Functional Precision Medicine: Putting drugs on patient cancer cells and seeing what happens

Abstract

For too long, assays exposing patient tumor cells to drugs to identify active therapies have been dismissed as ineffective. In this issue of Cancer Discovery, two groups independently demonstrate clinical utility of such functional precision medicine assays in hematologic malignancies.

Some twenty years ago, a long-forgotten, non-medical acquaintance asked me what I did as a cancer researcher: “What do you do, like, put drugs on cancer cells and see if they work?” I suppressed a complacent chuckle at the absurd simplicity of this notion from someone so obviously ignorant of the splendid arcana of cancer biology. “No, no, it is much more complicated than that. Genes… signaling pathways… axes….mutations, very complex.”

And yet, there is something very obvious and compelling in the logic that if you want to know if a particular drug will kill a patient’s cancer, put the drug on the patient’s cancer cells and see what happens. Why don’t we do that? There was a time, roughly 1980–2000, when there was considerably more enthusiasm for this idea. However, the so-called ex vivo chemosensitivity assays investigated two decades ago never provided compelling evidence of improving patient care. For this reason, several influential articles discouraged their routine use in the clinic(1–3). The general response I got when I asked my colleagues about these assays was, “Yeah, people have tried it and it doesn’t work.”

Why was the utility of these assays limited? For one, they were being studied on very few drugs in an era before targeted therapies. For another, ex vivo culture conditions were relatively primitive. Overgrowth of normal cells was a problem, so that more normal cells than cancer cells would sometimes be studied. Technology to study single cells was primordial, so simple bulk assays dominated. Very often these assays measured bulk metabolic properties that imperfectly correlated with cell death. Finally, prospective clinical trials demonstrating patient benefit were lacking.

A couple of important events drove attention further from ex vivo assays. In a landmark event for cancer biology in 2001, a small molecule kinase inhibitor, imatinib, was shown to dramatically improve the outcome of patients with chronic myeloid leukemia (CML) by targeting a genetic alteration nearly universal in this disease(4). Also in 2001, the first draft human genome was completed, ushering in an era of ever-improving genomic sequencing techniques, bringing genomic analysis of any tumor into practical reality(5). Cancer centers and commercial entities began touting their ability to use these next-generation genomic technologies to match patients to the drugs that would treat their individual tumors. The pathway to precision medicine, identifying the right drugs for the right cancer patient, seemed clear. Sequence everyone’s tumor, identify the genetic abnormalities, and match them with drugs targeting those abnormalities just as in CML.

This strategy has certainly produced some true clinical successes, including targeting EGFR mutations in non-small cell lung cancer, BRAF in melanoma, and TRK mutations in a variety of tumors. However, clinical reality has forced a recalibration in expectations of a purely genomic based precision oncology strategy. For several reasons, including the lack of targetable mutations and the lack of useful drugs for certain promising targets, most cancer patients do not benefit from genomic precision medicine. These limitations have contributed to a re-examination of alternative precision medicine strategies.

The last 20 years have seen many technological advances that enhance ex vivo study of patient tumor samples. For one, we have much better and more varied culture systems for the study of patient samples ex vivo in both 2D and 3D formats. We have many more and better assays to measure changes induced by drug perturbations. We have the ability to study single cells in detail impossible two decades ago. We have vastly improved bioinformatic capabilities that allow the combination of complex drug response data with any number of clinical and molecular annotations. Finally, there are simply vastly more cancer drugs and tool compounds to test, greatly increasing the chances of finding at least one active drug.

Important work from Tyner and colleagues demonstrated the feasibility of functional precision medicine strategies in hematological malignancies and lent confidence to other related efforts(6,7). Many papers followed showing the feasibility of such platforms or describing anecdotes of clinical benefit. However, there is a lingering need for prospective clinical trials to estimate the clinical benefit of FPM. Two papers in this issue of Cancer Discovery begin to address this need(8,9).

Kornauth et al report findings of the EXALT trial, a study deploying their single-cell functional precision medicine (scFPM) assay(8). They used high content microscopy and automated image analysis to evaluate the effects of 139 drugs on samples from 143 patients with hematologic malignancies including acute myelogenous leukemia (AML) and B- and T- non-Hodgkins lymphoma. These were patients without standard of care options remaining, median age 64, and a median of 3 prior therapies. 76 patients were evaluable, 56 of which were treated according to scFPM results as determined by an expert tumor board. Since this was essentially a collection of N=1 trials, to evaluate the quality of the therapy assigned by scFPM each patient’s progression-free survival (PFS) was compared to PFS from their prior therapy. Normally, the observation in oncology is that subsequent therapies generally produce shorter and shorter PFS. In this trial, however, 30 out of 56 (54%) demonstrated a PFS of at least 1.3 times the duration of that from prior therapy, with a median PFS ratio of 3.4. Perhaps even more impressive was the 21% rate of exceptional response, defined, as by others previously, as a PFS triple the expected median response(10,11). Some of these were patients who were previously ineligible for stem cell transplant but who subsequently received one after achieving a complete remission. The 20 evaluable patients who were treated according to physician choice rather than scFPM, though not a pre-specified control arm, served as a comparator. Compared to physician choice, scFPM-treated patients showed both a PFS and an overall survival benefit.

Malani et al focused on AML samples(9). Their simpler drug sensitivity and resistance testing (DSRT) assay relied on bulk ATP measurements of mononuclear cell samples from AML patients that contained blasts, but also non-malignant cells. While the tumor board had the option to consider genomic and transcriptomic data, these were usually not available by the time a treatment decision was made, due to their longer turnaround time compared to DSRT, which took roughly 4 days to complete. They found an actionable drug for a remarkable 97% of patients via these methods. DSRT recommendations were implemented, however, only in 37 of the 186 patients tested. The main reason for this attrition is that most patients were treatment-naïve and had standard treatment options available. Of the 37 patients treated according to DSRT, all relapsed or refractory, 59% exhibited a clinical response including 13/37 complete responses.

How does the clinical utility of these functional assays compare to that of widely used genomic precision medicine assays? Given the near universal adoption of genomic precision medicine assays for a variety of cancers, this question is surprisingly hard to answer. While publications on genomic precision medicine studies often report rates of logistical success or of identification of actionable mutations, studies of clinical response are remarkably difficult to find. Kornauth et al provide a helpful summary in their Table 3(8). Populations among all these studies vary widely, so comparison is necessarily inexact. However, in the genomic studies response rates of patients receiving genomic testing were rarely above 10%, so that the functional assays here generally compare favorably. However, there is no need to force -omic and functional approaches into opposition. In the future, a rational use of both classes of assays is likely to be better than either alone.

A decade of clinical experience has made clear that finding the right drugs for individual patients, the central job of precision oncology, requires more than genomics. These papers show that, at least in hematologic malignancies, functional precision medicine provides a very credible adjunct to widely accepted genomic methods. To find a place in everyday clinical practice, FPM will benefit from more prospective trials evaluating patient clinical response across a wider variety of tumors. To this end, the EXALT 2 trial (NCT04470947), run by the same people who produced the EXALT trial, will randomize advanced cancer patients to arms in which therapy is directed by either functional means, genomic means, or physician choice.

Both studies demonstrate that “it doesn’t work” is now too blithe a response to queries about functional precision medicine. That FPM does “work”, at least in the hematologic malignancy context, now seems clear. It now remains to be seen how rapidly and to what extent this exciting approach, simultaneously novel and old-fashioned, takes its place in standard clinical care of the cancer patient.