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ESMO Oncologists Debate Optimal Timing for Broad NGS, Align on Key Barriers to Precision Oncology

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NEW YORK – In an interactive session during the European Society for Medical Oncology Congress on Tuesday, oncologists debated whether performing comprehensive molecular profiling on a patient's cancer as early as possible following diagnosis is always the best choice.

Although the two presenters — Benedikt Westphalen, head of the molecular diagnostics and therapy program at the University of Munich Comprehensive Cancer Center, and Felipe Roitberg, a clinical oncologist at the Hospital Sirio Libanes in São Paulo, Brazil — were assigned to debate the supporting and opposing positions, respectively, both discussed some of the most pressing challenges facing doctors and patients when it comes to precision oncology, including molecular profiling access, cost, interpretability, and the evidence supporting the value of molecularly matched cancer treatment.

Both Westphalen and Roitberg acknowledged that access to comprehensive, multigene tumor profiling varies drastically depending on the country and treatment setting and that not all clinicians are adequately prepared to make therapeutic decisions based on comprehensive molecular profiling results. Before they could debate the best time to implement such testing for patients, the presenters acknowledged that they must first address whether patients even have access to testing and if results are interpretable.

Where do other oncologists stand?

The structure of the ESMO session was such that audience members were initially surveyed on their position on three key questions. The audience then listened to both Westphalen and Roitberg's presentations and voted again on the same three questions to determine whether the talks had swayed their sentiments.

The first question asked participants to select the most important limitation affecting the clinical application of tumor molecular profiling. At the onset, 16 percent of audience members flagged the most important limitation as the limited efficacy of these tests, and the rest were evenly split, with 42 percent citing access barriers and 42 percent voting for interpretation difficulties. Following Westphalen and Roitberg's presentations, responses to this first question remained more or less unchanged.

The presenters' debate did shift opinions a bit on the second question, however, which asked oncologists to consider if they would recommend molecular profiling early on to guide therapeutic decisions if there were theoretically no constraints or barriers to test access. At the start, the vast majority of respondents — 96 percent — said, "yes," they would offer patients early molecular profiling. After the presentations, however, the audience was a bit more divided, with 76 percent voting "yes," 19 percent voting "no," and 5 percent voting that they were unsure.

Finally, the third question asked the audience whether early molecular tumor profiling should be limited to clinical trials, whereas customized panels should be used in clinical practice. At the start, 37 percent agreed, 50 percent disagreed, and 13 percent were unsure. After the talks, the audience was almost evenly split, with 47 percent agreeing that early tumor profiling should be limited to getting patients on clinical trials and 53 percent disagreeing,

Drawbacks of early profiling

Notably, most of Roitberg's arguments opposing molecular profiling at the earliest possible time point were related to access barriers. For patients diagnosed at cancer centers that don't have their own in-house next-generation sequencing technology, which is more often the case, patients' samples must be sent out to commercial labs for profiling. This is not a major hassle when the commercial labs are nearby, but it can take a detrimentally long time when the sample must be sent to a lab abroad.

"Do you have NGS panel [technology] in your institution, or only PCR or Sanger?" he asked hypothetically. "This is important, because if you want to send the sample abroad, you spend time waiting for the [results] from a panel that is perhaps done in another country in another setting, so it takes time." The lag time could hold up patients' ability to get on first-line therapy, and depending on the patient's type and stage of cancer, this could negatively affect their survival outcomes.

Even at centers with in-house test access, Roitberg said that trying to rush comprehensive molecular profiling for urgent cases, where patients must begin treatment as soon as possible, can compromise biopsy and test quality and increase the risk of false positives or negatives.

"If we aim to run, we must make sure we go fast but safe," he said. "What I mean here is quality."

Roitberg also spoke to education and interpretation limits. Before deciding to send a newly diagnosed patient's sample out for molecular profiling, he said, an oncologist needs to already have a good understanding of the range of molecular alterations that testing might uncover, the likelihood of specific, therapeutically actionable alterations showing up in different cancer types, and the benefits and risks of prescribing biomarker-guided treatments for patients.

"Clinical benefit to patients involves understanding that the diagnosis that you're expecting to obtain is clearly related to a treatment that you're able to offer and that [there is] value," he said. "Because if there is no meaningful benefit, what is the point of putting the patient in a rush and also exposing them to financial and psychological considerations and drawbacks related to this?"

Necessity for early molecular profiling

Westphalen, speaking in favor of early molecular profiling, focused less on the logistics and quality concerns and more on the future direction of the field of oncology. By 2024, he estimated, there will be more than a dozen new molecularly targeted drugs, many of which will have tumor-agnostic implications. "It won't be enough to test single genes in single patients," Westphalen said. "We need to cover all of our bases."

This type of broad profiling is also necessary for driving innovation, he added, because the success of clinical trials evaluating these targeted drugs depends on biomarker tests identifying eligible patients. Westphalen cited data from Memorial Sloan Kettering's IMPACT study showing that by comprehensively profiling 10,000 patients for molecular biomarkers, they were able to enroll 11 percent of those patients onto clinical trials, including patients with ultra-rare alterations that likely would not have been identified with single-gene tests or limited panels.

A chief component of Westphalen's argument for earliest-possible molecular profiling was also the fact that by assessing all relevant biomarkers in a single test there is no need to do sequential, multiple single-gene tests.

"This can save time because you cover all biomarkers at once; resources, because it's cheaper to test all these biomarkers in one shot; and tissue because you don't have to go back and test again and again," he said, adding that patients tend to derive the most benefit with targeted treatment when it's incorporated into the first- or second-line setting.

Financial constraints

While the two oncologists presented the advantages and drawbacks of early molecular profiling, during a post-debate discussion, they were of the same mind when it came to the matter of financial toxicity associated with these tests, the cost constraints of precision medicine as a whole, and the risks of using cost-effectiveness as a measure of value.

In many health systems, presenting clear evidence of precision oncology's cost-effectiveness is the key to improving access. Payors — governments or private and commercial insurers alike — want proof that an NGS test with a high price tag in the short term will match a patient to the right treatment, which theoretically could lower future costs if it meant that the patient would stop progressing and wouldn't need further tests, procedures, and additional lines of treatment.

But parameters for proving this are challenging and vary tremendously by location and healthcare systems.

Roitberg characterized cost-effectiveness analysis as "tricky" due to this variation. At its core, cost-benefit analysis is an assessment of the benefit of healthcare interventions within the constraints of a budget, he explained. "But for some countries like my country, Brazil, where the inequality is so large … where you have a few people with lots of money and a large number of people with [very little], this equation does not fit a threshold in terms of understanding the overall ability to pay. … So, the reimbursement model matters."

Importantly, Roitberg underscored the need to have cost-related discussions not only about the price of the comprehensive NGS test itself but also of the targeted drugs that come next and the additional care that could be needed if the patient progresses on that drug.

These discussions need to take place not only among payors and health systems at large, Roitberg said in his presentation, but also between oncologists and patients directly. He cited survey data showing that nearly a quarter of oncologists who discussed genomic or genetic testing with their patients reported never or rarely discussing their associated costs.

Westphalen echoed Roitberg's points on the importance of discussing cost openly and transparently.

"All patients should have the ability to undergo comprehensive genomic profiling," he said. "And only if we have this in our back pocket and talk about this openly and clearly will we ever get to a point where it's not about financial toxicity, but a given that we profile."

"What is going to happen in the next five years," he predicted, is that "we aren’t [going to be] arguing, 'Is it too early or too late?' but 'Has it been done?'"

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