exceptional Responders study accrual goals have been met, and the study is now closed to accrual. Tissue samples from more than 100 cases have been received and molecular analysis is ongoing. 

3.  What were the eligibility requirements for this study?

Exceptional responders are patients who met the following criteria:

  • Received a treatment in which fewer than 10% of patients had a complete response or a durable (lasting at least 6 months) partial response based on clinical trial data or extensive historical experience in the context of the patient’s tumor type
  • Achieved either a complete response (CR) or a partial response (PR) with duration of at least 6 months as defined by RECIST (Response Evaluation Criteria in Solid Tumors) criteria for solid tumors or response criteria as defined where RECIST is not commonly used
  • Sustained a complete or partial response for at least three times longer than the median duration of response from literature resources for that treatment

Other requirements included:

  • The patient, if still living, must have given appropriate consent for future research on their tumor tissue. If a patient is deceased, their tissue can be used for genomic analysis, unless a previous consent indicated their tissue could not be used for further research.
  • Available tumor tissue was collected prior to administration of the drug to which the exceptional response occurred. Ideally this would be just prior to treatment, but any prior tissue will be acceptable. The amount of tissue needs to be either a core biopsy or larger; fine needle aspirations will not provide enough tissue for analysis.
  • If available, blood or other biospecimens could undergo germline (non-cancerous) genomic sequencing to help clarify if molecular abnormalities seen in tumor are also seen in normal (germline) tissue.
  • Tumor treatment history, other than the drug to which the exceptional response occurred, will be collected if possible.

4.  To be eligible, did the patient need to be treated on a clinical trial?

No. The Exceptional Responders study did not require that patients be treated on a clinical trial. If the patient was treated on a clinical trial, the overall percentage of patients who responded to the therapy should be 10% or less of all patients (e.g., less than 10% had a complete response, or less than 10% had a partial response lasting at least 6 months). The study also accepted cases from patients who were treated with any treatment (except local treatments like surgery and radiation therapy), but the case must have had a documented response to that treatment that would not be expected to occur in more than 10% of similarly treated patients (i.e., the same disease symptoms and the same drug). Because a response needed to be documented, adjuvant treatments were generally not applicable.

5.  Was an initial feasibility study conducted?

As a proof of principle, experts in NCI’s Cancer Therapy Evaluation Program (CTEP) searched a database of phase 2 trials covering a period of 10 years (2002–2012) for cases that experienced exceptional responses. About 100 cases were identified to demonstrate that cases of the type needed for the ERI did exist, and in sufficient numbers to establish this initiative.

Investigators believe that obtaining successful exome-sequencing results and deep targeted sequencing and mRNA sequencing, if possible, from about 100 cases will provide sufficient information about the likelihood of finding promising discoveries. The exome regions of the genome are the protein-coding regions. The sample size was based on 95% confidence intervals (i.e., the estimate is 95% reliable) for various measures of feasibility and success. The investigators have also allowed enough flexibility to add additional cases through other means as appropriate. The results are not expected to meet rigorous statistical standards but to indicate whether this line of investigation has promise.

6.  How will molecular testing be performed?

DNA and RNA will be isolated from tissues submitted to the ERI and will undergo whole-exome sequencing and/or mRNA sequencing. Whole-exome sequencing is used to analyze the exons of thousands of genes simultaneously using advanced sequencing techniques. The exome comprises only 1% of the human genome, yet it houses as many as 85% of disease-related mutations. As a research tool, exome sequencing is a powerful way to investigate common and rare genetic variations that play a role in complex human diseases.

Cases with sufficient nucleic acids will undergo additional analyses (e.g., deep targeted sequencing, microRNA sequencing, promoter methylation analysis, single-nucleotide polymorphism genotyping and/or whole genome sequencing). Each case will be annotated with demographic and clinical information, along with sufficient follow-up information, to correlate molecular profiles with response. Both retrospective and prospective specimen collections will be considered.

7.  Was there a particular case that prompted this initiative?

Yes. In the case that sparked this initiative, mutations in genes called TSC1 and NF2, which result in a loss of function (the genes are defective and don’t produce an active protein product), were detected in a patient with a form of bladder cancer. This person had a complete response that lasted more than 2 years in a clinical trial of everolimus, an agent targeting a molecular pathway that is regulated by the TSC1 and NF2 genes. Separately, investigators sequenced tumors from 96 other individuals with high-grade bladder cancer, and found five additional TSC1 gene mutations. They then sequenced tumors from 13 patients with bladder cancer who had received everolimus, and found that three of four patients with TSC1 gene mutations had some tumor shrinkage in response to receiving everolimus, whereas eight of nine patients whose tumor progressed did not have such a mutation. This example demonstrates how exceptional responders could help identify novel or known molecular abnormalities that are likely to be predictive of response to agents with targets in a relevant biological pathway.

In subsequent workshops and discussions, it became obvious that all clinicians have seen a few exceptional responders.

8.  When will the molecular characterization data be available?

Processing of the tissues to obtain nucleic acids will take place at the Biospecimen Core Resource facility and is expected to take approximately 30 days. Whole-exome sequence characterization at the Genome Sequencing and Characterization Center is expected to take 120 days. Thirty days after the relevant information is deposited in the data center, it will be made available through a controlled access mechanism. Controlled access will be provided via the database for Genotypes and Phenotypes (dbGaP). Investigators will be able to apply for access by submitting a Data Access Request to the Exceptional Responders Data Access Committee through the dbGAP.

9.  Where can I obtain more details about this initiative?

The trial number is NCT02243592. More information is available in the protocol summary and from NCI's Division of Cancer Treatment and Diagnosis.

  • Updated: February 13, 2018

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