Can agnostic therapies revolutionize precision oncology? Are we ready to treat cancer without looking at the organ? For decades, cancer has been told as a story of organs: lungs, breast, colon, etc. Each diagnosis implied a predictable therapeutic path. In recent years that map has begun to blur, and in oncology clinics it is increasingly common for specialists to focus less on the patient’s cancer type and more on the molecular alteration driving its growth. The idea is to concentrate on the molecular footprint rather than the organ — a shift that is transforming precision oncology.

Agnostic tumors are defined by sharing a specific molecular alteration — a biomarker — that acts as the driving force of the disease, regardless of the affected organ. If that marker is present, the treatment can be the same even if the tumor arises in different tissues. This difference, seemingly technical, is redefining how cancer is researched, regulated, and treated in the 21st century.

In recent years, this approach has been consolidated with agnostic indications approved by regulatory agencies. These indications are being progressively incorporated into European and Spanish guidelines. They have a particularly relevant impact on rare tumors and patients without therapeutic alternatives. Nonetheless, this innovation requires caution because most of these approvals are based on single-arm studies with few patients and no direct comparators. And anatomy has proven to remain relevant.

Three Therapeutic Families

This therapeutic shift began in 2017, when immunotherapy with pembrolizumab became the first treatment approved with a truly agnostic indication. It was aimed at tumors with microsatellite instability or DNA repair deficiency. Six years later, that approval was reinforced with data from more than 500 patients and more than 30 different cancer types, confirming that the benefit transcended classical histology boundaries.

Since then, the catalog has expanded and nine tissue-independent therapies have now been approved by the FDA. They fall into three major families. First, targeted treatments against targets such as neurotrophic tyrosine receptor kinase (NTRK) fusions, BRAF V600E mutations or rearranged during transfection (RET) fusions, with highly selective inhibitors and high response rates across multiple histologies. Second, immunotherapy guided by global genomic biomarkers such as microsatellite instability-high/deficient mismatch repair (MSI-H/dMMR) or high tumor mutational burden. And, more recently, an antibody-drug conjugate against HER2 for tumors with intense overexpression (HER2 3+), regardless of tissue of origin. In some cases, these indications do not distinguish between adults and children, something unprecedented in traditional oncology regulation.

The key is that these alterations do not “belong” to a single cancer type. An NTRK fusion can appear in a sarcoma, a lung tumor or a salivary gland tumor. An MSI-H phenotype can occur in colon, endometrial, or stomach cancers. When that happens, the treatment is the same. This has driven the development of transverse clinical trials called basket trials, which group patients by biomarker rather than organ. That strategy has been decisive for progress in rare tumors where classic trials are unfeasible.

Real-World Evidence

In this context, biology remains important. The accumulated evidence shows that histologic context and genetic alterations influence the magnitude and duration of the response, even when the primary biomarker is the same. Therefore, agnostic oncology does not replace classical tumor knowledge but rather redefines it. First, the molecular fingerprint, then the context in which it acts.

Real-world implementation of the model depends on universal genomic testing, clinicians trained in oncogenomics, and more innovative trial designs. It also depends on regulatory frameworks capable of adapting to a medicine that no longer focuses solely on organs. Current work focuses on generating real-world evidence to demonstrate a tangible improvement in patients’ lives.

A study published in Nature Communications (2025) analyzed nearly 300,000 tumors — one of the largest studies to date — and found that 21.5% had at least one alteration with an approved agnostic indication. A proportion unthinkable just a decade ago.

At the same time, 5.4% did not fit any specific indication, highlighting both the progress of the model and the gaps that remain. Thus, not all tumors are covered by precision oncology, but fewer are falling outside the molecular radar.

Distribution is also highly uneven. Depending on tissue of origin, the prevalence of tissue-independent indications ranges from 0% to 87%. That variability confirms that the agnostic approach does not eliminate tumor biology. Some cancers concentrate clear targets while others remain territories without effective molecular options.

Real but Uneven Efficacy

NTRK fusions, for example, show objective response rates above 70% with larotrectinib or entrectinib, regardless of tissue of origin. Similarly, MSI-H/dMMR tumors treated with PD-1 inhibitors exhibit durable responses across multiple histologies. However, efficacy is not uniform.

The presence of co-occurring genetic alterations can significantly modify treatment response. This is seen in tumors with concurrent KRAS G12C mutations or in genes such as STK11 and KEAP1, where reduced sensitivity to targeted inhibitors has been observed, even when the primary biomarker is present. Therefore, tumor biology remains a determining factor.

Moreover, even if a colon tumor and a sarcoma share an NTRK fusion, the immune microenvironment and epigenetic factors can influence efficacy and the duration of response, as noted by the European Society for Medical Oncology’s (ESMO)Precision Medicine Working Group. This reinforces the need to combine molecular information with knowledge of tissue of origin to optimize therapy selection.

An Invisible Gap

Another blind spot is that the same data that confirm the potential of the agnostic model also expose its main vulnerability: the gap between identifying a target and effectively treating it.

For rare but treatable alterations such as NTRK fusions, the Nature Communications study confirms that only about a third of patients receive a specific inhibitor. That is striking given that three regulators have approved agents: larotrectinib, entrectinib, and repotrectinib with high response rates and better tolerability than conventional chemotherapy. Still, their use remains low. Identifying the molecular needle does not guarantee that it will be implemented into clinical practice, the researchers warn.

The problem is not only diagnostic. Adoption of agnostic therapies, ESMO notes, depends on multiple factors: access to advanced next-generation sequencing (NGS), speed in diagnostic pathways, experience of multidisciplinary teams and regulation adapted to agnostic models. Even in lung cancer — the paradigm of precision oncology, where there are more than 10 biomarker-guided therapies — proper adoption of molecular testing and treatments is only about 50% in clinical practice.

This gap is amplified in regions with limited access to drugs or diagnostic technology, creating inequality among patients with identical molecular profiles. Healthcare systems remain organized around anatomical classifications, while precision oncology requires a transversal, biomarker-based approach. This disconnect is one of the main barriers today to turning scientific innovation into tangible improvements in patient survival and quality of life.

Vanguard and System Limits

In Spain, agnostic oncology has begun to be explicitly incorporated into the Spanish Society of Medical Oncology and GEMCAD-TTD group’s Guide to the Management of Biliary Tumors and Agnostic Therapies (2025). They recommend broad genomic sequencing, determination of molecular biomarkers and the search for rare fusions such as NTRK and RET — especially to select targeted therapies or immunotherapy.

The therapeutic positioning report from the Spanish Agency for Medicines and Medical Devices on larotrectinib recognizes the rarity of NTRK fusions. It also emphasizes the need for genomic sequencing and recommends its use in advanced solid tumors that are NTRK-positive and lack effective therapeutic alternatives. Both documents lay the groundwork for the approval and funding of agnostic therapies in the public health system.

At the hospital level, reference centers such as the Vall d’Hebron Institute of Oncology,Barcelona, Spain,and other tertiary hospitals have systematically integrated NGS panels into diagnostic pathways. They participate actively in basket trials and expanded access programs, evaluating targeted drugs for NTRK, RET, BRAF and HER2 in a pan-tumor approach.

This story was translated from El Medico Interactivo, part of the Medscape Professional Network.