Lutetium Lu-177 Vipivotide Tetraxetan

Molecularly Targeted Radiotherapy

Therapeutic advances have contributed to the improvement in survival of patients with metastatic castration-resistant prostate cancer (CRPC), but there is still an unmet need for those who exhaust established life-prolonging therapies.^1-3 The ability to target tumor biomarkers, such as prostate-specific membrane antigen (PSMA), holds promise for treating diffuse disease while limiting toxicity in this heavily pretreated population.

The radiopharmaceutical lutetium (Lu-177) vipivotide tetraxetan (Pluvicto) binds PSMA, delivering beta radiation to PSMA-expressing cancer cells and surrounding cells.⁴ The phase III VISION trial evaluated this agent, formerly known as 177-Lu–PSMA-617, among 831 patients with PSMA-positive metastatic CRPC who had been treated with an androgen-receptor pathway inhibitor and taxane-based chemotherapy.⁵ Compared with standard care alone, the radiopharmaceutical plus standard care prolonged median radiographic progression–free survival by 5.3 months (hazard ratio for disease progression or death = 0.40) and overall survival by 4.0 months (hazard ratio for death = 0.62). Although the incidence of adverse events was higher, quality of life was better maintained with the radiopharmaceutical.

The trial’s findings led to approval of Lu-177 vipivotide tetraxetan by the U.S. Food and Drug Administration (FDA) for the treatment of patients with PSMA-positive metastatic CRPC who have been treated with an androgen-receptor pathway inhibitor and taxane-based chemotherapy.⁶ The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer recommend this radiopharmaceutical as an option in the same population and define PSMA positivity as at least one PSMA-positive lesion and/or metastatic disease that is predominantly PSMA-positive and who do not have dominant PSMA-negative metastatic lesions.⁷

There is no doubt that molecularly targeted radiotherapy is an important new part of our armamentarium.“Lu-177–PSMA-617 represents a conceptually important advance. There is no doubt that molecularly targeted radiotherapy is an important new part of our armamentarium,” commented Oliver Sartor, MD, Medical Director of the Tulane Cancer Center and Associate Dean for Oncology at the Tulane Medical School in New Orleans. “I know unequivocally that selected patients can have a very substantial benefit,” he told JNCCN 360. “We need to learn more about which patients benefit and which patients do not, but regardless, there’s a lot of excitement now about a new modality to treat this disease.”

Patient Selection

According to the NCCN Guidelines, PSMA uptake on positron-emission tomography (PET) imaging can be ascertained with either of two radiolabeled diagnostic agents: gallium (Ga-68) gozetotide, the first such agent specifically approved by the FDA for patient selection in the use of a radiopharmaceutical and the one used in the VISION trial, and fluorine (F-18) piflufolastat.^4,6-8 Ga-68 gozetotide may be prepared using an FDA-approved injection kit.⁹

PSMA positivity is only part of the story, as the amount of uptake by individual lesions is also relevant. “Patients whose lesions are extremely PSMA PET avid, very hot, do the best, while those whose lesions are cooler don’t fare as well,” Dr. Sartor noted. Equally important are PSMA-negative lesions, which will not be targeted. Nomograms that incorporate PSMA PET parameters (tumor-node-metastases classification and tumor burden determined by molecular imaging) and clinical factors can help predict overall survival.¹⁰

Patients must have adequate organ and bone marrow function to safely receive Lu-177 vipivotide tetraxetan and will ideally have better physical functioning and limited metastases. “I like to catch people when they still have a good performance status and a lower volume of disease, because they are more likely to have a robust response,” Dr. Sartor explained. Sites of metastases also seem to influence benefit: Patients with predominantly liver metastases fare more poorly, patients with lymph node metastases tend to fare well, and those with bone metastases fall in the middle.

Data from Australia suggest that F-18 fluorodeoxyglucose (FDG) PET imaging, a measure of disease aggressiveness, can further refine patient selection for Lu-177 vipivotide tetraxetan,^11-14 although this imaging is not routinely used in the United States at present, according to Andrei H. Iagaru, MD, Professor of Radiology–Nuclear Medicine and Chief of the Division of Nuclear Medicine and Molecular Imaging at Stanford University Medical Center, Stanford, California.

“I would say the Australian trials have gotten better results than the VISION trial because their eligibility was stricter,” Dr. Iagaru told JNCCN 360. Their experience suggests that patients having more FDG-positive lesions than PSMA-positive lesions, and patients having a high volume of FDG-positive disease, even if less than the volume of PSMA-positive disease, seem to be unlikely to be good responders. “We try not to make it too cumbersome for patients,” he added. “But there is value in doing more than just PSMA imaging, so whenever possible, we also use an FDG scan for patient eligibility.”

