Atezolizumab and Bevacizumab Pre-Liver Transplantation for Patients With Hepatocellular Carcinoma Beyond Milan Criteria

Hepatocellular carcinoma (HCC) represents the second most common cause of cancer-related death and accounts for over 80% of primary liver cancers worldwide.(1) Curative treatment options include surgical resection in patients with well compensated liver function and radio frequency ablation in small tumors. However, in 90% of patients, HCC occurs in the setting of cirrhosis(2) where optimal management remains liver transplantation (LT) with 5-year survival rates of approximately 80%.(3) Despite the success of LT in treating HCC, only a small portion of patients fit into standard Milan Criteria to receive a LT due to 1) advanced-stage disease and/or large tumor size preventing/delaying organ allocation and 2) a lack of neoadjuvant (bridging) therapies that can effectively down-stage or delay tumor progression for patients while on the LT waiting list. The proposed clinical trial will evaluate the feasibility of using a combination of the chemotherapeutic interventions atezolizumab(4) and bevacizumab(5) in a group of patients with HCC who have tumors beyond the Milan Criteria (in brief, 5 - 10 cm), in order to appropriately bridge them to liver transplantation without increasing the risk of graft rejection within 1-year post-LT. Globally, Milan Criteria (MC),(6) defined as one single tumor \< 5cm or 3 tumors \< 3cm, is the most commonly recognized criteria for selecting patients for deceased donor LT. However, it is increasingly recognized that these criteria may be restrictive and not always reflect biology of the disease.(3) Variable extended strategies have been employed including the i) extended Toronto Criteria(7) (where no limitation in tumor burden is imposed provided the tumor is not poorly differentiated and there is no evidence of extrahepatic disease or vascular invasion), ii) Ontario criteria, where patients are eligible based on Total Tumor Volume (TTV, ≤ 145cm\^3) and alpha fetoprotein (AFP \< 1000 ng/mL), or iii) University of California San Francisco criteria (tumor size ≤6.5 cm) and beyond. A number of centers have implemented downstaging strategies incorporating AFP dynamics to help select who may benefit.(8) Despite similar survival in patients beyond MC successfully receiving a transplant,(7) a considerably higher rate of drop-off from the waiting list exists and survival in this population is particularly poor.(9) Downstaging patients to MC and transplant most commonly involves locoregional therapies (LRT); however, for patients who do not reach transplant, the long term survival after receiving systemic treatments is low. The IMbrave150 study of atezolizumab and bevacizumab versus sorafenib demonstrated response rates of 29.8% vs 12%, respectively, and median overall survival of 19.8 months in the combination arm versus 13.4 months in the sorafenib alone arm (HR 0.66, 95% CI 0.52, 0.85; p=0.0009).(10) The synergistic effect of an antiangiogenic plus immune checkpoint inhibitor (CPI) can reactivate the intra-tumoral trafficking of cytotoxic T cells and create a favorable immune microenvironment for CPI antitumoral activity.(11) This study has now shifted the treatment paradigm in HCC, suggesting a new standard of care in intermediate stage HCC refractory to local therapies and those with advanced stage disease eligible for first line treatment.(12) This data highlights the importance of systemic treatment in the management of HCC and challenges historical treatment paradigms. It further emphasizes the need to maintain liver function so that patients can receive systemic therapies. There is little data to support systemic treatments both in the neoadjuvant setting and as a bridging or downstaging strategy to liver transplantation. Continued eligibility and timing of transplantation are crucial factors which can be influenced by donor availability, Model for End-stage Liver Disease (MELD) score and blood group. A recent case report has, however, demonstrated the feasibility of PD-1 blockade prior to orthotopic liver transplantation with no evidence of disease recurrence 1-year post-transplant. Nivolumab (OPDIVO, Bristol-Myers Squibb Co., Princeton, NJ USA)(13) was stopped in this case 6 weeks prior to transplant.(14) The half-life of 27 days for atezolizumab and 20 days for bevacizumab suggests a need to stop at a similar time point when using atezolizumab/bevacizumab. Atezolizumab (TECENTRIQ®, Genentech, Inc., South San Francisco, CA) is a humanized immunoglobulin (Ig) G1 monoclonal antibody that targets PD L1 and inhibits the interaction between PD-L1 and its receptors, PD-1 and B7-1 (also known as CD80), both of which function as inhibitory receptors expressed on T cells. Therapeutic blockade of PD-L1 binding by atezolizumab has been shown to enhance the magnitude and quality of tumor-specific T-cell responses, resulting in improved anti tumor activity.