Toripalimab, Lenvatinib, plus Chemotherapy a Promising Combination in Advanced Unresectable Intrahepatic Cholangiocarcinoma

The multidrug combination of toripalimab, a new PD-1 inhibitor, plus lenvatinib (Lenvima), a multikinase inhibitor, and the chemotherapy drugs gemcitabine and oxaliplatin demonstrated promising efficacy in patients with advanced, unresectable intrahepatic cholangiocarcinoma (CCA), according to results of a phase 2 clinical trial presented at the 2020 virtual meeting of the European Society for Medical Oncology.

The results were presented by Jian Zhou, MD, PhD, Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China, and colleagues.

This was a phase 2, open-label, single-arm study of 30 patients with advanced unresectable intrahepatic CCA. The patients received 240-mg toripalimab intravenously every 3 weeks, 8-mg lenvatinib once daily orally, and 1 g/m² of gemcitabine on days 1 and 8, and 85 g/m² of oxaliplatin every 3 weeks intravenously for 6 cycles.

The study’s primary end point was objective response rate (ORR) based on the Response Evaluation Criteria in Solid Tumors version 1.1; the secondary outcomes included progression-free survival (PFS), overall survival (OS), and safety. Whole-exome sequencing was performed on the tumor tissue, and PD-L1 expression was determined by immunohistochemistry staining.

Overall, 43.3% of the patients had stage IIIB CCA, 40% of the patients had stage IV disease, and 53.3% of the patients had no PD-L1 expression. In addition, 80% of the patients had a positive blood test for hepatitis B. None of the patients had received previous therapy. The majority (70%) of patients had DNA damage repair (DDR) gene mutations.

The ORR with this multidrug combination was 80% (95% confidence interval [CI], 61.4%-92.3%), including 1 complete response. The disease control rate was 93.3% (95% CI, 77.9%-99.2%), and in 2 patients, the tumor was downstaged and subsequently resected.

The 6-month OS rate was 90%. The median PFS, median OS, and median duration of response were not reached.

The ORR was significantly associated with DDR mutations and PD-L1 expression. The ORR in patients with CCA and DDR mutations but no PD-L1 was 95% compared with 55.6% in patients without DDR mutations (P = .022). The ORR was 100% in patients with PD-L1 expression versus 68.8% (P = .048) in patients with no PD-L1 expression.

The most common (>10%) adverse events were vomiting, abnormal electrocardiogram, elevated aspartate transaminase levels, neutropenia, fatigue, nausea, and numbness. Of the 30 patients in the study, 13 (43%) patients had a grade ≥3 adverse event, with the most common events being neutropenia, rash, and jaundice.

Recently, immune checkpoint inhibitors that target PD-1 or PD-L1 have promoted an important breakthrough in the treatment of multiple solid tumor cancers.^1-3 Multikinase inhibitors hold a prominent place in chemotherapy. However, the combination of PD-1 and PD-L1 inhibitors and chemotherapy can lead to significant improvements in OS and PFS in some cancers.^4-7

Predictors of response to PD-1 and PD-L1 inhibitors include PD-L1 expression, tumor mutational burden, microsatellite instability, and mismatch repair-deficiency.^8-10 Although the number of patients in this study was small, Zhou and colleagues have demonstrated that patients with a high PD-1 expression and the presence of DDR mutations responded favorably to the addition of chemotherapy and an anti–PD-1 antibody to a multikinase inhibitor.

In this study, the investigators concluded that the combination of toripalimab, lenvatinib, and chemotherapy with gemcitabine and oxaliplatin was tolerable and demonstrated promising efficacy in patients with intrahepatic CCA. The study results warrant further review of this treatment combination.

References

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