NEW YORK – Drugmakers are increasingly investing in radiopharmaceuticals, or theranostics, as a new precision oncology approach that may broaden populations of eligible patients beyond those with rare genetic alterations in their tumors.
However, since theranostics rely on imaging technologies and radioactive materials that may not be widely accessible outside of major cancer centers, some industry observers and radiation oncologists are worried that these new advances may further exacerbate health disparities in precision oncology.
The concerns are top of mind ahead of a US Food and Drug Administration regulatory decision on Novartis' 177Lu-PSMA-617 as a treatment for prostate-specific membrane antigen (PSMA)-expressing metastatic castration-resistant prostate cancer in the first half of the New Year.
According to Cameron Foster, the clinical director of nuclear medicine at UC Davis Health, the data from the Phase III VISION trial, which Novartis presented at the American Society of Clinical Oncology annual meeting in June, makes it likely that the FDA will approve the treatment. In that study, the targeted radioligand improved survival versus standard-of-care treatment in PSMA-expressing mCRPC patients.
Radiopharmaceuticals are often called theranostics because, using radiation-based imaging, they bring together drug and diagnostic workflows. Foster jokes with his colleagues that it would make sense to call the approach "diapeutics," since the diagnostic portion comes before the therapeutic. Patients receive injections containing molecules that bind to receptors on cancer cells. These molecules, depending on the radioisotopes they're attached to, can be diagnostics that light up target receptors on cancer cells using PET imaging, or therapeutics that deliver toxic radiation directly to the tumor expressing the target receptors while limiting damage to surrounding normal tissue.
With 177Lu-PSMA-617, for instance, the binding molecules target PSMA, which is overexpressed on nearly 90 percent of mCRPC cells. Once the molecules bind to PSMA-positive cancer cells, the therapy delivers the radioactive isotope lutetium-177 to them, limiting off-target effects. The FDA has already approved several PSMA-PET imaging kits, including piflufolastat F 18 (Lantheus' fluorine 18-based Pylarify) and gallium 68-based imaging products like Telix Pharmaceuticals' 68Ga-PSMA-11 (Illuccix), approved late last month.
The FDA does not yet require these imaging products to determine which patients should receive radionuclide therapies in the same way that a companion diagnostic genetic test might be required for assessing patient eligibility for targeted precision oncology drugs, but the imaging products are nonetheless widely used prior to the therapeutics to ensure that patients have tumors expressing the targets of interest and that the radioactive drug is reaching tumor cells.
"You've got a scanning component, the diagnostic component, and then the therapeutic component," explained Foster. "You do a scan to say, 'OK, this tracer is lighting up all these [cancerous areas] in the patient.' Then, you have high confidence when you go to do the therapy, because you're using the same compound [as a tracer] just with a different radioactive particle. You know it's going to go to these same locations."
Radiopharmaceuticals are not a new treatment paradigm altogether, but their commercial use has been somewhat limited to date. Notably, in 2018, the FDA approved lutetium Lu 177 dotatate (Lutathera), a product of Novartis subsidiary Advanced Accelerator Applications (AAA) for somatostatin-expressing gastro-enteropancreatic neuroendocrine tumors, or GEP-NETs. Although somatostatin expression defines up to 90 percent of such tumors, the cancer itself is still rare, affecting around seven people out of every 100,000. Several targeted radiopharmaceuticals are also approved for certain thyroid cancers and non-Hodgkin lymphoma patients but have had mixed commercial success due in part to the challenges that patients and oncologists have in accessing these theranostics.
Imminent growth but access inequities
There has been significant investment and interest in radiopharmaceuticals in recent years. According to one estimate from Market Data Forecast, the global nuclear medicine market, valued at $7.44 billion in 2021, is estimated to nearly double to $13.95 billion by 2026. Novartis, for example, spent $3.9 billion to acquire AAA in 2017 and bring Lutathera into its own portfolio. The following year, it spent $2.1 billion to acquire Endocyte, 177Lu-PSMA-617's developer.
It's not just Big Pharma that's pouring money into this subsection of precision oncology. New biotechs and spinoffs are cropping up to develop these therapies across numerous tumor types, selecting targets that they hope will deliver DNA-damaging radiation specifically to cancer cells for as many patients as possible.
