RESUMO
Microsatellite stable metastatic colorectal cancer (MSS mCRC; mismatch repair proficient) has previously responded poorly to immune checkpoint blockade. Botensilimab (BOT) is an Fc-enhanced multifunctional anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody designed to expand therapy to cold/poorly immunogenic solid tumors, such as MSS mCRC. BOT with or without balstilimab (BAL; anti-PD-1 antibody) is being evaluated in an ongoing expanded phase 1 study. The primary endpoint is safety and tolerability, which was evaluated separately in the dose-escalation portion of the study and in patients with MSS mCRC (using combined dose-escalation/dose-expansion data). Secondary endpoints include investigator-assessed RECIST version 1.1-confirmed objective response rate (ORR), disease control rate (DCR), duration of response (DOR) and progression-free survival (PFS). Here we present outcomes in 148 heavily pre-treated patients with MSS mCRC (six from the dose-escalation cohort; 142 from the dose-expansion cohort) treated with BOT and BAL, 101 of whom were considered response evaluable with at least 6 months of follow-up. Treatment-related adverse events (TRAEs) occurred in 89% of patients with MSS mCRC (131/148), most commonly fatigue (35%, 52/148), diarrhea (32%, 47/148) and pyrexia (24%, 36/148), with no grade 5 TRAEs reported and a 12% discontinuation rate due to a TRAE (18/148; data fully mature). In the response-evaluable population (n = 101), ORR was 17% (17/101; 95% confidence interval (CI), 10-26%), and DCR was 61% (62/101; 95% CI, 51-71%). Median DOR was not reached (NR; 95% CI, 5.7 months-NR), and median PFS was 3.5 months (95% CI, 2.7-4.1 months), at a median follow-up of 10.3 months (range, 0.5-42.6 months; data continuing to mature). The combination of BOT plus BAL demonstrated a manageable safety profile with no new immune-mediated safety signals and encouraging clinical activity with durable responses. ClinicalTrials.gov identifier: NCT03860272 .
Assuntos
Antineoplásicos/uso terapêutico , Indóis/uso terapêutico , Melanoma/secundário , Terapia de Alvo Molecular , Mutação , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Neoplasias Cutâneas/patologia , Sulfonamidas/uso terapêutico , Síndrome da Veia Cava Superior/etiologia , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Esquema de Medicação , Humanos , Indóis/administração & dosagem , Indóis/efeitos adversos , Metástase Linfática , Masculino , Melanoma/genética , Terapia de Alvo Molecular/métodos , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/genética , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Síndrome da Veia Cava Superior/tratamento farmacológico , Síndrome da Veia Cava Superior/metabolismo , Tomografia Computadorizada por Raios X , Resultado do Tratamento , VemurafenibRESUMO
The field of melanoma therapeutics has experienced a dramatic paradigm shift over the last 12 months through recent discoveries of novel therapeutics targeting known oncogenes and immunotherapeutic antibodies. In this article, we review these findings and provide a framework to understand these discoveries, their significance in melanoma therapy, and role in clinical care. As this understanding grows, enduring therapeutic success may be achieved through tailored use of molecular markers and immunotherapies in sequential or combinatorial methods.