If there are two key issues that come up almost constantly in the matter of diagnosing and treating various cancers—aside, of course, from the overarching notion of finding true cures—they would be the issues of side effects of treatments and invasiveness of both therapeutic and diagnostic modalities. On the latter topic, “liquid biopsies”—the term for use of any type of specimen for assessing tumors other than tissue, including blood, urine and cerebral spinal fluid—address the issue of being less invasive in most cases while maintaining reliable results.
To get a better handle on the state of liquid biopsies right now, especially with regard to clinical trials and contract research organizations (CROs) we spent a little time online with Joy Yucaitis, senior director of oncology strategy at Novella Clinical.
DDNews: By way of introduction, what are the key strengths and limitations of liquid biopsy, for those not entirely familiar with that area of diagnostics?
Joy Yucaitis: Today, liquid biopsy technology can leverage blood or other body fluids, such as urine, saliva or cervical fluid, because all of the body’s cells emit genetic information. Liquid biopsy provides an alternative to tissue biopsy.
Processing and analyzing tissue biopsies are time-consuming, invasive and expensive. In contrast, liquid biopsies can be taken and analyzed quickly—the cobas EGFR Mutation Test v2 is reported to take less than four hours.
The question of sensitivity is an important one as well. Tumors are not homogeneous and liquid biopsies rely on material shed from the tumor. The tumor source in circulation, most commonly circulating tumor cells (CTCs) and cell-free nucleic acids (cfNAs), is typically not 100-percent informative of the entire tumor. However, the same can be said for tissue biopsy. This obstacle is more likely to result in false negatives. If a target mutation is identified, that may be reliable enough to qualify a patient for treatment. This can also be explored using serial samples as currently done with fecal occult blood testing, to improve the chances of observing stochastic events.
DDNews: Obviously, with the selection process and monitoring needs, diagnostics play a huge role in clinical trials, whether liquid biopsy-style tests or otherwise. But what is liquid biopsy’s “status” right now? How important are such tests in the trials process right now and where do you see them going, market-wise, in that sector in the future?
Yucaitis: At least three dozen companies are currently developing liquid biopsy diagnostics. The commercial market valuation is growing because of the breadth of potential cancer applications, which when considered with non-cancer applications, such as noninvasive prenatal testing and transplantation monitoring, is projected to grow beyond $10 billion by 2020.
Ultimately, as more liquid biopsies receive regulatory approval, they could become clinical standards to detect changes in tumor genetics well before imaging reveals changes in growth, enabling earlier treatment intervention or modification.
DDNews: What kind of special protocol implications are there in terms of including liquid biopsies in clinical trials?
Yucaitis: Sponsors intending to use liquid biopsies know patient safety is paramount and protocols must generate evidentiary data to document certainty and reproducibility of the new technology performance and relationship to patient outcomes. Currently, redundancies with using tissue biopsies, imaging technology and other diagnostics are necessary, which can impact trial timelines and resources. One strategy for ongoing long-term trial sponsors or those with near-term study launches might be to amend their approved protocols and patient consent to add experimental endpoints that use liquid biopsies, even if retroactively on stored samples.
For studies designed to assess the validity of liquid biopsies, outcomes are different than those of in-vitro diagnostics. Rather than the assessment of sensitivity and specificity (which are challenging when the gold standard may not be as informative as the study assay), the U.S. Food and Drug Administration (FDA) has encouraged endpoints based on the clinical outcomes of patients for whom liquid biopsy was used to make treatment decisions.
DDNews: Is there any special role you see CROs capable of playing in terms of liquid biopsies and clinical trials compared to other key agents in the trials process?
Yucaitis: Our vast experience managing oncology clinical trials provides insight that would be difficult to find elsewhere. An experienced oncology CRO can advise on several aspects of planning for future trials using liquid biopsies, such as protocol design, selecting targets, composing tumor boards and counseling treatment decisions. A CRO with expertise in the development of both drugs and diagnostics is ideal.
DDNews: To what extent do you think liquid biopsies need to be advanced more aggressively in clinical trials and how best do you think that can be carried out?
