By Udhayvir Singh Grewal, MD, Assistant Professor of Medical Oncology, Emory University School of Medicine
Guest Contributor
The Annual NANETS Multi-Disciplinary Symposium 2025 was a remarkably rich program, with several studies that clearly demonstrated scientific novelty and carry immense potential to influence clinical practice. Here, I summarize some key abstracts that particularly stood out to me.
Novel Neuroendocrine Carcinoma Therapy
Some key trials investigating novel therapies were presented. Dr. Jaume Capdevila (Vall d’Hebron Institute of Oncology) shared impressive results from the phase 1 trial of obrixtamig, a DLL3/CD3 bispecific T-cell engager. Responses were dramatically enriched in DLL3-high extrapulmonary neuroendocrine carcinoma (NEC), with a 40% overall response rate (ORR) and median DoR of nearly 8 months, compared with only 3.3% ORR in DLL3-low disease. Notably, there was an overall low incidence of toxicities such as cytokine release syndrome and neurotoxicity. This is much-needed progress for patients with extrapulmonary NECs, where we are sorely in need of better therapies.
Radioligand Therapies
In the well-differentiated neuroendocrine tumors (NETs) space, alpha radioligand therapy is the new kid on the block that we are all very excited about. Dr. Jonathan Strosberg (Moffitt Cancer Center) highlighted two-year follow-up data from ALPHAMEDIX 02, showing 57% ORR, durable responses exceeding 12–24 months in many patients, and excellent 2-year progression-free survival (71.3%) with Pb212-DOTAMTATE in PRRT-naïve SSTR+ GEP-NETs. Gastrointestinal toxicities such as dysphagia remain a key concern here and in general. We are waiting for long-term follow-up and outcomes to get a better understanding of the safety and efficacy of these products. Dr. Thorvardur Halfdanarson (Mayo Clinic) also presented early results from the [212Pb]VMT-alpha-NET dose escalation study. Even at 185 MBq, patients experienced no DLTs, no grade 4/5 toxicities, and demonstrated a 57% objective response rate among DLT-phase participants. It is indeed great to see these data unfold. Alpha RLT appears to hold good promise as a future therapeutic option for many of our patients with both PRRT-naïve and PRRT-pre-treated disease.
There is also a growing interest in combination strategies to improve upon the outcomes with beta PRRT. Dr. Aman Chauhan (University of Miami) shared encouraging findings from the NCI-sponsored Phase 1 trial of triapine + 177Lu-dotatate. Despite expected but transient cytopenias, the regimen delivered a 21% ORR and a median PFS ~ 38 months, with early signals that the PFS in the RP2D cohort could exceed 40 months. A randomized Phase 2 trial is now enrolling.
As we are making strides with novel radioligand therapies, it is also important to focus on long-term hematological toxicities associated with these therapies. Dr. Abhay Singh (Cleveland Clinic) discussed longitudinal evidence showing that PPM1D mutations emerge in nearly one-third of NET patients after chemotherapy and/or PRRT, despite being almost absent at baseline. These therapy-selected clones demonstrated significant expansion and were associated with worse outcomes, suggesting that PPM1D may be a key “malignant CHIP-erpetrator” in these patients and a potential target for future preventive strategies.
It is also important to highlight here that therapy sequencing in NETs has been an area of constant debate and exploration. However, the pieces of this puzzle seem to be finally coming together for at least radioligand therapy. Dr. Capdevila shared subgroup analyses from the phase III COMPETE trial, where 177Lu-edotreotide outperformed everolimus across most clinically relevant subgroups. With a median PFS of 23.9 vs 14.1 months and an ORR of 21.9% vs 4.2%, the consistency of benefit further cements beta-PRRT as a cornerstone in well-differentiated GEP-NET care. Evolving data suggest that, in the appropriate patient population, PRRT as an intervention is perhaps best used earlier in the sequence of therapies.
Locoregional Therapies
In the realm of locoregional therapies, we also saw results of the much-awaited RETNET study. Dr. Michael Soulen (University of Pennsylvania) presented results from this multicenter randomized study comparing bland embolization (TAE) with conventional lipiodol TACE (transarterial chemoembolization). DEB-TACE was abandoned early due to excessive toxicity, while TAE and cTACE produced similar hepatic PFS. Notably, serious toxicities were more common in the TAE arm, raising important questions about risk–benefit considerations in embolization strategy selection.
Developing Patient-Centered Therapeutics
Rounding out the meeting, Dr. Michael O’Rorke (University of Iowa) presented baseline findings from NET-PRO, a landmark PCORI-funded PRO cohort spanning more than 2,300 NET patients across 14 centers. Fatigue, insomnia, and diarrhea ranked as the most burdensome symptoms, with lung NET patients reporting the poorest global QoL. Despite strong satisfaction with care, concerns about toxicity, cost, and travel burden were widespread—underscoring the urgent need for patient-centered delivery models. As we continue to make strides in bringing novel and more effective therapies to the clinic, it is also important to ensure that this progress is patient-centered and keeps quality of life and patient-reported outcomes at the very core of therapeutic
development.