Atezolizumab Plus Bevacizumab Offers a Promising Option for Unresectable HCC

Kyung-Hun Lee, MD

Clinically meaningful and durable objective responses were observed in the phase Ib (GO30140) subgroup efficacy analysis of atezolizumab (Tecentriq) plus bevacizumab (Avastin) in patients with previously untreated, unresectable hepatocellular carcinoma (HCC). In his presentation at the 13th Annual Conference of the International Liver Cancer Association in Chicago, investigator Kyung-Hun Lee, MD, said the combination of 2 anti-VEGF monoclonal antibodies may provide patients with unresectable HCC with a new treatment option that was well tolerated with manageable toxicities.¹

Approximately 80% of patients with HCC present with unresectable cancer requiring other therapies. VEGFR tyrosine kinase inhibitors are the first-line systemic standard of care for patients with unresectable or metastatic HCC. These are associated with modest survival benefits but considerable toxicities. A phase III non-inferiority trial put unconfirmed overall response rates per RECIST 1.1 at 19% for lenvatinib (Lenvima) and 7% for sorafenib (Nexavar).²

In randomized studies, single-agent PD-L1/PD-1 immune checkpoint inhibitors have shown clinical activity against HCC, but not superiority over standards of care, noted Lee, of the department of Hemato Oncology, Medical Oncology Center, Seoul National University Hospital, South Korea.

“Many HCC tumors are hypervascularised and overexpress VEGF and PD-L1, and we know that the anti-VEGF monoclonal antibody bevacizumab has shown modest single-agent activity in HCC,” said Lee. “In addition to anti-angiogenic activity, bevacizumab also showed immunomodulatory effects. We also know that PD-L1 with VEGF has shown clinical benefit in other tumor types.”

The study design of the phase Ib trial focused on various tumor types, including gastric, pancreatic and esophageal cancers, with measurable disease per independent review facility (IRF)—assessed RECIST 1.1 criteria, and EGOG performance status of 0 or 1, and adequate hematologic and organ function. Patients with prior systemic therapy were excluded.

Arm A, the HCC study arm, enrolled 104 patients with unresectable HCC with a Child-Pugh score up to B7. Patients were given atezolizumab 1200 mg IV every 3 weeks plus bevacizumab 15 mg/kg IV every 3 weeks.

The primary endpoints in arm A were treatment safety and IRF-assessed object response rate (ORR) per RECIST 1.1. Key secondary endpoints also include duration of response (DOR) and progression-free survival (PFS) per IRF RECIST, ORR, DOR and PFS per IRF HCC modified RECIST criteria (HCC mRECIST). Lee said data on some key secondary endpoints will be available at upcoming conferences.

The majority of patients enrolled were male (81%) with a median age of 62, with 57% from Asia, excluding Japan. Forty-nine percent of patients had hepatitis B (HBV) and 30% had hepatitis C (HCV). Extrahepatic spread (EHS) or macrovascular invasion (MVI) was present in 88% of patients.

In the study arm, 36%of patients had confirmed ORR, with 12% of patients achieving complete response. “We had duration response with this study, ranging from 1.6 months to 31 months. More than half of the patients (54%) enjoyed a duration of response of more than nine months,” said Lee, adding that DOR was consistent across analyses: HCC mRECIST (61% of patients) and investigator (INV)-assessed RECIST (62%). In addition, 76% of responses per IRF-assessed RECIST 1.1 are ongoing and the median duration of response was not reached, noted Lee.

The combination of atezolizumab and bevacizumab resulted in a median PFS also consistent across the 3 analyses: Both RECIST and HCC mRECIST showed 66% of patients with a median PFS of 7.3 months. INV RECIST showed 72% of patients with a median PFS of 7.4 months. Median overall survival, measured by HCC mRECIST, was 17.1 months, with a 6-month overall survival rate of 82% and a 12-month OS of 63%.   

“The benefits of atezolizumab and bevacizumab was generally consistent among patient subgroups, with clinical activity observed irrespective of PD-L1 status,” said Lee.

Median treatment duration was 8.3 months on atezolizumab and 8.2 months on bevacizumab. Eighty-eight percent of patients experienced any grade treatment-related adverse events (TRAEs), with 39% having grade 3/4 treatment-related AEs and 3% grade 5. The most common AEs were proteinuria (37%), decreased appetite (35%) and fatigue (28%). The most common Grade 3/4 AE was hypertension, noted Lee, with 14% of patients experiencing it. In addition, 24% of patients had serious treatment-related AEs, including pyrexia (5%), cholangitis (3%), and upper gastrointestinal hemorrhage (3%).

The most common adverse event of special interest (AESIs) related to atezolizumab was rash (23%) and to bevacizumab was proteinuria (37%). Grade 3-4 bleeding AESIs associated with bevacizumab included 2% of patients with upper gastrointestinal bleeding and 2% of patients with esophageal varices hemorrhage.

“Fifteen patients (14%) required systemic corticosteroids within 30 days of experiencing an adverse event on atezolizumab,” said Lee. Increased AST and ALT levels (3% of patients each) were the most common hepatic events requiring systemic steroids within 30 days of an AE. No new safety signals were identified beyond the established single-agent safety profiles, said Lee.

“In conclusion, this combination of atezolizumab and bevacizumab may become a promising treatment option for patients with unresectable HCC,” said Lee. This combination is being evaluated further in the IMbrave150 phase III study (NCT03434379).

References:

1. Lee KH, Ryoo BY, Hsu C-H, et al. Phase IB study results: safety and efficacy of atezolizumab + bevacizumab versus atezolizumab in patients with previously untreated, unresectable, or advanced hepatocellular carcinoma. Presented at: 13th Annual Conferences of the International Liver Cancer Association; September 20-22, 2019; Chicago, IL. Abstract 0-32.
2. Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial.Lancet. 2018;391(10126):1163-1173. doi: 10.1016/S0140-6736(18)30207-1.