(15,16) Atezolizumab has minimal binding to Fc receptors, thus eliminating detectable Fc effector function and associated antibody-mediated clearance of activated effector T cells. Atezolizumab shows anti-tumor activity in both nonclinical models and cancer patients and is being investigated as a potential therapy in a wide variety of malignancies. Atezolizumab is being studied as a single agent in the advanced cancer and adjuvant therapy settings, as well as in combination with chemotherapy, targeted therapy, and cancer immunotherapy. Atezolizumab is approved for the treatment of urothelial carcinoma, non-small cell lung cancer, small-cell lung cancer, liver and triple-negative lung cancer. Please refer to the Atezolizumab Investigator Brochure (IB) for details on nonclinical and clinical studies. Bevacizumab (AVASTIN®, Genentech, Inc., South San Francisco, CA) is a recombinant humanized monoclonal IgG1 antibody that binds to and inhibits the biologic activity of human vascular endothelial growth factor (VEGF) in vitro and in vivo assay systems. Bevacizumab was first granted marketing approval in the US on 26 February 2004 in combination with IV 5-fluorouracil-based chemotherapy for the first-line treatment of patients with metastatic carcinoma of the colon or rectum. Bevacizumab is approved in over 100 countries for one or more of the following indications: breast cancer, non-small cell lung cancer (NSCLC), renal cell cancer, glioblastoma multiforme, cervical cancer, epithelial ovarian cancer, primary peritoneal cancer, and fallopian-tube cancer. Bevacizumab has been studied in a multitude of Phase I, II, and III clinical trials in more than 22,000 patients and in multiple tumor types. Approximately 1,720,000 patients have been exposed to bevacizumab as a marketed product or in clinical trials. Please refer to the bevacizumab Investigator Brochure for descriptions of all completed Phase I, II, and III trials reported to date. The combination of atezolizumab and bevacizumab as first-line treatment for non-resectable or metastatic HCC was assessed for safety and efficacy in two studies: GO30140 and YO40245 (IMbrave150). Study GO30140 investigated atezolizumab plus bevacizumab in combination as first-line therapy for patients with metastatic HCC.(17) It was a Phase Ib, multicenter, open-label study trial with many arms. Arm A evaluated patients who had not received prior systemic therapy. Arm F included 119 patients with locally advanced or metastatic HCC who were randomized 1:1 to atezolizumab plus bevacizumab or atezolizumab monotherapy as first-line therapy. Study results for Arm A demonstrated an objective response rate (ORR) assessment per Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) of 37% (36%; 95% CI 26-46). For the patients who responded, 12 patients (12%) achieved a complete response (CR) and 25 patients (24%) achieved a partial response (PR). The combination of atezolizumab plus bevacizumab was generally well tolerated. Arm F demonstrated an objective response rate in 20% (95% CI 11-32), with 1 patient (2%) showing complete response and 11 (18%) with partial response. Study YO40245, called IMbrave 150, was a phase III study including 501 randomized patients with unresectable HCC.10 Patients were randomized 2:1 to atezolizumab (1,200 mg intravenously every 3 weeks) plus bevacizumab (15 mg/kg intravenously every 3 weeks) or sorafenib (400 mg twice daily). The duration of their treatment extended until unacceptable toxicity or reduced clinical benefit per the study investigators. There was a significant improvement in overall survival response rates of 29.8% vs 12%, respectively, and median overall survival of 19.8 months in the combination arm versus 13.4 months in the sorafenib alone arm (HR 0.66, 95% CI 0.52, 0.85; p=0.0009). The median follow-up was 15.6 months. Median progression-free survival improved to 6.8 months (combination arm) compared to 4.3 months in the sorafenib group (HR 0.59; 95% CI 0.47-0.76, p\< .0001). ORR was also significantly better in the combination group compared to sorafenib (27% vs 12% p\<0.0001) based on RECIST v1.1. Similar increases were demonstrated using HCC mRECIST18 criteria (33% vs 13%, p\<0.0001). A comparable amount of Grade 3 - 5 adverse events were seen between groups. This trial will enroll patients with locally advanced HCC. Given the relatively poor prognosis and limited treatment options for these patients, this population is considered appropriate for trials of novel therapeutic candidates. The benefit-risk ratio for atezolizumab + bevacizumab is expected to be acceptable in this setting. Encouraging clinical data emerging in the field of tumor immunotherapy have demonstrated that therapies focused on enhancing T-cell responses against cancer can result in a significant survival benefit in patients with advanced malignancies.(19-21) The PD-L1 pathway serves as an immune checkpoint to temporarily dampen immune responses in states of chronic antigen stimulation, such as chronic infection or cancer. PD L1 is an extracellular protein that downregulates immune responses through binding to its two receptors, PD-1 and B7-1. PD-1 is an inhibitory receptor expressed on T cells following T-cell activation, and expression is sustained in states of chronic stimulation.(22,23) B7-1 is a molecule expressed on antigen presenting cells and activated T cells. Binding of PD-L1 to PD-1 and B7-1 inhibits T-cell proliferation and activation, cytokine production, and cytolytic activity, leading to the functional inactivation or exhaustion of T cells.(24,25) Overexpression of PD-L1 on tumor cells has been reported to impede anti tumor immunity, resulting in immune evasion.(26) Therefore, interruption of the PD-L1 pathway represents an attractive strategy for restoring tumor-specific T-cell immunity. The combination of atezolizumab with bevacizumab is expected to down-grade the tumor size and potentially allow patients to reach the smaller tumor criteria of MC for qualifying for exception points for a liver transplant. Even if the growth is halted and not reduced to MC, stable patients may be able to achieve liver transplant without exception points if a matching donor can be located that would not be suitable for another recipient. These extended criteria donor livers would be discarded yet have shown success in circumstances such as the purpose for the current trial. Liver transplantation provides the life-saving benefit and curative therapy for liver-limited HCC. Although there has been some success with therapeutics and LRT management for HCC, liver transplantation provides the highest survival outcome (85% at 5-yrs).