"We're trying to lead with targets that would be expressed in most patients," said Scott Struthers, founder and CEO of endocrinology-focused firm Crinetics and cofounder of its radiopharmaceutical-focused spinoff, Radionetics. While Radionetics has not yet unveiled specifics of its therapeutic pipeline, Struthers shared that the spinout firm has identified 10 nonpeptide receptors to target initially and has homed in on three initial indications to take into clinical trials.
Melbourne, Australia-based Telix Pharmaceuticals is also developing these diagnostics and therapies, and has clinical trials ongoing in renal cell carcinoma, prostate cancer, and brain cancer. The firm's just-approved PSMA-PET imaging kit Illuccix was among the imaging products used to enroll patients to Novartis' VISION trial, and Telix is currently using it to determine patient eligibility for its own Phase III mCRPC theranostics trial, PROSTACT.
To enroll in both trials, patients had to be "68Ga-PSMA-11 PET/CT scan positive," meaning they had to undergo PET imaging after receiving a gallium 68 injection, and the resulting scans had to reveal at least one PSMA-positive lesion and no PSMA-negative lesions of moderate size. Roughly 87 percent of patients screened for the VISION trial were deemed PSMA-positive.
The high prevalence of these biomarkers bodes well for drugmakers' commercialization strategy for these therapies. By targeting tumor receptors that are decidedly common, if not ubiquitous, like PSMA, drugmakers can market these products broadly and brand them as "precision medicine" due to the improved ability to discriminate between cancer and normal cells.
But within community practices where most patients are treated, just as inequitable access to next-generation sequencing-based biomarker testing is hindering molecularly informed treatment, oncologists are concerned that limited access to the imaging technologies and the radioactive isotopes these newer radiopharmaceuticals rely on may further widen the gulf between the haves and have nots in precision oncology.
In a conference call to discuss Novartis' third-quarter financial results in October, Susanne Schaffert, the firm's president of oncology, shared that the drugmaker is focusing on the "top 200 treatment centers" in its education and process optimization efforts ahead of 177Lu-PSMA-617's commercial launch. It is yet unclear how successful this strategy will be in ensuring access in rural and low socioeconomic regions of the country. It's well known that the vast majority of cancer patients receive care not at the top treatment centers but within smaller practices in their communities.
While Struthers expects that most major cancer centers will soon be equipped with the necessary technologies to offer these diagnostics and therapies, if they aren't already, he acknowledged that this won't be the case for community practices. "What I worry about is that in some of the rural communities, they may have to travel to get this type of therapy, because it's not something that's suitable to your local infusion center," he said.
Space, equipment, personnel requirements
According to both UC Davis' Foster and Munir Ghesani, the chief of nuclear medicine at Mount Sinai Health in New York, the nature of targeted radiopharmaceuticals requires more physical space, more specialized equipment, and more expert personnel than traditional infusion therapies or external radiation therapies. Part of the reason for this is that these treatments are considered "unsealed" radiation therapies that can cause contamination without extremely careful handling. External beam radiation, in contrast, is considered "sealed" and doesn't carry the same risks.
What this means logistically is that patients receiving treatment with an unsealed isotope have to undergo their infusion more or less in isolation, for example, in an area of an infusion center significantly set apart from other patients. In contrast, patients receiving "sealed" radiation therapy don't have to be isolated from others.
Radioactive isotopes themselves also require specialized storage areas with lead walls. Specialized centers with modern theranostics capabilities are few and far between, said Ghesani, "because of all the components we need, including proper training, proper personnel, proper infrastructure."
For these reasons, the therapy is probably "not going to be in a rural center, with a low population and not a lot of infrastructure," Foster agreed. Consequently, patients receiving targeted radiopharmaceuticals will need to travel to a specialized cancer center, likely one that's affiliated with an academic hospital.
Ghesani, who is also the incoming president of the Society of Nuclear Medicine and Molecular Imaging, further observed that there is a problematic shortage of physicians trained and certified to practice nuclear medicine. Growing the expert workforce in this space is a priority for the professional society, which had been closely tracking the Resident Physician Shortage Act of 2021 (H.R.2556/S.834) in the hopes it might offer some opportunities for expanding the ranks of all healthcare professionals, including nuclear medicine oncologists. But the legislative effort, part of the larger Build Back Better plan, is stalled for now.
The barriers are greater yet for centers interested in conducting clinical trials or developing new versions of these diagnostics and therapies for new cancer indications and new targets.
