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Despite Precision Oncology Drug Approval Boom, 'Success' Isn't So Easily Won, Researchers Admit

DNA and cells

NEW YORK – At Memorial Sloan Kettering, researchers are hoping a nuanced analysis of clinical actionability and US Food and Drug Administration treatment approval data will spark a more realistic discussion of precision oncology's progress.

The researchers acknowledged that one can't leap to the conclusion that precision oncology is helping patients live longer and better just because there are more biomarker-informed treatments on the market over the last two and a half decades. Growth in patient eligibility and FDA-approved drugs isn't synonymous with the field's triumph over cancer, recognized Debyani Chakravarty, a molecular geneticist at MSK and the lead author of a study published in Cancer Discovery last month.

Measuring the impact of precision oncology has been challenging, according to Chakravarty, because "success" is a subjective word. "How does one measure success?" she posited. Chakravarty was clear that in charting the boom in FDA-approved precision oncology drugs and the growing proportion of patients eligible for such therapies, her group's analysis wasn't meant to downplay the many access, cost, and efficacy issues that continue to thwart the field's progress.

That said, the researchers found in their Cancer Discovery study that in the US, a sizable proportion of all FDA-approved cancer drugs since 1998 — 43 percent — have been precision oncology drugs that require biomarker testing to define the treatment-eligible population.

To conduct the analysis, Chakravarty and colleagues reviewed the eligibility criteria for all cancer drugs approved since 1998, which is when Genentech's Herceptin (trastuzumab) entered the market for HER2-positive breast cancer. Since then, they counted 86 drugs out of the 198 FDA-approved cancer treatments have been biomarker-informed precision oncology drugs. Next-generation sequencing could be used to identify eligible patients for 69 of these FDA-approved drugs.

Chakravarty said she was surprised precision oncology drugs appeared to comprise such a large slice of the cancer therapy market. As the researchers dug into the therapy approvals, they found trends that suggested that the impact of these new therapies may be limited to certain cancer and biomarker types.

For instance, of the 69 precision oncology drugs that use NGS to determine patient eligibility, 29 were "me too" drugs, meaning follow-on approvals that targeted the same molecular biomarker as another marketed agent or targeted a resistance variation of that biomarker. Of those 29, the majority — 20 drugs — targeted the same seven biomarkers, namely ERBB2 amplification, BCR-ABL1 translocation, BRAF V600E mutations, ALK fusions and mutations, BRCA1/2 mutations, and FGFR fusions. The number of "me too" drugs, wrote Chakravarty and colleagues, highlighted "the narrow scope of precision oncology drug development during this era."

The MSK researchers also highlighted what they saw as a slight dip recently in the expansion of truly first-in-class precision oncology drugs that target entirely new molecular biomarkers. The number of first-in-class FDA cancer drug approvals for molecularly defined cancer indications peaked in 2020, with eight such drug approvals. That same year, four precision oncology drugs were approved for follow-on indications.

"Our data raise concern that the recent acceleration of new first-in-class precision oncology agents may have peaked in 2020, and novel strategies will be needed to further advance the field," wrote Chakravarty and colleagues, suggesting that further advancement will likely require new strategies to treat patients with tumors driven by altered suppressor genes like TP53, CDKN2A/B, APC, PTEN, RB1, TERT, and MYC.

Beyond counting and categorizing the FDA-approved oncology drugs, Chakravarty and colleagues wanted to estimate how many patients might actually be eligible for these drugs and describe how this metric has changed over the years. Using the 2017 and 2022 versions of MSK's OncoKB database of cancer variants, they assessed 47,271 clinically sequenced solid tumors. They annotated the tumor samples' mutations, focal copy number alterations, and structural variants. These data were all available publicly as part of a recent AACR Project GENIE public release.

