Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Feb 8;12(2):e008210.
doi: 10.1136/jitc-2023-008210.

Multiomic molecular characterization of the response to combination immunotherapy in MSS/pMMR metastatic colorectal cancer

Shogo Takei  1   2 , Yosuke Tanaka  3 , Yi-Tzu Lin  4 , Shohei Koyama  4 , Shota Fukuoka  5 , Hiroki Hara  6 , Yoshiaki Nakamura  1 , Yasutoshi Kuboki  1 , Daisuke Kotani  1 , Takashi Kojima  1 , Hideaki Bando  1 , Saori Mishima  1 , Toshihide Ueno  3 , Shinya Kojima  3 , Masashi Wakabayashi  7 , Naoya Sakamoto  8 , Motohiro Kojima  8 , Takeshi Kuwata  8   9 , Takayuki Yoshino  1 , Hiroyoshi Nishikawa  4   10 , Hiroyuki Mano  3 , Itaru Endo  2 , Kohei Shitara  11   10 , Akihito Kawazoe  11
Affiliations

Multiomic molecular characterization of the response to combination immunotherapy in MSS/pMMR metastatic colorectal cancer

Shogo Takei et al. J Immunother Cancer. .

Abstract

Background: Immune checkpoint inhibitor (ICI) combinations represent an emerging treatment strategies in cancer. However, their efficacy in microsatellite stable (MSS) or mismatch repair-proficient (pMMR) colorectal cancer (CRC) is variable. Here, a multiomic characterization was performed to identify predictive biomarkers associated with patient response to ICI combinations in MSS/pMMR CRC for the further development of ICI combinations.

Methods: Whole-exome sequencing, RNA sequencing, and multiplex fluorescence immunohistochemistry of tumors from patients with MSS/pMMR CRC, who received regorafenib plus nivolumab (REGONIVO) or TAS-116 plus nivolumab (TASNIVO) in clinical trials were conducted. Twenty-two and 23 patients without prior ICI from the REGONIVO and TASNIVO trials were included in this study. A biomarker analysis was performed using samples from each of these studies.

Results: The epithelial-mesenchymal transition pathway and genes related to cancer-associated fibroblasts were upregulated in the REGONIVO responder group, and the G2M checkpoint pathway was upregulated in the TASNIVO responder group. The MYC pathway was upregulated in the REGONIVO non-responder group. Consensus molecular subtype 4 was significantly associated with response (p=0.035) and longer progression-free survival (p=0.006) in the REGONIVO trial. CD8+ T cells, regulatory T cells, and M2 macrophages density was significantly higher in the REGONIVO trial responders than in non-responders. Mutations in the POLE gene and patient response were significantly associated in the TASNIVO trial; however, the frequencies of other mutations or tumor mutational burden were not significantly different between responders and non-responders in either trial.

Conclusions: We identified molecular features associated with the response to the REGONIVO and TASNIVO, particularly those related to tumor microenvironmental factors. These findings are likely to contribute to the development of biomarkers to predict treatment efficacy for MSS/pMMR CRC and future immunotherapy combinations for treatment.

Keywords: Drug Therapy, Combination; Gastrointestinal Neoplasms; Nivolumab; Tumor Biomarkers.

