Surgical resection and liver transplantation (LT) are the primary curative treatment options for patients with hepatocellular carcinoma (HCC); however, these therapies were historically limited to those detected at an early stage. There has been increasing data demonstrating excellent outcomes among patients who are detected beyond an early stage and downstaged with locoregional therapy (LRT). Algorithms, including the Barcelona Clinic Liver Cancer (BCLC) system and the American Association for the Study of Liver Disease (AASLD), recommend downstaging for patients to undergo LT, when detected beyond an early stage.1,2

Recently, immuno-oncological agents have revolutionized the management of HCC. There have been few reports of successful LT following nivolumab and pembrolizumab therapy for unresectable HCC (uHCC).3-5 However, neither of these drugs significantly improved overall survival in the advanced stage setting and failed to receive Food and Drug Administration (FDA) approval. Subsequent studies have demonstrated excellent safety and efficacy of atezolizumab-bevacizumab (atezo-bev) in uHCC; 8-12% of patients achieved complete response (CR), while 20-30% achieved partial response (PR).6,7 The usage of atezo-bev has increased exponentially following FDA approval, with increasing number of patients achieving downstaging.

Considering potential bevacizumab-related adverse events such as the increased risk of gastrointestinal (GI) bleeding and wound healing, it is imperative to understand the outcomes of patients who are downstaged using atezo-bev. Currently, there are few case reports of successful LT following atezo-bev therapy.8-10 Herein, we aimed to describe the outcomes of patients who were downstaged with atezo-bev and subsequently underwent surgical therapy, including LT.

Of the 115 patients (Supplementary Table 1) who received atezo-bev (with either palliative or downstaging intent), 12 achieved a CR or PR and were willing to be considered for LT after being downstaged to adhere to Milan criteria. The clinical, biochemical, and treatment parameters are summarized in Table 1. The median age of patients was 58.5 years, and 16.7% were women. The most common etiology of cirrhosis was metabolic-dysfunction-associated steatohepatitis (MASH) in 50.0%, followed by viral liver disease in 41.7% of patients. At presentation, 58.3% and 41.7% had Child-Pugh class A and B cirrhosis, respectively; all had ECOG PS 0 except for two with ECOG PS 1. Five patients had BCLC stage B disease at presentation, while the rest had BCLC stage C HCC. A median of three lesions (range, 1-8) was found in each patient, and the largest median diameter among the 12 patients was 8 cm (range, 4-16). Four patients had received prior LRT (two TARE, one local ablation, and one SBRT). Individual case details are presented below and detailed in Supplementary Table 2.

Case 1 is a 57-year-old female with MASH cirrhosis and unifocal 13 cm HCC who was treated with TARE followed by atezo-bev 3 weeks later. She had a radiologic CR after four doses, but continued for three more doses given the initial hesitation to proceed with LT. After repeated counselling, the patient consented to undergo LT and underwent living donor LT (LDLT) 54 days after the last dose of atezo-bev. Cross-sectional imaging pre and post atezo-bev and explant pathology showing cirrhotic morphology with a completely necrosed tumor is depicted in Fig. 1. Liquid biopsy at the time of LT had no elevated tumor fraction (fraction of circulatory tumor DNA vs. total DNA in plasma), was negative for MSI, and the blood TMB was 1 muts/mb. Post LT, the patient had delayed wound healing but no other complications. The patient is currently on tacrolimus, everolimus, and MMF 11 months post-LT with no evidence of rejection or HCC recurrence.

Case 2 is a 58-year-old male who had hepatitis B-related cirrhosis who was started on atezo-bev for multifocal HCC recurrence with Vp2 PVTT after prior local ablation. After five doses of atezo-bev, the patient achieved radiographic PR but developed ascites and was subsequently listed for LT. He underwent LDLT 80 days after the last dose of atezo-bev. Fig. 2 show the explant features of the liver without any active HCC lesions. Post-transplant, the patient developed wound gaping and underwent stapling. He recently developed bacterial pneumonia (right lower lobe), which resolved with antibiotics (pipercillin+tazobactum). The patient is 10 months post-LT and has not had any evidence of rejection or HCC recurrence while being maintained on tacrolimus, everolimus, and MMF.

Case 3 is a 60-year-old male who had alcohol-related cirrhosis and multifocal HCC; the largest lesion was 8.6 cm. The patient was initiated on atezo-bev because LRT was not possible due to a large arterioportal shunt; after three doses, he had a radiologic CR, and was listed for cadaveric LT because there was no suitable donor. Therapy was continued for six more cycles as his model for end-stage liver disease (MELD) score was <10, and there were no active lesions, after which atezo-bev was discontinued. Liquid biopsy revealed no elevated tumor fraction, blood TMB of 0 muts/mb, and no high MSI or elevated tumor fractions. The patient had mutations in ASXL (S1131*) and DNMT3A (R882H), which are known to be associated with HCC, but had no poor prognostic markers. He is currently stable and awaiting LT.

