Reimagining the future of cancer clinical trials

Oncology is facing a growing disconnect. Decades of advancement in basic research have spurred an unparalleled understanding of the pathology, molecular mechanisms, development, and immunology of cancers—spurring big dreams of personalized therapies and lasting cures. In 2024, however, taking a new anticancer drug from bench to bedside still requires nearly 8 years and $1.5 billion to $2.5 billion according to recent estimates, and the vast majority of efforts end in failure.¹ Meanwhile, clinical trial enrollment has lagged even at large academic medical centers, in part because information about particular trials often never reaches eligible patients.

New ideas are desperately needed, says Vivek Subbiah, MD, chief of early-phase drug development at the Sarah Cannon Research Institute in Nashville, Tennessee. The high cost and failure rate, “combined with the inherited inefficiencies and deficiencies that plague the siloed healthcare ecosystem, has led to a crisis in clinical research and drug development,” he says.

The coronavirus disease 2019 pandemic, interestingly, provided an unexpected opening for experimentation and reconsideration, Dr Subbiah and other experts note. Amid major disruptions to medical infrastructure and drug delivery systems, the US Food and Drug Administration (FDA) and other clinical trial sponsors permitted more flexible designs and a shift toward more patient-centric and intuitive evidence-generating strategies. The drug development community now is pondering whether some allowances could become permanent or least provide a framework for more flexibility in key areas without compromising patient safety.

One big trend is front-loading preclinical assessments and phase 1 trials to ramp up the early indications of a drug’s likelihood of success. Reformers have advocated leaning into the undeniably complex but rapidly expanding power of -omics technology—not just genomics and proteomics but also epigenetics, metabolomics, immunogenomics, and lipidomics—to make better sense of the data. The more granular information could give researchers a jump on understanding a drug’s promise in preclinical and early-phase trials and on identifying which patient subgroups are most likely to benefit. Phase 1 trials, for their part, traditionally have focused primarily on optimal dosage and safety. More recently, however, they also have begun to include demonstrations of a drug’s proof of mechanism or the treatment’s proof of concept.

“This upfront information, and all the information about the molecular portrait of every patient walking in the door with cancer, can enhance efficiency of trials by enrolling patients with a specific biomarker who have a higher likelihood of benefiting from an experimental drug—or any drug for that matter,” Dr Subbiah says.

Advances in precision medicine are adding new layers of complexity to the patient selection process. Clinicians are conducting increasingly intricate analyses to identify the most likely responders, such as verifying the presence of genetic targets in a patient’s tumors and the absence of potentially complicating factors. If improving patient selection creates more upfront work, experts such as Shivaani Kummar, MD, chair of molecular oncology and codirector of the Center for Experimental Therapeutics at the Knight Cancer Institute at Oregon Health & Science University in Portland, say that the added effort may be well worth it.

Dr Kummar points to the FDA’s recent approval of the anticancer drug tovorafenib as cause for excitement. The accelerated approval provided the first systemic therapy for pediatric patients with relapsed or treatment-refractory BRAF-altered low-grade gliomas. In the 76-patient, multicenter, open-label trial that helped tovorafenib to win approval, clinicians excluded children who were harboring additional activating molecular alterations such as IDH1/2 or FGFR mutations or who had a known or suspected diagnosis of neurofibromatosis type 1.

A big advantage of well-considered patient selection, Dr Kummar says, is that fewer enrollees may be needed to show a significant treatment effect. For tovorafenib, an overall response rate of 51% among the 76 patients was enough to win over regulators. “Creating and sustaining that infrastructure to do better patient selection, get more patients on these trials to expedite the evaluation of these drugs is, I think, one of the major challenges that we are facing,” she says. Earlier hints of clinical activity, in turn, could increase the motivation of oncologists to refer their patients to such trials and thereby aid enrollment, Dr Kummar says.

Observers have long cited a lack of data sharing among clinical trial sponsors as yet another obstacle to a more efficient drug-approval process. The publication of negative trial results, Dr Kummar and Dr Subbiah agree, could be particularly helpful. “If you work on a particular target and some things don’t work out in your pipeline or you learn something, if that was out in the scientific literature, then maybe the next sponsor that tries to do it may end up thinking about it differently and having a different development plan,” Dr Kummar says.

The US government may be the best positioned entity to bring more data sharing to cancer drug development. Since the FDA launched Project Optimus, which is aimed at encouraging the most efficacious dose in clinical drug trials by requiring sponsors to justify doses beyond just toxicity concerns, Dr Kummar says that she has seen a change in how trial sponsors are considering optimizing the recommended dose. The federal government could spur a similar change for data sharing, although she and other experts acknowledge the challenges of getting pharmaceutical companies to share more data—positive or negative—without being overly prescriptive and discouraging the considerable investment necessary for drug development.

Even so, the FDA has a global regulatory influence, Dr Subbiah says; what it requires in the United States tends to have a major impact on trials in other countries too. Through efforts such as Project Orbis, in fact, the FDA is seeking to improve regulatory coordination across the globe with the goal of providing earlier access to anticancer drugs approved in partnering countries.

“Harmonizing regulatory requirements and sharing data across continents and countries can reduce the duplication of efforts, decrease trial timelines, and ensure patient safety,” Dr Subbiah says. International collaboration also can improve access to clinical trials for patients in countries with limited resources and expertise, he adds. Reworking anticancer drug trials will not be an easy lift, but consensus is building on the need for fundamental change. “The status quo is not sustainable,” Dr Subbiah says.