Patient Education

In educating patients about treatment with Lu-177 vipivotide tetraxetan, Dr. Sartor uses illustrations showing the radiopharmaceutical’s mechanism of action along with the patient’s PSMA PET scan. “We explain that we can target the PSMA expression as seen on PET, and it really is a visual representation that the patients can understand, that it’s a molecularly targeted radiotherapy,” he said.

Dr. Iagaru and his colleagues have a consultation with the patient and family about 1 to 2 weeks before the first treatment. “During this visit, we go over what to expect during and after the treatment, and what the follow-up entails, and we answer any questions they may have. Patients come in hearing, ‘You are going to receive radiation,’ so obviously there are a lot of questions, and it’s better to address them in advance, rather than rushing through information at the time of treatment,” he said. “This is a model that is becoming more and more accepted as the standard of care.” In addition, Stanford periodically holds all-day educational events for patients with prostate cancer and their families, which include topics such as advances in imaging and radiopharmaceutical therapy.

Administration Procedure

Lu-177 vipivotide tetraxetan is given intravenously as a fixed dose once every 6 weeks for up to six doses.⁴ It is typically administered by a nuclear medicine physician (as at Dr. Iagaru’s institution) or a radiation oncologist (as at Dr. Sartor’s institution).

There are three options for infusing Lu-177 vipivotide tetraxetan—a syringe method, a vial method, and a gravity method—each with its pros and cons.¹⁴ A procedure guideline for using this and similar radiopharmaceuticals, jointly developed by the European Association of Nuclear Medicine and the Society of Nuclear Medicine and Molecular Imaging, is being finalized.¹⁵

At Stanford, administration of this radiotherapy takes place in private infusion rooms, which patients helped to design for comfort, according to Dr. Iagaru. “We try to keep the procedure simple,” he commented. Typically, patients first have an IV placed in a clinic with ultrasound imaging capability. On their arrival in nuclear medicine, they are assessed by a nurse or nurse practitioner and then meet with the physician, who checks their treatment eligibility that day, obtains consent (if not already done), and answers any remaining questions.

“The nuclear medicine physician and technologist review the Lu-177 vipivotide tetraxetan dosage in the lab and make sure that what we ordered is what we received,” Dr. Iagaru explained. “We then administer it via pump over 10 to 15 minutes, observe the patient for another 10 to 15 minutes, image after infusion with SPECT [single-photon emission computed tomography (CT)] or CT, and then they go home. So, administration is quite straightforward.”

Patients are advised to increase fluid intake and to void frequently to reduce bladder radiation.⁴ In addition, they are counseled about limiting proximity to household and other contacts for 2 to 15 days, depending on factors such as the contact’s age and pregnancy status.

“Don’t be afraid of radioligand therapy,” Dr. Iagaru advised. “But, at the same time, if you are just starting to use it, it is a good idea to attend educational conferences or to participate in an exchange with a facility that has used this therapy for a while. Proctoring is available. And when in doubt, send patients to a tertiary center with multidisciplinary care, where the best course of treatment can be suggested and followed.”

Predicting Response

“Some people will have a spectacular response to Lu-177 vipivotide tetraxetan, and others will not respond at all. Even though there are certain parameters that predict for success, it’s not completely clear before you start dosing how a given patient will respond,” Dr. Sartor noted. “There’s a lot more to learn about the agent and the individual responses in particular.”

Even though there are certain parameters that predict for success, it’s not completely clear before you start dosing how a given patient will respond.

Differences in response are often (but not always) evident by 12 weeks and give some sense of longer-term outcomes, Dr. Sartor said. “The super-responders typically respond very quickly. After two doses, you’ve got a pretty good idea. It’s not perfect, but you do have some important prognostic information based on the prostate-specific antigen [PSA] response.”

Forthcoming VISION trial analyses include multivariate analysis of baseline predictors of prognosis, according to Dr. Sartor. A post hoc analysis showed that early PSA kinetics were tied to benefit, with patients who had a greater decline by 12 weeks achieving better radiographic progression-free and overall survival.¹⁶ Pretreatment circulating tumor DNA may also help estimate prognosis.¹⁷

Preventing and Managing Adverse Effects

In the VISION trial, the most common adverse effects of any grade in the Lu-177 vipivotide tetraxetan group were fatigue (affecting 43.1% of patients), dry mouth (38.8%), and nausea (35.3%).^4,5 The most common grade 3 and higher adverse effects were related to myelosuppression: anemia (12.9%), thrombocytopenia (7.9%), lymphopenia (7.8%), and leukopenia (2.5%).

