This retrospective study evaluated the efficacy and safety of lenvatinib and anti-PD-1 therapy with or without the combination of chemotherapy in patients with unresectable or recurrent BTC. We found that the combination of chemotherapy with lenvatinib and PD-1 inhibitors might exert a better anti-tumor effect and lead to a longer PFS. Although the combination therapy increased the frequency of TRAEs, they were mostly controllable. These findings provide evidence for future large prospective randomized clinical studies of this combination therapy for the treatment of advanced BTC.
Surgical resection is a curative treatment for patients with resectable BTC; however, there are few therapeutic options for unresectable or recurrent patients. Chemotherapy such as the GC or GS regimen is recommended as the standard of care for advanced BTC, yet high toxicity of this regimen can lead to poor tolerance. The development of novel TKIs and immune checkpoint inhibitors brought new treatment options for advanced BTC. A recent study analyzing the therapeutic outcomes of lenvatinib and PD-1 inhibitors in advanced BTC achieved a median PFS of 4.9 months and OS of 11.0 months[10]. Our previous phase II study using lenvatinib and PD-1 inhibitors as first-line treatment to treat unresectable BTC reported that the median PFS was 8.0 months and OS was 17.7 months[11]. In the present study, the median PFS was 4.5 months and OS was 12.4 months among the patients receiving lenvatinib and PD-1 inhibitors, which were consistent with the results reported in previous studies. These findings indicate that combination therapy with TKIs and PD-1 inhibitors can achieve a promising survival outcome, suggesting that it may be a potential treatment strategy for advanced BTC, especially for the patients cannot tolerate or refuse standard chemotherapy.
Combined therapy with immune checkpoint inhibitors and chemotherapy has been investigated in advanced BTC. Several studies have shown that the combination of anti-PD-1 antibodies and chemotherapy significantly improved the PFS and OS (PFS, 4.2 to 6.1 months; OS, 11.8 to 15.4 months) compared to anti-PD-1 monotherapy or chemotherapy alone[13, 14, 16, 17]. However, reports on triple therapy with TKIs, PD-1 inhibitors and chemotherapy for the treatment of BTC are scarce. Recently, a series demonstrated that lenvatinib plus PD-1 inhibitors in combination with locoregional chemotherapy was associated with a significantly better tumor response and survival benefits in patients with advanced hepatocellular carcinoma[18–20]. These patients achieved an ORR of 40-80.6% and DCR of 77.6–93.5%. These promising results encouraged us to investigate the efficacy of triple therapy with lenvatinib, PD-1 inhibitors and chemotherapy in BTC patients. A phase 2 clinical trial of GEMOX chemotherapy in combination with anti-PD1 antibody and lenvatinib for advanced intrahepatic cholangiocarcinoma reported robust anti-tumor efficacy of the triple therapy with an ORR of 80% and DCR of 93.3%[21].
In the present study, we compared the efficacy of triple therapy (lenvatinib, PD-1 inhibitors plus chemotherapy) with dual therapy (lenvatinib plus PD-1 inhibitors). Patients enrolled in this study had relatively late-stage disease and the majority had metastases or poorly differentiated adenocarcinoma. Among the 40 patients receiving triple therapy, one achieved a CR, 16 PR, 21 SD, and yielded an ORR of 42.5% and DCR of 95.0%. The study showed that patients receiving triple therapy exhibited a better median PFS (8.3 vs. 4.5 months) and DCR (95.0% vs. 75.9%) compared to those receiving dual therapy. Although no significant difference in ORR was found, it was relatively high in patients treated with triple therapy (42.5%) compared to 27.6% in the LenP group. With regards to tumor regression, tumor size reduction was observed in 82.5% of patients receiving triple therapy, compared with 67.2% in the LenP group. Taken together, these results suggest that triple therapy with lenvatinib, PD-1 inhibitors plus chemotherapy was effective in advanced BTC. However, better anti-tumor efficacy did not translate into longer survival. The median OS was 13.7 months in the LenP + C group and 12.4 months in the LenP group, respectively. This may be due to the following reasons: Radical resection is considered the only curative treatment for BTC; however, surgical conversion was similar between the two groups (LenP + C, 22.5% vs. LenP, 17.2%). Secondly, the difference in later-line therapy after failure to each treatment also impacted the OS. In the present study, 22 patients in the LenP + C group and 39 patients in the LenP group underwent disease progression at the data cutoff. However, only 4 (18.1%) patients in the LenP + C group received later-line systemic therapy, compared to 19 (48.7%) patients in the LenP group. Thirdly, a more intensive therapy is usually associated with more toxic effects. The incidences of any grade and grade ⩾3 TRAEs were higher in patients receiving triple therapy compared to dual therapy, which might also influence the OS of the patients in the LenP + C group.
The efficacy benefit observed in the present study might be attributed to the synergistic anti-tumor effect of lenvatinib, PD-1 inhibitors and chemotherapy. Lenvatinib is an anti-angiogenic agent, and preclinical data revealed that it can also improve the anti-tumor efficacy of immunotherapy targeting PD-1/PD-L1 by enhancing the activity of T lymphocytes[22, 23]. PD-1 inhibitors magnify the anti-tumor activity of T lymphocytes by blocking the negative regulatory signaling of PD-1/PD-L1[24]. Chemotherapy exerts an anti-tumor effect by cytotoxicity; however, increasing evidence has indicated that chemotherapy can enhance the anti-tumor efficacy of immunotherapy by increasing antigen presentation and T lymphocyte recruitment[25]. Taken together, the synergistic effects of triple therapy exhibit a better tumor response.
In terms of safety, the most frequent TRAEs in the present study were liver function injury and hematological toxicities. Any grade of neutropenia, anemia, thrombocytopenia, nausea/vomiting, fever and grade ⩾3 neutropenia significantly increased in the LenP + C group, which might be attributed to the chemotherapy[26, 27]. Although triple therapy was associated with more TRAEs, they were generally controllable. Treatment-related death occurred in one patient receiving lenvatinib and PD-1 inhibitors. The cause of death was autoimmune myocarditis, which was considered an immune-related adverse effect and is consistent with reports from previous studies[28, 29].
This study had several limitations. First, this was a retrospective study with a small sample size, which may have led to selection bias. Second, the anti-PD-1 antibodies used in this study were not unified. Therefore, well-designed randomized controlled trials with a specified therapeutic regimen are needed to verify the benefits of triple therapy in BTC patients.