Attention in cancer treatment has increasingly been turning to targeted therapies, with a goal of addressing unmet needs and improving patient survival and quality of life. One field that is growing rapidly is radiopharmaceutical therapy (RPT), also known as radioligand therapy (RLT).
Both a diagnostic and a therapy, RPTs consist of a molecule targeting a specific cancer cell receptor, combined with a radioactive element emitting cytotoxic radiation. However, unlike traditional focal radiation therapy, treatment is administered systemically and can therefore target more-widespread disease. Imaging confirms the treatment is delivered to the target and allows for the radiation dose to be quantified. In other words, radioligands also allow clinicians to visualize the tumor and thereby treat what they see[i].
So far, two radioligand therapies have been approved – both by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). These are Lu-DOTA-TATE (Lutathera®) to treat gastroenteropancreatic neuroendocrine tumors[ii] and Lu-PSMA-617 (Pluvicto®) for advanced metastatic prostate cancer[iii]. Both have been approved with complementary diagnostic imaging agents[iv].
While this emerging field offers huge promise for oncologists and cancer patients, there are challenges to overcome. This article explores the top three considerations for successfully developing radioligand therapy.
Radiation exposure
When using RPT, it is important to monitor the patient’s exposure to radiation both to determine if the treatment is effective while minimizing toxicity [v]. Dosimetry assessments are crucial to calculate the radiation dose that is absorbed by an individual’s tissues and organs to optimize treatment outcomes.
Some researchers in the field of radiotheranostics have coined the phrase Theranostics Audit Trail (ThAT), akin to the Pharmacological as a framework using individual dosimetry assessments for evidence-based decision-making on:
- Patient selection, as an entry point for ThAT, e. which patient is eligible to the proposed targeted therapy
- Patient monitoring to determine whether the treatment has been effective and to optimize its therapeutic index, and
- Review, for example at the end of every second cycle, to enable decision-making on further treatment continuation or restriction5.
Dosimetry plays an integral role in treatment optimization with targeted RLT.
Regulatory expectations
While Lutathera® and Pluvicto® came to the market fairly quickly, the FDA has since published a non-clinical guideline including all recommendations relating to biodistribution and dosimetry [vi]. Regulators now demand that submission dossiers contain solid justification for the doses used, not only of the radioligand but also of the carrier molecule.
The FDA’s 2019 guidance provides extensive recommendations for industry on the non-clinical program for RLT development in oncology, i.e. on the evaluation of toxicities from the ligand and evaluation of radiation toxicities. It offers clarity on the conduct of non-clinical distribution and dosimetry studies to guide dose selection from first-in-human trials, and provides guidance for product labeling related to reproductive toxicity, carcinogenicity, lactation, etc.
In 2024, the European Medicines Agency (EMA) issued a concept paper to identify issues specific to the development of RLTs[vii]. Among the issues it raises are the need for:
- Standardization of relevant terminology, e., “dose” in relation to “administered activity” and “absorbed dose”; “activity” in relation to anti-tumor effect and amount of RLT
- Systematic exploration of a wide range of administered activity early in the development, to establish maximum tolerated activity, identify dose-limiting toxicities, understand the relationship between administered activity and absorbed (radiation) dose, and start gathering data on dose-response relationship for late radiation-induced toxicity
- Systematic evaluation of dosimetry in clinical development and specification of the data requirements supporting individual posology recommendations
- Guidance for the management of RLT’s acute toxicity and when challenges are identified in performing direct dosimetry analyses
- Discussion on development strategies including study designs that are specific to RLTs to optimize patient treatment
- Discussion on the objectives of individually optimized treatment and how these might vary according to treatment setting.
Finding experts in this complex and niche field
Clinical pharmacology is crucial in the development of RLTs in order to demonstrate the doses and administration schedules used are both safe and efficacious. Characterization of the product’s efficacy and safety profile begins with a good understanding of the product’s biodistribution and the analysis of dosimetry data.
This analysis requires pharmacologists with expertise in the development of quantitative models to interpret and predict the kinetics, not only of the radionuclide but also of the ligand, since the availability of the radionuclide on tumor targets and in healthy organs is interdependent on the distribution, metabolism, and elimination of the ligand.
To demonstrate this interdependency, we advise that clinical pharmacologists and pharmacometricians integrate and interpret all the relevant data, from pre-clinical to clinical stage. They should adopt a strategic, iterative analysis of all upcoming data during the development supporting dosing recommendation that will meet regulatory requirements.
What makes this field complex and highly niche is that it requires experts in radioactivity combined with biodistribution of chemical and biological molecules to carry out quantitative and clinical interpretation of the data in order to precisely understand the exposure-response relationship with regards to efficacy and safety.
Conclusion: The future of RLT
RLT represents a promising advancement in cancer treatment, offering targeted approaches to improve patient outcomes. However, the development process requires careful consideration of issues such as radiation exposure requiring dosimetry assessments. Tightened regulatory guidelines also create new challenges for developers.
By leveraging specialized expertise, particularly in clinical pharmacology, innovators can harness the full potential of RLT, ultimately paving the way for new treatment options for cancer patients.
About the authors:
Alexia Blesius, PharmD, MSc, is Director, Development Consulting and Scientific Affairs, at PharmaLex. She has 20 years of experience in R&D pharma company acting first as clinical pharmacologist and then as asset leader of several drug development programs from preclinical stage up to registration at global level.
Elisabeth Rouits, PharmD, PhD is Senior Director, Head of Clinical Pharmacology and Translational Medicine in Development Consulting and Scientific Affairs. She brings to the role more than 20 years of industrial and academia (hospital) experience in clinical and quantitative pharmacology and translational science. She is committed to optimize anticancer agents’ chance of success by developing several individualized therapeutic approaches by maximizing efficacy while limiting safety risk.
[i] Radiotheranostics in oncology: current challenges and emerging opportunities, Nature, Aug 2022.
[ii] Lutathera®: The First FDA- and EMA-Approved Radiopharmaceutical for Peptide Receptor Radionuclide Therapy, Pharmaceuticals, July 2019
[iii] FDA expands Pluvicto’s metastatic castration-resistant prostate cancer indication, FDA, March 2025. FDA expands Pluvicto’s metastatic castration-resistant prostate cancer indication | FDA
[iv] Radiopharmaceuticals and their applications in medicine, Signal Transduction and Targeted Therapy, Jan 2025.
[v] Radiotheranostics in oncology: Making precision medicine possible, A Cancer Journal for Clinicians, 2023.
[vi] Oncology Therapeutic Radiopharmaceuticals: Nonclinical Studies and Labeling Recommendations Guidance for Industry, FDA, Aug 2019. https://www.fda.gov/media/129547/download
[vii] Concept paper on clinical evaluation of therapeutic radiopharmaceuticals in oncology, EMA, Oct 2024. https://www.ema.europa.eu/en/documents/scientific-guideline/concept-paper-clinical-evaluation-therapeutic-radiopharmaceuticals-oncology_en.pdf
