Behind the FDA Approval: Lu 177 Vipivotide Tetraxetan for mCRPC

The FDA recently approved Lu 177 vipivotide tetraxetan (Pluvicto; formerly 177Lu-PSMA-617), the first PSMA-targeted therapy, for use in patients with metastatic castration-resistant prostate cancer (mCRPC).

The decision to approve this new treatment option was based on the findings from an international, prospective, open-label, multicenter, randomized, phase 3 study (VISION; NCT03511664 which examined Lu 177 vipivotide tetraxetan combined with standard of care (SOC) therapy compared with SOC alone in patients with prostate-specific membrane antigen (PSMA)-positive mCRPC.

Lu 177 vipivotide tetraxetan works by targeting the PSMA protein on the surface of prostate cancer. Where some standard therapies have failed, when injected into the patient, the Lu 177 label molecule attaches to tumors and delivers radiation specifically to that tumor.

Results from the trial demonstrated Lu 177 vipvotide tetraxetan to prolong survival and improve radiographic progression-free survival.

In an interview with Targeted Oncology^TM, Richard Wahl, president of the Society of Nuclear Medicine and Molecular Imaging and director of the Mallinckrodt Institute of Radiology at Washington University School of Medicine in St. Louis, discusses the approval of Lu 177 vipvotide tetraxetan and how it can impact the future of prostate cancer treatment.

TARGETED ONCOLOGY: Can you discuss the mechanism of action of Lu 177 vipvotide tetraxetan and how it is used to treat mCRPC?

Wahl: This is an exciting new nuclear medicine therapy of cancer, in this case, prostate cancer. Prostate cancer affects loads of men each year in the US and disproportionately affects African American males. Localized disease can be treated with local therapy, surgery, radiation, but when the disease is spread systemically or metastatic, that's where we need new therapies. Typically, the first therapy could be a hormonal therapy, hormone blocking therapy to limit testosterone levels, but at some point, patients can become what they call castrate resistance and have prostate cancer that progresses and sometimes those patients will get chemotherapy as well.

This particular therapy, Pluvicto, targets the PSMA protein that's on the surface of prostate cancer. This this nuclear medicine therapy is a radioactive molecule that that will accumulate in PSMA expression. Most metastatic prostate cancers have a lot of this PSMA on their surface, so this lutetium 177 label molecule, when it's injected, will home to those tumors and deliver radiation selectively to the tumor in comparison to most normal tissues. It's a targeted therapy and target is actual physical targeting of this radioactive molecule.

Pluvicto is now FDA approved in patients who have this metastatic prostate cancer that have the PSMA expression as evidence by a PSMA PET scan, that's another nuclear medicine procedure, so there's a scan with a PET scan to see if a small, safe tracer dose of the PSMA targeting agent will accumulate in tumors and if those tumors do accumulate to a sufficient extent, then they will be candidates for the therapy. These would be patients who were hormone refractory who had failed and who was no longer responding to chemotherapy including a taxane based chemotherapy. Long story short, it’s a radioactive molecule that homes to PSMA that selectively creates those tumors in patients where other more standard therapies have failed.

What are some key takeaways about this agent from the VISION study?

The vision trial was a large study published at New England Journal of Medicine and it was randomized trial. The key take home point was that the, Lu lutetium 177 PSMA therapy, the Pluvicto, prolonged survival of patients substantially. There is about a 4 month improvement in survival. The data in the abstract had a 38% reduced risk of death, a 60%, reduced risk of progression in the Pluvicto arm versus the control arm.

The overall survival increase was from 11.3 to 15.3 months, so the encouraging thing is the therapy works. It was better than the control arm. The control arm was that there were other therapies available, sort of standard therapy. But it also shows us that we have a ways to go because these patients with advanced disease still are dying of the disease, though their survivals are prolonged.

The other exciting thing about therapy was how well tolerated it was. The side effect profile was quite manageable. Some modest reduction in appetite was not uncommon and some drops in red blood cell count and white cell count occurred. The other thing is some of this accumulates in the salivary glands, so some patients could have dry mouth as a side effect of this. But most patients were able to receive this and there were relatively few contraindications to this therapy in this patient group. Of course, it's all done in the US as an outpatient as an intravenous injection. Then of course, patients are followed, but it's an outpatient therapy. Unlike chemotherapy, vomiting, and so on are not a common feature of the therapy.

For those who are referring their patients to this treatment for the first time, what is your advice on how to select eligible patients?

I'd say the package insert describes the group of patients who would be eligible. These are patients whose disease has spread beyond the prostate, and whose disease is progressing after having the hormone blocking therapy, the hormone reactive, refractory tumor. The label says they should have chemotherapy as well. There's a substantial number of patients in this population, and those patients need to be referred to the Nuclear Medicine Center for the PSMA PET scan to determine if their tumors have the target on them.

There are approved agents for the PSMA PET. They're not available everywhere, but they're increasingly available and depending on the results of the scan, they may be candidates for the therapy. I would say sites of that participated in the vision trial are probably going to be the sites that will be able to bring this therapy forward soon. Of course, the manufacturer has information and the Society of Nuclear Medicine also has a program to help identify centers of excellence in therapeutic nuclear medicine, and we recently have credentialed our first sites in that space.

It won't be available everywhere, but I think it will soon be available much more widely. But just remember there is a scan that has to be done, a PET scan to tell in the appropriate patients if they have the target. Most patients do who are considered for this and then if they the scan is positive, then maybe candidates for the therapy. If in the Midwest, we'd be happy to help accommodate scans and care and there are other centers division trial who could similarly help.

What do you think the impact will be now that this drug is approved?

I think that this drug will be increasingly applied in patients who have not had good responses to these more standard therapies. I think we're going to see it quite widely deployed, and I think it will become a relatively standard part of the care of patients with advanced prostate cancer. I think one of the interesting issues will be can this therapy be moved up earlier in the care of patients so that it could potentially be applied earlier in the disease. To possibly take the place of some of the other therapies that are being offered potentially at an earlier time. I'd say one of the intriguing aspects, and I think there are studies ongoing, is can this kind of therapy begin to replace chemotherapy as a possible therapeutic approach? But those studies are not yet done.

The scans that are done for this are important and necessary to identify patients who have the PSMA target. But one of the challenges we're facing in nuclear medicine right now is the availability of funding from Medicare to pay for these scans. What's happening right now is that when these scans are introduced, there's a period, a so-called pass-through period of 2 to 3 years, when Medicare will pay the cost. Roughly the cost of the drug after that 3-year period, due to some unusual aspects of Medicare laws, for inpatient in particular. When many of these scans are done at outpatient center hospitals, the reimbursement after 3 years drops to that of a generic, non-targeted agent. One of the concerns is that the availability of the diagnostic agents may become limited. There is an effort to get this unusual situation corrected called the FIND act, financing innovative nuclear diagnostics.

A concern I have looking out a couple of 3 years is that if the diagnostic agents weren't paid for appropriately, that might limit access for patients to these innovative therapies, and that's something we want to avoid. I think this stuff will make a real difference and change the way that prostate cancer is managed going forward. The FIND act has been introduced to congress and we're hoping that it can be passed. It’s budget neutral, but it corrects for this particular problem, which could lead to lack of availability of the of the gateway imaging agent for that for the therapy.