I-131-MIP-1095 has entered a phase 2 randomized clinical trial

As I reported last year, a new radiopharmaceutical has entered the pack. I-131-MIP-1095, a powerful beta-particle emitter attached to a PSMA-targeted ligand, will enter a multicenter phase 2 randomized clinical trial. Progenics®, the manufacturer, put out a press release, which can be read here. (Update 4/2020) The clinical trial has begun recruiting in 17 locations in the US and Canada.

They will be testing a combination of I-131-MIP-1095 with enzalutamide (Xtandi) in patients who are metastatic, castration resistant, have not yet had chemotherapy, and who have become resistant to Zytiga. It is hoped that Xtandi will radiosensitize the cancer to the radiopharmaceutical with a resultant PSA decrease.

175 evaluable patients will be recruited; half will get the radiopharmaceutical + Xtandi, half will get Xtandi alone. All patients will be screened using DCFPyL PET/CT to assure that their metastases are PSMA-avid. The primary endpoint - the percent who have greater than 50% PSA reduction - will be collected for a year. Secondary endpoints - radiographic response, progression-free survival, and overall survival - will be reported at the end of two years.

Another radiopharmaceutical in clinical trials is Lu-177-PSMA-617 .  There are various phase 1 and 2 clinical trials in the US and internationally (see list at the end of this link).

I recently reported about the very promising outcomes of Ac-225-PSMA-617 in Germany. Patients report that they are combining Ac-225-PSMA-617 and Lu-177-PSMA-617 to get the advantages of each. Weill Cornell in NYC is investigating Ac-225-J591 in a phase 1 trial.

For information on the trial of Th-227-PSMA, see this link.

Does Lu-177-PSMA-617 increase survival?

We have enthusiastically reported the encouraging outcomes of the early clinical trials of the radiopharmaceutical Lu-177-PSMA, most recently at this link. Based on reduction in PSA, it performs well. But medicines have no real benefit if all they do is treat PSA. We want medicines that increase survival.

Rahbar et al. reported the outcomes of 104 patients treated with Lu-177-PSMA-617 at University Hospital Muenster, Germany. All patients had metastatic castration-resistant prostate cancer (mCRPC) and had already received docetaxel and at least one of abiraterone or enzalutamide. After the first of an average of 3.5 cycles, they had the following outcomes:

• 67% of patients had some PSA decline
• 33% of patients had a PSA decline of at least 50%
• Median overall survival was 56 weeks (13 months)

The authors conclude:

177Lu-PSMA-617 RLT is a new effective therapeutic and seems to prolong survival in patients with advanced mCRPC pretreated with chemotherapy, abiraterone and/or enzalutamide. 

But is this conclusion justified? It's hard to know without a prospective clinical trial where patients are randomized to receive the radiopharmaceutical or standard-of-care. The best we can do is look at the overall survival from clinical trials involving patients with symptomatic mCRPC. In the "ALSYMPCA" trial of Xofigo, among the subgroup of patients who had received docetaxel for their painful mCRPC (see this link), overall survival was:

• 14 months with Xofigo
• 11 months with placebo

The ALSYMPCA trial was conducted before abiraterone and enzalutamide were approved, so it is impossible to know how prior treatment with one of those might have changed survival. There have been a couple of small trials of "third-line" medicines after docetaxel and abiraterone were used.

In a non-randomized trial among 24 mCRPC patients after treatment with docetaxel and abiraterone, overall survival was:

• 9 months with cabazitaxel

In a Danish study among 24 mCRPC patients after treatment with docetaxel and abiraterone, overall survival was:

• 5 months with enzalutamide

So these data suggest that Lu-177-PSMA-617 may have prolonged life more than third-line treatment with another taxane or another hormonal agent. However, we expect much cross-resistance between abiraterone and enzalutamide, and resistance building up with prolonged use of taxanes. It is always hazardous to compare patient outcomes or declare success when they have not been randomized. Certainly there is enough suggestive data to warrant a Phase 3 randomized clinical trial.

