Abstract LB003: Combined BRAF, MEK, and PD-1 inhibition in BRAFV600E colorectal cancer patients: Correlative studies from a phase 2 trial
Authors: Tian Jun , Chen Jonathan H. , Chao Sherry X. , Pelka Karin , Jorgji Vjola , Baiev Islam , Bradford William B. , Wong Edmond , Sindurakar Princy , Oka Tomonori , Demehri Shadmehr , Hacohen Nir , Corcoran Ryan B. 
Published: June 2022

Background: Although BRAF inhibitors combined with EGFR and/or MEK inhibitors have improved efficacy in BRAFV600E colorectal cancer (CRC), response rates remain low and clinical benefit is not durable. Preclinical studies suggest that BRAF-targeted therapy in combination with immune checkpoint blockade could enhance anti-tumor activity. We have previously reported on the efficacy from an ongoing phase 2 clinical trial of anti-PD-1 antibody spartalizumab in combination with BRAF inhibitor dabrafenib and MEK inhibitor trametinib in BRAFV600E CRC patients. Of 26 patients, overall response rate (ORR) was 38% (10/26) and compares favorably to the historical controls in BRAFV600E CRC, yet the mechanisms of patient response in this trial need further investigation.

Methods: Single-cell RNA-seq (scRNA-seq) was performed on 23 paired baseline and day 15 tumor biopsies. Patient-derived organoids (PDOs) were generated from baseline tumor biopsies.

Results: scRNA-seq of paired biopsies revealed increased CD8+ T cell infiltration after treatment in patients with better clinical outcome (PFS &gt; 6 months, n=11). From the on- versus pre-treatment differentially expression analysis and gene set enrichment analysis in the tumor epithelial compartment, we observed greater induction and enrichment of immune gene signatures such as antigen processing and presentation, type I and II interferon response, chemokine activity, as well as superior MAPK pathway inhibition with therapy in patients with PFS &gt; 6 months. In comparison, patients with PFS &lt; 6 months (n=12) showed less immune gene upregulation and MAPK pathway inhibition in tumor cells. PDOs treated with dabrafenib and trametinib exhibited gene expression changes that mirrored the changes observed in scRNA-seq of tumor cells in the same patients from which they were derived. BRAF/ERKi treatment in PDOs produced greater MAPK pathway inhibition and immune genes induction than BRAF/MEKi.

Conclusion: Correlative studies of combined anti-PD-1 and BRAF/MEK inhibition suggest that the tumor-intrinsic immune response induced by MAPK pathway inhibition might underlie cooperativity between BRAF-targeted therapy and immune checkpoint blockade. A greater degree of immune gene induction in tumor cells could be enhanced by superior MAPK pathway inhibition, which provides rationale for further clinical studies.

Citation Format: Jun Tian, Jonathan H. Chen, Sherry X. Chao, Karin Pelka, Vjola Jorgji, Islam Baiev, William B. Bradford, Edmond Wong, Princy Sindurakar, Tomonori Oka, Shadmehr Demehri, Nir Hacohen, Ryan B. Corcoran. Combined BRAF, MEK, and PD-1 inhibition in BRAFV600E colorectal cancer patients: Correlative studies from a phase 2 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB003.