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

Abstract

Background: Monotherapy 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.

Methods: Open-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.

Results: Twenty 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).

Conclusions: T+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 number: NCT03428126.

Keywords: Clinical Trials, Phase II as Topic; Immunotherapy.

Conflict of interest statement

Competing interests: BJ has a consulting or advisory role with Gritstone bio, Incyte, Taiho Oncology and Insmed Oncology. He has received research support from Bristol Myers Squibb, Syntrix and Gateway for Cancer Research. CLH reports speaker’s fees from the Society for Immunotherapy of Cancer, serves as an advisory board member for Briacell and the Mesothelioma Applied Research Foundation, has received personal fees from Nanobiotix and receives funding to the MD Anderson Cancer Center from Iovance, Sanofi, Dragonfly Therapeutics, and BTG outside the submitted work. EV has a consulting or advisory role with Janssen Research and Development and Recursion Pharma. He has received research support from Janssen Research and Development. CE has a consulting or advisory role with Bayer, Boston Scientific, GSK, Halio Dx, J&J, Merck, and Natera. MJO has a consulting or advisory role with Phanes therapeutics, Pfizer, Merck, Glaxosmithkline, 3D Medicine, Nouscom, Gritstone bio, Tempus, Roche. He has received research support from Roche, Merck, BMS and Astrazeneca.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

(A) Progression-free and (B) overall survival, (C) exceptional responder—partial response with CEA trend and (D) ctDNA Dynamics while on T+D. CEA, carcinoembryonic antigen; ctDNA, circulating tumor DNA.

Figure 2

Discrepant responses between lung and liver metastases in patients treated with T+D.

Figure 3

Low PD-L1 expression in the TME prior to therapy and early on-treatment. (A) PD-L1 chromogenic IHC staining at baseline (n=12) and on-treatment (OT) (n=10) as a percentage of malignant cells (MC) with representative images shown in (B). (C) The density of PD-L1+ MCs (n/mm2) as determined using multiplex immunofluorescence staining at baseline (BL) and OT (n=10 BL, 8 OT and 6 pairs). Representative staining is shown in D. (E, F) The density of CD68+ cells and PD-L1+CD68+ cells at BL (green) and OT (blue) is shown respectively with representative staining (n=10 BL, 8 OT and 6 pairs). Statistical comparisons were performed for paired cases only using a paired, parametric t-test. Only one trend was identified and shown. IHC, immunohistochemical; TME, tumor microenvironment.

Figure 4

Changes in immune infiltration densities. Multiplex immunofluorescence staining of TIL phenotype densities at baseline (BL, green) and on-treatment (OT, blue) is shown. The lines indicate paired BL and OT cases. (A) CD3+ (n=10 BL, 8 OT, 6 pairs), (B) CD3+CD8+ (n=10 BL, 8 OT, 6 pairs), (C) CD3+CD45RO+ (n=12 BL, 9 OT, 9 pairs), (D) CD3+CD8+PD-1+ (n=10 BL, 8 OT, 6 pairs), (E) Tregs (CD3+CD8-FoxP3+) (n=12 BL, 9 OT, 9 pairs), (F) CD3+CD8+GzmB+ (n=12 BL, 9 OT, 9 pairs). Representative images are included for phenotypes shown in D–F. Statistical comparisons were performed for paired cases only using a paired, parametric t test. Only one trend was identified and shown. TIL, tumor-infiltrating lymphocyte.

Figure 5

Increased checkpoint expression on CD8+ and CD4+ TIL subsets early on-treatment. Flow cytometry staining of fresh tumor tissue was performed at baseline and early on-treatment. (A, B) Phenotypic profile of CD8+ (+=8) and CD4+ (n=5) TIL at baseline. Tregs were excluded as shown in the gating strategy and were below the QC threshold set for subgating. (C, D) Paired baseline (green) and on-treatment (blue) cases are shown for CD8+ (n=6 pairs) and CD4+ (n=4 pairs) TIL. P values are indicated if a trend or significance was determined using a paired, non-parametric t-test. TIL, tumor-infiltrating lymphocyte.