NCCN Clinical Practice Guidelines in Prostate Cancer 177-Lutetium PSMA (LuPSMA) Radioligand Therapy - Zachary Klaassen
March 16, 2023
Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Georgia Cancer Center
Chris Wallis: Hello, and thank you for joining us for this UroToday, NCCN Clinical Practice Guideline Discussion. Today, we're talking about the recently updated 2023 version of the NCCN Clinical Practice Guidelines in Oncology focusing on prostate cancer. These were released September 16th, 2022. In particular, one of the major highlights and changes from last year's version of these guidelines is the discussion regarding 177-Lutetium PSMA radioligand therapy.
Discussing this further, I'm Chris Wallis, an Assistant Professor in the Division of Urology at the University of Toronto. With me today is Zach Klaassen, Assistant Professor in the Division of Urology at the Medical College of Georgia.
Lutetium PSMA radioligand therapy is now indicated for the treatment of some patients with metastatic castration resistant prostate cancer. I'm going to dive into those data a little bit further here.
So Lutetium PSMA also goes by this full scientific name here, but importantly, is a radiopharmaceutical that is administered intravenously, compared to historical radiopharmaceuticals, it has some advantages, and may be administered in more settings including cancer clinics, as opposed to relying on administration in nuclear medicine facilities.
In terms of the recent FDA approval, the clinical indication criteria for patients to receive Lutetium PSMA theranostic treatment is PSMA-positive M1 CRPC. And we'll talk about what that means a little more when we look at the data underpinning this approval. As well as prior treatment with both androgen receptor pathway inhibitors, typically abiraterone or enzalutamide, as well as taxane based chemotherapy.
As an introduction to Lutetium PSMA, these are combination molecules, and so we have a PSMA targeting component linked to an active moiety, that's a radionuclide, the 177-Lutetium, that delivers radiation to the PSMA expressing cells, as well as surrounding cells. This radiation induces DNA damage leading to cellular death.
Lutetium PSMA has recently been approved on the basis of the international open label Phase III VISION trial, and we're going to discuss VISION in some somewhat more detail.
This is the citation for this recent publication led by Dr. Sartor, as well as his colleagues.
This figure, which has probably been seen in many conferences so far, highlights the design and conduct of the VISION trial, to emphasize eligible patients included those with mCRPC who had previously received treatment with both one or more engine receptor pathway inhibitors, and one or two lines of taxane based chemotherapy.
Prior to randomization, patients had to have a decided upon protocol permitted standard of care. This standard of care could not include further lines of chemotherapy. Immunotherapy, Radium-223, or investigational medications. Patients further had to have an ECOG performance status of zero to two, a life expectancy of at least six months, and evidence of PSMA positivity on PET/CT scan performed with 68 Gallium PSMA-11. Randomization was stratified according to performance status, LDH level, presence of liver metastasis, and ongoing use of an androgen receptor pathway inhibitor in the standard of care. Patients were randomized in a 2:1 fashion, to receive either protocol permitted standard of care with Lutetium, or standard of care alone.
This was an open label, randomized, international Phase III trial. We've highlighted many of the considerations here regarding randomization already, but it's important to know that these patients with advanced disease, treatment continued until there's evidence of disease progression, unacceptable toxicity, where an investigator decided lack of benefit of therapy.
In terms of outcomes, the trial had two alternate primary endpoints. The first was imaging based progression-free survival, which was defined as the time from randomization to disease progression or death. The second primary endpoint was overall survival.
The authors considered a number of other secondary endpoints, including objective response rates, disease control rate, time to first symptomatic skeletal event or death, safety, health-related quality of life, pain, as well as biomarker outcomes, including PSA response rates.
At this point in time, I want to hand over to Zach, to walk us through the results of the VISION trial, as well as the implications for updated NCCN guidelines.
Zachary Klaassen: Thanks so much, Chris. So this is the results from the VISION trial. As Chris mentioned. This is the key trial that led to the approval, and the recommendations of Lutetium PSMA in men with metastatic CRPC.
So this is the characteristics of the patients at baseline, and we'll focus on the far right of this table, which is looking at all patients who underwent randomization. So you can see here, the median age was 70 for those receiving Lutetium PSMA, 71.5 for those receiving standard of care. As you can see, even in this highly pretreated population, the ECOG performance status of zero to one was over 90% in all of these patients. And we look at site of disease, you can see that the majority, over 90%, had bone metastases, with roughly half of these patients having lymph node metastases. In terms of median PSA, over 75, 77.5, for those with Lutetium PSMA, and 74.6 for standard of care.
Moving down to the patients that had previous androgen receptor pathway inhibitors, the most common was one regimen at 54.1% for those receiving Lutetium PSMA, compared to 45.7% for those receiving standard of care. But you can see that, a good portion of patients also had two regimens, or even more than two regimens, of androgen receptor pathway inhibitors. With regards to previous taxane chemotherapy, nearly all patients had received docetaxel, and over one third of patients had received cabazitaxel.
