A scientific session presented at the Society of Nuclear Medicine and Molecular Imaging (SNMMI) meeting detailed the use of Lutetium-177-PSMA-617 (177Lu-PSMA-617), a prostate-specific membrane antigen (PSMA) radioligand therapy, and results from the VISION trial, which found that the therapy prolonged survival when used in conjunction with standard care in patients with advanced PSMA-positive metastatic castration-resistant prostate (mCRPC) cancer. The review was presented by Michael Morris, MD, Medical Oncologist, Memorial Sloan Kettering Cancer Center.
Dr. Morris initiated the review by providing information on PSMA, which is a protein expressed across different disease states and sites, including the bone, bone node, or internal organs, making it a robust diagnostic and therapeutic target. PSMA’s expression also can be augmented by reducing signaling through the androgen receptor (AR)axis, highlighting another reason for its effectiveness as a target for treating patients with mCRPC. Dr. Morris noted that the protein might make for an ideal therapeutic and diagnostic target because its expression is restricted in healthy tissues.
Assessing Current Standards of Care
PSMA-617 is a tiny molecule with a high affinity for the outside domain of PSMA, Dr. Morris explained. This molecule carries a payload of Lutetium-177. Once bound to PSMA, the molecule PSMA-617 undergoes endocytosis, where it radiates the bound cell and neighboring cells while Lutetium is radiating with beta particles.
Dr. Morris then discussed the different standards of care currently used for advanced PC, which informed the treatment options used for the control arm of VISION. Some patients with advanced disease are administered AR-directed therapy; however, there exists cross-resistance mechanisms conferred by first-line therapy, thus rendering second-line therapy ineffective in many cases. PARP inhibitors are used occasionally, but those are only effective for patients with DNA repair defects. For a wider population, immune checkpoint inhibitors are used, but these inhibitors only apply to 1.5% of patients with microsatellite instability or mismatch DNA repair defects. Radium can be used, but only on patients with bony disease, and no affected internal organs. The discussion then shifts to chemotherapy, but once patients receive docetaxel, cabazitaxel is the only remaining treatment for prolonged survival. “The treatment options for late-stage patients are still relatively restricted and limited,” Dr. Morris stated.
PSMA-directed therapy was innovated in European countries, especially Germany, and it was Prof. Michael Hofman and his colleagues at the Peter MacCallum Cancer Centre in Australia who conducted the first prospective trial of 177Lu-PSMA-617, which assessed 45 patients on the basis of dual positron emission tomography (PET) imaging with both fluorodeoxyglucose (FDG) and PSMA-PET imaging pretreatment. This population received 177Lu-PSMA-617 and demonstrated robust responses, even without significant treatment and independent of other treatment options. This study set the stage for a larger study of 200 male patients who were randomized 1:1 to receive either 177Lu-PSMA-617 or chemotherapy, with a primary endpoint of prostate-specific androgen (PSA) decline. This study showed that 66% of patients achieved a PSA decline with 177Lu-PSMA-617 therapy, compared to only 37% who achieved the primary endpoint with chemotherapy.
A Detailed VISION
After providing context, Dr. Morris delved into his review of VISION, the first phase III trial to assess 177Lu-PSMA-617. The clinical endpoints were overall survival (OS), and radiographic progression-free survival (RPFS), according to Prostate Cancer Working Group 3 (PCWG3) criteria. Eligible patients had mCRPC who had progressive disease while on at least one androgen receptor pathway inhibitor, such as enzalutamide, or apalutamide, and were required to have a PSMA-positive PET scan based on gallium-68-PSMA-11.
The trial began in June 2018, with 250 patients initially enrolled. However, there was a 56% early dropout rate, subsequent to standard care, which led to temporary suspension of enrollment. The trial sponsor developed a remediation plan with the U.S. Food and Drug Administration that capped centers with a high dropout rate and provided re-education to investigators about the trial design and execution. After implementing the plan, the dropout rate decreased from 56% to 16%. Overall, 1,179 patients were screened, and the final population consisted of 831 individuals, who were randomized 2:1 to receive either 177Lu-PSMA-617 plus protocol- permitted standard care (which excluded chemotherapy, immunotherapy, radium 223, and other investigational agents) or standard care alone.
