This is a follow on from the 8th October 2025 update below.
Commentary by Dr Mary Maluccio from NOLA NETs. The figures looks great and you can read it or listen to her talking. Click here for that. The phase 3 trials will be PRRT niave patients ony (i.e. those who have had no previous PRRT (beta or alpha)).
Paris, October 8, 2025. Positive results from the ALPHAMEDIX-02 phase 2 study (clinical study identifier: NCT05153772) showed AlphaMedixTM (212Pb-DOTAMTATE), an investigational somatostatin receptor (SSTR)-Targeted Alpha Therapy using the lead-212 isotope, met all primary efficacy endpoints and showed clinically meaningful overall response rates (ORR) and prolonged clinical benefits in both peptide receptor radionuclide therapy (PRRT)-naïve and PRRT-exposed patients with unresectable or metastatic SSTR positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Benefits in key secondary endpoints, including progression-free survival (PFS) and overall survival (OS), were also observed across both cohorts. AlphaMedix™ had a manageable safety profile that was similar across both cohorts.
Author’s note: The wording is interesting because the trial end date is published for 2028. But be aware the study is ongoing, and the full results will be presented at the 2025 European Society for Medical Oncology (ESMO) Congress (October) and NANETS 2025 shortly after. The results will also form the basis of discussions with health authorities. AlphaMedix™ has not been approved by any regulatory authority.
I get the feeling things might move faster with this one.
Background: 212Pb-DOTAMTATE is a Targeted Alpha Therapy (TAT) in clinical development for subjects with SSTR+ neuroendocrine tumors. A phase I dose-escalation study has already been completed (Delpassand et al. J Nucl Med 2022). TAT holds the promise to improve outcomes versus Peptide Receptor Radionuclide Therapy (PRRT) with beta-emitters like 177Lu-DOTATATE, currently considered the standard of care for subjects with GEP-NETs.
Methods: ALPHAMEDIX 02 is a Phase II, open-label, multicenter study evaluating the safety, tolerability and efficacy of 212Pb-DOTAMTATE in PRRT-naïve (Cohort 1, N = 36) and PRRT-refractory (Cohort 2, Target N = 30) subjects with histologically confirmed unresectable or metastatic GEP-NETs, positive somatostatin analogue imaging and at least 1 site of measurable disease per RECIST 1.1. 212Pb-DOTAMTATE was administered at 67.6 μCi/kg per cycle, with a maximum activity administered per cycle of 5.5 mCi every 8 weeks, for up to 4 cycles. Primary endpoints include overall response rate (ORR) per RECIST1.1, and incidence and severity of adverse events (AEs). Secondary endpoints include progression free survival, overall survival , and health-related quality of life. Initial results of the already completed cohort 1 are presented.
Results: In cohort 1, 17 out of 36 subjects with metastatic SSTR+ GEP-NETs achieved a confirmed response (ORR 47.2% (32.0-63.0%)). In the Phase I trial, five out of eight PRRT- naïve subjects with SSTR+ GEP-NETs treated with the same regimen of 212Pb-DOTAMTATE achieved a response (ORR 62.5% (30.6-86.3%)): the combined ORR from both studies is 50% (22 out of 44, 95%-CI:36% – 64%). Median Duration of Response (DOR) has not been reached in both studies. Four out of five subjects (80%) with confirmed response in Phase I had a DOR of ≥ 12 months. In the ongoing Phase II study the response follow-up for 10 subjects with confirmed response is currently shorter than 6 months: so far 7 out of 17 subjects (41%) with confirmed response had a DOR of ≥ 6 months, and one of these subjects had a DOR of ≥ 12 months. Lymphocytopenia is a lead cause of the 59% grade 3 and 4 AEs reported in subjects in cohort 1. Overall, 4 fatal AEs were reported: death / progressive disease (N = 2), carcinoid syndrome (N = 1) and sepsis (N = 1).
Conclusions: In PRRT-naïve subjects with SSTR+ unresectable or metastatic GEP-NETs treatment with up to 4 cycles of ²¹²Pb-DOTAMTATE (67.6 μCi/kg/cycle) was well-tolerated, with a safety profile consistent with the underlying disease and expected toxicities of radioligand therapy, similar to 177Lu-DOTATATE. The ORR of 47.2% in cohort 1 (50% in the pooled dataset) appears to be substantially higher than the ORR previously reported for 177Lu-DOTATATE in the pivotal NETTER-1 study (ORR 18% (10–25%)). Clinical trial information: NCT05153772.
Points to note, these data from Phase 2 cohort 1 are based on PRRT niave patients (i.e. first time PRRT).
Phase 2 cohort 2 will be based on refractory PRRT patients (i.e. patients who have already had PRRT). These data may be more interesting and really test Alpha v Beta PRRT. Phase 2 cohort 2 is ongoing and data will be coming soon. But to quote an expert comment on X (formely twtter) …..”Can the impressive objective reponse rate (ORR) be sustained in Phase 3?”
