Betalutin (177Lu-lilotomab satetraxetan)

177Lu-lilotomab satetraxetan (Betalutin) is an anti-CD37 radioimmunoconjugate evaluated as a single administration therapy for the treatment of patients with relapsed/refractory follicular lymphoma or diffuse large B-cell lymphoma (DLBCL)...However, BCL2 expression was higher in resistant than in sensitive GCB-DLBCL cell lines, and the addition of the BCL2 inhibitor venetoclax showed synergism when added to the radioimmunoconjugate. Finally, the pattern of activity of 177Lu-lilotomab satetraxetan differed from what was achieved with a CD37-targeting antibody-drug conjugate or with Rituximab cyclophosphamide hydroxydaunorubicin (doxorubicin) oncovin prednisone (R-CHOP), indicating the potential benefit of the beta-emitter payload. This systematic analysis of the responsiveness of lymphoma cell lines to CD37-targeting radioimmunotherapy consolidated 177Lu-lilotomab satetraxetan as a promising compound for the treatment of CD37-positive malignancies and identified candidate biomarkers and co-targets to detect and overcome cancer cell-intrinsic resistance mechanisms.

P1/2, N=191, Completed, Nordic Nanovector | Active, not recruiting --> Completed

P1, N=7, Completed, Nordic Nanovector | Phase classification: P1b --> P1

The CD37 targeting radioimmunoconjugate 177Lu-lilotomab satetraxetan (Betalutin®) is currently being evaluated as monotherapy in a clinical phase 2b trial for patients with follicular lymphoma (FL) and in a phase 1 trial for patients with diffuse large B-cell lymphoma (DLBCL), as well as in a phase 1b trial in combination with rituximab for patients with relapsed/refractory FL. These findings may be of potential relevance for ongoing clinical trials of 177Lu-lilotomab satetraxetan in relapsed, ASCT-non-eligible DLBCL, and may also be more generally applicable to other 177Lu-based RITs and alternative radionuclide utilizing targeted therapies. Future pre-clinical investigations are required to elucidate the potential application of CDK1/2 and AURKA/B inhibitors as a strategy to revert RIT resistance in TP53 deficient cancers.