In Efforts to Ramp Up Adoption of Liquid Biopsies, Lung Cancer Becomes Proving Ground

NEW YORK (GenomeWeb) – Although liquid biopsy tests have proliferated widely over the last few years — with everything from single-mutation assays to sequencing panels of 100s of genes now available — broad acceptance among clinicians is following a more cautious path, with the setting of advanced non-small cell lung cancer taking the lead as a first proving ground.

Lung cancer makes sense as the front line for liquid biopsies. Taking tissue from late-stage lung cancer patients can be dangerous, painful, or both. Meanwhile, a growing bloc of molecularly targeted therapies is now available that can dramatically improve patient survival with much fewer and less severe side effects than cytotoxic chemotherapy. This combination creates a strong rationale for exploring noninvasive biomarker tests.

According to many participants at the recent annual meeting of the American Society for Clinical Oncology, while blood-based tests haven’t yet proved their utility definitively, their potential value has been persuasive enough to drive increasing adoption.

Fittingly, a PCR-based assay for EGFR mutations developed by Roche became the first — and so far only — liquid biopsy test approved by the US Food and Drug Administration last year.

Roche received approval for its Cobas EGFR Mutation Test v2 as a companion diagnostic for Genentech's Tarceva (erlotinib) last June, and in September, the FDA expanded the test label, adding an indication as a companion diagnostic for non-small cell lung cancer patients considering treatment with AstraZeneca's Tagrisso (osimertinib).

But with this regulatory milestone, the clinical community is now challenged to make sure it adopts this new generation of diagnostic in a way that truly benefits patients.

In a commentary published online ahead of print last week in the Journal of Thoracic Oncology, Columbia University physicians Adrian Sachler and Kimberly Komatsubara, and Dana Farber oncologist Geoffrey Oxnard wrote that the sheer number of new liquid biopsy platforms has led to confusion among lung cancer doctors as to both the test characteristics and limitations of individual assays, "as well as the clinical context in which these tests may be utilized either alone or in combination with traditional tissue genotyping."

Oxnard said in an interview this week that there are two open questions for doctors — even as his own institution, like many others, has now integrated blood-based EGFR testing into clinical practice.

The first is how exactly these tests should and shouldn’t be used. In its approval of the Roche Cobas assays last year for example, the FDA clearly cautioned physicians that negative liquid biopsy results must not be taken as definitive and should be followed up with tissue testing to make sure a mutation was not missed.

In light of this, some clinicians have argued that use of these new tests should be limited to situations in which a tissue test absolutely can't be done. But discussion at this month's ASCO meeting suggested that in practice, blood-based tests are increasingly being ordered not just for patients for whom biopsy is impossible, but also as a rapid diagnostic alongside or before tissue-based testing.

Liquid biopsy firm Biocept, for example, said recently that it has launched a marketing campaign to try to encourage clinicians to order a liquid test alongside tissue testing at the time of diagnosis as a standard practice.

"In lung cancer there is a real problem in that a high percentage of patients are not getting molecular profiling done in time – when they see their oncologist," Biocept President and CEO Michael Nall said in an interview.

Although the utility of genomic testing overall is still being debated, oncologists have argued that in lung cancer, patients are, if anything, being undertested rather than overtested. 

Because it offers the potential for more rapid genotyping, wider use of blood testing could mean that more patients get on targeted therapy as a first-line treatment when it may be more effective, Nall argued.

According to Oxnard, simultaneous tissue and blood analysis doesn't necessarily present an issue, as long as doctors recognize that a negative liquid biopsy result doesn’t necessarily mean that a patient doesn't have the mutation in question.

"In my presentations on the topic, I say that I think that tumor is still clearly the reference standard – and is the most rigorously validated for determining who will and won't respond, for example, to osimertinib in the case of T790M. But liquid biopsy [can offer a] practical advantage in that it can get you a quick answer," Oxnard said.

However, he added, "it can't be a replacement  for biopsy. If people don’t do that biopsy, you could make care worse — it could make outcomes worse – so it's very important that as we learn how to use this new diagnostic we do it right."

Holding fast to recommendations like the FDA's that stress that negative liquid biopsy results should not be taken as hard fact is a start, but Oxnard said it's important to recognize that the field also simply doesn't know yet what the ultimate benefit will be to patients.

A diagnostic strategy that has been tested prospectively to say what works still does not exist, he noted.  "Yes, it's compelling, but clinical utility is elusive and not available yet," Oxnard said.

Another emerging question as EGFR blood tests find a place in the clinic is what test to use, Oxnard said this week. "There is only one FDA-approved assay and you can count [the well-validated tests on one hand] but the number of available assays is enormous."

Despite the availability of an FDA-approved assay for both EGFR-sensitizing and T790M-resistance mutations, Oxnard and his Dana Farber colleagues have embraced droplet digital PCR, he confirmed at the meeting.

Others at the ASCO event, like Levine Cancer Institute oncologist Edward Kim, said they are using next-gen sequencing tests. During one session, Kim said that he and his colleagues at Levine chose British firm Inivata for its blood-based EGFR testing.

"The Cobas assay is not the most popular because it's EDTA based and not widely available as a send-out," Oxnard said. At least in the US, he explained, doctors like being able to draw blood and ship it out.

"If your question is [whether] T790M [is] present or absent, then ddPCR might be fine," he added. "So far it hasn’t been shown that a broader assay offers more than a focused one, in that setting at least."

But as the field evolves, he said, there may by multiple technologies that emerge as popular options that all offer sensitivities that are close to one another. For example, in a poster at the ASCO meeting, Oxnard and colleagues presented data comparing the results of Inivata's NGS testing to ddPCR in a retrospective blinded study, concluding that sequencing was even more sensitive than ddPCR, at least in this cohort.

"We need these kinds of trials if we are going to pick a winner, to tell [doctors] how to do this," Oxnard said. "But my guess is not that assays will distinguish themselves based on incremental increases in sensitivity, but [rather] that poor assays will distinguish themselves in being overly noisy, having artifacts and false positives."

"None of the [available technologies] are sensitive enough to replace biopsy, so what clinicians have to look out for are poorly validated assays to avoid," he added.

Physicians will also have to monitor emerging evidence on the overall clinical utility of liquid biopsy as it is incorporated into clinical practice either for patients who can't be biopsied, or to test more rapidly, increasing the number of patients directed to targeted therapy as a first-line, instead of chemotherapy.

Inivata believes that this type of clinical utility and outcome may help distinguish its own test from competing assays, the company's medical officer Clive Morris said in an interview at the ASCO meeting.

For example, in a small prospective study the firm published earlier this year, about half the patients were positive for T790M using the company's blood-based assay, which is consistent with the detection rate reported for tissue-based tests. Other liquid biopsy tests haven't always picked up this many mutation carriers.

The Inivata study also demonstrated that at least in this small cohort, patients who were tested with the company's liquid biopsy assay and then treated based on the results, benefitted from molecularly targeted treatment just as much as subjects who got tissue tests in prior clinical trials.

Looking forward, Oxnard said that the question of advantages of one assay over another may change as the application of these tests changes. Right now, when clinicians are adopting blood tests in more limited niches — like testing patients rapidly for sensitizing or resistance mutations in EGFR — various PCR methods and sensitive, targeted sequencing panels may jockey for equal recognition.

But, imagine, Oxnard said, once the majority of patients are getting liquid biopsy in the context of rapid testing to guide treatment with EGFR inhibitors. "If this is really something everyone is going to be getting, the question will become what is the best assay that opens up other possibilities … so we can use this as a dynamic marker, reassessing patients as resistance occurs."