Praful Ravi, MB, BChir, MRCP, discusses the LASER futility readout, PSMA heterogeneity in clear cell RCC, and next steps for radiopharmaceuticals.
The phase 2 LASER trial (NCT06964958) closed for futility after lutetium Lu 177 vipivotide tetraxetan (Pluvicto) produced no objective responses in heavily pretreated patients with prostate-specific membrane antigen (PSMA)–positive metastatic clear cell renal cell carcinoma (ccRCC).1,2 The radioligand was well tolerated, and screening imaging uncovered more PSMA-negative disease than is typical in prostate cancer, according to Praful Ravi, MB, BChir, MRCP.
PSMA is expressed on the tumor neovasculature of several solid tumors, including clear cell RCC, where its presence has been confirmed by immunohistochemistry and RNA sequencing.1 With lutetium Lu 177 vipivotide tetraxetan currently approved by the FDA for
“This particular chapter for PSMA-directed therapy in kidney cancer is closed, but the whole book on radiopharmaceuticals and kidney cancer, that’s very much open still,” Ravi said in an exclusive interview with OncLive®.
LASER enrolled patients with advanced ccRCC who had received at least 1 immune checkpoint inhibitor and at least 1 TKI, and who had at least 1 PSMA-avid lesion on screening PET.2 Patients could receive up to 6 cycles of lutetium-177–PSMA-617, and the primary end point was objective response rate per RECIST 1.1 criteria.1
Among treated patients (n = 9), best responses were stable disease (22%) progressive disease (33%), and unevaluable (44%); all patients who were unevaluable discontinued treatment after 1 cycle because of clinical progression. The median progression-free survival (PFS) was 2.3 months (95% CI, 0.5-5.3), and the 6-month overall survival (OS) rate was 62% (95% CI, 21%-86%) at a median follow-up of 3.2 months.
In the interview, Ravi discussed the LASER findings presented at the
Ravi is the medical director of genitourinary (GU) theranostics and a medical oncologist at the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, as well as an assistant professor of medicine at Harvard Medical School, in Boston, Massachusetts.
Ravi: PSMA is a protein that we traditionally think of as being on prostate cancer cells. However, there have been limited data showing expression on the blood vessels of other solid tumors, including kidney cancer.
There was a meta-analysis done a couple of years ago showing that approximately 70% to 80% of both primary and metastatic ccRCC express PSMA. However, these data have been based on small case series, a few case studies, and small studies. A deep dive into the expression is lacking.
We do think it is there, and it is probably there in most patients, but the extent of expression, how much there is, is perhaps not as fully defined as it is for prostate cancer.
LASER was an investigator-initiated trial looking at lutetium Lu 177 vipivotide tetraxetan, which is approved in PSMA-positive advanced prostate cancer. We wanted to look at this same drug in PSMA-positive ccRCC.
We knew there were data showing PSMA expression in ccRCC. It is on the neovasculature; it is not on the cancer per se, but on the tumor vessels. It is a tumor-adjacent target. We knew it was there, and if we could get the drug to the tumor, perhaps that radioactivity could be released and kill adjacent tumor cells.
We also know that this drug is generally well tolerated, at least in prostate cancer, and is efficacious in prostate cancer. The natural extension was to do a small study exploring its use in advanced kidney cancer that is PSMA-positive.
Patients had to have received at least 1 prior TKI, such as axitinib [Inlyta], cabozantinib [Cabometyx], and so forth, and at least 1 prior immunotherapy, or have a major contraindication to immunotherapy.
Most patients were heavily pretreated. Of the 9 patients we enrolled, the median number of prior lines of therapy was 4. These patients had received multiple prior lines, and they had to have PSMA-positive disease on the screening [PET] scan.
Here is where the story gets more complicated. Initially, when we designed the trial, the eligibility criteria were quite strict. We needed at least 1 PSMA-positive lesion with avidity greater than liver, and no negative lesions were allowed; that is, no lesions with avidity less than or equal to the liver.
In the first part of the trial, approximately 50% to 60% of patients screened did not meet this criterion, mostly because of the presence of negative disease, which we found was more common in kidney cancer than in prostate cancer.
Approximately 3 or 4 months in, we adjusted the eligibility. Patients still needed at least 1 positive lesion, but we allowed limited PSMA-negative lesions. Up to 25% of the disease could be PSMA-negative.
This change meant that the percentage screening positive for eligibility went from approximately 50% to approximately 90%. That made a difference in getting more patients in, and that was ultimately the eligibility.
Patients also had to have adequate organ function, with acceptable hemoglobin, platelet count, and creatinine clearance, as would be expected for other advanced RCC studies and radiopharmaceutical trials.
Unfortunately, we did not see major signs of efficacy. It was a 2-stage design. We were supposed to enroll 9 patients, and if we had at least 1 responder by RECIST 1.1 criteria, we would enroll another 15 patients, for a total of 24.
We enrolled the first 9 patients, and when we looked at the response data. No patient had a complete or partial response to therapy. There were a few patients[ with stable disease as their best response.
One patient had a little shrinkage in their lesions, approximately 4%, but response is defined as a reduction of 30% or more. There was no one near that vicinity. None of the 9 patients had a response, so the trial closed for futility. If we had seen a response, it would have opened up and kickstarted a potential new role for this therapy. However, I do not think the avenues for radiopharmaceutical therapy are closed. This trial was negative, but we can still learn a lot from a negative study.
We have learned about heterogeneity of PSMA expression in kidney cancer, because no one has ever done a prospective trial to look at PSMA-PET in ccRCC. Here, we have a dataset of 20-odd patients with PET scans showing the percentage with positive disease and a substantial number with negative disease.
This can inform future development, not just of PSMA-targeted therapies, but, more importantly, other radiopharmaceuticals against other targets in this disease.
Safety was as expected. The median number of cycles patients received was only 1, so bear in mind that the safety data relate to a relatively small amount of therapy. Dry mouth was common, and it was all grade 1. There was some fatigue, including some grade 2 events. Those were the main adverse effects [AEs].
There were not any cytopenias, but those would generally come with more cycles of therapy. It is not unexpected that we did not see cytopenias. Dry mouth is common with this drug, so even with 1 cycle, patients can get some dry mouth.
We did not see major AEs or safety concerns, but that is caveated by the fact that most patients did not receive a large amount of treatment.
If I am being honest, I do not see much of a future with this particular drug, lutetium Lu 177 vipivotide tetraxetan, in kidney cancer. As a single agent, it has not shown anything. Could there be a role for combining it with something? That is a possibility. However, generally, if you do not see activity with a drug on its own, it is hard to envision a future where you could use it with something else and expect something magical to happen.
Where I do see a potential future is with other targets on the kidney cancer cell. These are actually on the tumor cell. One is CA9 and there are others. These could be good targets for radiopharmaceuticals, and there are ongoing studies looking at them.
Editor’s Note: This transcript has been edited for grammar and clarity using artificial intelligence tools.