Adverse events led to dose reduction in 5.7% of patients, dose interruption in 16.1%, and permanent treatment discontinuation in 11.9%.^4,5 Some 36.3% of patients had serious adverse events, and 3.6% had fatal adverse events.

“For dry mouth, we recommend a water bottle and sugarless chewing gum or sugarless hard candy to stimulate salivary secretion and help moisturize the mouth,” Dr. Sartor told JNCCN 360. “We make sure people have appropriate medications (eg, anti-nausea drugs) and are counseled about the potential for bone marrow suppression, and we monitor with regular blood counts during the treatment course.” Dose delays are used to manage higher-grade bone marrow suppression.

“There are very few immediate side effects from the radiation of Lu-177 vipivotide tetraxetan. It can cause direct side effects, for example, if the patient does not have good IV access and develops an infiltrate,” Dr. Iagaru noted. “But we keep an eye on patients during the infusion, so that should not occur.”

Close clinical and laboratory monitoring are important for longer-term safety, he noted. “Many of these patients have already received multiple lines of toxic drugs, and although they don’t feel anything during the administration, they are still receiving a drug. We need to keep an eye on them and make sure that if and when there are side effects, we support them to recover, and then we continue the treatment.”

Multidisciplinary Care

Although institutions vary regarding which specialist takes the lead on patient care during treatment with Lu-177 vipivotide tetraxetan, use of the multidisciplinary care model is standard. “The key to using this regimen successfully is teamwork. No one can claim they can give this treatment in a vacuum, so working together with all the other specialties in a multidisciplinary setting and being respectful of each other’s work and expertise is the best way to do these treatments,” Dr. Iagaru told JNCCN 360.

The key to using this regimen successfully is teamwork. No one can claim they can give this treatment in a vacuum.

Medical oncology takes the lead at Tulane. “Patients with advanced prostate cancer are often ill. They have a variety of problems related to the disease and may need management for pain crises, blood support, and interventions to prevent fractures and manage cord compression,” Dr. Sartor reported. “The advanced disease needs to be managed, and that’s typically done by somebody who has expertise in this area. At our institution, that's medical oncology. We require that patients are followed both by medical oncology and radiation oncology.”

Nuclear medicine takes the lead at Stanford, according to Dr. Iagaru. “We see these patients in consultation before the first treatment visit, and then we are usually the ones managing them for the duration of the treatment, meaning we order and review labs and check eligibility before each cycle,” he explained. “But it’s all done in close partnership with our colleagues in medical oncology, who make the decision to refer patients to us for treatment with Lu-177 vipivotide tetraxetan.”

Looking Ahead

“The initial group of patients being treated with Lu-177 vipivotide tetraxetan are really sick and don’t have many other options, yet we hope to provide some benefit to them,” Dr. Iagaru commented. “However, as this therapy becomes more mainstream, we will see patients who are likely to benefit even more because they will have fewer lesions and won’t have already received a multitude of agents, so they will have good functional reserve.”

To optimize efficacy and minimize toxicity of Lu-177 vipivotide tetraxetan, ongoing research supported by variability in dosimetry across patients¹⁴ is looking at tailoring the dose, number of cycles, and interval between cycles, Dr. Iagaru noted. “We are getting into patient-individualized dosimetry. That’s something that patients, in my opinion, will benefit from.”

Some trials are testing Lu-177 vipivotide tetraxetan in combination with immunotherapies, poly (ADP ribose) polymerase (PARP) inhibitors, and radiosensitizers.^18,19 “We need to learn whether and when to combine, and what combinations to use. Like so many things in medicine, there’s a little bit of chemistry involved. But I do think that if we find the right ingredients, in the right amounts, we might be able to get even better results,” Dr. Iagaru said.

Other trials are exploring the potential of Lu-177 vipivotide tetraxetan in patients with less advanced disease, such as those with chemotherapy-naive metastatic CRPC and those with metastatic hormone-sensitive prostate cancer.¹⁸ Results of some trials, such as the PSMAfore trial, are expected as early as this year, according to Dr. Sartor.

“These clinical trials will potentially help move this treatment earlier in the treatment paradigm,” he commented. In addition, they may also start to provide data on sequencing of the radiopharmaceutical with other therapies. “It really depends on successful trial design and trial execution, but I do believe that tomorrow’s patient population treated with Lu-177 vipivotide tetraxetan will be different from today’s,” Dr. Sartor concluded.

Disclosures

Oliver Sartor, MD, has served as a consultant to Novartis, Endocyte, Point Biopharma, and Bayer.

Andrei H. Iagaru, MD, has served as a consultant for Novartis.

References

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