A new Lu-177-PSMA ligand has good results in a new study

Targeted nuclear medicine has shown some impressive outcomes in several small studies, mostly conducted in Germany. Most of the studies have used a radioactive beta-particle emitter, Lutetium 177, attached to a ligand that has high and specific affinity for prostate cancer cells. Most medicines developed for this purpose have a ligand that attaches to Prostate-Specific Membrane Antigen (PSMA), a protein found on 90% of all prostate cancer cells. The ligand for Lu-177-PSMA has to have a "grappling hook" on one end (called a chelator) that holds onto the Lu-177. On the other end is a "magnet" of sorts that binds tightly to the PSMA. The beta particles then kill the cell that the ligand attaches to and some nearby cells as well.

There are also ligands that attach to prostate cancer proteins other than PSMA, and radioactive elements other than Lu-177 that are in clinical trials. This is a rapidly developing field.

The new ligand is called PSMA-I&T (imaging and therapy) or sometimes PSMA-DOTAGA. The ligand used in most of the other studies was PSMA-617 (also known as PSMA-DKFZ) or PSMA-J591. The ideal ligand attaches strongly to PSMA in prostate cancer tumors and to nothing else. Importantly, it should not accumulate in the kidneys to a great extent because it could damage them.

Last year, the Central Clinic of Bad Berka, Germany reported on 56 patients treated with Lu-177-PSMA-I&T (see this link). 80% of treated patients had a PSA response and toxicity was minor. Heck et al.  at the Technical University of Munich reported on 19 metastatic castration-resistant patients who were treated with 7.4 GBq per cycle and up to 4 cycles.

• In 56%, PSA decreased by at least 30%
• In 33%, PSA decreased by at least 50%
• In 11%, PSA decreased by at least 90%
• Complete remission of metastases in 5%
• Metastases stayed stable in 63%
• Metastases progressed in 32%
• Performance status was stable or improved in 74%
• In those with bone pain, it was reduced partially or completely in 58%
• Mild (Grade 1 or 2) toxicities included dry mouth (37%), anemia (32%), and platelet loss (25%)
• There were no severe (Grade 3 or 4) toxicities.
• There was no kidney toxicity up to 40 GBq (see this link)

(Update 11/2018) Heck et al. updated the above with information on 100 patients. They were heavily pre-treated with a median of 3 pre-treatments. In fact, they were required to have had Zytiga or Xtandi, and at least one cycle of taxane chemo. They were all mCRPC and 35% had visceral metastases. They may have had up to 6 cycles of Lu-177-PSMA-617 (average was 3.2 cycles).

• In 38%, PSA decreased by at least 50%
• Median clinical progression-free survival was 4.1 months
• Median overall survival was 12.9 months
• Treatment-emergent hematologic grade 3/4 toxicities were anemia (9%), thrombocytopenia (4%), and neutropenia (6%)

A meta-analysis looked at the PSMA-I&T and PSMA-617 ligands in relation to the PSMA-J591 ligand. With a combined sample size of 369 patients across 10 studies, Calopedos et al. reported that:

• 68% of patients had some PSA decline
• 37% of patients had a PSA decline of at least 50%
• More patients had a PSA decline with the PSMA-I&T and PSMA-617 ligands, but there was a wide range of outcomes

These early indicators look good. Even if it just stabilizes performance status and mitigates bone pain in these end-stage patients, there is an important benefit. Of course, what we really want to see is evidence that it increases overall survival

While PSMA-I&T was developed to be a good ligand for imaging purposes as well as therapeutic purposes, a recent study found that, when used with Ga-68 (a positron emitter), PSMA-HBED-CC (also known as PSMA-11) was slightly better at detecting metastases (see this link). Another PSMA ligand, DCFPyL, that incorporates the positron emitter F18 into the ligand more tightly (avoiding chelation, which can easily be reversed), seems to be superior to the Ga-68-PSMA-HBED-CC PET tracer (see this link). Both DCFPyL PET and Ga-68-HBED-CC PET are in numerous clinical trials in the US and Canada. Lu-177 is a gamma emitter that can be seen by a gamma camera or via SPECT. However, it is usually used in conjunction with a positron-emitter in order to obtain a superior image.