"You need people who can build these tracers from scratch, and that's a unique skill set," Foster said. "There are not a lot of people who can do that well." And in the case of the clinical trials, he added that centers need dedicated faculty and staff who can interpret the safety and efficacy of these therapies.
"That's where we're kind of at a turning point in theranostics, where we're asking, 'Who's going to step up and design these centers?'"
Scan before therapy?
The diagnostics piece of these theranostics might also present access barriers. Some oncologists have wondered how Novartis' radiopharmaceutical, if approved, would be accessible to most patients if it required them to receive specific PSMA-PET imaging to determine therapeutic eligibility first. The access disparities would be even worse in countries outside the US, some observed, where funding and availability of imaging technologies may be even more sparse outside of centers of excellence.
For instance, one investment analyst asked Novartis' Schaffert during the October earnings call whether the firm is considering expanding the types of imaging agents used for determining which patients in the UK are eligible for 177Lu-PSMA-617, since gallium 68 can be harder to come by in the UK. "There is some concern about [the therapy's] utility beyond large centers because of the need for gallium-PSMA screening will make it harder to use more broadly," Simon Baker, head of global biopharma research at equities broker Redburn, said, further asking if Novartis would consider allowing the more widely available, if slightly less precise, agent technetium. Schaffert responded that the firm would be initially focusing on gallium 68 for the most part and potentially fluorine 18.
Given these access issues and the ubiquity of PSMA expression on mCRPC cells, some have wondered if foregoing the imaging requirement altogether could improve access.
"Despite 177Lu-PSMA-617 being a targeted therapy, the high positivity rate begs the question if the imaging requirement is needed," Mary-Ellen Taplin, director of clinical research at the Dana-Farber Cancer Institute's Lank Center for Genitourinary Oncology, pointed out during a discussion of the VISION trial data at ASCO's annual meeting in June. "Given the cost and inconvenience to patients, hopefully future work will determine the utility of the PSMA imaging requirement."
While from a regulatory standpoint it's unclear if it will be required that patients' PSMA expression is established via imaging before giving the treatment, Foster said it is undoubtedly "best practice" to do the imaging first. "The gold standard would be doing the scan before you do the therapy to make sure that the therapy is actually going to go where you want it to go," he said.
But there have been workarounds in other cases. For example, with the radioimmunotherapy ibritumomab tiuxetan (Acrotech Biopharma's Zevalin), which is approved for certain lymphoma patients, Foster said that the field eventually found that "all you needed was the proper tissue diagnosis of a lymphoma and an appropriate lack of bone marrow involvement, and you could just go straight to therapy … without needing the imaging."
Still, the ibritumomab tiuxetan example may be an outlier, and imaging may still be needed to ensure that the latest theranostics are reaching their intended targets. Using a targeted agent bound to an imaging isotope, "you can see the extent of tumors much more clearly … and you have a lot of confidence to know that the patient will have the right set of receptors on their tumors to be treated with therapeutic isotopes," Radionetics' Struthers explained.
Moreover, PET imaging can be a crucial tool for measuring therapy efficacy. With traditional imaging techniques without a radiotracer, Foster explained, a tumor mass might show up on a scan after therapy, making it seem like the therapy didn't work. But if you use PET imaging, the mass that previously lit up with the radioactive agent might, on a post-treatment scan, appear "cold" if it's no longer expressing PSMA. The tissue may physically remain, but as dead tissue, indicating that the treatment did in fact work.
Despite their myriad utility, many of the approved imaging kits, including Telix's Illuccix, lack specific FDA indications as diagnostics to be performed alongside specific radiopharmaceuticals — but they're being advanced for this purpose. "Whilst not part of the current FDA label, Telix ultimately aims for [Illuccix] to be used with the company's … PSMA-targeting prostate cancer investigational therapy," Telix CEO Christian Behrenbruch said, adding that it is also "possible that Illuccix will be used with Novartis' therapy once approved."
Telix is a proponent of imaging to guide radiopharmaceutical development. Colin Hayward, the firm's chief medical officer, acknowledged similar access concerns to those voiced about Novartis' pending product, but he also highlighted additional benefits of imaging. Even if patients were to undergo the imaging but not wind up getting the therapeutic, he said, the diagnostic PET imaging would inform their treatment decisions in other ways, such as differentiating benign masses from cancerous tumors, or perhaps guiding treatment decisions beyond theranostics.
Early studies, for example, have suggested an association between CA9 expression — the target Telix is using for its kidney cancer theranostics program — and resistance to certain immunotherapies, which he said suggests that CA9 screening could also help guide immunotherapy treatment decisions.
