Atezolizumab (Tecentriq) plus bevacizumab (Avastin) resulted in clinically meaningful and durable objective responses as first-line therapy for patients with previously untreated, unresectable disease.
Kyung-Hun Lee, MD
A combined attack on hepatocellular carcinoma (HCC) with the PD-L1 inhibitor atezolizumab (Tecentriq) plus the anti-VEGF monoclonal antibody bevacizumab (Avastin) resulted in clinically meaningful and durable objective responses as first-line therapy for patients with previously untreated, unresectable disease, according to findings presented at the 2019 International Liver Cancer Association Annual Conference.
The results of the phase IB GO30140 study may provide patients in this setting with a new treatment option, investigator Kyung-Hun Lee, MD, said in reporting the f indings. He said the regimen was well tolerated.1
Approximately 80% of patients with HCC present with unresectable cancer requiring treatment with therapies other than surgery. Receptor tyrosine kinase inhibitors that inhibit VEGF 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 noninferiority trial demonstrated unconfirmed overall response rates per RECIST 1.1 criteria of 18.8% for lenvatinib (Lenvima) and 6.5% 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 hypervascularized 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 antiangiogenic activity, bevacizumab also showed immunomodulatory effects. We also know that PD-L1 with VEGF has shown clinical benefit in other tumor types.”
GO30140 (NCT02715531) included cohorts for patients with HCC, gastric, pancreatic, and esophageal cancers. Eligibility included measurable disease assessed per RECIST 1.1 criteria, EGOG performance status of 0 or 1, and adequate hematologic and organ function. Patients with HCC were required to have metastatic or unresectable disease and no prior systemic therapy.
Arm A, the HCC study arm, enrolled 104 patients with unresectable HCC with a ChildPugh score up to B7. Patients were given atezolizumab 1200 mg intravenously every 3 weeks plus bevacizumab 15 mg/kg intravenously every 3 weeks.
The primary endpoints in arm A were treatment safety and independent review facility (IRF)—assessed objective response rate (ORR) per RECIST 1.1 criteria. Key secondary endpoints included 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 and 57% from Asia, excluding Japan. Forty-nine percent of patients had hepatitis B, and 30% had hepatitis C. Extrahepatic spread or macrovascular invasion was present in 88% of patients.
In the study arm, 36% of patients had a confirmed ORR, with 12% of patients achieving complete response. “We had duration response with this study ranging from 1.6 months to 31.0 months. More than half of the patients [54%] enjoyed a duration of response of more than 9.0 months,” said Lee.
He said 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 were 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 TRAEs and 3% having grade 5. The most common AEs were proteinuria (37%), decreased appetite (35%) and fatigue (28%). The most common grade 3/4 AE was hypertension (14%), Lee noted. In addition, 24% of patients had serious TRAEs, including pyrexia (5%), cholangitis (3%), and upper gastrointestinal hemorrhage (3%).
The most common AE of special interest (AESI) related to atezolizumab was rash (23%), and the most common AESI related 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 aspartate aminotransferase and alanine aminotransferase 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. Investigators are further evaluating the combination in the IMbrave150 phase III study (NCT03434379).