Toripalimab combined with lenvatinib and GEMOX is a promising regimen as first-line treatment for advanced intrahepatic cholangiocarcinoma: a single-center, single-arm, phase 2 study

Abstract

Advanced intrahepatic cholangiocarcinoma (ICC) has a dismal prognosis. Here, we report the efficacy and safety of combining toripalimab, lenvatinib, and gemcitabine plus oxaliplatin (GEMOX) as first-line therapy for advanced ICC. Thirty patients with pathologically confirmed advanced ICC received intravenous gemcitabine (1 g/m²) on Days 1 and 8 and oxaliplatin (85 mg/m²) Q3W for six cycles along with intravenous toripalimab (240 mg) Q3W and oral lenvatinib (8 mg) once daily for one year. The expression of programmed death-ligand 1 (PD-L1) and genetic status was investigated in paraffin-embedded tissues using immunohistochemistry and whole-exome sequencing (WES) analysis. The primary endpoint was the objective response rate (ORR). Secondary outcomes included safety, overall survival (OS), progression-free survival (PFS), disease control rate (DCR) and duration of response (DoR). As of July 1, 2022, the median follow-up time was 23.5 months, and the ORR was 80%. Twenty-three patients achieved partial response, and one achieved complete response. Patients (21/30) with DNA damage response (DDR)-related gene mutations showed a higher ORR, while patients (14/30) with tumor area positivity ≥1 (PD-L1 staining) showed a trend of high ORR, but without significant difference. The median OS, PFS, and DoR were 22.5, 10.2, and 11.0 months, respectively. The DCR was 93.3%. Further, 56.7% of patients experienced manageable grade ≥3 adverse events (AEs), commonly neutropenia (40.0%) and leukocytopenia (23.3%). In conclusion, toripalimab plus lenvatinib and GEMOX are promising first-line regimens for the treatment of advanced ICC. A phase-III, multicenter, double-blinded, randomized study to validate our findings was approved by the National Medical Products Administration (NMPA, No. 2021LP01825).Trial registration Clinical trials: NCT03951597.

Fig. 1

Flowchart for participants’ selection

Fig. 2

Tumor response to combined therapy of toripalimab combined with lenvatinib and GEMOX. a Combined therapy on changes in tumor size for each patient; one patient was not evaluated due to withdrawal of informed consent after one dose of medication. b Representative image with different tumor response to the combined therapy (case 11 with PD; case 18 with SD; case 23 with PR, case 30 with PR) (Red arrow in case 11 refers to new lesion after the combined therapy; red circle in case 23 refers to disappear of bone metastasis; and red circle in case 30 refers to disappear of lymph node metastasis.) c Kaplan–Meier Survival Curves for estimating the probability of overall survival of the entire cohort; d Kaplan–Meier Survival Curves for estimating the probability of progression-free survival of the entire cohort

Fig. 3

Representative case with different expression of PD-L1 protein and DDR mutation of each patient. a Positive PD-L1 (TAP ≥ 1%) in case 11, 23, and 30; negative PD-L1 in case 18 (TAP < 1%); Tumor area positivity (TAP) ≥ 1% was defined as positive. Proportion of tumor and/or immune cells with PD-L1 staining at any intensity. b. DDR-related genetic alternations and pathways identified by WES analysis in 30 patients. Red arrow refers to representative cases (case 23, 30, with multi-DDR mutation, and case 11, 18 without DDR mutation)