Efficacy and safety of TAS-102 plus Surufatinib in third and later line metastatic pancreatic cancer: a prospective, single center and biomarker exploratory, phase II study

Abstract

Background: Metastatic pancreatic cancer (mPC) has a dismal prognosis, with first line systemic therapy relying primarily on FOLFIRINOX (5FU/irinotecan/oxaliplatin) or AG (Gemcitabine/Nab-Paclitaxel). Therapeutic options for mPC refractory to these regimens remain poorly defined, and data on later-line options are scarce. This prospective, single-arm study evaluated the safety and preliminary efficacy of combining the anti-angiogenic agent surufatinib with the cytotoxic drug TAS-102 (Trifluridine/Tipiracil) in mPC patients who had progressed on ≥ 2 prior lines of therapy.

Methods: mPC patients who were refractory to at least 2 previous regimens were enrolled and received TAS-102 (35 mg/m², po, bid, D1-D5, D8-D12) plus surufatinib (250 mg, po, qd) in a 4-week cycle. The tumor response was assessed by the researcher every 8 weeks and treatment continued until disease progression, unacceptable toxicity, investigator discretion, or patient withdrawal of informed consent. Primary and secondary endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety.

Results: Between January 2023 and June 2024, 22 patients were enrolled into this study. Among 20 patients analyzed for efficacy, median PFS was 2.35 months (95% CI: 1.91-3.94) and median OS was 6.34 months (95% CI: 3.81-10.09). The ORR and DCR were 20% (4/20; all partial response) and 30% (6/20), respectively. All patients experienced treatment emergent adverse events (TEAEs), with anemia (59.1%), neutropenia (54.6%), leukocytopenia (50.0%), and lymphocytopenia (45.5%) as the most common any-grade events. Grade ≥ 3 TEAEs including neutropenia (31.8%), lymphocytopenia (13.6%), and anemia (9.1%), were observed in 50.0% (11/22) of patients. Subgroup analysis identified metastases involving > 2 organs or hepatic sites as potential predicative biomarkers for inferior efficacy. Proteomic screening revealed that overexpressed OCIAD2 correlated with poor prognosis, a finding validated in two publicly available external cohorts (CPTAC database and RuiJin cohort).

Conclusions: Combination of TAS-102 and surufatinib demonstrates clinically meaningful efficacy and manageable toxicity as therapeutic option for later-line mPC. The biomarkers identified in this study may hold the potential to guide patient stratification and warrant further investigation to optimize precision application of this regimen. This study was prospectively registered at clinicaltrials.gov with the number NCT05481463 on August 1st 2022.

Keywords: OCIAD2; Refractory metastatic pancreatic cancer; Surufatinib; TAS-102.

Fig. 1

Flow diagram of this study. A Patient dispositions. 25 participants were screened for eligibility, and 22 who met the inclusion criteria were enrolled into this study. Treatment efficacy was evaluated by objective response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS) and median overall survival (mOS) (efficacy evaluation set, N = 20). Safety evaluation was performed in the full analysis set (N = 22). Exploratory analysis was performed via multigene panel sequencing (N = 13) and proteomics pooling (N = 19). B The diagram of the timeline shows the treatment regimen until progression or intolerable toxicity

Fig. 2

Efficacy of this study. A Waterfall plot of the best percent change in target lesion diameter from baseline, colored according to best of response (BOR) (N = 20). The pentagram indicates presence of new lesions and was evaluated as progressive disease (PD). Tumor evaluation in three patients was performed according to radiological images in local center. Stable disease (SD), partial response (PR) and PD are shown in green, blue, and red bars, respectively. B Swimmer plot illustrating PFS for the entire cohort (N = 20). PR and PD are shown with blue circle and red inverted triangle, respectively. The length of the bars represents the duration from enrolment to PD or death. Death events are represented by black diamond. C Spider plot of the change in target lesion diameter from baseline (N = 20). SD, PR and PD are shown in green, blue, and red bars, respectively

Fig. 3

PFS and OS of enrolled patients. A Kaplan–Meier estimation of PFS for participants who enrolled into this study (N = 20). B Kaplan–Meier estimation of OS for participants who enrolled into this study (N = 20). C The representative computed tomography (CT) scans of the subject No. 08 who was still on treatment including baseline and three posttreatment evaluations. The irregular polygon indicates tumor relapse in the operation region and peritoneal metastasis

Fig. 4

PFS and OS in the subgroup analysis. A Kaplan–Meier estimation of PFS and OS for participants who have clinical benefit (N = 6) or not (N = 14). B Kaplan–Meier estimation of PFS and OS for participants who have more than 2 organ metastases (N = 11) or less (N = 9). C Kaplan–Meier estimation of PFS and OS for participants who have liver metastases (N = 10) or not (N = 10). All P values were compared using log-rank test

Fig. 5

Genomic and proteomic analysis in this study. A Mutational landscape of top 20 mutated genes. B Kaplan–Meier estimation of PFS and OS for participants who have KRAS^G12C/D mutation (N = 6) and others (N = 13). C Volcano plot describing differential expressed proteins between clinical benefit and non-benefit groups. The log₂-fold change indicated the mean expression level for each protein. D Venn diagram of top ten overexpressed proteins and proteins that significantly correlated with PFS and OS. E Associations of OCIAD2 with OS in pancreatic cancer patients from the TCGA database. F Kaplan–Meier estimation of PFS and OS for participants with overexpressed (N = 13) or underexpressed OCIAD2 (N = 6). G Percentage of patients with clinical benefit or not in OCIAD2 low and high groups. H Kaplan–Meier estimation of disease-free survival (DFS) and OS for pancreatic cancer patients who have received chemotherapy in the RuiJin cohort according to OCIAD2 expression. I Kaplan–Meier estimation of PFS for pancreatic cancer patients in the CPTAC (Clinical Proteomic Tumor Analysis Consortium) database according to OCIAD2 expression. P value in G was compared in OCIAD2 low and high group using Fisher’s exact test. P values in B, E, F, H and I were compared using log-rank test

Fig. 6

Role of OCIAD2 in pancreatic cancer. A Enriched pathways of cancer hallmarks between the benefit and non-benefit groups. B GSEA (Gene set enrichment analysis) of the hallmark oxidative phosphorylation and Reactome biological oxidations in OCIAD2 low and high group. C The stemness score in patients with or without clinical benefit. D Correlations between OCIAD2 and genes in the stemness score set in RuiJin, TCGA and our own cohort. Different colors indicate the correlation coefficient and P values were shown in pentagrams. E Correlations of OCIAD2 and KRT19 in our own cohort and RuiJin cohort. F H score of OCIAD2 and KRT19 expression in 12 patients who have available tumor samples after proteomic analysis with or without clinical benefit. G Representative immunohistochemical images of OCIAD2 and KRT19 in two patients with or without clinical benefit. Scale bars: 1000 μm. H Kaplan–Meier estimation of PFS and OS for participants who have low and high OCIAD2 H score. P value in C and F was compared in patients with or without benefit using Wilcoxon rank-sum test. The P values in D and E were generated via the Pearson’s test. The P values in H were compared using log-rank test. * P less than 0.05; ** P less than 0.01; *** P less than 0.001