The lack of clinical access to N-of-1 personalized treatment for those hosting advanced cancer is a downstream crisis that rivals our upstream failure in comprehensive prevention through lifestyle and behavioral change. For decades, oncology has revolved around the drug rather than the patient, treating organs—lungs, breasts, colons—using guidelines designed for an assumed ‘average’ responder. That era must end.
We are witnessing a fundamental pivot from a drug-centric model to a patient-centric future. It is critical to distinguish between standard precision oncology, which matches biomarkers to population data, and N-of-1 care. N-of-1 integrates diverse datasets—ranging from molecular and multiomic testing to pharmacogenomics and live-tissue functional assays—to inform a strategy tailored to the individual.
This inexorable transition acknowledges a brutal biological reality: every metastatic tumor is a distinct, heterogeneous ecosystem. Each patient’s tumor microenvironment is unique; each patient’s host environment is unique. We must stop asking which organ the drug was built for and start asking what the patient’s unique molecular, metabolic and immune landscape demands. It is time to stop forcing individuals into the rigid boxes of legacy trials and finally place the patient at the center of the therapeutic universe.
While NCCN Guidelines are effective for many early-stage diagnoses, they are largely impractical for the ~600,000 patients with advanced, metastatic, refractory, or rare cancers. For many newly diagnosed advanced cancer patients, the standard of care is insufficient from the outset, leaving them with few options outside of clinical trials.
The sobering reality is that standard-of-care approaches for advanced disease—especially following multiple lines of treatment—may temporarily reduce tumor burden, but rarely improve key clinical endpoints like progression-free survival (PFS) or overall survival (OS). For these patients, the standard of care has effectively reached its limit.
Comprehensive clinical care for these patients with intractable disease must be inextricably tied to an N-of-1 investigational rubric. Only by treating within this regulatory framework can we provide access to the truly individualized care demanded by their molecular, metabolic, and immune landscapes. Without this shift, treatment effectiveness remains measured by extending survival by only a matter of weeks or months.
Those living with advanced malignancies have a profound unmet need for expert guidance and access to:
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Oncology trials were built for drug development, not for the delivery of N-of-1 personalized care. Traditional precision trials, such as NCI-MATCH and ASCO-TAPUR, remain population-level inquiries. They ask: “Does drug X work for the average person with mutation Y?”
The shift from traditional precision oncology to N-of-1 investigation marks a critical move away from population inquiries, which prioritize the average responder. While traditional trials rely on group-based statistics to determine if a drug works for a hypothetical average person, the WIN/UCSD strategy—shared below—focuses entirely on the individual’s unique molecular landscape. This statistical pivot replaces abstract p-values with the patient as their own control, utilizing the progression-free survival ratio to measure success.
By comparing a patient’s response on an N-of-1 regimen against their last ‘failed’ standard-of-care regimen, the treatment is deemed a statistical success if it extends stability by at least 30%. This anchors efficacy in individual survival reality rather than a population mean.
This paradigm relies on an open-label, prospective, and navigational basket model rather than the rigid RCT. By being open-label, these trials eliminate the ethical and clinical hurdle of placebos in advanced disease, ensuring full transparency for both physician and patient. As a prospective framework, the study is designed to capture real-world data in real-time, allowing for a master protocol that adapts as a tumor evolves.
This navigational agility empowers clinician-investigators to deploy the most effective therapies immediately—circumventing traditional trial “arms” to treat the patient not as a data point in a cohort, but as the study’s singular focus.
The WIN Consortium’s WINTHER precision oncology trial was a step in the right direction. It was followed by the more ambitious I-PREDICT N-of-1 personalized oncology investigation led by UCSD. However, plans for WINGPO represent the next leap in design and technological innovation. Here’s a closer look at this trio of investigations:
Pioneering as WIN’s research and the plan for WINGPO may be, charting the pragmatic path toward N-of-1 care is only part of the challenge. Formidable systemic barriers still stand between cutting-edge innovation and the clinical care needed most by patients living with advanced disease.
