During a live virtual event, Emmanuel S. Antonarakis, MD, discussed the VISION trial supporting the use of 177-lutetium-PSMA-617 for patients with metastatic castration-resistant prostate cancer. This is the second of 2 articles from this event.
Targeted OncologyTM: Please discuss the background of the phase 3 VISION trial (NCT03511664) of 177Lutetium-PSMA-617 (Pluvicto).
ANTONARAKIS: This is the study that led to the March 23 FDA approval of 177Lu-PSMA-617, which is now called Pluvicto.1 This was a phase 3 trial. It was a third-line, metastatic castration-resistant prostate cancer [mCRPC] study. Patients had to have received at least 1 androgen receptor [AR]–pathway inhibitor and at least 1 or up to 2 taxane regimens, had to have an ECOG performance status of 0 to 2, life expectancy greater than 6 months, and very importantly, had to undergo a PSMA [prostate-specific membrane antigen] PET scan. In this trial, it happened to be a 68Gallium-PSMA-11 PSMA PET scan. And they had to have at least 1 PSMA-positive lesion. They were then randomized to the active radioligand therapy 177Lu-PSMA-617, which was given intravenously every 6 weeks for 4 cycles, and if patients had stable disease or better, they could receive 2 additional cycles with a maximum of up to 6 cycles of 177Lu-PSMA-617. In the control arm, they were committed to receive any best supportive care; however, the best supportive care excluded a cytotoxic chemotherapy, radium-223 dichloride [Xifigo], and sipuleucel-T [Provenge]. Therapies that were permitted were alternative AR-directed agents, steroids, or other palliative maneuvers like palliative radiotherapy, etc.
The primary end point was radiographic progression-free survival [PFS] with overall survival [OS] being a key secondary end point but not a coprimary end point.
Why were there discrepancies in the patient population of this trial?
This is where it gets a little bit complicated. There were 2 evaluable populations. One was 581 patients, and then the total was 831.2 There was a difference because when the study was first initiated, a number of sites were enrolling patients who would only agree to continue on the study if they were randomized to lutetium. This was mainly in sites such as Europe, where 177Lu-PSMA-617 was liberally available outside of the trial.
So what ended up happening was in many sites in the first 3 to 6 months of the trial, if a patient in Germany, for example, was randomized to the best-supportive-care arm, they would basically drop out, and after about a quarter of the patients were enrolled, the FDA realized that there was going to be a very large skew in favor of people dropping out of the control arm. So they tightened up the protocol to mandate that patients had to guarantee ahead of time that if they get randomized to the control arm, they will stay on the study, and they basically closed down all the sites where the investigators were encouraging their patients to drop out if they did not get 177Lu-PSMA-617, which frankly was happening.
So after that amendment was made to the protocol, they felt that they could reliably evaluate PFS in those patients that subsequently enrolled, which was the remaining 581, but they could also do an OS analysis of the entire intention-to-treat population even after they included those dropouts. It is a slightly complicated explanation but that is why there are 2 populations that were evaluated.
Overall, about 10% of these patients had lung metastases, about 12% to 13% had liver metastases, and also importantly a very significant proportion, approximately 40%, had in fact received cabazitaxel [Jevtana]. Again, a lot of these were European sites. Virtually all had received docetaxel but about 40% received cabazitaxel as well.
What were the efficacy and safety results of this trial?
There was a very robust improvement in the primary end point of radiographic PFS [HR, 0.40; 99.2% CI, 0.29-0.57; 1-sided P < .001].2
I have to admit I did not expect such a big difference in OS. Not only was the HR [hazard ratio] 0.62 [95% CI, 0.52-0.74; one-sided P < .001], which I think is the most impressive HR for OS that we have seen yet in a mCRPC study but also the absolute difference in median OS going from the median OS of [11.3] months to [15.3 months], which I think is quite impressive.
[Looking at how] the 2 arms compare in terms of adverse events [AEs], first of all bone marrow suppression was definitely more prevalent in the 177Lu-PSMA-617 group. The rate of bone marrow suppression was 47% versus 17% in the control arm. Then in terms of grade 3 to 5 bone marrow suppression, it was 23% versus [about] 7% which is pretty significant.
PSMA is highly expressed in the parotid, submandibular, and sublingual salivary glands. It is also expressed in the lacrimal glands. So when you give 177Lu-PSMA-617, you essentially ablate, sometimes permanently, the salivary glands and sometimes the lacrimal glands. So dry mouth and dry eyes are a troublesome AE. Dry mouth occurred in 39% who received 177Lu-PSMA-617 versus 1% with best supportive care. Oftentimes when this occurs, it does tend to be permanent. There is not that much improvement after the treatment is stopped.
What is the current state of 177Lu-PSMA-617 treatment?
The VISION trial led to the FDA approval on March 23, 20221; however, there is a global pause in the production of 177Lu-PSMA-617. No one is able to get it, because Novartis released in a press release on May 5, that the 2 manufacturing facilities, one of which is in New Jersey and the second one of which is in Italy, had a problem with a contaminant.3 The product was contaminated, and Novartis voluntarily paused production. This pause…affected every single clinical trial using this agent as an investigational agent and also affected the standard-of-care treatment throughout the world.
We are all hoping that by early to middle of June, production will be restored because as of now, no one in the world is able to get 177Lu-PSMA-617. So let us all hope that this will change. [Editor’s note: Following this event, the manufacturer announced that production has resumed.4]
The second thing that we have to talk about is that these patients requiring a PSMA PET scan. We were all surprised that the FDA specifically called out the 68Gallium-PSMA-11 PET scan as opposed to just saying any PSMA PET scan,1 and there are some questions in my mind about whether any PSMA PET scan will be sufficient or whether it will have to be 68Gallium-PSMA-11, which is not widely available.
1. Novartis PluvictoTM approved by FDA as first targeted radioligand therapy for treatment of progressive, PSMA positive metastatic castration-resistant prostate cancer. Novartis. Published March 23, 2022. Accessed June 10, 2022. https://bit.ly/3iw9bab
2. Sartor O, de Bono J, Chi Km, et al. Lutetium-177–PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. 2021; 385(12):1091-1103. doi: 10.1056/NEJMoa210732
3. Novartis provides update on production of radioligand therapy medicines. Novartis. Published May 5, 2022. Accessed June 13, 2022. https://bit.ly/3NUxY60
4. Novartis resumes production and delivery of radioligand therapy medicines ahead of schedule. Novartis. Published June 30, 2022. Accessed June 30, 2022. https://bit.ly/3R048id