| Title: |
Checkpoint Blockade Combinations in Tumor Mutational Burden/Load-High Tumors:Insights from the Atezolizumab + Bevacizumab and Nivolumab + Ipilimumab Cohorts in the Drug Rediscovery Protocol |
| Authors: |
Verkerk,Karlijn; Haj Mohammad,Soemeya F; Zeverijn,Laurien J; Geurts, Birgit S; Spiekman,Ilse A C; Verbeek,Florentine A J; Timmer,Hans; van Maren,Maud A; van der Noort,V; Parra Martinez,Miguel; Roepman,Paul; Jansen, Anne M L; de Leng, Wendy W J; Marchetti,Serena; Monkhorst,Kim; Verheul,Henk M W; Gelderblom,Hans; Voest, Emile E; Pathologie Moleculair; Pathologie Pathologen staf; Cancer |
| Publication Year: |
2025 |
| Subject Terms: |
Taverne; Journal Article |
| Description: |
PURPOSE: To evaluate the efficacy of atezolizumab plus bevacizumab (atezo + beva) in tumors with high tumor mutational burden (TMB; number of mutations per megabase) and nivolumab plus ipilimumab (nivo + ipi) in tumors with high TMB or tumor mutational load (TML; total number of nonsynonymous mutations across the genome). PATIENTS AND METHODS: Patients with treatment-refractory, solid tumors were treated in the Drug Rediscovery Protocol (2023-509152-33-00). Patients with microsatellite-stable tumors harboring a TML of 200 to 1,000 or TMB of 11 to 24 (Oncomine) or 15 to 39 (TSO500) were eligible for nivo + ipi. Similar patients with a panel-independent TMB ≥16 received atezo + beva. Clinical benefit (CB; confirmed objective response or stable disease ≥16 weeks) was the primary endpoint. Whole-genome sequencing and RNA sequencing were performed on pretreatment tumor biopsies. RESULTS: Among 25 evaluable patients with 14 different tumor types treated with atezo + beva, the CB rate was 60% [95% confidence interval (CI), 39-79], with an objective response rate of 24% (95% CI, 9-45) and a median duration of response of 25.0 months (95% CI, 13.8-not applicable). In the nivo + ipi cohort, the CB rate was 50% (95% CI, 29-71) and objective response rate was 37.5% (95% CI, 19-59) among 24 evaluable patients with 13 distinct tumor types. The median duration of response was not reached after a median follow-up of 36 months. In both cohorts, responses were observed only in patients with TMB >20, and TMB and (clonal) TML were significantly correlated with response. Various markers of adaptive immune infiltration were associated with longer progression-free survival. CONCLUSIONS: Atezo + beva and nivo + ipi showed durable responses in patients with TMB >20, underscoring their tumor-agnostic efficacy in this patient population. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| ISSN: |
1078-0432 |
| Relation: |
https://dspace.library.uu.nl/handle/1874/467801 |
| Availability: |
https://dspace.library.uu.nl/handle/1874/467801 |
| Rights: |
info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.52CAC055 |
| Database: |
BASE |