Atezolizumab and Bevacizumab for Treatment of Patients With Unresectable / Non-transplantable Advanced Hepatocellular Carcinoma: A Real-World Single Center Experience from North India

None. We read with interest the study by Kulkarni et al. on the experience of check point inhibitor-based combination of Atezolizumab and Bevacizumab (Atez-Bev) in patients with unresectable Hepatocellular carcinoma (HCC)1Kulkarni AV, Krishna V, Kumar K, et al. Safety and Efficacy of Atezolizumab-Bevacizumab in Real World: The First Indian Experience. Journal of Clinical and Experimental Hepatology. https://doi.org/10.1016/j.jceh.2023.02.003.Google Scholar. The authors have shown median overall survival (OS) of 12 months with an objective response rate (ORR) of 38.7% as compared to 19.2 months OS in IMbrave1502Finn R.S. Qin S. Ikeda M. et al.Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma.N Engl J Med. 2020; 382: 1894-1905Crossref PubMed Scopus (2723) Google Scholar. We would like to share our initial experience of patients who received Atez-Bev in unresectable/non-transplantable HCC. Thirty patients with advanced HCC (BCLC-C) who were not candidates for liver transplantation because of disease extent and/or unsuccessful downstaging by loco-regional therapy or radiation were screened of which 13 were prospectively included. Our DS protocol has been published previously by Soin et al.3Soin A.S. Bhangui P. Kataria T. et al.Experience With LDLT in Patients With Hepatocellular Carcinoma and Portal Vein Tumor Thrombosis Post downstaging.Transplantation. 2020; 104: 2334-2345Crossref PubMed Scopus (0) Google Scholar in which selected patients with PVTT underwent DS with stereotactic body radiation (SBRT), usually in combination with tumor ablative therapy, transarterial chemoembolization (TACE) or transarterial radioembolization (TARE), followed by LDLT if downstaging is successful. Inclusion criteria were patients with advanced HCC without clinical decompensation (CTP≤9), with or without macrovascular invasion and/or extrahepatic disease after ruling out high risk varices on endoscopy. Seventeen patients were excluded because of decompensation (i.e. ascites, hepatic encephalopathy, renal dysfunction, Bilirubin >3mg/dl) or Child C status at evaluation and/or financial constraints. Atezolizumab (1200mg) and Bevacizumab (15mg/kg, up to a maximum dosage of 1200mg) was given every 3 weeks. Patients were followed for at least 6 months and response assessment was done after every 4 cycles or 12 weeks of therapy. Of 13 patients (11 with vascular invasion and extrahepatic disease both, and 1 each with vascular invasion and extrahepatic disease alone), the mean age at inclusion was 57.3 ± 9.4 years (12 male & 1 female). Etiology of liver disease was predominantly viral 10 (76.9%) with HBV in 6 (46.1%), HCV & and HBV + HCV co-infection in 2 (15.4%) each, and alcohol, non-alcoholic steatohepatitis and cryptogenic in 1 (7.7%) patient each (Table 1). Mean CTP and median MELD scores were 6 ± 1.3 and 9 (IQR 8-14.5) respectively. Baseline ALBI grades were 1 in 4 (30.7%), 2 in 8 (61.5%) and 3 in 1 (7.7%) patient. Previous downstaging was attempted in 5 (38.5%) patients. Modalities for DS were Y90 TARE/TACE in 3 (23.1%), SBRT and local ablation in 1 (7.7%) each patient. Three (23.1%) of these DS patients were also on Lenvatinib before the initiation of Atez-Bev. Atez-Bev was used as first line therapy in 10 (76.9%), and second line therapy in 3 (23.1%) patients.Table 1Baseline and on treatment response characteristics in all patients (n=13).Baseline Characteristicsn=13Treatment response Characteristicsn=13Etiology of liver diseaseMedian Number of cycles (Range)3 (1-27) HBV6 (46.1%)Response assessment at 3 months11 (84.6%) HCV2 (15.4%)Death before response assessment2 (15.4%) HBV + HCV Co-infection2 (15.4%) Ethanol1 (7.7%)Median OS (months)8 (IQR 6.5-11.5) NASH1 (7.7%) Cryptogenic1 (7.7%)At 12 weeksDeath2 (15.4%)Mean CTP6 ± 1.3PD5 (38.5%)Median MELD9 (IQR 8-14.5)PR5 (38.5%)ALBI Grade 14 (30.7%)SD1 (7.7%)ALBI Grade 28 (61.5%)ALBI Grade 31 (7.7%)At 24 weeksDeath2 (15.4%)Performance Status ECOGPD7 (53.9%) PS 05 (38.5%)PR3 (23.1%) PS 17 (53.9%)CR1 (7.7%) PS 21 (7.7%)At 48 weeksDeath9 (69.2%) BCLC C13 (100%)PR3 (23.1%)CR1 (7.7%) AFP >400 (ng/ml)7 (53.9%) Macrovascular invasion11 (84.6%)Adverse Events Extrahepatic