PubMed Disclaimer

Conflict of interest statement

Competing interests: ST, YT, and Y-TL have nothing to disclose. SKoy has received research funding from Otsuka Pharmaceutical, Shionogi Pharmaceutical and Chugai Pharmaceutical outside the submitted work. SF has nothing to disclose. HH has received honoraria from Bayer, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Kyowa Hakko Kirin, Lilly, Merck Biopharma, MSD, Ono, Taiho, Takeda, and Yakult; fees for consulting or advisory roles for Bristol-Myers Squibb, Boehringer Ingelheim and Daiichi-Sankyo; and research grants from ALX Oncology, Amgen, Astellas, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Janssen, Merck Biopharma, MSD, Ono Pharmaceutical, and Taiho Pharmaceutical outside the submitted work. YN has received honoraria from Chugai, Merck, and Guardant Health AMEA and research grants from Taiho, Chugai, Guardant Health, Genomedia, Daiichi-Sankyo, Seagen, and Roche Diagnostics outside the submitted work. YK has nothing to disclose. DK has received personal fees for advisory roles from Takeda and Eisai; honoraria from MSD, Pfizer, Chugai, Merck biopharma, Lilly, Sysmex, Nipponkayaku, Bristol-Myers Squibb, Ono Pharmaceutical, Taiho Pharmaceutical, Takeda, Eisai, and Daiichi-Sankyo; and research funding from Ono Pharmaceutical, MSD, Novartis, Sanofi, Janssen, Pierre Fabre Medicament, Isofol Medical AB, Hutchison MediPharma Limited, and Nippon Servier outside the submitted work. TKo has received honoraria from MSD, Bristol-Myers Squibb and Ono Pharmaceutical; personal fees for advisory roles from Boehringer Ingelheim, Kyowa Kirin and Taiho Pharmaceutical; and research funding from AstraZeneca, BeiGene, MSD, Amgen, Chugai Pharmaceutical, Taiho Pharmaceutical, Shionogi Pharma, and Amgen Astellas BioPharma outside the submitted work. HB has received honoraria from Ono Pharmaceutical, Taiho Pharmaceutical, and Eli Lilly Japan and research funding from Ono Pharmaceutical outside the submitted work. SM, TU, SKoj, MW, NS, and MK have nothing to disclose. TKu has received honoraria from AstraZeneca, Astellas Pharma, Ono Pharmaceutical, Bristol-Myers Squibb Japan, Daiichi-Sankyo, and Roche Diagnostics; personal fees for consulting or advisory roles from Astellas Pharma; and research funding from Daiichi-Sankyo and Roche Diagnostics outside the submitted work. TY has received research grants from Taiho, Ono, Chugai, Amgen, MSD, Daiichi-Sankyo, Eisai, FALCO biosystems, Genomedia, Molecular Health, Nippon Boehringer Ingelheim, Pfizer, Roche Diagnostics, Sysmex, and Sanofi outside the submitted work and honoraria from Bayer, Chugai, Merck Biopharma, MSD, Ono, and Takeda. HN has received research funding and honoraria from Ono Pharmaceutical, MSD, Bristol-Myers Squibb, and Chugai Pharmaceutical and research funding from Taiho Pharmaceutical, Daiichi-Sankyo, Kyowa Kirin, Zenyaku Kogyo, Oncolys BioPharma, Debiopharma, Asahi-Kasei, Sysmex, Fujifilm, SRL, Astellas Pharmaceutical, Sumitomo Dainippon Pharma, and BD Japan outside the submitted work. HM has nothing to disclose. IE has received research grants from Taiho Pharmaceutical and Ono Pharmaceutical outside the submitted work. AK has received personal fees for advisory roles from Roche and Lilly; honoraria from Roche, Merck Biopharma, Lilly, Bristol-Myers Squibb, Ono Pharmaceutical, Taiho Pharmaceutical, and Daiichi-Sankyo; and research funding from Ono Pharmaceutical, MSD, Sanofi, AstraZeneca, and Eisai outside the submitted work.