Readers may wish to read these other articles on this subject:

Will Lutetium-177-anti-PSMA be the next Xofigo?
Lu-177-PSMA update
Lu-177-PSMA: another update
First in-human trial of Actinium-225-PSMA-617
Ac-225-PSMA-617 extends survival (update)
Ac-225-PSMA-617 (update)
I-131-MIP-135, a new radiopharmaceutical, in clinical trial at Memorial Sloan Kettering

Lu-177-PSMA-617: Another update

Because there is great interest in systemic therapies for metastatic prostate cancer, I want to provide readers with the latest news about the Lu-177-PSMA-617 trials in Germany.

I recently reported (see this link) on 74 patients – 31% had PSA declines greater than 50%. A new report by Rahbar et al. expands the patient base to include PSA data on 99 patients and toxicity data on 121 patients treated at 12 therapy centers.  After median follow-up of 16 weeks, and up to 4 therapy cycles:

·      45% had a PSA decline greater than 50%

o   40% after a single cycle

·      18/121 patients (15%) had serious or life-threatening hematotoxicity, affecting red blood cells (10%), platelets (4%), and white blood cells (3%)

·      Xerostomia (loss of saliva) occurred in 8%

This is a very encouraging PSA response. For comparison, only 13% had a PSA reduction greater than 50% in the Xofigo clinical trial. However in that trial, 66% had a 50%+ decline in bone alkaline phosphatase, which may be a better biomarker for bone metastases. The hematotoxicity was identical.

What we really want to know is whether the treatment increases survival, and whether it is any better than Xofigo in doing so. The potential benefit of Lu-177-PSMA-617 is that it can treat non-osseous metastases too. We await future clinical trials to prove its benefit.

Lu-177-PSMA Update

One of the more important emerging radiotherapies for metastatic castrate-resistant prostate cancer is Lu-177 that is chemically bonded to a ligand -- an antibody or a small molecule that attaches to the prostate-specific membrane antigen (PSMA). We’ll call this class of medications Lu-177-PSMA. PSMA is expressed on the surface of 95% of all metastatic prostate cancer cells. See this link for a fuller explanation. Many of the studies on Lu-177-PSMA have been conducted in Germany. Recently, there was a report on a small study from Bad Berka, Germany with some early encouraging results. There have been a few more trial reports since then.

All of the more recently published studies used a ligand called PSMA-617, a small molecule that attaches to PSMA, rather than a PSMA antibody. It was hoped that this ligand would be more specific to prostate cancer cells, with less affinity for salivary glands and kidneys where it can cause side effects and false positives.

Kratchowil et al. at the University of Heidelberg reported on 30 patients treated with one to three cycles of Lu-177-PSMA-617.

• ·      PSA decreased in 21/30 patients (70 percent).

o   PSA decreased by > 50% in 13/30 (43 percent)

o   Among 11 patients who had 3 cycles of therapy, 8 (73%) had PSA declines >50% that were sustained for over 24 weeks. Number and size of metastases decreased as well.

• ·      Hematotoxicity (from bone marrow suppression) was mild.
• ·      Xerostomia (dry mouth), nausea and fatigue were transient and occurred in <10 percent.
• ·      Excess radioactivity was cleared from the kidneys within 48 hours.

Rahbar et al. at the University Hospital Münster reported on 74 patients treated with a single dose of Lu-177-PSMA-617.

• ·      PSA decreased in 47/74 patients (64 percent).

o   PSA decreased by > 50% in 23/74 patients (31%)

• ·      PSA was stable (- 50% to +25%) in 35/74 patients (47%)
• ·      PSA increased by > 25% in 17/74 patients (23%)
• ·      No significant loss of red blood cells, white blood cells or kidney function
• ·      Mild decline in platelets, but within normal range

Rahbar et al. also report outcomes on 28 patients after one vs. two treatments.

• ·      PSA decreased in 59% of patients after 1 treatment and in 75 percent after 2 treatments.

o   PSA decreased by > 50% in 32 percent of patients after 1 treatment and in 50% after 2 treatments.

• ·      Median survival was 29 weeks, compared to 20 weeks based on historical expectations.
• ·      No clinically significant or lasting toxicity occurred.

Radiotherapy with Lu-177, though encouraging, is still in its early days. There is much work to be done in identifying the optimal ligand, optimal dose, optimal number of treatments, optimal patient/disease characteristics, and adjuvant therapies. I encourage participation in clinical trials in the US (NCT00859781) and in Germany.

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.

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.