“Patients Are Having Toxicity and Effectiveness Concerns with Pluvicto”

“Patients Are Having Toxicity and Effectiveness Concerns with Pluvicto” (Brian McCloskey) [#55] Brian McCloskey and Brad Power May 3, 2023 “While 6 of 7 Pluvicto patients interviewed would recommend Pluvicto to a friend, that recommendation wasn’t enthusiastic, with an average satisfaction rating of 3 out of 5. With an average response duration of 6.

5 months, patients found the treatment fell short of expectations.” – Brian McCloskey “Heterogeneity of cancer limits the effectiveness of Pluvicto. Five of seven patients saw PSA declines during their treatment, but resistance occurred usually after the fourth round. Only two patients received the six full rounds of treatment.

” - Brian McCloskey Background Pluvicto (a drug which kills cancer cells by binding to the Prostate-Specific Membrane Antigen on prostate cancer cells with a radioactive molecule, lutetium) has become a very popular treatment option for advanced, metastatic prostate cancer patients. It was approved by the FDA and came on the market in March 2022.

It is a frequently prescribed treatment option and has been hard to get due to more demand than supply. In March 2023, the manufacturer (Novartis) said that the drug "is in such short supply that it cannot allow further supply to new patients until it can produce more of the drug. The company said it is working to produce enough doses to treat existing patients.

" The intent of this discussion was to understand Pluvicto from patients who have experienced it, and help prospective Pluvicto patients make their treatment decisions. Some of our Prostate Cancer Lab members have been early adopters of Pluvicto, and in this discussion they raised some questions about the efficacy of the treatment and potential toxicity.

In this interactive discussion, we interviewed seven Prostate Cancer Lab patients who have been on Pluvicto to explore their experiences. Six of the seven have completed and changed to new treatments, while one patient just completed his third round of treatment and will proceed to his fourth round.

Summary Findings ●Patient Profile (seven patients) ○These are all advanced prostate cancer patients who have seen, on average, four systemic therapies. ○All but one has been on first and second-line hormone therapy. ○All but one has been on chemotherapy. ○All patients have bone metastases, with the exception of one who has lymph node metastases only.

“Patients Are Having Toxicity and Effectiveness Concerns with Pluvicto” (Brian McCloskey) [#55] ○Pylarify-only: Plylarify (PSMA-PET, a scan that lights up cells with prostate- specific membrane antigen) SUVs (Standard Uptake Values) are the primary means to determine Pluvicto candidacy. SUVs ranged from 7-24.

○Pylarify + Axumin PET: One patient treated at MD Anderson used a combination of Pylarify and Axumin PET to assess the concordance of PSMA-avid disease.

mary means to determine Pluvicto candidacy. SUVs ranged from 7-24. ○Pylarify + Axumin PET: One patient treated at MD Anderson used a combination of Pylarify and Axumin PET to assess the concordance of PSMA-avid disease. ○Genomics/RNAseq: No Pluvicto patient used RNA sequencing or other genomic insights to assess candidacy.

PSMA gene expression relative to other prostate cancer patients could help determine patient fit with Pluvicto treatment. However, one Prostate Cancer Lab patient has used his PSMA RNA gene expression relative to a 1,000 prostate cancer cohort to deprioritize Pluvicto as a treatment option. ●Treatment Response ○Durability: With an average response duration of 6.

5 months, patients found the treatment fell short of durability expectations. ○PSA response: Five of the seven patients saw a PSA decline through the third round. However, those patients saw PSA increases after the fourth round and discontinued. Two patients continued through the prescribed sixth round. ■Note: Two patients experienced immediate PSA increases.

●Side Effects ○Most common: Fatigue was the most common side effect. One patient felt that exercise was important to minimize fatigue. ○Most serious: ■One patient lost his salivary glands and his appetite. He was very sick from treatment. ■One patient experienced myelosuppression, but it is not clear that Pluvicto was the driver.

●Follow-up to Pluvicto Treatment ○Three patients switched from Pluvicto to a chemotherapy ○Two patients moved to Bipolar Androgen Therapy (BAT) ○One patient pursued spot radiation Patient Data Table Pluvicto Patient Interviews 20230503 (Please click on the link above or see the table at the end of the transcript.) Additional Context The manufacturer of Pluvicto is Novartis.