Even for the most affluent and proactive patients, wealth, connections, and a willingness to pay out-of-pocket are often no match for the structural obstacles blocking maximalist, data-driven personalized care.
We are currently in an era where AI and technology have outpaced NCCN clinical guidelines for treating most advanced, refractory cancers. While the development of novel agents remains critical, our primary challenge is not a drug deficit; it is an integration crisis.
There are currently ~250 FDA-approved anticancer drugs on the market. While 3- and 4-drug combinations are often necessary for highly refractory cancers, the sheer volume of possibilities is staggering:
These figures account only for approved anticancer agents—excluding roughly 1,700 other FDA-approved pharmaceuticals and numerous natural products with noted anticancer properties. Testing even a fraction of these through a traditional Randomized Controlled Trial (RCT) model is mathematically impossible. Furthermore, RCTs prioritize population averages, whereas N-of-1 care requires a focus on the individual.
While data is historically under-tracked, an estimated 30% of anticancer drugs are prescribed off-label—the highest rate of any medical specialty. Despite this clinical reality, insurance coverage remains precarious. Without prior authorization, reimbursement from Medicare or private insurers is never guaranteed. For a busy community oncologist, the administrative burden of constructing a compelling clinical rationale for these interventions is often prohibitive.
These advocacy efforts—much like navigating expanded access, compassionate use or Right-to-Try pathways—represent significant non-reimbursable time. Moreover, medications acquired through these programs cannot be marked up by the provider. Because drug markup is a primary driver of profitability for community clinics, the current system creates a practical economic disincentive to pursue personalized, off-label therapies.
Oncologists who treat patients as N-of-1 cases face significant reputational risk and potential legal exposure for deviating from guideline-driven care. In tumor boards, colleagues often default to caution, citing uninvestigated toxicities and a lack of established dosing protocols for novel regimens. This skepticism frequently persists regardless of the molecular data, live tissue functional testing, or sophisticated algorithms informing the recommendation.
WIN Consortium has the right vision with WINGPO. I truly hope Drs. El-Deiry and Kurzrock, et al. secure the necessary funding soon to continue this vital, next-gen personalized oncology trial.
However, for those hosting advanced, refractory, and rare cancers today, we must move with speed to positively impact the human condition. We need a clinical-investigation platform that is nimble, accessible, and orders of magnitude more efficient—at a fraction of the cost—than traditional trials.
We require a decentralized clinical-investigation platform that is both agile and accessible. By anchoring a regulatory-grade registry and a 24/7 IRB with a master protocol, we move beyond anecdotal treatment to high-fidelity science. This infrastructure provides advanced care to patients where they live while generating real-world evidence in near real-time. This is the cornerstone of an N-of-1 personalized cancer learning health system: a framework that captures longitudinal data from every patient to directly benefit the very next.
The transition to N-of-1 personalized oncology offers profound advantages across the entire oncology landscape:
The transition to N-of-1 personalized oncology is no longer a theoretical preference; it is a moral, clinical, and economic inevitability. However, the speed of this shift depends on every stakeholder across the ecosystem adopting a unified development framework.
Because this mission requires a massive technological lift and the disruption of some legacy business models, a nonprofit entity must steer the development of a pragmatic N-of-1 platform. Such neutral leadership is essential to launching the initial pilot while ensuring progress remains patient-centered.
This transition will be expensive, demanding, and time-consuming. Yet, it remains the only viable path to fundamentally elevating the human condition for many living with advanced disease.
Glenn Sabin, founder of FON and author of n of 1, is a nationally recognized thought leader who positions health innovators, enterprises, and organizations for sustainable growth. Leveraging deep experience in media, strategy, marketing, and business development—and his own compelling cancer journey—he champions personalized medicine and the generation of real-world data and evidence to help define a new, accessible standard of care.
Read Glenn’s story.
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