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A comment on 177Lu-PSMA therapy and the LuPIN study data

177Lu-PSMA-617 (177Lu-PSMA) therapy suddenly has become a big talking point in prostate cancer circles. Delivering radiotherapy via injectable radiopharmaceuticals is being talked up as a coming mega trend in cancer therapy in general, but 177Lu-PSMA and prostate cancer is where the big story lies at the moment.

177Lu-PSMA-617 (177Lu-PSMA) therapy suddenly has become a big talking point in prostate cancer circles. Delivering radiotherapy via injectable radiopharmaceuticals is being talked up as a coming mega trend in cancer therapy in general, but 177Lu-PSMA and prostate cancer is where the big story lies at the moment. In part, because of the size of the problem and therefore the size of the opportunity (1 in 40 men die of prostate cancer), and in part because of the US$6 billion Novartis paid in 2018 that led to them acquiring the technology. 

Once prostate cancer becomes metastatic and fails to respond to chemical castration therapy and taxane chemotherapy (docetaxel, cabazitaxel), prognosis is poor. Recent novel agents abiraterone and enzalutamide, along with radiation treatment of bone secondaries with Radium-233 are reported to provide limited survival benefits of about 4-5 months each.1,2,3  It is in this setting where all treatment options have been exhausted, that 177Lu-PSMA therapy is being introduced. 

Just how good is 177Lu-PSMA therapy?
This is the big question, with the precise extent of the benefit of 177Lu-PSMA therapy being hard to answer yet. Novartis/Endocyte currently are running their Phase 3 VISION clinical study which is comparing 177Lu-PSMA against best-practice treatment in 750 men, and that will be the first randomized controlled (head-to-head) study that will provide definitive, statistical evidence on the benefit of  177Lu-PSMA therapy, particularly when it comes to the all-important question of the effect on overall survival times. 

The evidence we have at the moment comes from reports of 177Lu-PSMA therapy in smallish groups of men measured against historical data. The conclusion that can be stated with confidence is that 177Lu-PSMA clearly is doing something beneficial – it is providing symptomatic relief. Achieving pain relief and improved quality of life in a high proportion of men who otherwise are sliding towards death, suggests that something positive is happening. 

But while comparisons against historical data can still be useful, any conclusions on just how good it is are confounded by a lack of consistency in patient selection, with:

  • differences in the stage of disease - some patients have exhausted all treatment options, while others still have some remaining treatment options;
  • differences in the degree to which cancer cells take up the 177Lu-PSMA - cancers with low rates of uptake are far less likely to respond than those with high rates of uptake. 

The VISION study has been designed to minimise those differences, giving regulators, doctors and patients a realistic assessment of the benefit of the treatment. 

What is the point of the LuPIN study?

Even before we know the VISION study outcome, it is obvious from current experience that 177Lu-PSMA doesn’t work in every patient. And even where it does work, there is a lot of variation in the degree of the response (from just stopping cancer growth, through to causing tumours to disappear) and how long it lasts (from several months to several years). That’s the case with any cancer therapy, and 177Lu-PSMA won’t be any different. 

The LuPIN study was set up to see if Veyonda could tip the balance and improve response rates, and to do so safely. One of the key outcomes being looked at was whether Veyonda could help patients complete their full course of 177Lu-PSMA therapy. 177Lu-PSMA injections are spaced 6-weeks apart. Some groups give a course of 4 injections over 5 months, others up to 6 injections over 8 months. Patients continue to receive the injections providing that their PSA levels indicate that the cancer is continuing to respond to treatment. The injections stop once the PSA levels start rising or their general symptoms worsen.

In other words, the longer the patient can continue to stay on 177Lu-PSMA therapy (5-8 months), the better their response, and the more likely they are to have a better outcome. 

Interpreting the recent LuPIN data

The first thing to say about the recent data is that it is preliminary. It is looking just at the first 16 patients. There are another 40 patients to go, and the final data from all 56 patients will carry a lot more weight than preliminary data from 16 patients. 

The second thing is that LuPIN is a single-arm study – there is no head-to-head comparison of 177Lu-PSMA therapy with or without Veyondaâ. This is a snapshot view of how well the combination of two experimental drugs (Veyondaâ + 177Lu-PSMA) is working. 

As a snapshot, the Company views the current interim combination data as highly encouraging, with 11 of the 16 men (69%) able to reach their 4th 177Lu-PSMA injection without disease progression, with all these men demonstrating a strong anti-cancer response (as distinct from simply stopping tumour growth) as evidenced by >50% fall in PSA levels. In light of the advanced nature of the disease in these men, this is by any measure an impressive stand-alone outcome. The next important measure is how long this effect will last and how much extra life it provides. 

The disease status of the patients is a critical factor in interpreting this data. The clinicians running the LuPIN study are selecting patients who have exhausted all standard treatment options of two courses of taxane therapy (docetaxel, cabazitaxel) and at least one course of enzalutamide or abiraterone. 

This is important because some reports, such as the oft-cited paper of Hofman et al (2018)4, speak of using 177Lu-PSMA in some men who have not yet exhausted all these treatments, meaning that their disease is not as advanced.

https://www.ncbi.nlm.nih.gov/pubmed/29752180

https://www.ncbi.nlm.nih.gov/pubmed/27506431

https://www.ncbi.nlm.nih.gov/pubmed/28986618 

Both LuPIN and VISION studies will read-out late-next year, at which time we expect to be well-placed to assess the likely benefit of combination therapy versus 177Lu-PSMA therapy on its own.

Nevertheless, the clinicians running LuPIN attempted to put this interim data into perspective by comparing it with the first 14 men they ever treated using 177Lu-PSMA on its own. This comparison comes with the qualification that those first 14 men were a learning experience in terms of patient selection, with certain lessons then applied to patient selection in LuPIN. 

However, those clinicians viewed the status of the two groups of patients as sufficiently similar to make a side-by-side comparison and to conduct a statistical evaluation. That evaluation showed that with two key anti-cancer end-points of (i) time to disease progression and (ii) ability to reach the 4th 177Lu-PSMA injection, the combination of Veyondaâ + 177Lu-PSMA was significantly better than 177Lu-PSMA alone. 

The Company looks forward to ongoing release of LuPIN data and its measure against the final VISION study data, but we are moving forward with confidence that Veyondaâ is heading to an assured place in the treatment of prostate cancer. 

References:

  1. Morris MJ et al (2015) J Clin Oncol 33:1356
  2. Ramadan WH et al (2015) Onco Targets Ther 8:871
  3. Parker C et al (2013) 369:213
  4. Hofman M et al. Lancet Oncology (2018)  19:825