Yucaitis: I would like to see more inclusion of liquid biopsies in addition to tumor biopsy testing, to better characterize the value of the data available from liquid biopsy assessment. I believe it would provide the most value immediately in the screening of patients for studies of targeted treatments. Currently, patients in whom a fresh core needle biopsy is not feasible and for whom adequate archival tissue samples are not available are excluded from studies of targeted therapies, since it cannot be confirmed their cancer carries the targeted mutation or antigens. Liquid biopsy may provide a pathway to an effective treatment for patients who would otherwise not be considered for targeted treatment studies.
DDNews: What are the some strategies for successfully implementing liquid biopsies in clinical trials?
Yucaitis: Clinical trial teams can, theoretically, use liquid biopsy results to screen patients for targeted therapy studies, especially when tissue samples are not available for screening. On study, liquid biopsy can be used to reassess patients’ responses to treatments with each blood draw, catching tumor progression earlier than current practices, which can involve waiting weeks after treatment to use imaging to determine tumor shrinkage. Additionally, in theory, liquid biopsies may provide confirmation of the persistence of micro-metastases, which are not detectable by standard medical imaging.
DDNews: As you’ve noted with us before this Q&A, only two FDA approvals have been issued among the three dozen or so companies developing liquid biopsy tests, but also that not every company is necessarily seeking FDA approval. What are some of the rationales for choosing to develop a test but not seek approval? What are the key market applications for non-approved diagnostic tests?
Yucaitis: At the time of this interview, only one liquid biopsy test, Roche Molecular Systems’ cobas EGFR Mutation Test v2, had received approval from the FDA as a companion diagnostic. This test, U.S.-approved June 1, 2016, is a companion diagnostic for treatment decisions for non-small cell lung cancer patients. Janssen’s CellSearch CTC (circulating tumor cells) test is the first actionable CTC test cleared by the FDA for monitoring patients with metastatic breast, prostate or colorectal cancer. The regulatory pathway for liquid biopsies can be lengthy and expensive, but the potential return on investment is significant. Companies developing liquid biopsies must evaluate whether or not CLIA-facilitated access is an adequate first step to obtain broader experience with the assays en route to FDA clearance. Reimbursement is an important factor for consideration, and whether laboratories can use existing stacking codes for laboratory services to obtain reasonable reimbursement. Ultimately, most payers will expect clear scientific evidence demonstrating improvements on net health outcomes.
DDNews: Also, as long as we’re talking more generally about the diagnostic aspect of liquid biopsies beyond just clinical trials, what are some of the best practices for advancing trials of liquid biopsy tests themselves for those who do want regulatory approval?
Yucaitis: As mentioned earlier, consideration of endpoints is essential. Both in terms of regulatory clearance and reimbursement, agencies are expecting clear evidence of improved clinical outcomes (overall survival, progression-free survival, etc.). This may be approached in the context of directing a more effective course of treatment targeted to the patient, or perhaps in the earlier diagnosis of cancer at a stage when treatment outcomes are improved. Processing assays under CLIA-approved conditions and well documented SOPs is essential.
DDNews: Is there anything else you want to add on the topic of liquid biopsies?
Yucaitis: As a clinical researcher, I am very excited about the future of liquid biopsies. In July 2016, investigators successfully applied the technology to significantly determine the prognoses of patients with Stage II colon cancer that had not metastasized, a form with a high post-surgery cure rate. By using liquid biopsies during the two-year study, investigators found that among patients with the target ctDNA after surgery, 79 percent relapsed and at a median of 27 months. In contrast, relapses occurred in only 9.8 percent of the patients without identifiable target cfDNA (p<0.001). The findings demonstrate how liquid biopsies might help clinicians prioritize patients in need of post-surgical treatment because of their increased risk of recurrence, while reassuring others of a very low likelihood of relapse. Such outcomes data are exactly what regulators and clinicians need to move forward confidently in adopting liquid biopsy technology.
Joy Yucaitis is senior director of oncology strategy at Novella Clinical, where she provides therapeutic and development consulting to oncology customers, strategic planning for new protocols and executive oversight for key projects. She has more than 18 years of oncology drug and diagnostic development experience as both a sponsor and CRO director. For more information, visit novellaclinical.com/oncology
- Sullivan, Laurie. “Liquid Biopsies for Cancer Screening: An Emerging Sector of the POC Blood Testing Market.” BCC Research. June 15, 2015.
- Winslow, R. “Genomic Health Plans Line of Liquid-Biopsy Tests for Cancer.” Wall Street Journal. Jan. 11, 2015.