You can see and hear a short video clip from Dr Strosberg by clicking here.
Credit ASCO
See more data graphics at this link Grupo GETNE on X: “#ASCO24 ➡️ NET Jonathan Strosberg presents data of 212Pb-DOTAMTATE in GEP-NET (PRRT-naive) Phase 1+2 (n=44) ✅️ORR 56% ✅️PFS 24m 74% ☣️Mild hematological toxicity ☣️Alopecia 93%, acalasia 14% 🔍👀Cohort 2 ongoing (PRRT refractory) @Netespana https://t.co/JuQ0ABpbIZ” / X
(Lung and other Non-GEPNETs – see author’s comments below)
The FDA has granted breakthrough therapy designation to AlphaMedix (212Pb-DOTAMTATE) for the treatment of adult patients with unresectable or metastatic, progressive somatostatin receptor (SSTR)–expressing gastroenteropancreatic neuroendocrine tumors (GEP-NETs) who have not previously received peptide receptor radioligand therapy (PRRT). AlphaMedix represents the first Targeted Alpha Therapy to receive this designation. Breakthrough Therapy designation is a process designed to expedite the development and review of drugs that are intended to treat a serious condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint(s).
The decision is based on findings from phase 1 and ongoing phase 2 trials evaluating the safety and efficacy of AlphaMedix. In the phase 1 dose-escalation trial (NCT03466216), AlphaMedix treatment was well tolerated and generated an overall response rate (ORR) of 62.5% per RECIST v1.1 criteria in patients with GEP-NETs who were naive to PRRT with lutetium Lu 177 dotatate (Lutathera; n = 20). Data from this trial, which were presented at the 2021 ASCO Annual Meeting, demonstrated that the most common any-grade adverse effects (AEs) included fatigue (35%), alopecia (30%), hyperglycemia (30%), lymphopenia (30%), and diarrhea (20%).2 A total of 5 grade 3 AEs were reported: acute kidney injury, back pain, dysarthria, and dyspnea. No grade 4 AEs occurred, and 1 grade 5 AE was reported. Most patients who responded to AlphaMedix (n = 5) experienced significant improvements in quality of life (QOL), pain reduction, shortness of breath, and energy increases.
In the phase 2 ALPHAMEDIX02 trial (NCT05153772), AlphaMedix has already achieved the trial’s target response rate, and topline data are expected midway through 2024. Read more by clicking here.
The Phase 2 trial included those with somatostatin receptor positive with or without previous PRRR treatment (but see precise inclusion and exclusion criteria in the clinical trial document references). All information to date has described the NET type as “somatostatin receptor positive” but the recent announcement above would indicate the breakthrough treatment designation only includes Gastroenteropancreatic NETs (GEPNETs), i.e. it excludes somatostatin receptor positive Lung NETs and others not in the GEPNET boundary.
And if you look at the source document from the same organisation dated 16th May 2023, you will see that they confirmed “regardless of the location of the primary tumor”.
I queried the source of the 12th February 2024 announcement and their Chief Medical Officer (CMO) responded as follows.
Patients with advanced GEP-NET represent the largest group of patients who participated in our phase 1 and phase 2 studies so far. As the emerging data from these studies may suggest that 212Pb-DOTAMTATE could provide substantial improvement over Lutathera, the current standard of care in this setting, this was the basis for the BTD grant. In addition, lung NET and other NETs are still biologically distinct in many ways from GEP-NET, eg considering that the standard of care for lung NET is everolimus. Therefore, the recent BTD is focused on treatment of adult patients with unresectable or metastatic, progressive somatostatin receptor expressing gastroenteropancreatic neuroendocrine tumors who are naïve to peptide receptor radionuclide therapy (PRRT). But this doesn’t mean that lung NET or other primary NETs are excluded from future development: it just means that these non-GEP NETs will have to follow their own development paths independent from GEP-NET.
Trial’s Objective Response Rate Endpoint Already Achieved.
RadioMedix and Orano Med, two clinical stage radiopharmaceutical companies, today announced that the last patient has been dosed in the Phase II trial of the targeted alpha emitter therapy, 212Pb-DOTAMTATE (AlphaMedix™). This trial is being conducted to evaluate the safety and effectiveness of AlphaMedix™ in peptide receptor radionuclide therapy (PRRT) of naive patients with somatostatin receptor-expressing neuroendocrine tumors (NET), regardless of the location of the primary tumor. Top-line data from the trial is expected in mid-2024.
Remarkably, based on data already collected, the objective response rate (ORR) endpoint has already been achieved and is more than twice as high as the current standard of care. Read more here
Substitution of an alpha emitter (e.g. ²¹²Pb) for the beta emitters currently being used (i.e., 177Lu or 90Y) will provide significantly higher Linear Energy Transfer (LET) and a shorter path length. Higher LET particles should cause more tumour cell death. Shorter path length should result in less collateral damage of the normal tissue and therefore less side effects for subjects receiving the drug.