This is the primary efficacy outcome for VISION, looking at imaging based progression-free survival. You can see the Lutetium arm is in blue, and the standard of care arm is in red. And the median time to imaging based PFS was 8.7 months for Lutetium, compared to 3.4 months for standard of care, with a significant hazard ratio of favoring Lutetium PSMA at 0.40, and a 99.2% confidence interval of 0.29 to 0.57.
This is the other primary efficacy outcome, which was overall survival. Again, an early and consistent splitting of the Kaplan-Meier curve, with a median overall survival for Lutetium of 15.3 months, and a median overall survival for standard of care of 11.3 months, with a hazard ratio, again favoring Lutetium PSMA of 0.62, and a 95% confidence interval of 0.52 to 0.74.
This is one of the key secondary outcomes, which was time to first symptomatic skeletal event. Time to first SSE for Lutetium PSMA was 11.5 months, and a median of 6.8 months for standard of care, with a hazard ratio, again favoring Lutetium PSMA. 0.50 to 95% confidence interval of 0.40 to 0.62.
This is looking at the PSA responses, and you can see on the left is Lutetium PSMA in blue, and on the right is standard of care. This is quite dramatic. You can see the greater than 50% confirmed decreased PSA for Lutetium PSMA was 46%, versus 7.1% for those receiving standard of care. And in terms of greater than 80% PSA response, 33% for Lutetium PSMA, compared to only 2% for standard of care.
This is several of the health related quality of life outcomes. Again, the same color scheme as the previous Kaplan-Meier curve, and you can see that for FACT-P total score, this favored Lutetium PSMA, with a hazard ratio of 0.54, and a 95% confidence interval of, 0.45 to 0.66. And at the bottom we can see for BPI SF pain intensity, again favoring Lutetium PSMA, with a hazard ratio of 0.52, and a 95% confidence interval of 0.43 to 0.63.
With regards to adverse events, we'll focus on the greater than three or higher adverse events. And this included 52.7% of patients for Lutetium PSMA, compared to 38% of patients for standard of care alone. Some adverse events to highlight, which was more than 12% of patients. Overall, we can see that 12.9% of patients had anemia with Lutetium PSMA, compared to 4.9% for those with standard of care. Thrombocytopenia was also more common in Lutetium PSMA patients at 7.9% compared, to 1.0% in standard of care. As well as lymphopenia, 7.8% for those receiving Lutetium PSMA, compared to 0.5% for those receiving standard of care.
So with regards to the NCCN panel recommendations, there's two key recommendations that we'll discuss. So the first one is that, Lutetium PSMA as a category one treatment, is useful in certain circumstances, for patients with one or more PSMA-positive lesions and/or metastatic disease that is predominantly PSMA-positive, and with no dominant PSMA-negative metastatic lesions, who have been treated, as Chris mentioned previously, with androgen receptor directed therapy and taxane based chemotherapy.
The NCCN defined PSMA-negative lesions as metastatic disease that lacks PSMA uptake, including bone and soft tissue components greater than or equal to one centimeter. Lymph nodes greater than or equal to 2.5 centimeters in the short axis, and solid organ metastases greater than one centimeter in size.
If we look back at the 2021 NCCN update, which was version 1.2022, this is where the NCCN starts to mention DCFPyL PSMA-PET Imaging.
So you can see this quote here, "there are multiple PSMA radiopharmaceuticals at various stages of investigation. The NCCN guidelines recommend both DCFPyL and Gallium 68 PSMA." So at this point, they're starting to demonstrate some equivocal recommendations for both Gallium and DCFPyL.
And secondly, which is also important for this discussion, PSMA-PET/CT can be considered an alternative to standard imaging for staging, detection of biochemical occurrence, and importantly, for workup for progression; which is the case for patients with mCRPC that are being considered for Lutetium PSMA. And this is based on conventional imaging not being a prerequisite for the use of PSMA-PET imaging.
This leads us to our second panel recommendations from the NCCN in that, both Gallium PSMA-11 or DCFPyL PSMA imaging, can be used to determine eligibility for Lutetium PSMA. So the context of the statement is, as Chris highlighted in the methods of the VISION trial, this only included Gallium 68 PSMA-11 imaged patients. And this is important with regards to the uptake, potentially, of Lutetium PSMA in the United States.
So Gallium 68 PSMA is approved at only UCLA and UCSF, and it does have a short half life of 68 minutes, whereas DCFPyL PSMA is widely distributed across the United States, has 110 minute half life, and basically, is being made in the cyclotrons in different areas of the country, given its three hour distribution radius, which makes it much more accessible across the country with regards to PSMA imaging.
The ramifications of this are quite straightforward in that, by using DCFPyL PSMA PET/CT for Lutetium PSMA eligibility, this may potentially increase the utilization of Lutetium PSMA in the United States.
So to summarize, this is the quite busy and exciting figure for systemic therapy for M1 CRPC from the NCCN guidelines. And clearly, under the prior docetaxel and prior novel hormone therapy is listed Lutetium PSMA in useful in circumstances for patients with PSMA-positive metastases.
We thank you very much for your attention. We hope you enjoyed this NCCN update, focusing on the utilization of Lutetium PSMA in mCRPC patients.