Regorafenib plus toripalimab in patients with metastatic colorectal cancer: a phase Ib/II clinical trial and gut microbiome analysis

Feng Wang, Ming-Ming He, Yi-Chen Yao, Xia Zhao, Zhi-Qiang Wang, Ying Jin, Hui-Yan Luo, Ji-Bin Li, Feng-Hua Wang, Miao-Zhen Qiu, Zhi-Da Lv, De-Shen Wang, Yu-Hong Li, Dong-Sheng Zhang, Rui-Hua Xu, Feng Wang, Ming-Ming He, Yi-Chen Yao, Xia Zhao, Zhi-Qiang Wang, Ying Jin, Hui-Yan Luo, Ji-Bin Li, Feng-Hua Wang, Miao-Zhen Qiu, Zhi-Da Lv, De-Shen Wang, Yu-Hong Li, Dong-Sheng Zhang, Rui-Hua Xu

Abstract

This is a phase Ib/II study of regorafenib plus toripalimab for colorectal cancer. The objective response rate (ORR) is 15.2% and the disease control rate is 36.4% in evaluable patients with recommended phase II dose (80 mg regorafenib plus toripalimab). The median progression-free survival (PFS) and the median overall survival are 2.1 months and 15.5 months, respectively. Patients with liver metastases have lower ORR than those without (8.7% versus 30.0%). All patients (3/3) with lung-only metastasis respond, whereas no patients (0/4) with liver-only metastasis respond. 94.9% and 38.5% of patients have grade 1 and grade 3 treatment-related adverse events, respectively. Gut microbiome analysis of the baseline fecal samples shows significantly increased relative abundance and positive detection rate of Fusobacterium in non-responders than responders. Patients with high-abundance Fusobacterium have shorter PFS than those with low abundance (median PFS = 2.0 versus 5.2 months; p = 0.002).

Keywords: colorectal cancer; immunotherapy; microbiome; programmed cell death protein 1; regorafenib; toripalimab.

Conflict of interest statement

The authors declare no competing interests.

© 2021 The Author(s).

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
The mTPI design spreadsheet for phase Ib dose escalation (A) The spreadsheet of the modified toxicity probability interval (mTPI) method. The letters in different colors are computed based on the decision rules under the mTPI method and represent different dose-finding actions. In addition to actions de-escalate the dose (D), stay at the same dose (S), and escalate the dose (E), the table includes action unacceptable toxicity (DU), which is defined as the execution of the dose-exclusion rule in mTPI. (B) The dose escalation of phase Ib. 3 patients were enrolled at 80 mg regorafenib plus 3 mg/kg toripalimab (dose 1), and no one had dose-limiting toxicity (DLT), then 3 patients were enrolled at 120 mg regorafenib plus 3 mg/kg toripalimab (dose 2) and all patients had DLT, and then 6 patients were enrolled at dose 1 and only 1 patient had DLT (pT = 11.1%). The maximum tolerated dose (MTD) was 80 mg regorafenib plus 3 mg/kg toripalimab. HFS, hand-foot syndrome.
Figure 2
Figure 2
Tumor response assessment with Waterfall and Spider plots and treatment exposure and duration with Swimmer plot (A) Waterfall plot of maximum percent change in tumor size from baseline as measured according to RECIST 1.1 in 33 evaluated patients with regorafenib 80 mg and 3 evaluated patients with regorafenib 120 mg. (B) Spider plot of longitudinal change in individual tumor burden over time in RECIST percentage from baseline in 33 evaluated patients with regorafenib 80 mg and 3 evaluated patients with regorafenib 120 mg. (C) Swimmer plot according to dose level in 42 overall patients.
Figure 3
Figure 3
Kaplan-Meier plots of progression-free survival, overall survival, and duration of response (A and B) Kaplan-Meier plot (A) of progression-free survival (PFS) and Kaplan-Meier plot (B) of overall survival (OS) in 33 patients with regorafenib 80 mg as recommended dose. (C) Kaplan-Meier plot of duration of response (DOR) in 5 patients with partial response.
Figure 4
Figure 4
Gut microbiome analysis (A) Composition of gut microbiome at phylum level for the non-responders (NR) and responders (R), with the density plots for the distribution of the number of patients at different relative abundance region for each bacterial phylum. (B) Relative abundance of Fusobacterium in NR and R, with the boxplots for the alpha-diversity Shannon index of the NR and R (∗p < 0.05). (C) Kaplan-Meier plot of PFS in 32 patients with high versus low abundance of Fusobacterium with the best cutoff value of 2.6e−05. (D) Forest plot for multivariate Cox regression analysis of the effect of risk factors (BMI, Fusobacterium, and Alistipes) on patient’s PFS. (E) Time-dependent receiver operating characteristic (ROC) for three-variable (BMI, Fusobacterium, and Alistipes) model at PFS of 3 and 6 months. (F) PFS comparison between the high- and low-risk groups based on Cox model using Kaplan-Meier analysis. See also Tables S2–S6 and Figures S2–S4.

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