Obinutuzumab Pretreatment as a Novel Approach to Mitigate Formation of Anti-Drug Antibodies Against Cergutuzumab Amunaleukin in Patients with Solid Tumors

• Published in: Clinical cancer research Vol. 30; no. 8; pp. 1630 - 1641
• Main Authors: Peters, Solange, Angevin, Eric, Alonso-Gordoa, Teresa, Rohrberg, Kristoffer, Melero, Ignacio, Mellado, Begoña, Perez-Gracia, Jose-Luis, Tabernero, Josep, Adessi, Celine, Boetsch, Christophe, Watson, Carl, Dal Porto, Joseph, Dejardin, David, Del Nagro, Christopher, Nicolini, Valeria, Evers, Stefan, Klein, Christian, Leutgeb, Barbara, Pisa, Pavel, Rossmann, Eva, Saro, José, Umana, Pablo, Charo, Jehad, Teichgräber, Volker, Steeghs, Neeltje
• Format: Journal Article
• Language: English
• Published: United States 15.04.2024
• Subjects: Antibodies, Monoclonal, Humanized; Carcinoembryonic Antigen; Humans; Neoplasms - drug therapy; Rituximab
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-23-2658

The immunocytokine cergutuzumab amunaleukin (CEA-IL2v) showed manageable safety and favorable pharmacodynamics in phase I/Ib trials in patients with advanced/metastatic carcinoembryonic antigen-positive (CEA+) solid tumors, but this was accompanied by a high incidence of anti-drug antibodies (ADA). We examined B-cell depletion with obinutuzumab as a potential mitigation strategy. Preclinical data comparing B-cell depletion with rituximab versus obinutuzumab are summarized. Substudies of phase I/Ib trials investigated the effect of obinutuzumab pretreatment on ADA development, safety, pharmacodynamics, and antitumor activity of CEA-IL2v ± atezolizumab in patients with advanced/metastatic or unresectable CEA+ solid tumors who had progressed on standard of care. Preclinical data showed superior B-cell depletion with obinutuzumab versus rituximab. In clinical studies, patients received CEA-IL2v monotherapy with (n = 16) or without (n = 6) obinutuzumab pretreatment (monotherapy study), or CEA-IL2v + atezolizumab + obinutuzumab pretreatment (n = 5; combination study). In the monotherapy study, after four cycles (every 2 weeks treatment), 0/15 evaluable patients administered obinutuzumab pretreatment had ADAs versus 4/6 patients without obinutuzumab. Obinutuzumab pretreatment with CEA-IL2v monotherapy showed no new safety signals and pharmacodynamic data suggested minimal impact on T cells and natural killer cells. Conversely, increased liver toxicity was observed in the combination study (CEA-IL2v + atezolizumab + obinutuzumab pretreatment). These preliminary findings suggest that obinutuzumab pretreatment before CEA-IL2v administration in patients with CEA+ solid tumors may be a feasible and potent ADA mitigation strategy, with an acceptable safety profile, supporting broader investigation of obinutuzumab pretreatment for ADA mitigation in other settings.