Biopsy Requirements Impede Enrollment in Clinical Trials for Advanced NSCLC

January 18, 2016
Colin G. Evans, PhD

A study analysis tackles the ethical debate surrounding the impact of the increasing requirement for research biopsies on the participation of patients with advanced non-small lung cancer in clinical trials.

Benjamin Levy MD

A study1analysis tackles the ethical debate surrounding the impact of the increasing requirement for research biopsies on the participation of patients with advanced non—small lung cancer (NSCLC) in clinical trials.

The study, published in theJournal of Thoracic Oncology, found that more patients were enrolled in clinical trials without mandatory tissue specimen requirements versus trials with tissue requirements. Furthermore, patients enrolled in trials without this requirement received study treatment sooner than patients from whom samples had to be taken and subsequently analyzed.1

The study authors highlight the need to obtain research biopsies to clarify whether or not overall treatment may be improved by molecular selection. The use of research biopsies can inform medical professionals on effective treatment mechanisms of action and provide information on making decisions regarding appropriate parameters for future patients.

Opponents of this school of thought argue that research biopsies, especially for early phase trials, expose patients to risks in the absence of any immediate clinical advantage. They also cite the disappointment for patients barred from trials of investigative agents, because they may be unable to undergo the biopsy.1

“Obtaining tissue for clinical trial purposes requires a balanced approach where pros of putting a patient on a clinical trial exposing him/her to a novel drug have to be weighed against the cons of procedural risks and further time,” said Benjamin Levy MD, medical director of thoracic medical oncology for Mount Sinai Health Systems and the associate medical director of the cancer clinical trials office for Mount Sinai Hospital, in an exclusive interview withTargeted Oncology.

The authors reviewed cases of patients with advanced NSCLC who had been evaluated for clinical trial entry. The study was undertaken at the Princess Margaret Cancer Center and included patients considered for recruitment between January 2007 through March 2015.1

The researchers identified 55 clinical trials, and 38 of them required tumor specimens. The study analysis had two objectives:

  • Determine the influence of mandatory tumor tissue requirements on the proportion of patients with advanced NSCLC who progressed to enroll in the trial and receive treatment
  • Assess the impact of mandatory tissue sample requirement on the time to starting study therapy.

NSCLC Trials Requirements

Patients evaluated for entry to phase I,II, and III trials for systemic therapies were reviewed, except those screened for radiation oncology, surgical or supportive care trials, and observational and survey studies. All but one of the 55 trials were using investigational therapies, and the remaining trial involved molecular profiling with no study drug.

Tumor tissue was required for enrollment in 38 (69%) trials, and 6 (11%) required a repeat biopsy. When available, archival specimens were allowed for 32 trials. Absence of a particular biomarker precluded enrollment in 24 trials. The majority of trials mandating tumor sample collection required core needle or alternative surgical specimens. Only two trials allowed the use of cytology or fine needle aspirate samples.1

Patient Characteristics

The authors found that trial entry was offered to 636 patients during 940 unique consultations, and some patients entered several trials. The majority of patients were female (54%), 36% had never smoked, the median patient age was 61 years (18-89), and 21% were Asian. Study treatment was subsequently received by 60% of the patients encountered during 549 consultations.

However, if trials had mandatory tissue sample requirements, fewer patients received study treatment versus patients entering trials without a mandatory tissue specimen requirement, (55% vs 83%,P<.0001), and patients in trials with mandatory tissue requirements started study treatment at later time points (16 days later, vs 9 days,P= .002).

“Even if tissue is available, many patients seen at major academic cancer centers have undergone diagnostic biopsy elsewhere. The need to request tissue from another facility adds even more time to the process, which can result in considerable distress for the patient,” said David E. Gerber, MD, associate professor of internal medicine in the Division of Hematology and Oncology and director of the Experimental Therapeutics program at UT Southwestern Medical Center in Dallas Texas, in an interview withTargeted Oncology.

Similar results were seen for trials requiring mandatory repeat biopsies versus those permitting the use of archival materials. Patients considering entering trials using archival material were more likely to receive study treatment than those contemplating enrollment in studies that mandated repeat biopsies (59% vs 38%,P= .0007). Use of archival tissues versus biopsies also resulted in a shorter time interval from initial consent to start of treatment (median 14 days vs 54 days,P<.001).1

Two hundred and twenty (40%) of the patients involved in the 549 consultations did not proceed to study treatment. The main reason (34%) was the absence of a required biomarker. Other barriers to study enrollment were withdrawal of consent during 20% of consultations and exclusion criteria preventing enrollment in 15% of patients.

Death, or worsening status, accounted for nonenrollment of 17% of patients following initial consent. Insufficient tissue for molecular analysis precluded study entry of 10% of patients, and 3% of patients died before results of the molecular profiling were available.1

“This has indeed been an issue at our institution where patients have either not had enough archival tissue to be enrolled on a trial and thus have to be rebiopsied or the trial mandates a rebiopsy prior to enrollment,” commented Levy. “Often times we have been successful in obtaining more tissue, but other times have had to exclude the patient from the clinical trial. In addition, there have been several instances where patients were waiting for biopsies and experienced rapid clinical decline.”

David E. Gerber, MD

Reviewing the Issues

“Undoubtedly we need to procure the relevant information from a patient’s tumor to assess eligibility and help better understand those patients most likely to respond to an investigational therapy. How to go about doing this, however, is evolving,” said Levy.

Gerber added his opinion, stating “Tissue testing for predictive and pharmacodynamic biomarkers is critical to the rational development of new therapies.”

Overall, the study authors found that the majority of the trials required tumor specimens for enrollment. The tumor specimen requirement was linked to a reduced number of patients screened for trial entry. The requirement for biopsies, introduced clinically significant delays, indeed mandatory repeat biopsies were associated with a threefold greater time to starting study treatment. They also noted that the complexity of screening (application of inclusion criteria) and the time entailed in central laboratory analysis of specimens (versus analysis by local laboratories), likely accounted for the documented delays. In addition, a few patients needed hospitalization due to biopsy-related complications.1

Potential Solutions

The paper concluded by offering a range of possible solutions. These include a faster turnaround time for samples analyzed at central laboratories, or permission to use local validated services.1

“Central testing must become more efficient in attempts not to delay treatment to a potential subject,” said Levy. Adoption of routine tissue banking at diagnosis and making it easier to obtain diagnostic samples for trials, along with the development of peripheral blood assays would also hopefully improve the process.1

Agreeing with the authors that plasma genotyping via genetic interrogation of cell-free DNA (liquid biopsy) may allow investigators to circumvent repeat biopsies, Levy added, “While this technology is still in its infancy, the diagnostic platforms are developing quite rapidly and will eventually move into routine clinical practice.”

Suggesting another solution, Gerber said, “Another strategy may be to allow prescreening of patients for trials that have enrollment biomarkers. With this approach, tissue acquisition, processing, and analysis are performed while a patient is still receiving active therapy. Results are then available before the patient requires a change to new therapy.”


  1. Lim C, Sung M, Shepherd FA, et al. Patients with advanced non-small cell lung cancer: Are research biopsies a barrier to participation in clinical trials?J Thorac Oncol. 2016;11(1):79-84