How Genetic Drivers Are Driving New Approaches To Clinical Trials For Rare, Genomically Defined Cancers
By Shawn Leland, PharmD, RPh, Founder and CEO, Elevation Oncology
Advances in genome sequencing, coupled with the understanding of how certain genomic alterations drive tumor growth, have ushered in the era of precision medicine. Utilizing precision medicine, patients with cancer can be specifically matched to a targeted therapy based on the genomic alterations found in their individual tumor. As the numbers of these genomic drivers and the therapies developed to target them continues to increase, the oncology community is also witnessing a shift away from long-standing approaches to the management and design of clinical trials.
Clinical development of cancer therapies has traditionally relied on a contract research organization (CRO)-based model in which the trial sponsor selects a CRO partner that identifies and sets up multiple trial sites, recruits patients, and activates the sites as patients are enrolled. These trials are usually in “all comers,” whose tumors have a particular tissue of origin, such as the breast or lung; but they may be in a tumor type that is driven by a relatively frequent genomic alteration, such as BRCA1 mutations in breast cancer and EGFR mutations in lung cancer, where recruiting enough patients for the trial is not especially difficult.
However, the traditional model is not feasible for genomically defined cancers that are driven by rare genomic alterations, for example, oncogenic fusions of NRTK1 or NRG1. Many trial sites must be set up in order to recruit enough patients to power the trial in a timely fashion. Given the rarity of the alteration, the vast majority of sites will probably not enroll a single patient because the likelihood of finding patients with the target alteration in any one tumor type is exceedingly low; yet maintaining those sites still incurs significant overhead, regardless of enrollment. Unfortunately, it is likely the sponsor will never find enough patients to run the trial to completion at all when using the traditional model to develop a precision medicine.
For these reasons, the time and cost of developing a drug for a genomically defined cancer in a single tumor type is not a commercially viable proposition within the traditional models of clinical trial design and site management.
These factors have precipitated a paradigm shift to a “driver alteration-first” model of clinical development, in which the genomic alteration driving tumor growth, not its tissue of origin, determines the clinical development pathway. This paradigm is based on the concept that if the biology induced by the mutation is the same across multiple tumor types, then it is scientifically and clinically sound to develop a drug for any tumor type with that mutation – a tumor-agnostic approach – rather than one tumor type at a time. Indeed, multiple published studies have demonstrated that tumor-agnostic clinical trials in genomically defined populations have a twofold higher success rate than trials of “all comers” in unselected patient populations.
The emergence of the “just-in-time” model of clinical development further bolsters the tumor-agnostic approach. In this model, a trial site is only activated when it identifies and enrolls a patient whose tumor harbors the specific driver alteration. A site can be activated quickly, typically less than two weeks after finding the patient; hence the name “just-in-time”. But the real beauty of this model is that the trial sponsor carries overhead only for the sites that are activated. These features make the just-in-time model very capital- and time-efficient, particularly for clinical trials in a rare, genomically defined patient population.
Driving the Paradigm Shift
Several factors are driving this shift to tumor-agnostic clinical trials of targeted therapies for tumors with rare mutations.
Chief among them are the advances in next-generation sequencing (NGS) technology that now enable the detection of rare alterations in tumors with high sensitivity. This is especially true for NGS of RNA, which has a higher sensitivity than NGS of DNA for certain types of alterations, such as oncogenic fusions, whose DNA has large intronic (non-coding) regions that makes it difficult to accurately identify the individual fusions. But these intronic regions are removed from the final RNA during gene splicing, making the detection of the fusion transcript more sensitive and robust. Thus, while the sensitivity of NGS DNA for oncogenic fusions is about 33%, it is 90% or higher for NGS RNA.
Tumor-agnostic trials in genomically defined cancers are also aided by growing number of diagnostic companies with tests to detect rare genomic alterations of interest. For example, over the past couple of years, the number of companies with tests capable of detecting NRG1 oncogenic fusions has grown from only two, to upwards of ten.
Another key factor is regulatory buy-in on the new paradigm: since 2017, FDA has issued four approvals for drugs whose clinical trials were run in a tumor-agnostic manner, including the anti-PD-1 antibody pembrolizumab for microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) tumors, as well as larotrectinib and entrectinib for solid tumors harboring NTRK fusions.
Although FDA and other regulatory bodies have not issued formal guidance for a tumor-agnostic development pathway, these approvals have established a regulatory precedent, paving the way for other drugs to follow. The perception that the tumor-agnostic approach is gaining traction within FDA has inspired more companies to consider developing drugs for genomically defined cancers in this way.
Boosting Genomic Testing
Despite the cost-effectiveness and better success rates for the tumor-agnostic paradigm, there are still barriers that limit how widely the paradigm can be implemented.
Inertia is one barrier. Many companies continue to design and conduct trials along traditional lines, despite the demonstrable benefits of cost-effectiveness and better success rates for the newer approach.
That said, the largest barrier to surmount is the relatively low rate of genomic testing among patients with cancer. Ideally we would want to see 50-90% of tumors tested, as we now see for patients with NSCLC, but the low rates of 15-20% we currently see across many other tumor types highlight the importance of educating both patients and physicians on the benefits of testing.
Patients should be made aware that genomic testing of their tumors could open the door to effective treatment options beyond chemotherapy or immunotherapy, by matching them to a drug tailored to the cause of the cancer itself. These targeted therapies tend to come with significant safety benefits, a higher likelihood of a positive response to treatment, and a better quality of life.
Physicians, understandably, are often reluctant to refer a patient for genomic testing unless there is a matching approved drug that would warrant the test. Otherwise, there is little benefit or cost-effectiveness in testing; and many genomic tests, while approved, are not reimbursed by insurers unless a corresponding therapeutic is matched. It’s the classic “chicken-and-egg” conundrum: without the matching drugs, genomic testing is limited; but without the testing, development of those drugs is limited.
Escaping the conundrum means testing and drug development must progress in parallel – and that would be aided by raising awareness about the importance of genomic testing among patients and physicians. Identifying more patients with rare genomic alterations could help power tumor-agnostic clinical trials of therapies targeting those alterations; a larger number of such trials would result in more of those therapies receiving approval and reaching the market; and with more therapies on the market, the number of patients “matched” to a therapy for their tumors will increase.
This is the true importance of tumor-agnostic trials for therapies to treat genomically defined cancers: by speeding their development and enhancing their commercial viability, more patients with cancer will experience the therapeutic benefits and quality of life improvements these therapies may offer.
Shawn M. Leland is the Founder and Chief Executive Officer of Elevation Oncology overseeing all day-to-day operations. Shawn brings over a decade of experience in medical affairs and business development for the pharmaceutical/biotech industry, with a focus on building collaborations to realize the full potential of targeted and personalized therapeutics. Shawn has been involved in global transactions totaling more than $450 million in upfront payments and milestone payments at Eli Lilly, ARIAD Pharmaceuticals, Argos Therapeutics and Verastem Oncology. Shawn has also served as an expert strategic consultant for Catenion providing guidance on portfolio management for pharmaceutical/biotech companies.