Case 4 is a 71-year-old female who had MASH cirrhosis and unifocal 16 cm HCC, and achieved a radiologic CR after six doses of atezo-bev. Therapy was continued for another six cycles and the patient was then referred for LT. Given the presence of compensated cirrhosis without clinically significant portal hypertension (hepatic venous pressure gradient 9 mmHg), the patient instead underwent surgical resection. Her pathology specimen showed no active HCC. Fig. 3 show the cross-sectional images of the patient pre and post atezo-bev and 2.5 years after resection. The patient is stable without recurrence after 2.5 years.

Case 5 is a 64-year-old male who had hepatitis B cirrhosis and multifocal HCC (largest lesion 6.1 cm), and achieved radiologic CR after three doses of atezo-bev. However, the patient developed proteinuria, penile ulceration, and herpes labialis after the 5th dose, leading to discontinuation. The patient had HCC recurrence on day 98. At listing, he had a blood TMB of 6 muts/mb with mutations in CTNNB1 (1S45Y) and TP53 (Y236N), which are both associated with poor survival. The pateint died of pneumonia and liver failure on day 133 after the last atezo-bev dose.

Case 6 is a 70-year-old male who had MASH cirrhosis and HCC with Vp4 PVTT and lymph node metastases. The patient achieved radiologic PR after TARE and two doses of atezo-bev, and was listed for cadaveric LT due to lack of a living donor. Atezo-bev was discontinued after the third dose, given the development of large ascites. He died on the waitlist due to spontaneous bacterial peritonitis and acute kidney injury (AKI) on day 128 after the last atezo-bev dose.

Case 7 is a 55-year-old male who had hepatitis C cirrhosis and HCC with Vp4 PVTT who achieved radiologic PR after four doses of atezo-bev, with maximum tumor diameter decreasing from 8.5 to 3.5 cm, although there was a persistent enhancement in the portal vein. Despite prior variceal screening elsewhere 6 months prior to the initiation of atezo-bev, the patient developed variceal bleeding after the 4th dose, requiring variceal ligation for grade II varices, leading to discontinuation of atezo-bev. He was scheduled to undergo SBRT to treat the likely remaining PVTT followed by possible LDLT if he were to respond and fulfil the Milan criteria; however, the patient developed pneumonia and hepatic encephalopathy and died of multiorgan failure 43 days after the last dose of atezo-bev.

Case 8 is a 59-year-old male who had MASH cirrhosis and HCC with Vp3 PVTT and bone metastases. After six cycles of palliative atezo-bev, he had radiologic CR, although AFP remained elevated at 930 ng/mL. He received three further doses and completed evaluation for LDLT. Liquid biopsy revealed blood TMB of 3 muts/mb but without high MSI or elevated tumor fraction. The patient also has telomerase reverse transcriptase (TERT) promoter (124c>T) mutation and TP53 (E171*) mutation, which are associated with extrahepatic metastasis and high tumor burden. Therefore, a longer observation period is essential prior to proceeding with LDLT. At this time, the patient has stopped atezo-bev and has not had any evidence of recurrence. Fig. 4 shows the cross-sectional images of the patient pre and post atezo-bev.

Case 9 is a 41-year-old male who had MASH cirrhosis and multifocal HCC with Vp4 PVTT. His imaging revealed a lack of enhancement in the portal vein and reduced enhancement of the intrahepatic lesions after three doses of atezo-bev. He experienced hepatic decompensation with worsening jaundice and ascites. Autoimmune markers, including antinuclear and anti-smooth muscle cell antibodies, were negative, although immunoglobulin G was slightly elevated at 2,543 ng/mL. He was managed conservatively with ursodeoxycholic acid, albumin infusions, and diuretics. He underwent LDLT 79 days after the last dose of atezo-bev. There were no intraoperative complications, and his explant showed no active HCC lesions; however, he developed burst abdomen requiring re-exploration on day 23. He subsequently died on day 48 from sepsis and early graft dysfunction.

Case 10 is a 53-year-old who had hepatitis B virus (HBV)-related cirrhosis and was diagnosed with multifocal HCC with Vp3 PVTT. The patient achieved radiologic PR after five cycles of atezo-bev, followed by SBRT for residual PVTT. Although the course was complicated by ascites, AKI, and jaundice 3 weeks after SBRT, the patient underwent LDLT 114 days after the last dose of atezo-bev. There were multiple collaterals around the bile duct due to PVTT, and therefore, the patient underwent Roux-en-Y hepaticojejunostomy. His explant pathology showed a necrosed tumor with no active lesions. He is on tacrolimus, everolimus, and MMF 7 months post-LT, without evidence of rejection or HCC recurrence.

Case 11 is a 62-year-old male who had HBV-related cirrhosis, and presented with multifocal HCC. He achieved radiologic PR after three doses of atezo-bev, with loss of enhancement in three lesions and decreased size of the largest lesion from 6.5 to 3 cm. As there were no donors, the patient underwent deceased donor liver transplantation 38 days after the last dose of atezo-bev. Explant showed one active lesion but necrosis in the others. He is 4 months post-LT, without evidence of rejection or HCC recurrence and is on tacrolimus, everolimus, and MMF.