AlphaMedix™ (²¹²Pb-DOTAMTATE) is a radiotherapeutic drug indicated in subjects with unresectable, metastatic somatostatin receptor (SSTR) positive neuroendocrine tumors (NETs). Because 212Pb is an in vivo generator of alpha particles, it is particularly suitable for SSTR therapy applications, i.e. it’s a type of PRRT.
This drug addresses an unmet need in the field of peptide receptor radionuclide therapy (PRRT) for NETs. Substitution of an alpha emitter (²¹²Pb) for the beta emitters currently being used (i.e., 177Lu or 90Y) will provide significantly higher Linear Energy Transfer (LET) and a shorter path length. Higher LET particles should cause more tumor cell death. A shorter path length should result in less collateral damage to the normal tissue and therefore fewer side effects for subjects receiving the drug. The phase 1 trial completed in July 2022 with some interesting feedback incuding this Lung NET experience featued on the graphic in the next section.
Phase 2 Clinical Trial – NCT05153772
Multicenter Phase 2 study of 212Pb-DOTAMTATE enrolling adult subjects with positive somatostatin positive neuroendocrine tumors with either no prior history of peptide receptor radionuclide therapy (PRRT naive) or prior history of peptide receptor radionuclide therapy (Previous PRRT)
Detailed Description:
In this open-label, multicenter, single-arm Phase 2 study, adult subjects with histologically confirmed NETs and positive somatostatin analog imaging, with either no prior PRRT (PRRT naive) or prior history of peptide receptor radionuclide therapy (previous PRRT) will be enrolled to receive 212Pb-DOTAMTATE 67.6 μCi/kg dose per cycle.
it’s important to note the specific incusion and exclusion criteria for this trail (documents linked below) as “Previous PRRT” does not mean all types” e.g.
– For subjects who previously received PRRT, Prior treatment with 90Y- DOTATATE/ DOTATOC, 225Ac-DOTATATE/DOTATOC, and/or 111In-DOTATATE/ DOTATOC
– Prior regional hepatic radionuclide therapy within 4 months prior to enrollment or prior nonradioactive regional hepatic therapy within 6 months prior to enrollment. (authors note: I guess that means radioeboliiation e.g. SIR-Spheres. If in doubt, contact the trial sponsor (see info in clincial trials document below).
Official Title
A Phase 2 Open Label Study to Evaluate the Safety and Effectiveness of 212Pb-DOTAMTATE in Subjects With Somatostatin Receptor Expressing Neuroendocrine Tumors
Dates:
| Actual Study Start Date Phase 2: | December 21, 2021 |
| Estimated Primary Completion Date : | October 1, 2028 |
| Estimated Study Completion Date : | October 1, 2028 |
Locations:
The original source document below includes a picture of one patient from Phase 1 who appears to have had a great response (a lung NET) but remember, this may not be the same response in all participants. We await any interim results from Phase 2 but they would appear to be good so far given the announcement above dated 12 Feb 2024.
Ebrahim S Delpassand, Izabela Tworowska, Rouzbeh Esfandiari, Julien Torgue, Jason Hurt, Afshin Shafie and Rodolfo Núñez Journal of Nuclear Medicine, January 2022, jnumed.121.263230; DOI: https://doi.org/10.2967/jnumed.121.263230
Read more here
1. Phase 1 ClinicalTrials.gov Identifier: NCT03466216
2. Phase 2 ClinicalTrials.gov Identifier: NCT05153772
3. Phase 3 Clinical Trials.gov identifier to follow
4. Targeted Alpha Therapy (PRRT) blog post – click here
The industry has settled on two different radionuclides so far, AC225 and Pb212. This blog post covers 212Pb but AC225 is also another option. The biggest trial is contained in this post below. Click here or on the picture to read more.
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided in the clinical trials document. It’s very important to check the trial inclusion and exclusion criteria before making any contact. If you need questions, the articles here is very useful Questions to Ask About Clinical Trials | Cancer.Net
The inclusion of any trial within this blog should not be taken as a recommendation by Ronny Allan.
I am not a doctor or any form of medical professional, practitioner or counsellor. None of the information on my website, or linked to my website(s), or conveyed by me on any social media or presentation, should be interpreted as medical advice given or advised by me.
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Whenever I post about a trial or study, some people get excited without understanding that these new treatments and capabilities can very often take years to come to fruition and it’s also possible that clinical trials can be halted, or that national approval agencies will not approve the final product. Plus, not everyone will be eligible, so always check the exclusion and inclusion criteria in the relevant clinical trials document. Please bear that in mind when reading studies/clinical trials posted on RonnyAllan.NET
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