Phase II study of durvalumab (anti-PD-L1) and trametinib (MEKi) in microsatellite stable (MSS) metastatic colorectal cancer (mCRC)

Abstract

BackgroundMonotherapy with immune checkpoint blockade is ineffective for patients (pts) with microsatellite stable (MSS) metastatic colorectal cancer (mCRC). This study investigates whether the combination of trametinib (T) with durvalumab (D) can alter the immune tumor microenvironment (TME) by successfully priming and activating T-cells.MethodsOpen-label, single-center, phase II trial with primary endpoint of immune-related response rate for combination of T+D in refractory MSS mCRC pts (NCT03428126). T is 2 mg/day orally starting 1 week prior to D, which is given 1500 mg intravenously every 4 weeks. Simon 2-stage design used to enroll 29 pts into first stage, requiring a response in two or more pts to proceed to stage 2. Tumor biopsies were collected at baseline (BL) and early on-treatment (OT) at week 4.ResultsTwenty nine treated pts include 48% females, median age 48 years (range 28–75), and median prior therapies 2 (range 1–5). No grade (G) 4 or 5 treatment-related adverse events (TRAE). The most common TRAE of any grade was acneiform rash, 17% being G3. One of 29 pts had confirmed partial response (PR) lasting 9.3 months (mo) for an overall response rate of 3.4%. Seven pts had stable disease (SD) and five pts (1 PR, 4 SD) demonstrated decrease in total carcinoembryonic antigen ng/mL (best percentage reduction: 94%, 95%, 42%, 34%, and 22%, respectively). Median progression-free survival was 3.2 mo (range 1.1–9.3 months). Three pts with both liver and lung metastases demonstrated discrepant responses in which clinical benefit was present in the lung metastases but not liver metastases. Comparison of BL and 4-week OT tumor tissue flow cytometry demonstrated no changes in T-cell infiltration but upregulation expression of PD-1 and Tim3 on CD8 T cells. However, expression of PD-1 and Tim3 as single markers and as coexpressed markers was observed to increase OT relative to BL (p=0.03, p=0.06 and p=0.06, respectively).ConclusionsT+D demonstrated acceptable tolerability in pts with refractory MSS mCRC. The response rate in the first stage of the study did not meet efficacy criteria to proceed to the second stage. Specific site of metastatic disease may impact outcomes in novel immunotherapy combination trials.Trial registration numberNCT03428126.

Binimetinib in combination with nivolumab or nivolumab and ipilimumab in patients with previously treated microsatellite-stable metastatic colorectal cancer with RAS mutations in an open-label phase 1b/2 study

“…Furthermore, while no tissue samples were collected to look at possible modes of action, it could be that the extent and duration of MAPK pathway inhibition was insufficient to alter the immune environment or that the preclinical data on which this study design was based was not as relevant in the real world in this patient population. Prior studies have highlighted the challenges associated with treating patients with MSS mCRC with ICI therapy [ 28 – 31 ]. The combination of MEK inhibition and ICI therapy might not be sufficient to overcome the “immune cold” nature of the tumor microenvironment associated with MSS mCRC [ 32 , 33 ].…”

Identification of the molecular characteristics associated with microsatellite status of colorectal cancer patients for the clinical application of immunotherapy

“…Immunotherapy represented by ICIs has been approved as the second-line treatment for metastatic CRC with dMMR MSI status, but only a few CRC patients with pMMR MSS status can benefit from immunotherapy due to the lack of immune infiltration and low TMB status( Ganesh et al, 2019 ; Marcus et al, 2019 ; Johnson et al, 2022 ; Weng et al, 2022 ). Heterogeneities between dMMR MSI and pMMR MSS CRC patients have been preliminarily investigated at the single-cell level, and they have mainly focused on immune cell status( Bao et al, 2020 ).…”

Immune checkpoint blockade therapy for BRAF mutant metastatic colorectal cancer: the efficacy, new strategies, and potential biomarkers

“…Since Keynote 016 demonstrated a great leap forward in achieving an effective immunotherapeutic strategy for MSI-H/dMMR mCRC, less benefit was observed in MSS/pMMR mCRC by treating with immune checkpoint blockade alone [ 5 , 26 , 55 , 56 ]. In other words, MSS/pMMR mCRC patients are refractory to ICIs monotherapy thanks to intrinsic resistance by several mechanisms [ 57 ].…”

“…Recently, ICIs treatment has tremendous benefits towards durable response in MSI-H/dMMR mCRC [ 25 ]. In contrast, ICIs monotherapy is thought to have scarce efficacy in microsatellite instability (MSS) mCRC with BRAF mutation [ 26 ]. Thus, ICIs in combination with other antitumor drugs, such as BRAF inhibitors, are under consideration in this subset of patients [ 27 ].…”