disease11 (84.6%)Decompensation3 (23.1%)Thyroiditis2 (15.4%)Previous DS5 (38.5%)Hepatitis1 (7.7%) Y90 TARE/TACE3 (23.1%)GI bleed1 (7.7%) RFA/MWA1 (7.7%)Fever1 (7.7%) SBRT1 (7.7%)Discontinuation due to disease progression5 (38.5%)*Abbreviations: ALBI: Albumin-Bilirubin; ECOG: Eastern Cooperative Oncology Group; PS: Performance Status; DS: Downstaging; Y90 TARE: Yttrium90 Trans-arterial Radio-embolization; TACE: Trans-arterial Chemo-embolization; RFA: Radiofrequency ablation, MWA: Microwave ablation; SBRT: Stereotactic Body Radiation Therapy; OS: Overall survival; PD: Progressive disease; PR: Partial response; SD: Stable disease; CR: Complete response. Open table in a new tab *Abbreviations: ALBI: Albumin-Bilirubin; ECOG: Eastern Cooperative Oncology Group; PS: Performance Status; DS: Downstaging; Y90 TARE: Yttrium90 Trans-arterial Radio-embolization; TACE: Trans-arterial Chemo-embolization; RFA: Radiofrequency ablation, MWA: Microwave ablation; SBRT: Stereotactic Body Radiation Therapy; OS: Overall survival; PD: Progressive disease; PR: Partial response; SD: Stable disease; CR: Complete response. The median OS was 8 (IQR 6.5-11.5) months. ORR and survival at 12, 24 and 48 weeks were (46.1%, 30.8%, 30.8% and 84.6%, 84.6%, 30.7% respectively). Median OS in Child A & Child B patients was 8(IQR7-13), and 7(IQR 3.2-8.5) months, respectively. There were 9 (69.2%) deaths over median 7 (IQR 4-8.5) months, majority between 24 to 48 weeks of treatment due to progressive disease. Significant adverse events noted were thyroiditis in 2 (15.4%), and grade IV check point related hepatitis and life-threatening GI bleed in one patient (7.7%) each. Treatment was discontinued in 5 (38.5%) patients due to disease progression and 3 (23.1%) patients due to decompensation of liver disease. We studied factors like the etiology of liver disease (viral vs non-viral), severity of liver disease (MELD score, ALBI score at baseline), disease extent (macrovascular invasion, extrahepatic disease), biology of disease (AFP > 400ng/ml) to see an association with response or survival at 24 weeks. However, the sample size was too small to have any meaningful statistical analysis. Although small, there are several lessons to learn from our experience. Historically, the survival of patients with locally advanced HCC with macrovascular invasion and/or EHD is 2-4 months.4Cabibbo G. Enea M. Attanasio M. et al.A meta-analysis of survival rates of untreated patients in randomized clinical trials of hepatocellular carcinoma.Hepatology. 2010; 51: 1274-1283Crossref PubMed Scopus (349) Google Scholar Treatment with Atez-Bev improves survival in these relatively sick non-transplantable/unresectable HCC patients. However, in our experience, it is not suitable for the majority of the patients due to severity of liver disease, poor performance status, and prohibitive costs. Once initiated, there is significant attrition over 6-12 months due to progression of liver disease and/or progression of HCC. Our results show that ALBI score at baseline should be considered in treatment decisions, and patients beyond CTP-A do not benefit significantly from this expensive treatment. Similar results were shown by D'Alessio et al. with CTP B patients surviving only 6.7 months.5D’Alessio A. Fulgenzi C.A.M. Nishida N. et al.Preliminary evidence of safety and tolerability of atezolizumab plus bevacizumab in patients with hepatocellular carcinoma and Child-Pugh A and B cirrhosis: A real-world study.Hepatology. 2022 Oct; 76: 1000-1012Crossref PubMed Scopus (0) Google Scholar We do not consider patients with CTP-C class for this treatment, as poor survival (6.8months in CTP B and 1 month in CTP C) has been shown by de Castro et al.6de Castro T. Jochheim L.S. Bathon M. et al.Atezolizumab and bevacizumab in patients with advanced hepatocellular carcinoma with impaired liver function and prior systemic therapy: a real-world experience.Ther Adv Med Oncol. 2022 Feb 26; 1417588359221080298Crossref PubMed Scopus (19) Google Scholar Swapnil Dhampalwar: Writing- Original draft preparation, Investigation. Narendra S Choudhary: Data curation, Validation, Software. Neeraj Saraf: Writing- Reviewing and Editing, Supervision. Prashant Bhangui: Writing- Reviewing and Editing, Supervision. Arvinder S Soin: Writing- Reviewing and Editing, Supervision.