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A supplemental biologics license application has been submitted to the FDA for the combination of atezolizumab and bevacizumab for the treatment of patients with unresectable hepatocellular carcinoma who have not received prior systemic therapy.
Levi Garraway, MD, PhD
A supplemental biologics license application (BLA) has been submitted to the FDA for the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) for the treatment of patients with unresectable hepatocellular carcinoma (HCC) who have not received prior systemic therapy.1
The sBLA is based on findings of the phase III IMbrave150 study, which demonstrated that atezolizumab plus bevacizumab led to a 42% reduction in the risk of death compared with sorafenib (Nexavar; HR, 0.58; 95% CI, 0.42-0.79; P = .0006). The combination was also associated with a 41% reduction in the risk of disease progression or death versus sorafenib (HR, 0.59; 95% CI, 0.47-0.76; P <.0001).
Moreover, the safety profile of the combination was found to be consistent with the known tolerability of each agent alone. The FDA is reviewing the application under the Real-Time Oncology Review program, which is designed to explore a more efficient review process to ensure safe and effective therapies are made available to patients earlier.
“Liver cancer is the most rapidly increasing cause of cancer-related death in the United States. In the IMbrave150 study, Tecentriq in combination with Avastin became the first treatment in more than a decade to improve overall survival compared with the current standard of care,” Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development, Roche, the developer of both agents, stated in a press release. “We are pleased that these results are being reviewed under the FDA Real-Time Oncology Review pilot program, and we are working closely with the agency to bring this potential new treatment option to people with unresectable hepatocellular carcinoma as quickly as possible.”
In the international, multicenter, open-label, phase III IMbrave150 trial, 501 patients with unresectable HCC who did not receive prior systemic therapy were randomized 2:1 to receive the combination of atezolizumab and bevacizumab or sorafenib alone. Atezolizumab was administered intravenously (IV) at 1200 mg on day 1 of each 21-day cycle; IV bevacizumab was given at 15 mg/kg on day 1 of each 21-day cycle. Oral sorafenib was administered at 400 mg twice daily on days 1 to 21 of each 21-day cycle. In both arms, treatment was given until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
To be eligible for enrollment, patients had to have locally advanced or metastatic and/or unresectable HCC, had received no prior systemic therapy, had ≥1 measurable lesion, an ECOG performance status of 0 or 1, adequate hematologic and end-organ function, and had to have Child-Pugh class A disease.
Those with a history of leptomeningeal disease; active or history of autoimmune disease or immune deficiency; history of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography scan; active tuberculosis, history of cancer other than HCC within 5 years prior to screening; known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC; and a history of hepatic encephalopathy were excluded from enrollment.
The coprimary endpoints were overall survival and progression-free survival by an independent review facility (IRF) per RECIST v1.1 criteria. Secondary endpoints included overall response rate (ORR), time to progression, and duration of response as measured by RECIST v1.1 (investigator-assessed and IRF) and HCC mRECIST (IRF), patient-reported outcomes, safety, and pharmacokinetics.
The results, which were presented at the 2019 ESMO Asia Congress, also showed that grade 3/4 adverse events (AEs) occurred in 57% and 55% of the combination and sorafenib arms, respectively.2 The mortality rate was 5% with the combination versus 6% on the sorafenib arm.
In July 2018, the FDA granted a breakthrough therapy designation to the combination in HCC, based on results of an ongoing phase Ib trial (NCT02715531).
In earlier data from this study, independent reviewers determined that, at a median follow-up of 10.3 months, atezolizumab/bevacizumab elicited an ORR of 65% (n = 15) among the 23 evaluable patients.3 Additionally, the responses were observed across patient subgroups defined by etiology, geography, baseline alpha fetoprotein levels, and extrahepatic spread. The 65% ORR comprised a 4% (n = 1) complete response rate and a 61% (n = 14) partial response rate. Additionally, 7 (30%) patients had stable disease and 1 (4%) patient had progressive disease. A disease control rate of ≥6 months was reported for 16 (70%) patients.