Oncologists Discuss Practicalities, Challenges in Navigating Evolving Genomic Testing Market

NEW YORK (GenomeWeb) – Speakers at the annual meeting of the American Society for Clinical Oncology, which wrapped up earlier this week, largely agreed that molecular testing and precision treatment have reached a new maturity in the practice of cancer medicine.

However, as the landscape of clinical and commercial genomic tests become more and more intricate, navigating this new world continues to challenge clinicians, some of whom discussed these practicalities at an ASCO session on implementing precision medicine.

"We are now at the point where cancer genomic sequencing is becoming a routine diagnostic, but the question of how to use it is the question of today and going forward," said Lee Schwartzburg, introducing the discussion.

According to Schwartzburg, there is an emerging dichotomy in the oncology field. On one hand, clinicians agree that genomic testing is important, and believe that it has solidly entered the standard of care, at least in some areas. However, on an individual level, doctors still struggle to know when and how they should test their own patients.

For example, a survey of 132 oncologists published by Medscape last month found that though around 70 percent of oncologists consider genomic testing to be an important advance in cancer, only 30 percent said that they get guidance from their institution or practice leadership on when to order tests.

Though most surveyed said they had used genomic testing within the last weeks or months — mostly when standard of care options are no longer viable, when patients progress, or in the context of a clinical trial — many also said they were uncertain about when to order tests. There was also significant disagreement on how commonly testing actually benefits patient and how meaningful results are, particularly for less common mutations.

For some areas of oncology, the situation is much clearer than others. Levine Cancer Institute oncologist Edward Kim argued that for lung cancer, for example, molecular testing is now recognized as a crucial part of practice.

"I can't emphasize enough that molecular testing is an essential part of the diagnostic and staging workup," he said during the session. "It's something that has to be done, and it should be a basic part of the initial [assessment.]

In other words, newly diagnosed lung cancer patients should not be referred to chemotherapy as a first line without genomic testing results that show that they aren't eligible for genomically targeted or immunotherapeutic drugs.

Yet, many still are, meeting participants acknowledged. For lung cancer, things like EGFR mutations and tyrosine kinase inhibitors; ALK and ROS1 alterations and various generations of ALK inhibitors; and now immunotherapies with PD-L1, mismatch repair deficiency, or tumor mutational burden are considered to have Tier-1 evidence, said Dana Farber oncologist Deborah Schrag.

"The challenge in the context of Tier-1 is appropriate implementation," she said. "We know that not everyone that can benefit from targeted treatment gets a crack at it, so in this setting, under-testing and under -treatment is actually a problem … and we face a tremendous implementation challenge — so we don’t leave anyone behind."

Some estimate that in spite of guidelines from ASCO and the National Comprehensive Cancer Network recommending EGFR and ALK biomarker testing prior to initiating therapy, 40 percent of patients in a community setting are not tested for EGFR and 50 percent are not tested for ALK.

Moreover, even at this top-tier level where genomic testing would be considered standard of care, clinicians still grapple with difficult choices about which tests to use. For example, the recent emergence of blood-based or liquid biopsy testing, particularly for EGFR resistance mutations, has raised new challenges for lung cancer doctors.

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

But other companies offer LDTs for the same purpose, some of which may offer more attractive sensitivity.

Kim said that within Levine, practitioners in the lung cancer space follow a defined protocol for when to test patients and how. For tissue samples, the center sends out to Caris Life Sciences. For more recently adopted blood-based testing, the institution uses Inivata.

Outside of Tier-1 the waters are even muddier, and standardization of practice arguably unattainable. Schrag raised a case study of a middle-aged male patient with locally-advanced unresectable pancreatic cancer.

"Pancreatic cancer is not a poster child for precision medicine," she said. "It's not really a poster child for anything."

After chemotherapy and radiation fail to shrink this patient's tumor enough for it to be surgically removed, he seeks out comprehensive genomic testing from a commercial lab, which identifies an ALK alteration.

Returning to his oncologist, he asks for off-label crizotinib.

"What do you do?... Consult a tumor board?  Search the literature?  Look for a clinical trial?  Do you go ahead and prescribe off label crizotinib? … Or forge ahead with cytotoxic chemotherapy?" Schrag asked.

Positive anecdotal reports in the literature could help sway a decision toward an off-label prescription, she added. However, "a skeptic would said we've been burned before. Vemurafenib worked in BRAF-mutated melanoma but boy did it not work in BRAF-mutated colorectal cancer."

"This is real and it typifies, increasingly, daily oncology practice," Schrag said.

Meanwhile, the increasing complexity of commercial tests also poses utility and economic questions that the oncology field does not have a firm, or a homogenous handle on, she added.

Schwartzburg argued that the costs of sequencing have come down so far, that there is little economic argument for choosing single-gene testing over comprehensive panels, since the cost of following up negative results with further tests rapidly overtakes the price of starting with a broad panel from the beginning.

However, Schrag said, reimbursement does not always follow this line of reasoning, so cost considerations for broader versus narrower tests still present challenges for doctors.

Questions from audience members at the end of the session highlighted some anxiety about a lack of standardization or concordance as the market has exploded with different comprehensive sequencing options.

Kim agreed. "It's a sobering fact to look at how precision medicine has changed. The number of gene panels and comprehensive tests out there is really quite daunting," he said.

"I'm a thoracic oncologist, so I can just [focus on lung cancer] but if you have to keep up with … how many immunotherapies and TKIs have been approved over even the last two months, I applaud you … I don't know how anyone can keep track of this."

Schwartzburg advised members and other attendees at the session to recognize that genomic tests are not like traditional lab analyses, where ordering the same test from different vendors can be expected to return the same results.

Oncologists should take the initiative to read the fine print from comprehensive panel reports, and evaluate things like depth of sequencing, which can be a significant source of differences between a report from one company and another, even though both interrogate the same set of genes.

"You should understand the characteristics of a test.  Make sure you understand what you are getting back," said Schwartzburg.

Interpretation and variant calling is also obviously a source of discordance, though he advised that laboratory groups like the Association for Molecular Pathology are working on solutions.

According to Schrag, what the clinical oncology community really needs and wants is definitive randomized controlled data that demonstrates improved outcomes for patients who receive comprehensive genomic tests and are treated based on the results compared to those who are treated without this added information.

Unfortunately, she said, the field doesn't have these answers. Meanwhile, at least some of the evidence that has been collected so far has been negative, perhaps explaining the simultaneous enthusiasm for genomic medicine and skepticism about its value demonstrated in the Medscape survey results.

And finally, speakers discussed how some of the most recent moves in the space may make things even harder for physicians, specifically the recent approval of the first tissue-agnostic drug-biomarker relationship by the US Food and Drug Administration with the addition of a new, tissue-agnostic, biomarker-guided indication for Merck's Keytruda (pembrolizumab) in cancers characterized by high microsatellite instability or mismatch repair deficiency.

Such cancer site-agnostic approvals look like they may be likely to continue, with new data at ASCO showing, for example, that three-quarters of participants with TRK fusion-positive tumors responded to Loxo Oncology's larotrectinib regardless of cancer type.

Schrag called the example of Keytruda a "watershed moment," but cautioned that it creates its own challenges for practicing oncologists.

"I'm sure many of you have had your phone ringing off the hook with questions from patients about whether their tumor might be MSI-high," she said during the session.

Doctors might wonder which tests they should use, she noted. The FDA approved Keytruda for MSI-high cancers without a dedicated companion diagnostic test.

Who to test is also an open question. Figuring out whether a test should even be ordered requires knowledge of the MSI frequency across the range of different cancer types, and "there is no place to go to quickly look this up," Schrag said.