Combined PD-1, BRAF and MEK inhibition in BRAFV600E colorectal cancer: a phase 2 trial

Abstract

While BRAF inhibitor combinations with EGFR and/or MEK inhibitors have improved clinical efficacy in BRAFV600E colorectal cancer (CRC), response rates remain low and lack durability. Preclinical data suggest that BRAF/MAPK pathway inhibition may augment the tumor immune response. We performed a proof-of-concept single-arm phase 2 clinical trial of combined PD-1, BRAF and MEK inhibition with sparatlizumab (PDR001), dabrafenib and trametinib in 37 patients with BRAFV600E CRC. The primary end point was overall response rate, and the secondary end points were progression-free survival, disease control rate, duration of response and overall survival. The study met its primary end point with a confirmed response rate (24.3% in all patients; 25% in microsatellite stable patients) and durability that were favorable relative to historical controls of BRAF-targeted combinations alone. Single-cell RNA sequencing of 23 paired pretreatment and day 15 on-treatment tumor biopsies revealed greater induction of tumor cell-intrinsic immune programs and more complete MAPK inhibition in patients with better clinical outcome. Immune program induction in matched patient-derived organoids correlated with the degree of MAPK inhibition. These data suggest a potential tumor cell-intrinsic mechanism of cooperativity between MAPK inhibition and immune response, warranting further clinical evaluation of optimized targeted and immune combinations in CRC. ClinicalTrials.gov registration: NCT03668431.

Spatial analysis of human lung cancer reveals organized immune hubs enriched for stem-like CD8 T cells and associated with immunotherapy response

“…Immunity hubs likely represent the major site for aggregation of cells expressing interferon-stimulated genes 8,9,[46][47][48] , including CXCR3 ligands CXCL9/10/11, in melanoma 7,10 , CRC 49 , breast, ovarian and other tumor types 7 . These genes are critical for effective tumor immunity and were shown in numerous studies to be associated with PD-1-blockade responses in patients 2,50-52 .…”

Multikinase inhibitors modulate non-constitutive proteasome expression in colorectal cancer cells

“…Colorectal carcinomas with BRAF mutations show higher expression of PD-L1 ( Srivastava et al, 2021 ), which can contribute to immune evasion of cancer cells and in turn nuclear PD-L1 promotes cell cycle progression of BRAF mutant cells ( Ma et al, 2022 ). PD-L1 inhibition by sparatlizumab improved effectivity of combined inhibition of BRAF and MEK with dabrafenib and trametinib in phase 2 clinical trial for colorectal cancer ( Tian et al, 2023 ). Along these lines, we calculated the correlation of proteasome gene expression with expression of PD-L1 in colorectal tumors.…”

Ex vivo tissue modelling informs drug selection for rare cancers

“…Tissue slices were treated with the combination of 10 nM MEK inhibitor trametinib (GSK1120212) and 100 nM BRAF inhibitor dabrafenib (GSK2118436), and 0.1% DMSO as control, incubated for 72 h at 37 C in 5% CO 2 . These drug dosages were based on prior ex vivo analyses conducted on 3D organoids, 10 and differentiated treatment resistance and sensitivity in patient derived short-term melanoma cultures. 11,12 Media was changed once midway with fresh media and newly prepared dilution of compounds.…”