Figures

Figure 1
Figure 1
Flow diagram of the study The figure illustrates the process research sample selection and the number of analyses successfully completed with each method. Only patients with microsatellite stable or mismatch repair-proficient colorectal cancer were included in this study. Patients without WES data due to inadequate sample volume or unsuccessful WES were also included in the analysis if targeted gene panel analysis data were available. CRC, colorectal cancer; ICI, immune checkpoint inhibitors; IHC, immunohistochemistry; mIHC, multiplex fluorescence immunohistochemistry; MSI, microsatellite instability; NSCLC, non-small cell lung cancer; WES, whole-exome sequencing.
Figure 2
Figure 2
Efficacy of REGONIVO and TASNIVO treatment in patients included in this study waterfall plot (A) showing the maximum percentage change in tumor size from baseline as measured by Response Evaluation Criteria in Solid Tumors (RECIST) in the REGONIVO trial. Spider plot (B) showing the longitudinal change in RECIST percentage from baseline in the REGONIVO trial. Waterfall plot (C) and spider plot (D) as above but showing data from the TASNIVO trial. CR, complete response; PD, progressive disease; PR, partial response; REGONIVO, regorafenib plus nivolumab; SD, stable disease; TASNIVO, TAS116 plus nivolumab.
Figure 3
Figure 3
Molecular characterization The top section of the figure shows the duration of PFS. The middle section indicates the response status (CR, PR, or SD≥6 months), CMS, TMB, and PD-L1 CPS. The bottom section shows the distribution of gene mutations determined by WES or targeted gene panel analysis. CR, complete response; CPS, combined positive score; CMS, consensus molecular subtypes; NA, not available; PFS, progression-free survival; PR, partial response; REGONIVO, regorafenib plus nivolumab; SD≥6, stable disease duration of at least 6 months; TASNIVO, TAS116 plus nivolumab; TMB, tumor mutational burden; WES, WES, whole exome sequencing.
Figure 4
Figure 4
GSEA gene sets enriched in responders and non-responders in the REGONIVO and TASNIVO trial. ES, enrichment score; FDR, false discovery rate; GSEA, Gene Set Enrichment Analyses; NES, normalized enrichment score; REGONIVO, regorafenib plus nivolumab; TASNIVO, TAS116 plus nivolumab; TGF, transforming growth factor.
Figure 5
Figure 5
Survival curves based on the CMS classification Kaplan-Meier plots the PFS (A) and OS (B) of patients in the regorafenib plus nivolumab trial with tumors classified as CMS4, or as other CMS subtypes. PFS (C) and OS (D) of patients in the TAS116 plus nivolumab trial with tumors classified as CMS4 or as other CMS subtypes. CMS, consensus molecular subtypes; OS, overall survival PFS, progression-free survival.
Figure 6
Figure 6
Multiplex immunohistochemistry analysis of the tumor immune microenvironment. Representative multiplex IHC images of samples from responders and non-responders in the REGONIVO and TASNIVO trials (A). Comparative analysis of tumor-infiltrating immune cells, CD8+ T cells (CD3+CD8+), Treg cells (FOXP3+CD3+CD8−), and M2 macrophages (CD206+CD11b+), was performed by multiplex IHC and HALO image analysis software between responders and non-responders in the REGONIVO (B) and TASNIVO (C) trials. IHC, immunohistochemistry; REGONIVO, regorafenib plus nivolumab; TASNIVO, TAS116 plus nivolumab.
See this image and copyright information in PMC

References

    1. Sung H, Ferlay J, Siegel RL, et al. . Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021;71:209–49. 10.3322/caac.21660 - DOI - PubMed
    1. Herbst RS, Giaccone G, de Marinis F, et al. . Atezolizumab for First-Line Treatment of PD-L1-Selected Patients with NSCLC. N Engl J Med 2020;383:1328–39. 10.1056/NEJMoa1917346 - DOI - PubMed
    1. James L, Vanna C-S, Rene G, et al. . Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med 2015;373:1270–1. 10.1056/NEJMc1509660 - DOI - PubMed
    1. Bellmunt J, de Wit R, Vaughn DJ, et al. . Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med 2017;376:1015–26. 10.1056/NEJMoa1613683 - DOI - PMC - PubMed
    1. Garon EB, Rizvi NA, Hui R, et al. . Pembrolizumab for the Treatment of Non–Small-Cell Lung Cancer. N Engl J Med 2015;372:2018–28. 10.1056/NEJMoa1501824 - DOI - PubMed

Publication types