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The FDA has approved atezolizumab plus bevacizumab for the treatment of patients with unresectable or metastatic hepatocellular carcinoma who have not received prior systemic therapy.
The FDA has approved the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) for the treatment of patients with unresectable or metastatic hepatocellular carcinoma (HCC) who have not received prior systemic therapy.1
The approval is based on findings from the phase 3 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).
“The results of the IMbrave150 study are really transformative for patients with advanced liver cancer, one of the few cancers with a rising death rate and limited options in the first-line setting,” Richard Finn, MD professor of medicine at the David Geffen School of Medicine at UCLA and Director of the Signal Transduction and Therapeutics Program at the UCLA Jonsson Comprehensive Cancer Center, stated in a press release. “For the first-time we have a regimen that markedly improves survival over sorafenib, the standard of care for first-line hepatocellular carcinoma since 2007, and offers patients the opportunity for improved disease control with a favorable tolerability profile.”
In the international, multicenter, open-label, phase 3 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 end points were overall survival and progression-free survival by an independent review facility (IRF) per RECIST v1.1 criteria. Secondary end points 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 1b trial (NCT02715531).
In earlier data from this study, independent reviewers determined that, at a median follow-up of 10.3 months, atezolizumab plus 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.