Case 12 is a 51-year-old male who had MASH cirrhosis and HCC with Vp3 PVTT. The patient achieved CR after six doses of atezo-bev and was listed for cadaveric LT. Liquid biopsy showed 3 muts/mb blood TMB with no MSI and low tumor fraction. The patient has TP53 R249S mutation, is currently stable, and awaiting LT.

The changes in serum bilirubin levels, aspartate transaminase, and alanine transaminase levels in patients who underwent LT are depicted in Fig. 5.

Although LRT remains the primary downstaging modality for patients with HCC, immune checkpoint inhibitors (ICIs) have changed the HCC treatment landscape. Atezo-bev and durvalumab+tremelimumab both yield significantly longer survival and increased radiographic objective response rates compared to sorafenib.6,12 Further, ICIs are increasingly being evaluated in earlier stages of the disease, including recent data suggesting a possible benefit in an adjuvant setting after surgical resection and when used in combination with transarterial chemoembolization.13,14 Therefore, transplant centers must understand the safety and clinical outcomes of ICIs, including atezo-bev, prior to LT. Our study adds to the literature on administration of atezo-bev prior to LT by raising several important points: 1) over 10% of patients with large intermediate or advanced-stage HCC can be downstaged and made eligible for LT, 2) infection is a major cause of mortality in patients who are successfully downstaged, and 3) patients treated with atezo-bev appear to have low rates of rejection and early HCC recurrence but experience increased risk of poor wound healing.

Although atezo-bev can yield radiographic objective response rate in ≤30% of patients with HCC, the responses are not uniform due to tumor microenvironment heterogeneity, and many are not downstaged to adhere to Milan criteria.15 Notably, recent neoadjuvant studies have suggested that radiographic response may underestimate the degree of pathological response.16 In our study, we found that all but one patient who underwent LT or surgical resection had complete necrosis on pathology specimens despite some only having PR on imaging. Liquid biopsy is an upcoming strategy for patients with HCC, and several studies have reported that circulating tumor cells are useful in predicting the recurrence of HCC post-LT.17,18 Molecular-based targeted therapies are also being utilized to identify appropriate treatment regimens for HCC.19 This approach may be particularly beneficial in patients who present with advanced-stage HCC and are downstaged. Lack of any circulating tumor DNA, high tumor mutational burden, and microsatellite instability may help identify ideal candidates for LT.

ICIs are highly efficacious but are known to be associated with potential adverse events.20 A recent case series suggested the safety of using ICIs as a bridge to LT with few patients experiencing acute cellular rejection.3 Similarly, none of the patients in our study experienced rejection after LT with the described post-LT immunosuppression regimen. Atezo-bev is also associated with an increased risk of other adverse events, such as GI bleeding, proteinuria, and poor wound healing. In our study, the most commonly observed adverse event was poor wound healing, likely related to inadequate vascularization due to the inhibition of vascular endothelial growth factor (VEGF) by bevacizumab.21 Apart from stimulating endothelial cells to promote angiogenesis, VEGF is involved in re-epithelialization through the stimulation of keratinocytes, and also aids in pathogen elimination and resolution of inflammation through monocyte and macrophage infiltration.22 Although we did not note any issues in vascular anastomosis or intrabdominal bleeding, hepatologists and surgeons must be aware of such adverse events in the post-transplant period. It is unknown whether recombinant VEGF infusion in the post-transplant period may avoid such complications. Of note, most patients in our study had less than 1 year of follow-up, and further follow-up is needed to see if these patients will have downstream complications, including a higher risk of chronic rejection, cardiovascular disease, or HCC recurrence. Although previous studies have reported no higher risk of graft rejection/recurrence, this was not noted in our study.

The most common reason for delisting was infection. Pneumonitis is a known complication of programmed cell death protein 1 and programmed cell death ligand 1 inhibitors.23 However, infections (such as pneumonia) due to atezo-bev have not yet been reported. Therefore, we believe that the infections noted in our study were more likely related to poor hepatic function and cirrhosis-associated immune dysfunction rather than the drug itself.24

There are a few limitations to this retrospective study. The duration of atezo-bev and use of concurrent therapies (LRTs) were not uniform in all patients, as some patients developed liver dysfunction that precluded other therapies. Second, mRECIST is the recommended approach to monitoring treatment response in patients with HCC but may not be the optimal approach for patients undergoing ICI therapy.2,25,26 Some patients labelled as PR on mRECIST had complete pathologic response. It is unknown whether this was due to the residual action of ICIs or the underestimation of response by mRECIST. Lastly, liquid biopsy was not performed in all patients. Nevertheless, this is the first study to report the utility of liquid in patients with HCC who are considered for LT after downstaging with atezo-bev.

In summary, our data highlight that LT can be considered in well-selected patients after downstaging is achieved with ICI combinations, including atezo-bev. It is imperative that transplant hepatologists and surgeons work closely with medical oncologists in a multidisciplinary manner to identify these patients and consider LT at the appropriate interval.