How do you interpret data from a single study using a single treatment arm? A fair question.
The answer is, cautiously. We have been cautious, and we still think the data is exciting.
Some background first.
- The full name for Lu-PSMA is 177 lutetium-PSMA-617
- Lu-PSMA is an experimental drug – a type known as a radiopharmaceutical
- The 177lutetium is a radionuclide (radioactive isotope) (the warhead), while the PSMA-617 is a peptide delivering the warhead to cancer cells (the missile)
- Lu-PSMA is part of an emerging field of cancer therapy known as theranostics, not the easiest word to get your mind around, but one that you are going to hear a lot more about in the coming years
- Lu-PSMA is injected intravenously. The purpose is to deliver radioactivity directly to all prostate cancer cells in the body in men with late-stage, metastatic prostate cancer, something that is not possible with externally delivered radiation which needs to be focused just on small areas of the body
- Lu-PSMA targets a protein displayed on the surface of prostate cancer cells known as prostate-specific membrane antigen (PSMA). The PSMA-617 part of the drug seeks out this protein
- The 177lutetium part of the drug delivers the damage which hopefully slows down or even kills the cancer cell
- About 90% of men express PSMA and are suitable for Lu-PSMA treatment
- A standard course of treatment with Lu-PSMA is up to 6 injections 6 weeks apart
- During the treatment period, men are monitored closely and continue to receive injections providing that their disease is not progressing
- PSMA is mainly expressed by prostate cancer cells, and to a lesser extent by cells in the salivary glands and stomach lining, leading to some side-effects
- Lu-PSMA therapy is attracting considerable attention globally as a last-line salvage therapy for men whose prostate cancer has progressed on all available therapies. It is not curative, but it shows promise of reducing pain levels and having significant anti-cancer activity while potentially providing some extended life expectancy.
Interim data of the first 32 patients in the LuPIN trial was presented recently at the ASCO GU Symposium in the USA.
The first point to note is how well tolerated the combination treatment was. Safety was always a key question when this study started, given that the purpose of adding Veyonda ® was to boost the damaging effect of radiation on cancer cells. But there was always the risk that Veyonda ® could have increased off-target activity in tissues like the salivary glands, stomach and kidneys as well. Happily, and as we anticipated, that did not happen.
The second point is the nature of the patients in the LuPIN study. The LuPIN patients had to have failed all available therapies, which in metastatic castrate-resistant prostate cancer (mCRPC) means two lines of taxane chemotherapy (docetaxel followed by cabazitaxel) followed by androgen deprivation therapy (abiraterone or enzalutamide). 29/32 LuPIN patients had these 3 separate lines of therapy. Other studies aren’t necessarily so stringent in their patient selection. The all-important VISION Phase 3 study, the registration study for Lu-PSMA being conducted by Novartis, is open to men who have had only 1 line of taxane therapy.
The relevance of this is that the more lines of therapy a cancer like prostate cancer is exposed to, the more advanced the disease becomes, the more resistant it becomes to any subsequent form of therapy, and generally the sicker the patient is.
This makes the LuPIN study the most stringent of its kind, which means comparing its outcome to many other published studies is not an apple vs apple situation.
So, it is in this context, with 90% of patients having had an exhaustive treatment history and 65% of them having extensive tumour burden (>20 tumours), obtaining a median overall survival (OS) of 17.1 months has to be regarded as a major outcome for men facing imminent end of life.
It is only by running a two-arm study like the VISION study that we will have definitive proof of the survival advantage of adding Veyonda® . But, for the moment, given the stringency of the LuPIN study, a median OS of 17.1 months is looking highly promising.The LuPIN study involves a total of 56 patients, meaning that there are a further 24 patients to report on. The first 32 men reported on yesterday received 400mg and 800mg dosages of Veyonda® . The remaining 24 patients are receiving 1200mg.
The LuPIN study will continue for another approximately 18 months, including a 12-month follow-up review to determine overall survival outcomes.
What is theranostics?
- Lu-PSMA is used by specialised sections of nuclear medicine departments known as theranostic units
- The word ‘theranostics’ is a portmanteau word combining diagnostic and therapeutic
- The diagnostic form of the drug uses the peptide (PSMA-617) to deliver a safer isotope( 68gallium) w hich is visualised by PET/CT scanning allows the oncologist to see the extent of the spread of the disease
- The therapeutic form uses PSMA-617 to deliver a more potent radioisotope (177lutetium or 225actinium) to the cancer cells.
- PSMA-617 was developed by the German Cancer Research Center (DKFZ) in Heidelberg in 2011
- 177lutetium-PSMA-617 was licensed in 2018 to US-based Endoctye Inc and 225actinium-PSMA-617 to French-based Advanced Accelerator Applications (AAA)
- Endocyte commenced a Phase 3 registration study (VISION study) in mid-2018
- Late-2018, Novartis acquired Endocyte for US$2.1 billion and AAA for US$3.9 billion (total US$6 billion) and declares major interest in the development of adiopharmaceuticals in the management of a range of cancers.
Current clinical use
Lu-PSMA remains an experimental drug with use currently restricted to clinical trials or compassionate use. The number of men treated to date is thought to be over 3000, most of them compassionately.
Use of 225actinium-PSMA-617 (Ac-PSMA) is far more limited because of its considerably greater toxicity compared to Lu-PSMA.
The largest and latest study of Lu-PSMA is the Phase 3 VISION study initiated in 2018 by Endocyte. https://clinicaltrials.gov/ct2/show/NCT03511664
VISION is an unblinded (open label) study in 750 men with men randomized in a 2:1 ratio either to best supportive/standard care or Lu-PSMA + best supportive/standard care. The primary endpoint is overall survival over a 10-month review period. The study is expected to read-out in early-2021.
If the study meets its primary endpoint, we would expect to see Lu-PSMA receive marketing approval in the U.S. and EEC in late-2021 and become a widely used treatment for end-stage prostate cancer.
The effectiveness of Lu-PSMA or Ac-PSMA depends very largely on how much PSMA is expressed by the cancer cells. More PMSA = more isotope binding to the cancer cells = more radioactivity being delivered to the cancer cells = stronger anti-cancer effect.
However, in many men, PSMA expression appears to be low, leading to limited effectiveness of the Lu-PSMA treatment.
The idea behind adding Veyonda® to Lu-PSMA treatment is two-fold: (a) to boost the damaging effects of the radiation, converting a modest cancer-killing effect into a more potent effect, and (b) to restore immune cell-based cancer-fighting function to the tumours.