Showing posts with label Xofigo. Show all posts
Showing posts with label Xofigo. Show all posts

Friday, August 26, 2016

Will Lu-177-anti-PSMA be the next Xofigo?


Xofigo has been a game-changer in the treatment of prostate cancer metastatic to bone. Not only does it provide significant pain palliation and reduce skeletal-related adverse events, but it slows down progression of the disease, increasing median survival by about 30%. Unlike external beam radiation, it can be used when there are many widely distributed metastases.

Several new studies looked at a potentially important new radiotherapy. Lutetium 177 is a low-energy beta particle emitter. In this case, low energy is a good thing because it limits the distance the beta particles (actually electrons) can travel through tissue. Ideally, we want internal radiotherapies to deposit their energy in tumor tissue only; radioemitters that deposit their energy over long distances are too toxic for internal therapeutic applications. Xofigo (radium 223 chloride) is an alpha particle emitter (a helium nucleus consisting of 2 protons and 2 neutrons). Alpha particles are very heavy and can travel only a short distance through tissue; however, they deposit a lot of energy in the tissue they interact with, efficiently killing cancer cells in a small radius. One can safely hold a glass vial of Xofigo in one’s hand because it can’t penetrate beyond the thickness of the glass or penetrate skin. Because beta particles are thousands of times smaller than alpha particles, they can travel farther through tissue, but their cell-killing power is less.

Another desirable quality in radiotherapeutics is a half-life long enough to allow for convenient treatment and time in the body to kill off cancer cells, but short enough so that it doesn’t hang around too long, accumulate in the liver and kidneys, and kill healthy tissue. Both Ra-223 and Lu-177 fit that criterion.

Ra-223 is chemically similar to calcium, so tissues that uptake calcium, uptake radium as well. That means principally bone, especially in highly metabolically active sites like bone metastases.  However, calcium is ubiquitous in the human body, so small amounts of radium may accumulate in other tissues, causing toxicity.

Lu-177 by itself has little therapeutic use; however, scientists have attached it to an antibody found mostly on the surface prostate cancer cells, at least 95% of them, called prostate surface membrane antigen (PSMA). The radioactive Lu-177 is chemically bonded to a monoclonal PSMA antibody, called J591, which finds its way to prostate cancer cells anywhere in the body. Unlike Xofigo, which only attaches to bone metastases, Lu-177-anti-PSMA attaches to any metastasis – bone, lymph node or visceral. It can potentially treat systemic micrometastases as well. It has the ability to potentially kill many more cells because of the increased range of the beta particle. And because it does not attach to non-prostatic tissue, the toxicity is more limited.

Lu-177 has another important benefit that Ra-223 lacks: it emits small amounts of highly penetrating gamma rays. The gamma rays are not powerful enough to kill tissue, but they can be detected by a 2D gamma ray camera (scintigraphy), or a 3D SPECT scan. This means that we can see even small metastases that the radiotherapy is attacking; it is both therapeutic and diagnostic (sometimes called theranostic).

The table below summarizes some of the key characteristics of Ra-223 and Lu-177.


Xofigo (Ra-223 Chloride)
Lu-177-anti-PSMA
Emits:
Alpha particles (95%)
Beta particles, gamma rays
Half-life:
11.4 days
6.7 days
Attaches to:
Tissues that uptake calcium
Prostate cancer expressing the prostate specific membrane antigen (PSMA)
Destroys metastases in:
Bone only (areas of active calcium uptake)
Bone, lymph nodes, viscera, systemic micrometastases
Destructive range:
Shorter range:<0.1 mm or about 8 cells
Longer range: ~0.25 mm or about 125 cells
Cancer cell killing power:
Higher
Lower
Imaging:
Not detectable
Gamma camera (scintigraphy) or SPECT
Toxicity
Gastrointestinal, edema, myelosuppression
Myelosuppression: platelets, neutrophils & leukocytes

Tagawa et al.(2013) published the results of a Phase II clinical trial that demonstrated Lu-177-anti-PSMA resulted in declines in PSA among patients with metastatic castrate-resistant prostate cancer. In a follow-up analysis, they reported a better response, including increased survival, but with higher toxicity with increased dose. As with Radium-223, PSA response may not be the best measure of its efficacy. They also noted large declines in circulating tumor cells (CTCs). There was better response among patients who had better anti-PSMA uptake. Based on this, they suggested the following additional studies:

• Improved patient selection using PSMA-based imaging and circulating tumor cell (CTC) analysis
• Escalated cumulative doses using dose fractionation
• Concurrent use with docetaxel to radiosensitize tumors
• Earlier use as soon as biochemical recurrence is identified after initial therapy

At the 2015 Genitourinary Conference there were early reports on some of those studies.  Batra et al. reported on a small Phase II clinical trial of Lu-177-anti-PSMA used with or without docetaxel, and with fractionated dosing. The group that received both docetaxel and the higher cumulative dosing with fractionated dosing had the best response, with 81% having a reduction in PSA of over 30%, although their overall survival did not seem significantly improved compared to the low dose group. The group that received the highest fractionated dose, but without docetaxel, had an overall survival three times longer (43 months) than the group that received a low dose. Myelosuppression was reversible after treatment. Karir et al. reported on CTC counts of patients in the same study. Over 90% of those with an unfavorable CTC count (>5) had a favorable CTC count (<5) following treatment. Interestingly, they found that anti-PSMA alone, without the added Lu-177, had a favorable effect in a small subset they tested.

Agarwal et al. used Lu-177-EDTMP in 44 patients with metastatic castrate resistant prostate cancer or breast cancer with skeletal metastases to see if it provided significant pain palliation. Complete alleviation of pain was observed in 13%, a partial response in 48%, and a minimal response in 25%.

The results so far look promising, and certainly warrant expanded clinical trials.

For those interested, there is an open clinical trial (NCT00859781) at 10 locations around the U.S., testing Lu-177-anti-PSMA plus ketoconazole and hydrocortisone in patients with biochemical progression after primary RP or RT and castrate-resistance, but who have no detectable distant metastases.


Thursday, August 25, 2016

First in-human trial of Actinium-225-PSMA-617


Among the more interesting developments in radiation oncology/nuclear medicine in recent years are novel therapies created by attaching radioactive isotopes to molecules (called ligands) that attach to the prostate-specific membrane antigen (PSMA) that is found on the surface of most metastatic prostate cancer cells.

We have seen several small studies conducted throughout Germany using Lu-177-PSMA (see this link for latest update).  Lu-177 is a beta (β) particle emitter – its radioactivity is produced when a neutron decays into a proton and an energetic electron – a beta particle. Xofigo is an alpha (α) particle emitter – its radioactivity occurs when the radium 223 nucleus releases 2 protons and 2 neutrons – an alpha particle or helium nucleus. There are advantages and disadvantages to each (see table in this link).

Lu-177-PSMA was developed at the University of Heidelberg. Those researchers have developed a targeted therapy using an alpha emitter called actinium 225. Ac-225-PSMA-617 can potentially be used in some situations where Xofigo or Lu-177-PSMA cannot. Xofigo only treats bone metastases because radium is biologically similar to calcium and replaces it in areas of active bone growth, like metastases. Ac-225-PSMA-617 has several theoretical advantages:
  • ·      It can target metastases in any tissue or fluid, including undetectable, systemic micrometastases.
  • ·      Because its alpha particles are very short range, it doesn’t destroy very much healthy bone marrow.
  • ·      Because the alpha particles are highly energetic, they destroy nearby cells very effectively.
  • ·      Because it attaches to PSMA instead of calcium-active sites in bone or other tissue, it may be less toxic to other healthy tissue.

Kratochwil et al. report a proof-of-concept in two patients treated with Ac-225-PSMA-617. They used Ga-68-PSMA-11, which shows up on a PET scan, to detect metastases that were positive for PSMA and to detect response to the alpha- emitter. The two patients selected had progressed under other treatments and were in “highly challenging clinical situations,” which included tumor infiltration into the red bone marrow. After bi-monthly treatments, both patients:
  • ·      Exhibited complete PSA response, becoming undetectable
  • ·      Exhibited complete tumor response on PET imaging
  • ·      Exhibited no hematological toxicity; that is, no bone marrow suppression
  • ·      Exhibited dry mouth from decreased saliva (xerostomia)

This is a first-in-human trial, and larger trials will be needed to prove efficacy and safety. However, it is an early encouraging development worth taking note of.