The Brave New World of Radiotherapeutics

Radiotherapeutics have evolved from early proofs-of-concept to oncology powerhouses, propelled by treatment gaps, Novartis’ Pluvicto and better supply chains and logistics.

The field is ripe for exploration, with enormous potential due to the multiplicity of cancer surface targets to be addressed with different carriers, isotopes and formulation methods, said company executives in interviews with BioSpace.

Dr. Philip Kantoff is the co-founder & CEO of Convergent Therapeutics. Prior to the company’s initiation, early Prostate-Specific Membrane Antigen (PSMA)-targeted radioantibody data from Cornell University in New York intrigued him. The data showed that Actinium-225, an alpha-emitting isotope, in a single-dose study showed responses in roughly 45% to 50% of heavily pretreated prostate cancer patients.

The opportunity to further develop a therapy with an attractive safety profile development in metastatic castration-resistant prostate cancer (mCRPC), where treatment options are very limited after hormonal therapy and chemotherapy, convinced Kantoff to move from academic medicines to biotech leadership.

For Dr. Marc Hedrick, president and CEO of Plus Therapeutics, and a former academic surgeon and physician scientist, noted his motivation to join biotech leadership came from decades of largely flat survival outcomes for central nervous system (CNS) cancers.

While Plus started as a targeted radiotherapy company, it came to recognize that diagnostics have not kept pace with disease complexity, especially in leptomeningeal cancer, primary brain cancers and brain metastases. The company’s wider strategy now combines therapeutics, diagnostic and data analytics to improve those survival metrics.

Radioisotopes showed proven efficacy approximately 70 years ago with Iodine-131 (I-131) for treating thyroid diseases, Hedrick and Kantoff agreed.

But GlaxoSmithKline Bexxar (tositumomab and I-131 tositumomab), a targeted radioimmunotherapy used to treat specific, relapsed or refractory CD20-positive, follicular NHL, didn’t fare as well commercially. The company pulled the asset from the market in 2014.

The news elicited subsequent caution for radiotherapy development, Kantoff said.

A major turning point in radiotherapy development arrived with the commercial success of Novartis’ Pluvicto, they agreed. It demonstrated both clinical benefit and commercial viability in a large tumor setting, Kantoff said.

Pluvicto, approved by the FDA in 2022, is a targeted radioligand therapy for adult men with progressive, PSMA-positive mCRPC. The therapy combines a targeting compound (ligand) with a therapeutic radioactive isotope (Lutetium-177).

Another advance in radiotherapies in prostate cancer is Bayer’s Xofigo (Radium-223 dichloride), Kantoff said. Xofigo is an injection is used to treat prostate cancer that no longer responds to hormonal or surgical treatment that lowers testosterone. It is the first targeted alpha-particle therapy that not only controls bone pain but also significantly lengthens survival for patients with mCRPC that has spread to the bones.

Radiation to address brain cancer has a long history, particularly with external beam radiation, Hedrick said. Examples include X-rays, protons or electrons, directed at a tumor from outside the body. To overcome the complications of offsite toxicity, radiation oncologists will employ fractionation, where patients are given a specified maximum dose over multiple days to improve survival, Hedrick explained.

Plus Therapeutics’ approach aims to carry much more radiation directly to the tumor, with minimal systemic and bone marrow toxicity, Hedrick said. The delivery technology, formulation and isotope together allow the company to intensify dose. Early phase data in glioblastoma suggest improved survival, he added.

Back in 2021, industry concerns presented as to whether sufficient Actinium-225 could be produced for clinical and commercial use. Initial isotopes supply came from Department of Energy, and other material was derived from radioactive waste sources, Kantoff said.

But the scenario has improved substantially, due to pharma development interest, and there are now accelerated generated methods enabling commercial-scale production of multiple isotopes, Kantoff said.

Hedrick agreed the supply field has increased with a growing number of service providers, contract manufacturers and radiation specialists.

Lutetium-177 and Actinium-225 remain the most requested isotopes, “reflecting their dominant position in clinical radiopharmaceutical pipelines,” said Denis R. Beckford-Vera, PhD, head of radiopharmacology at CRO Champions Oncology.

For Plus Therapeutics, having both a primary and backup radiation service provider is important, especially because its isotope has a longer half-life, Hedrick said.

Still, one of the biggest challenges in radiotherapeutics remains ensuring drug is sent to the patient on time, he added, due to isotopes often having short half-lives. However, as Plus Therapeutics has a drug with a 90-hour half-life, “we have some wiggle room in terms of if the patient is late to clinic or so forth,” Hedrick said.

The field is bright for radiotherapy due to variable cancer surface targets that can be zeroed in by small molecules, peptides and antibodies, Kantoff said. The field is “still in its infancy” when it comes to matching isotopes, targets and delivery strategies, he added.

There are multiples variables to optimize, creating considerable opportunity, Hedrick added. These include isotopes, formulations, linkers, delivery methods and dosing.

While this can radiotherapy development complex, it also creates major opportunities, Hedrick concluded.

You can hear more on this week’s Denatured podcast episode.