Pluvicto is a key launch for Novartis and part of the company’s broader interest in radiotherapy. Banking on the potential to move into earlier prostate cancer treatment, Novartis put Pluvicto’s peak sales projection above $2 billion. Novartis aims to have a 250,000-dose annual capacity for Pluvicto in 2024.

From FiercePharma, "250,000 doses would translate into $8 billion of revenue at Pluvicto’s current U.S. price. Doctors’ experience thus far shows that Pluvicto has yet to reach its full potential in post-taxane mCRPC.

“Patients Are Having Toxicity and Effectiveness Concerns with Pluvicto” (Brian McCloskey) [#55] mCRPC patients who had tried an androgen receptor inhibitor and at least one taxane-based chemotherapy regimen. And Novartis just reported positive pre-taxane mCRPC data from the phase 3 PSMAfore trial. If approved in that setting, Pluvicto’s eligible patient pool could expand from 27,000 to 42,000 patients... The company is accumulating more data at the FDA’s request,

to determine Pluvicto candidacy. SUVs ranged from 7-24. ○Pylarify + Axumin PET: One patient treated at MD Anderson used a combination of Pylarify and Axumin PET to assess the concordance of PSMA-avid disease. ○Genomics/RNAseq: No Pluvicto patient used RNA sequencing or other genomic insights to assess candidacy.

PSMA gene expression relative to other prostate cancer patients could help determine patient fit with Pluvicto treatment. However, one Prostate Cancer Lab patient has used his PSMA RNA gene expression relative to a 1,000 prostate cancer cohort to deprioritize Pluvicto as a treatment option. ●Treatment Response ○Durability: With an average response duration of 6.

5 months, patients found the treatment fell short of durability expectations. ○PSA response: Five of the seven patients saw a PSA decline through the third round. However, those patients saw PSA increases after the fourth round and discontinued. Two patients continued through the prescribed sixth round. ■Note: Two patients experienced immediate PSA increases.

●Side Effects ○Most common: Fatigue was the most common side effect. One patient felt that exercise was important to minimize fatigue. ○Most serious: ■One patient lost his salivary glands and his appetite. He was very sick from treatment. ■One patient experienced myelosuppression, but it is not clear that Pluvicto was the driver.

●Follow-up to Pluvicto Treatment ○Three patients switched from Pluvicto to a chemotherapy ○Two patients moved to Bipolar Androgen Therapy (BAT) ○One patient pursued spot radiation Patient Data Table Pluvicto Patient Interviews 20230503 (Please click on the link above or see the table at the end of the transcript.) Additional Context The manufacturer of Pluvicto is Novartis.

Pluvicto is a key launch for Novartis and part of the company’s broader interest in radiotherapy. Banking on the potential to move into earlier prostate cancer treatment, Novartis put Pluvicto’s peak sales projection above $2 billion. Novartis aims to have a 250,000-dose annual capacity for Pluvicto in 2024.

From FiercePharma, "250,000 doses would translate into $8 billion of revenue at Pluvicto’s current U.S. price. Doctors’ experience thus far shows that Pluvicto has yet to reach its full potential in post-taxane mCRPC.

“Patients Are Having Toxicity and Effectiveness Concerns with Pluvicto” (Brian McCloskey) [#55] mCRPC patients who had tried an androgen receptor inhibitor and at least one taxane-based chemotherapy regimen. And Novartis just reported positive pre-taxane mCRPC data from the phase 3 PSMAfore trial.

If approved in that setting, Pluvicto’s eligible patient pool could expand from 27,000 to 42,000 patients...

sitive pre-taxane mCRPC data from the phase 3 PSMAfore trial. If approved in that setting, Pluvicto’s eligible patient pool could expand from 27,000 to 42,000 patients... The company is accumulating more data at the FDA’s request, with a plan to file for an approval in the second half of this year.

In addition, Novartis is testing Pluvicto in metastatic hormone-sensitive prostate cancer in the PSMAddition trial, which has a primary completion date in 2024.

" The information and opinions expressed on this website or platform, or during discussions and presentations (both verbal and written) are not intended as health care recommendations or medical advice by Prostate Cancer Lab, its principals, presenters, participants, or representatives for any medical treatment, product, or course of action.

