Whither Goest Thou, Radiopharmaceutical Therapy?

FEATURES OF TARGETED RADIOPHARMACEUTICAL THERAPY

With the exception of the latest entrant, ²²³Ra, an α emitter, all approved radiopharmaceutical therapies involve use of a β⁻ emitter. In some instances (¹³¹I, ¹⁵³Sm) the radionuclide emits photons that permit imaging; in others, the nuclide does not emit imageable photons and a surrogate image (bone scan for ⁸⁹Sr, ¹¹¹In for ⁹⁰Y) is used. Imaging is used only in a qualitative manner, to determine suitability. Rarely do we, in clinical practice, use imaging to quantify radiation-absorbed dose to the tumor (or normal tissue (7)). Although this may change with the increasing availability of quantifiable nuclides and imaging modalities, it is unlikely to become a standard part of our clinical practice. It is safe to say that imaging is used primarily to determine patient eligibility for therapy.

All approved radiopharmaceutical therapies used an imaging study performed to establish suitability of therapy. This is no longer universal—the requirement for an imaging study to evaluate satisfactory biodistribution of radiolabeled ibritumomab tiuxetan (Zevalin; Spectrum Pharmaceuticals, Inc.) in patients with follicular lymphoma is no longer essential (8); in differentiated thyroid cancer patients with rising serum biomarkers (thyroglobulin), too, ¹³¹I therapy is sometimes administered even when the diagnostic image is negative (though in this instance it is more of a last-ditch effort (9)). Most professionals engaged in radiopharmaceutical therapy will nevertheless rightfully insist that we are in the business of targeted therapy and therefore need to demonstrate targeting before therapy. The paper by Mier et al. (1) adheres to that tradition.

The paper also provides excellent justification for that tradition. Although the radiopharmaceutical targets melanin, it targets only 29% of lesions, and thus pretherapy demonstration of targeting is essential to prediction of efficacy. This use of a diagnostic biomarker to identify patients who may benefit from therapy is increasingly used in this era of molecularly targeted therapies, and examples include the use of a radioiodine scan before ¹³¹I therapy, bone scan before therapy for bone metastases, and immunohistochemical assays (in vitro imaging) to determine eligibility for immunotherapy (with trastuzumab or cetuximab).

Indeed, in this era of targeted therapy, it is becoming commonplace that a companion diagnostic will accompany a therapeutic through its development, with both undergoing comparable scrutiny on the road to Food and Drug Administration approval. It is therefore safe to conclude that the successful development (i.e., leading to regulatory and market approvals) of the agent proposed by Mier et al. (1) will involve the development of a predictive (imaging) assay and the radiotherapeutic itself.

TANDEM DEVELOPMENT OF COMPANION DIAGNOSTIC AND THERAPEUTIC RADIOPHARMACEUTICALS

Development seems fraught with peril not to mention financial jeopardy. If the purpose of the companion diagnostic is to identify patients likely to respond to the therapy (positive), how will such categorization be made? How will targeting be defined? Will excellent (however that is defined) targeting to a few of the lesions visualized on morphologic imaging be adequate, or will it be necessary to demonstrate targeting to all? How will the initial efficacy trials be constructed—will they be randomized: if yes, will randomization occur before or after imaging; if yes, will randomization be only in those patients with positive imaging, or in all? Questions roll on. All questions related to clinical trials of course have associated cost implications, and those in turn affect study design. It is imperative to address as many questions as possible before any efficacy studies are undertaken, so that as many clinical trials as possible fall under the carefully controlled rubric so beloved by regulators.

Issues related to product placement also need to be considered before initiation of the efficacy assessment process (an umbrella that includes all phase 2 and later trials leading to product approval). In this instance, given the increasing number of targeted therapies found efficacious in melanoma, what would be the patient population to be studied, and would that vary during the process (e.g., would efficacy studies select therapy-naïve or limited-therapy patients)?

Last but certainly not least: the therapy landscape is littered with promising therapeutic radiopharmaceuticals, none with a companion diagnostic imaging study: radioiodine in thyroid cancer is a grandfathered exception; bone scan positivity is similarly a clinically accepted term. Imaging before radioimmunotherapy may be considered diagnostic (to demonstrate adequate biodistribution), but it was sacrificed at the altar of convenience, with no substantive effect on use. Radiation phobia is a term tossed about to explain the lack of use of radiopharmaceuticals, and though its causes are ill-understood, its ill-effects cause angst over the future of radiopharmaceutical therapy. In sum, radiopharmaceutical therapy development currently is akin to traversal through uncharted territory to an uncertain goal.