They found that the percentage of tumor types treatable by precision oncology drugs nearly doubled from 2017 to 2022, going from 18.1 percent in 2017 to 35.9 percent in 2022. Using OncoKB, the researchers determined patients' eligibility for available drugs if they had somatic DNA mutations, fusions, or copy number alterations that matched up with either commercially available precision oncology drugs or a clinical trial for a precision oncology drug with promising clinical data. Of note, they did not include germline alterations in their analysis, even though, as Chakravarty pointed out, several precision oncology drugs have been approved for patients harboring inherited mutations.

Looking at the dramatic growth in precision oncology actionability from 2017 to 2022, the MSK researchers pointed out that the single largest jump in patient eligibility came with the FDA's tumor-agnostic approval of Merck's checkpoint inhibitor Keytruda (pembrolizumab) based on tumor mutational burden (TMB) in 2020. Between 2017 and 2022, the proportion of patients eligible for a precision oncology drug increased 9.2 percentage points attributable to this TMB-high Keytruda approval alone.

Chakravarty and her colleagues acknowledged from the start that they weren't setting out to measure the impact of precision oncology on patients' survival or response rates, and therefore, their analysis cannot provide any conclusions about the degree to which this field has benefited patients. But this caveat is precisely why the field of precision oncology has over the last two and a half decades garnered its fair share of detractors. While biomarker-informed treatments can help patients live longer and perhaps with less toxicity than they would with chemotherapy or radiation, few patients can hope for a cure. Cancer patients typically relapse on precision oncology drugs after a period of response.

When the incremental gains in survival and response rates seen with these drugs are viewed against their exorbitant price tags, many in the healthcare space begin to question whether precision oncology is a sustainable strategy. Chakravarty acknowledged these concerns are valid but also pointed out how precision oncology has altered the treatment landscape for certain tumor types, such as subsets of patients with chronic myeloid leukemia.

"There are two ends of the spectrum, those that over-promise and those that are highly critical, but what this study intends to do is to start the conversation," Chakravarty said. "Let's really look at what the situation is."

Just as the MSK analysis didn't measure clinical benefit, it also didn't chart real-world access to precision oncology drugs. Even though a patient's tumor may be deemed actionable using data from OncoKB, that doesn't mean the patient actually received or could afford a precision oncology treatment, Chakravarty acknowledged.

"This analysis was purely on the basis of whether an [actionable] biomarker was found in a patient sample and whether that patient would have been eligible for a given drug," she explained. Because the retrospective nature of the study meant that the patients whose samples were analyzed didn't necessarily receive the drugs for which their tumors were eligible, the MSK researchers couldn't assess clinical outcomes. That said, Chakravarty recognized that patients' clinical outcomes on these drugs are crucial to take into consideration when looking at precision oncology outcomes on the whole. 

The ability to spot eligible patients also varies across the healthcare system, she added. At a top-tier cancer center like MSK, an oncologist might be able to treat a patient based on a rare actionable variant, whereas the same might not be true at a community oncology practice with limited resources. 

"Not only were we looking within the US, but we were looking within MSK, which is, to be completely honest, a biased sample set," Chakravarty said. "It's an academic center with high expertise and intellectual capital focused in this center. … The likelihood of matching [a patient to a treatment based on a biomarker] would be far higher at MSK as compared to a community oncology hospital. Those are things that have to be taken into account while looking at this study."

Acknowledging that she and her colleagues looked into the "upper bound" of eligibility, Chakravarty said the Cancer Discovery analysis nonetheless underscores an important message that precision oncology is here to stay and that healthcare infrastructure and policies around test access need to change in step.

"Precision oncology is no longer as investigational as we used to believe," she said. "My hope is that all patients, in community cancer centers and safety net hospitals, when they get that diagnosis of cancer, the reflex option should be, 'let's test the tumor for biomarkers.'"

Insurers' willingness to cover biomarker tests remains unpredictable, especially on the commercial payor side. Chakravarty recognized that this, too, needs to change for precision oncology drugs to reach all eligible patients.