Abstract CT148: Efficacy, safety, and biomarker analysis of combined MEK (Cobimetinib) and PD-L1 (Atezolizumab) inhibition (COTEZO) in advanced small bowel adenocarcinoma (SBA)
Authors: Hornstein Nicholas , Shen John P. , Pellatt Andrew J. , Liu Suyu , Knafl Mark , Willett Anneleis F. , Zhu Haifeng , Maru Dipen M. , Darbonne Walter , Wistuba Ignacio I. , Futreal Andy , Yao James C. , Woodman Scott E. , Overman Michael J. , Raghav Kanwal P. 
Published: April 2023

Purpose: Preclinical evidence supporting immunomodulatory effect of MEK inhibition that augments anti-tumor activity of PD-1 inhibitors is a compelling rationale for investigating combined MEK and PD-L1 inhibition in advanced microsatellite-stable (MSS) SBA wherein immune checkpoint inhibitors (ICIs) have little clinical benefit. We conducted a prospective, phase 2 trial evaluating efficacy and safety of COTEZO regimen in treatment refractory SBA.

Procedures: Patients aged ≥ 18 years with metastatic MSS SBA, ECOG PS 0 - 2, and disease progression on prior systemic chemotherapy were enrolled and treated with cobimetinib (60 mg orally once daily for days 1 - 21) and atezolizumab (840 mg intravenously every 2 weeks) every 28-day cycle. The primary endpoint was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. by independent radiology review. Key pre-specified secondary endpoints were safety, disease control rate (DCR), progression-free (PFS) and overall (OS) survival. Pre/on-treatment biopsies were examined for response biomarkers.

Results: Between 4/2017 and 7/2020, 20 patients were enrolled. The confirmed ORR per RECISTv1.1 was 10% [2/20; 95%CI: 1.2 - 31.7] (1 complete response and 1 partial response). Seven patients had stable disease for a DCR of 45% (95%CI: 23.1 - 68.5). Median PFS and OS were 2.4 (95% CI 1.3-3.5) and 8.8 (95% CI 5.6 - 12) months, respectively. Grade 3 treatment-emergent adverse events (no grade 4/5) occurred in 7 (35%) patients; most common being elevated CPK (15%) and vomiting (10%). One (5%) patient had grade 3 vomiting, necessitating treatment discontinuation. There appeared to be a marked difference in OS between patients with increased pre-treatment tumor immune infiltration as compared to those lacking immune infiltration amongst patients with RNASeq data available (n=13). Specifically, increased immune infiltration as assessed by computational deconvolution of RNASeq data pointed to increased macrophage and monocyte infiltration as prognostic factors. This was additionally assessed via application of a global “immune score” algorithm, ESTIMATE. In order to generalize our findings, we expanded our computational deconvolution analysis to include additional small bowel adenocarcinoma patients who received standard-of-care treatment (n=7). For the combined standard-of-care and experimentally treated patients we saw that those with immune infiltration had significantly better OS (9 months vs greater than 3 years, HR 5.7, Padj = 0.017), suggesting that immune infiltration is a prognostic, rather than predictive biomarker.

Conclusions: Although our study did not meet its primary endpoint of ORR, we identified tumor immune infiltration as a prognostic biomarker in SBA, which could select patients with better outcomes on immunotherapy.

Citation Format: Nicholas Hornstein, John P. Shen, Andrew J. Pellatt, Suyu Liu, Mark Knafl, Anneleis F. Willett, Haifeng Zhu, Dipen M. Maru, Walter Darbonne, Ignacio I. Wistuba, Andy Futreal, James C. Yao, Scott E. Woodman, Michael J. Overman, Kanwal P. Raghav. Efficacy, safety, and biomarker analysis of combined MEK (Cobimetinib) and PD-L1 (Atezolizumab) inhibition (COTEZO) in advanced small bowel adenocarcinoma (SBA) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT148.