You should always consult a doctor about your specific situation before pursuing any health care program, treatment, product or other course of action that might affect your health.

“Patients Are Having Toxicity and Effectiveness Concerns with Pluvicto” (Brian McCloskey) [#55] Meeting Notes The information and opinions expressed on this website or platform, or during discussions and presentations (both verbal and written) are not intended as health care recommendations or medical advice by Prostate Cancer Lab, its principals, presenters, participants, or representatives for any medical treatment, product, or course of action.

You should always consult a doctor about your specific situation before pursuing any health care program, treatment, product or other course of action that might affect your health.

SUMMARY KEYWORDS docetaxel, psa, treatment, patients, russ, side effects, scan, neuroendocrine, prior, bone, infusions, suv, androgens, chemotherapy, salivary glands, bat, expression, started, fatigue, chemo SPEAKERS Robert Gurmankin, Brian McCloskey, Brad Power, Russ Hollyer, Chad Magnussen, Ken Anderson, Mike Yancey, Amit Gattani, Emma Shtivelman, Rick Stanton, Mark Lanctot Brian McCloskey The reason why we're having this discussion today is that a couple of weeks ago, there was some discussion around Pluvicto.

It centered around its effectiveness and the side effects that you had. I know personally, as well as talking to many of you, that depending upon where you are in your journey, it seems to be the go-to drug treatment. What we think would be helpful is to collect any information that we have from those who have gone through Pluvicto, to understand its effectiveness and its side effects.

We can use that obviously to educate other patients that come into the Prostate Cancer Lab. To that end, I put together a few unscientific questions. I'm going to read them just so that you all have a sense of what they are, and I'm going to go across the panel of patients who I know have been on Pluvicto. I'll prompt you through the questions, but let me give you a summary.

●It would be nice to know what your prior treatment is.

tions. I'm going to read them just so that you all have a sense of what they are, and I'm going to go across the panel of patients who I know have been on Pluvicto. I'll prompt you through the questions, but let me give you a summary. ●It would be nice to know what your prior treatment is. ●For many of you, I know when you were diagnosed.

If you are new, I may not know your diagnosis date and that would be helpful because that tells me where you are on your journey. ●What kind of screening did you have? Did they just look at Standard Uptake Values, SUVs? Did they look at PSMA expression, or were there other characteristics of your cancer that came to light? ●If you did start it, when did you start it? ●What was your starting PSA?

●How many rounds did you go through? Not everyone goes through all six rounds. ●What was the end date? ●What was your PSA Nadir through that process? ●Did you have any side effects? ●I'd like a very unscientific rating on the drug, such as, 1 being completely dissatisfied and 5 being completely satisfied. ●Would you recommend it to a friend?

●What's your post Pluvicto treatment, and any general commentary?

“Patients Are Having Toxicity and Effectiveness Concerns with Pluvicto” (Brian McCloskey) [#55] That's quite a few questions, so we should probably try to cap it at roughly seven minutes or so per patient. I will start off with Amit, if you can give me your perception of Pluvicto starting off with what your prior treatment was.

Just your immediate prior treatment, not your entire lineage but just the one prior to it. Amit Gattani 04:27 My immediately prior treatment was chemotherapy. I was on chemotherapy before that and I was kind of refractory to that. We tried docetaxel again while waiting for Pluvicto to become available. I started on Pluvicto around August of 2022. I got three doses every six weeks.

My PSA in that phase actually increased from around 284 to the 350 range over that period of time. My last dose was in December of 2022. The side effects were part of the reason we had to stop at three doses due to myelosuppression. All three cell lines were starting to do poorly at that time. Prior to that I had gone through VMAT radiation.

It's hard to say that it was only Pluvicto because VMAT radiation also reduced the bone marrow capacity. Was it Pluvicto that led me down myelosuppression? It wasn't a standalone variable, and we should keep that in mind. But the reason I had to stop after three doses was that my cell lines were too low and not safe to give me Pluvicto anymore.

And in that time period, we did not see any meaningful, positive result from Pluvicto either from a PSA perspective. I have had these PSMA scans in the past and my disease seemed pretty highly PSMA avid. SUV values were pretty high too. I was very eager to get this treatment, actually, because it's a targeted treatment compared to everything else.