The promise of precision medicine is that patients will benefit most if they are treated with a drug that is matched to their specific disease. Why, then, are most Phase 1 and Phase 2 cancer trials still performed on unselected patients, even when there is a strong biomarker hypothesis underlying the program? The problem is two-fold. First, most biotech or pharmaceutical companies are reluctant to pre-select patients in Phase 1 and often Phase 2 trials because, even if they know the biomarker, this requires screening many patients to find the few that are “biomarker positive”. If, for example, the biomarker is present at 5% frequency, this means screening 100 patients to find 5, which is slow, inefficient, and expensive. Companies thus resort to running trials in unselected patients, which means that most patients participating in these trials stand very little chance of benefiting from the drug. This is a gross disservice to the patient, but also puts the drug at risk, as lack of responses in early clinical trials frequently leads to discontinuation of entire programs.
Second, the problem is compounded by the very nature of cancer. Unlike other diseases, cancer rapidly evolves. As patients are treated with different agents, their tumors adapt, acquiring new mutations or activating different pathways in order to circumvent each new round of therapy. This means that, in order to match a patient to their ideal therapy, we need to assess their current disease state, not their disease when they were first diagnosed with cancer. This presents a significant challenge in the clinical trial setting. To obtain relevant tissue, patients often need to undergo a core needle biopsy, which is a painful and risky procedure. Although "liquid biopsy" technology (i.e., analyzing cell-free circulating tumor DNA) provides a way around this problem for genetic biomarkers, it is not applicable to non-genetic biomarkers such as proteins and metabolites. Nevertheless, most patients are willing to undergo a biopsy if it means being treated with a promising new therapy. They are not, however, willing to get biopsied if they then stand a 95% chance of not qualifying for the study. To circumvent this problem, most biomarker-selected trials (i.e., precision medicine trials) rely on archived tissue blocks that were obtained by surgery when the patient was first diagnosed with cancer, often 5-10 years earlier, rather than on fresh biopsy material, which is more representative of their current disease.
Both of these problems may be solved through a simple and efficient system that places the patient first, rather than the drug. Currently, biotech/pharma companies each run their own independent clinical trials, incurring substantial costs in both time and money devoted to trial design, startup activities, and advocacy efforts (Figure 1A). At best, these trials run independently and at worst, they compete with each other. As an alternative, Precision Medicine Clinical Trial Co-operatives could be set up in which any organization seeking to develop a drug could participate (Figure 1B). Initially, the co-operatives could be indication-specific, meaning that there would be a separate multi-arm trial for each major type of cancer (breast, colorectal, lung, etc.). Ultimately, if successful, this could be brought under a single umbrella program.
To participate in the co-operative, a company would have to supply a “drug/biomarker pair”: an investigational agent coupled with a fully qualified biomarker assay. A committee would then review the submission and, if appropriate, both the drug and assay would be incorporated into the ongoing multi-arm trial. Any patient consenting to the trial would provide tissue (core needle biopsy), as well as blood and urine for biomarker testing. Their samples would be tested by full genomic profiling, as well as the full suite of company-supplied biomarker assays that are not covered by genomic testing (i.e., protein- or metabolite-based tests). One big advantage of this system is that drugs that do not target genetic abnormalities, but instead focus on the myriad other ways in which tumors can arise, progress, or develop resistance, would receive equal attention, something that is often missed in this increasingly genomic-focused era. The challenge, of course, would be to ensure that all the tests could be run with the available tissue, possibly necessitating the multiplexing of some types of biomarker assays (e.g., immunohistochemistry assays, in-situ hybridization assays, metabolite assays, etc.).
To protect companies’ interests, data on each patient would only be provided to the company supplying the drug for that patient while that drug is being assessed. Companies can “buy in” to the trial at any point and pay for the study on a per-patient basis. This cost structure enables companies to pursue important but rare disease segments, thereby removing a large economic barrier to the development of drugs for orphan indications. Once a pre-specified number of patients enroll for a given drug/biomarker pair, the arm would close and the company would be required to publish their results within a reasonable period of time.
This idea of pay-as-you-go, multi-drug clinical trial co-operatives enables both single arm (Phase 1) and randomized (Phase 2/3) studies. In early stages of drug development (Phase 1), the goal is to obtain safety information on the drug, as well as early signs of efficacy. It is almost unprecedented to run first-in-human dose escalation studies in biomarker-selected patients, yet the concept of clinical trial co-operatives lowers the barrier doing this, ensuring that every patient counts. At the same time, one of the biggest challenges of developing precision medicines is that it is often not known how the status of a new biomarker affects patient prognosis. This means that there are often no reliable historical data to benchmark the performance of a new drug. It is therefore critical to obtain efficacy data on a new drug in comparison to a control arm when working in biomarker-selected populations. Clinical trial co-operatives could be set up to enable the seamless flow from single arm studies (dose escalation and Phase 1 expansions) into randomized studies with appropriate control arms (Phase 2 proof-of-concept). In principle, these co-operatives could even be used to feed enrollment into biomarker-selected Phase 3 registration studies.
The success of this idea depends on widespread participation: the greater the number of companies that participate, the higher the probability that a patient will be matched to an appropriate treatment arm. With enough participation, every patient would be matched to an arm (“no patient left behind”). As an initial test of this idea, Merrimack is currently running a multi-arm, biomarker-selected Phase 1 clinical trial in late-stage colorectal, head and neck, and non-small cell lung cancers (Figure 1C). Every patient entering the trial must submit a fresh core needle biopsy. The biopsy is then assayed for multiple biomarkers, including both genetic and non-genetic biomarkers. Based on the results of these assays, patients are assigned to one of four treatment arms. At this point, only patients that score positive for one type of mutation are excluded from the trial, which means that patients have a >95% chance of qualifying for the study once they consent to the biopsy. This trial is currently sponsored by Merrimack and addresses specific questions around the safety and preliminary efficacy of novel drug combinations. This seed idea, however, could be expanded dramatically and benefit far more patients if it included promising new precision medicines from many different drug companies and if the effort were driven by a neutral third party (such as the Kraft Family Foundation). As a significant additional benefit, trials like this could also promote collaboration between participating companies, particularly in the cases in which patients are found to score positive for more than one of the biomarkers in the panel. This situation presents an exciting opportunity for novel/novel drug combination therapy, which could ultimately move the needle to an even greater degree.