Presentation of: Michael J. Morris, MD, Prostate Cancer Section Head, Genitourinary Oncology Service, Division of Solid Tumor Oncology, at Memorial Sloan Kettering Cancer Center, who chaired the VISION Scientific Committee.
On June 16, 2021, the US Food and Drug Administration (FDA) designated lutetium-177 (177Lu)-PSMA-617, an investigational radioligand therapy for the treatment of metastatic castration-resistant prostate cancer (mCRPC), as Breakthrough Therapy, acknowledging that it may represent a “substantial improvement” over currently available treatments and expediting development and regulatory review.1 This designation was based on positive data from the pivotal, phase 3 VISION (NCT03511664) trial, in which 177Lu-PSMA-617 plus standard of care (SOC) significantly prolonged both radiographic progression-free survival (rPFS) and overall survival (OS) over SOC alone in patients with progressive PSMA-positive mCRPC.
Topline results from VISION were revealed in February2 and details followed at the 2021 ASCO annual meeting presented by Michael J. Morris, MD, Prostate Cancer Section Head, Genitourinary Oncology Service, Division of Solid Tumor Oncology, at Memorial Sloan Kettering Cancer Center, who chaired the VISION Scientific Committee.3 Dr. Morris later reviewed his presentation and discussed some of the questions generated by the trial.4 Shortly after the ASCO meeting, the VISION trial was published in The New England Journal of Medicine.5
177Lu-PSMA-617 – a new drug class
Lutetium-177 (177Lu)–PSMA-617 delivers beta-particle radiation to cells that express PSMA (prostate-specific membrane antigen) and the surrounding microenvironment. PSMA is a transmembrane glutamate carboxypeptidase that acts as a diagnostic ad therapeutic target. It is primarily expressed on prostate cancer cells across all phases of the disease in about 80% of the prostate cancer population who have mCRPC. High PSMA expression is an independent biomarker of poor prognosis throughout the course of prostate cancer and across anatomical sites.
“177Lu-PSMA-617 is treatment for the patient population that previously had very few treatment possibilities post abiraterone and enzalutamide and post-docetaxel/ cabazitaxel, so it represents a new opportunity to prolong life in patients with few opportunities right now, Dr. Morris explained. “It’s a new drug class for prostate cancer…with real clinical benefit, improving overall survival and rPFS,” he said. It is administered as a fixed-dose of 7.4 GBq (200 mCi) injected once every six weeks, for a maximum of six cycles. “It’s pretty easy to administer and it’s all outpatient therapy. It takes about a half an hour of chair time, basically, from room-in to room-out,” he said.
The VISION trial
The open-label VISION trial evaluated the efficacy and safety of 177Lu-PSMA-617 plus protocol-permitted SOC in a specific population of previously-treated patients with mCRPC who were selected for PSMA positivity on the basis of gallium-68 (68Ga)-PSMA-11 positron emission tomographic– computed tomographic (PET/CT) imaging. Patients had previously been treated with ≥1 androgen-receptor–pathway inhibitor and 1 or 2 taxane regimens and were considered inappropriate for further chemotherapy. If patients were later deemed appropriate for chemotherapy, however, they were able to withdraw from the trial and receive chemotherapy at the discretion of their physician, which occurred in about 20% of patients on each treatment arm.
Patients were randomly assigned in a 2:1 ratio to receive either 177Lu-PSMA-617 (7.4 GBq/220 mCi) every 6 weeks for 4-6 cycles plus SOC or SOC alone. Protocol- permitted SOC excluded chemotherapy, immunotherapy, radium-223, and investigational drugs. “We don’t have safety data on the radiopharmaceuticals plus docetaxel or cabazitaxel or pembrolizumab or many other drugs, so those combination regimens for which we do not have safety data were excluded,” Dr. Morris explained. “The primary treatments that they got for SOC were other hormonal therapies, glucocorticoids, and palliative radiation therapy – the usual supportive measures that we do for this very, very late patient population.”
A total of 1179 patients were screened at sites in the US, Canada, and Europe, of whom 831 eventually underwent randomization. Between June 2018, when enrollment started, and March 2019 there was a “significant problem” with the dropouts on the control arm, 56% of the patients assigned before any treatment had started, Dr. Morris noted. “So this wasn’t an intolerance or unacceptance issue,” he explained, “It was that the patients wanted to get lutetium and their investigators were allowing them to be randomized without having even started a standard of care. It was a physician and an investigator issue more than a patient issue.” With enhanced education and communication between nuclear medicine physicians and oncologists plus an enrollment cap at selected sites, dropouts on the control arm were reduced to 16%. The primary analysis of rPFS was changed to focus on patients randomized on or after March 5th, 2019.
