Alpha radioligand therapy in neuroendocrine neoplasms: current landscape and spotlight on RYZ101

The therapeutic landscape for neuroendocrine tumors (NETs) has rapidly evolved over the last three decades with the influx of a myriad of treatment options, such as somatostatin analogs (SSAs), targeted therapies, alkylating chemotherapies, and radioligand therapy (RLT). While the advent and regulatory approval of beta emitting RLT such as 177Lu-DOTATATE has offered a valuable therapeutic option for patients with NETs, there is still very significant room to tap the maximal therapeutic potential of RLT. Alpha RLT agents such as RYZ101 (225Ac-DOTATATE) offer a potential advantage over beta RLT due to more complex double-stranded DNA breaks and targeted cytotoxicity, as well as potential for minimizing off-target side-effects. Existing pre-clinical and clinical data suggest promising safety and efficacy of RYZ101 among patients with NETs. The ongoing phase 1b/3 trial ACTION-1 is poised to compare the safety and efficacy of RYZ101 against standard care therapies in advanced gastroenteropancreatic NETs (Ki67 ≤ 20%), after disease progression of prior 177Lu-SSA therapy. Yet, other alpha RLT agents are currently being investigated in both RLT-naïve as well-pre-treated patient populations. While long-term safety and efficacy data are awaited, alpha RLT agents such as RYZ101 offer a unique opportunity to enhance the therapeutic promise of RLT in NETs.