According to the results, patients who received 177Lu- PSMA-617 in combination with standard care saw a 38% decline in their risk of death compared to those who received standard treatment alone, yielding a hazard ratio of 0.62. The median survival improved by four months, raising it to 15.3 months in the 177Lu-PSMA-617 arm as opposed to 11.3 months in the control group. Also, 177Lu- PSMA-617 plus standard care improved RPFS by 60% (hazard ratio=0.4), prolonging survival to 8.7 months in patients, versus 3.4 months in patients who received standard care alone. Regarding response rates, patients in the 177Lu-PSMA-617 arm had a 9% complete response rate and a 42% partial response rate, compared with 0% and 3% in the standard care arm.
Researchers Provide Insights and Advice
A question-and-answer session followed Dr. Morris’ review, when he was asked the following questions: “What have you learned through the VISION trial and other radioligand therapies that helped make this successful? What specific recommendations do you have for nuclear medicine physicians who are new to this type of therapy?”
“One piece of advice that I would give is that, historically speaking, medical oncologists, radiation oncologists and urologists have tried, largely unsuccessfully, to do multidisciplinary clinics,” Dr. Morris said. “They have been historically inefficient to run and sometimes disappointing. On the other hand, we are now in an era when we have greater flexibility and more creative models of shared caregiving than we ever have had coming out of the pandemic.” These include virtual clinics, which provide more flexibility for collaboration and multidisciplinary care, as opposed to the rigid definitions of the past, “which is everyone’s in the same room with the patient at the same time,” he continued. “I think that we need to think very creatively, and strike right now, while the iron is hot.”
Questions were posed to Ghassan El-Haddad, MD, Moffitt Cancer Center, who was also involved in VISION. In response to a question about the importance of a strong collaboration between nuclear medicine and medical oncology to successfully implement 177Lu-PSMA-617 and similar therapies, Dr. El-Haddad said he could not “stress the importance enough.”: “At Moffitt, we do have a very close collaboration, we have our own clinic, we participate in the tumor boards and the GU tumor boards. This is where you get to have a much closer relationship,” Dr. El- Haddad explained.
“It is very important to be able to have a successful therapeutic program. One of the issues is with the dropouts from the VISION trial was initially [perhaps related to a] lack of collaboration. [The trial] required a little bit more education and communication between the nuclear medicine physicians and the medical oncologist. You could see that the dropout significantly dropped after the remediation plan. That is a very clear objective way to show you that the collaboration between nuclear medicine physicians, medical oncologists, and urologists is extremely important. We saw it in the VISION trial –just by doing more, by strengthening this collaboration, you can get good results and decrease the dropouts.”
Dr. El-Haddad added that: “[Nuclear physicians, oncologists, and urologists] cannot really work in a silo in nuclear medicine. This is a new era, we’re at the crossroads where we want to have to get more involved in the clinics. Otherwise, these new, exciting therapies will be just taken over by somebody else. We do have, for example, a clinic in nuclear medicine, where we see the patients, we have nurse practitioners that follow the patients, and we make sure that their labs are correct before each treatment.”
Those sentiments were echoed by Dr. Morris, who said: “The patient needs to be managed by someone who’s going to manage the overall patient issues, such as pain, constipation, the systemic component of their treatment, as well as the nuclear medicine–specific component. Now, there isn’t necessarily a specific prescriptive set of instructions that I would give on how to do that. Every center is going to have to sort that out. But it does take real energy.”
Morris MJ. SNMMI 2021 Annual Meeting Presentation. Available at: 1472143 (AM2021) – SNMMI Video. July 2021.