"You can see the utility opening up [for the imaging product] from a diagnostic or prognostic factor," Hayward said. "Even if [patients] are not going down the therapeutic route [after diagnostic imaging], you're potentially identifying tumors that may not be seen on conventional imaging."
On the other hand, if the FDA doesn't require diagnostic imaging alongside Novartis' 177Lu-PSMA-617, then patients theoretically wouldn't need two injections and additional imaging and could avoid unnecessary imaging and related costs.
With respect to cost concerns, Hayward believes payors will see the value of imaging diagnostics when it comes to deciding which patients should receive radionuclide treatment. "Payors always want that we're not spending unnecessarily," he said. "It makes a lot of sense that we can use our products in a more judicious way, identifying patients that are likely to benefit."
That said, it's taken a while to get insurers on board with both the imaging and therapeutic elements of radiopharmaceuticals, and challenges are still prevalent in practice. According to UC Davis' Foster, it is not uncommon for insurers to deny coverage for Lutathera for GEP-NET cancer patients, even though, in his view, the radiopharmaceutical would actually save them money relative to patients receiving multiple courses of expensive chemotherapy that aren't as effective.
"We are somewhat troubled when insurance companies say, 'No you can't get Lutathera,' but then approve chemo," Foster said, adding that coverage has improved in recent years but still has "room to grow."
The reimbursement model for these therapies has been problematic, too. "Reimbursement tends to happen in a stepwise fashion, first approving general imaging, then PET, then the therapy," Foster said, noting that the US Centers for Medicare & Medicaid Services recently granted transitional pass-through payment status for Lantheus' F 18 imaging, Pylarify, for imaging PSMA-positive mCRPC, meaning it will cover it for a period of time, usually a year or so, before making a more final determination based on the agent's efficacy in the real-world setting.
According to Bruce Quinn, a diagnostic reimbursement expert and consultant, the many components of these therapies make reimbursement "really messy." The PET scans required for imaging on their own can be priced in the mid-thousands of dollars for one scan without factoring the injections, and then the targeted molecule and the radioactive elements — either the imaging or therapeutic — have their own price tags. Under Medicare, the tracer and PET scan are usually bundled as a single cost in the outpatient setting following the expiration of temporary pass-through payment status, but determining a price for the whole regimen can be challenging, and the "average sales price" methodology used to calculate costs of traditional therapies doesn't work all too well.
"The antibody is manufactured in one place, but it has to be radiolabeled shortly before injection and done locally, so that there isn't a wholesale or single price for the compounded or 'assembled' final drug," Quinn said.
According to Mount Sinai's Ghesani, there are signs coverage is improving for diagnostic imaging and radionuclide therapy as payors become more familiar with the role that both components play, but there is still a long road ahead. He worries about patient access as the therapies expand their reach. While New York City-based Mount Sinai is not in the same boat as smaller, rural cancer centers that lack the infrastructure to offer theranostics, it is nonetheless still constrained in its physical space, nuclear medicine expertise, and capacity.
Just recently, for instance, the center ran out of available dedicated infusion rooms for these therapies to accommodate the patients who needed to come in during the two weeks ahead of the Christmas holiday, and Mount Sinai had to urgently convert other treatment rooms into these infusion rooms.
Adding further complications, Ghesani explained that most radioactive infusions cannot be rescheduled because the isotopes have very short shelf lives. Even pushing a scheduled treatment a few days may be impossible due to the radioactive decay. "That's one of the big things with these; in addition to all the necessary training and infrastructure you need, you also have to do it in a very timely manner," Ghesani said.
According to Foster and Ghesani, both their institutions, UC Davis and Mt. Sinai, have plans to expand their nuclear medicine departments and increase capacity ahead of the anticipated 177Lu-PSMA-617 approval this year, but the cost and logistics are daunting. "Here at UC Davis, we're asking the 'how big do we want it?' question," Foster said, acknowledging that he feels fortunate to have buy-in from a larger institution, but that isn't something every cancer center can say.
For the time being, while targeted theranostics seem poised to become a much more established part of cancer medicine, experts in industry and academia acknowledge that its adoption, like other advanced approaches in precision oncology, may be inequitable. The question for Foster is no longer whether theranostics are "going to proceed and become a significant portion of treatment options … in modern medicine," but rather "who's going to be doing it?"