Durvalumab as a Successful Downstaging Therapy for Liver Transplantation in Hepatocellular Carcinoma: The Importance of a Washout Period

Abstract

INTRODUCTION Liver transplantation (LT) is indicated in unresectable hepatocellular carcinoma (HCC) with limited tumor load. Evidence also supports LT as a rescue treatment when more advanced patients achieve stable downstaging after locoregional therapies. Immunotherapy with immune checkpoint inhibitors(ICIs) targeting programmed death 1 and its ligand (PDL1) are now used alone or in combination as first- or second-line systemic treatment. We present a case showing the feasibility and efficacy of rescue LT following response to the PDL1 inhibitor durvalumab. This study was exempt from approval from an ethics board. A 61-y-old male with chronic hepatitis B virus infection under tenofovir therapy had a moderately differentiated binodular (12 and 9 mm) HCC resected in April 2015, which showed no microvascular invasion. Four mo later, CT scan disclosed intrahepatic progression with multiple lesions involving both lobes (13 lesions, the largest one 47 mm in size). Chemoembolization was contraindicated based on the impossibility to perform superselective embolization (13 lesions). He started sorafenib in August 2015 and treatment resulted in disease stabilization and declining alpha-fetoprotein (Figure 1). When progression was confirmed in December 2016, he participated in a clinical trial that compared 4 different regimes of immunotherapy (Study D4190C00022). After randomization, he began treatment with durvalumab monotherapy in February 2017. A partial response developed with disappearance or lack of contrast enhancement of all the smaller lesions after 6 mo. Partial response remained stable for 15 mo until the main lesion started to grow and showed contrast enhancement. A slight increase in alpha-fetoprotein was observed. LT was positively assessed by his referral center. To minimize the risk of rejection induced by PDL1 inhibition, entry in the waiting list was delayed by 3 mo after durvalumab discontinuation. Selective chemoembolization of the active tumor was performed in August 2018, and the patient was transplanted in January 2019, within Milan criteria, Child-Pugh B7 MELD 23 with 1 lesion of 35 × 42 mm in the CT scan. Viable tumor tissue was not observed in any lesion in the explant. Immunosuppression consisted of corticosteroids, tacrolimus, and mycophenolate mofetil. No rejection events have been observed, and the patient remains disease-free 89 mo after diagnosis and 24 mo after LT.FIGURE 1.: Treatment sequence, changes in alpha-fetoprotein (AFP) levels and tumor burden from diagnosis to transplantation. TACE, transarterial chemoembolization.DISCUSSION There is little information on the outcome of patients transplanted while on ICIs. An HCC patient transplanted after almost 2 y of the programmed death 1 inhibitor nivolumab with an 8-d washout period died within a few days because of acute refractory rejection.1 Contrary, a patient transplanted after 15 wk off nivolumab had an uneventful postoperative period and remained free from recurrence or graft rejection after 1 y.2 More recently, a small series of 9 HCC patients successfully transplanted after nivolumab has been reported.3 Eight patients received their last dose of nivolumab (serum half life is approximately 27 d) within 4 wk before transplant. No severe allograft rejections, tumor recurrences, or deaths occurred during the follow-up (8–23 mo). Durvalumab has a half life of approximately 18 d, and PDL1 receptor occupancy has been observed for up to 85 d in phase 1 single-dose trials.4 Based on these data, our strategy was to wait at least 90 d after the last dose of durvalumab to perform the LT. Given the increased risk of rejection, an adequate washout period of ICIs before listing and the use of corticosteroids in initial immunosuppression may help avoid graft rejection in this scenario. The specific pharmacokinetics of each ICI should be taken into consideration when establishing the optimal timing of LT. More studies are needed to better understand the safety of these drugs in the LT setting before this approach can be widely recommended.

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