After a median follow-up of 20.9 months, median rPFS was 8.7 months for the 177Lu-PSMA-617-SOC arm vs 3.4 months for the SOC arm (HR for progression or death, 0.40; 99.2%CI: 0.29 to 0.57; P<0.001). Median OS was 15.3 versus 11.3 months, respectively (HR for death, 0.62; 95% CI: 0.52 to 0.74; P<0.001), “Four-month prolongation in OS is pretty typical for almost all recent FDA approvals in advanced patients,” Dr. Morris noted. “The improvement in the risk of death for chemotherapy was 20% to 30%, whereas this was 38%.” He recalled that in the TheraP study, which looked at 177Lu-PSMA-617 vs cabazitaxel in patients mCRPC, 68Ga- PSMA-11 and 2-fluorine-18 [18F] fluoro-2-deoxy-D-glucose (FDG) PET/CT scanning was used to select patients most likely to respond.6 “So VISION was much more liberal in terms of patient acceptance,” he stressed. “I think what this study shows is you can be a lot looser with your entry criteria, to the extent that you’re actually only excluding just over 10% of the population, and still, the majority of patients benefit. I think that’s a very important point,” he said.
None of the pre-stratified subsets of patients either responded “extraordinarily well” or “extraordinarily poorly,” Dr. Morris added. “In terms of biomarkers, the most important biomarker, both in terms of a therapeutic approach, as well as the utilization of social resources, is the relationship between imaging and therapy,” he suggested. “Doing PSMA PET scans on everyone who qualifies for this type of therapy is a major investment on society’s part. We need to understand better whether we can use those scans to their best effect, to really identify the population that will benefit. Also, we need to see whether those scans are actually contributing significantly to patient selection because it’s a big deal to get a scan on a patient before they receive the therapy. We’re talking about a lot of patients and a lot of resources.”
Toxicity of 177Lu-PSMA-617
177Lu-PSMA-617 was reported to be well tolerated during the trial, with no unexpected or concerned safety signals recorded. “The major concern with all PSMA-directed radioligand therapy is xerostomia because these molecules do insinuate themselves into both lacrimal and the salivary glands,” Dr. Morris cautioned. In the VISION trial, xerostomia occurred in 39% of the patients who received 177Lu-PSMA-617, all Grade <3. Nausea and vomiting occurred in around 40% of this population, “all controllable with pre-meds, with only 1.5% Grade ≥3. That’s an infusion-related issue, not a long-term toxicity.” In terms of high-grade toxicity, 13% of the patient population had anemia and 8% had thrombocytopenia, “Again, no new signal here. All these issues are present with radioligand therapy. He observed that a minority (12%) of patients discontinued treatment with 177Lu-PSMA-617 as a result of toxicity in VISION, “and most of these patients received all the full six doses that were intended.”
What next for 177Lu-PSMA-617?
The question of whether long-term duration of effect will only be answered by a separate trial when long-term safety data with further administration are available, Dr. Morris said, “The reality is that in prostate cancer, you get long-term responders to almost any therapy, then some patients either don’t respond or respond very, very briefly. We would love to know the characteristics of these patients.” he acknowledged. “Is it a question of just their disease biology and genomics, or, for example, we all speculate that the DNA repair-deficient patient population would be particularly responsive to this type of therapy? Or is it an issue of dosimetry, that is, how much radiation gets into the tumor and that correlates with the duration of response? Or are there some other features such as distribution of disease, for example, having primarily bone disease, bone and liver disease, or liver disease alone? All these questions are going to have to get teased apart over the next several years.”
Dr. Morris predicts that in the future, 177Lu-PSMA-617 will have a more significant role, both in terms of patient and clinician satisfaction as well as in the overall biologic advantages that radium doesn’t have. Other studies are currently evaluating 177Lu-PSMA-617 therapy in earlier lines of treatment of mCRPC, including one in taxane- naïve patients (PSMAfore) and another in metastatic hormone-sensitive PC (PSMAddition). “I certainly see a role for it,” Dr. Morris commented.
- Novartis receives FDA Breakthrough Therapy designation for investigational 177Lu-PS- MA-617 in patients with metastatic castration-resistant prostate cancer (mCRPC). Novartis; News release, June 16, 2021.
- Novartis announces positive result of phase III study with radioligand therapy 177Lu-PSMA-617 in patients with advanced prostate cancer. Novartis. News release; March 23, 2021.
- Morris MJ, De Bono JS, Chi KN, et al. Phase III study of lutetium-177-PSMA-617 in patients with metastatic castration-resistant prostate cancer (VISION). J Clin Oncol. 2021;39(suppl 15):Abstract LBA4.
- The Uromigos. Episode 104: Plenary session 177lu-PSMA-617 in prostate cancer. June 6, 2021. Available at: https://anchor.fm/the-uromigos/episodes/Episode-104-Plenary-Session- 177lu-PSMA-617-in-Prostate-Cancer-e129440 Accessed July 28, 2021.
- Sartor O, de Bono J, Chi KN, et al; VISION Investigators. Lutetium-177–PSMA-617 for meta- static castration-resistant prostate cancer. N Engl J Med. Published online June 23, 2021.
- Hofman MS, Emmett L, Sandhu S, et al; TheraP Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. [¹⁷⁷Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. Lancet. 2021;397(10276):797-804.