Atezolizumab/Bevacizumab Combo Improves Survival in Frontline HCC

Levi Garraway, MD, PhD

The combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) showed statistically significant and clinically meaningful improvements in both progression-free and overall survival (OS) compared with sorafenib (Nexavar) in patients with unresectable hepatocellular carcinoma (HCC) who have not received prior therapy, meeting the coprimary endpoints of the IMbrave150 trial (NCT03434379).¹

The safety findings for the combination were consistent with the known profiles of each agent alone, and no new safety signals were identified. The data will be submitted to regulatory authorities and will be presented at an upcoming medical meeting, announced Genentech (Roche), the developer of both agents, in a press release.

“We are very pleased with the results of our study testing the combination of Tecentriq and Avastin, which marks the first treatment in more than a decade to improve overall survival in people with unresectable hepatocellular carcinoma who have not received prior systemic therapy,” Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development of Genentech (Roche), stated in the press release.

“HCC is a major cause of death globally and particularly in Asia, making this study an important step in our mission of addressing unmet medical needs for patients around the world. We will submit these data to global health authorities as soon as possible. Our hope is to bring a new treatment to people with this aggressive disease who currently have limited options,” added Garraway.

In the international, multicenter, open-label, phase III IMbrave150 study, 501 patients with unresectable HCC who did not receive prior systemic therapy were randomized 2:1 to receive atezolizumab combined with bevacizumab or sorafenib. 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. Treatment in both arms 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 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 some of the exclusion criteria.

The coprimary endpoints were OS and progression-free survival (PFS) 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 (DOR), as measured by RECIST v1.1 (investigator-assessed and IRF) and HCC mRECIST (IRF), patient-reported outcomes, safety, and pharmacokinetics.

In July 2018, the FDA granted a breakthrough therapy designation to the combination of atezolizumab and bevacizumab as a first-line treatment for patients with advanced or metastatic HCC, based on results from an ongoing phase Ib trial (NCT02715531).²

In the study, patients received 1200 mg of atezolizumab IV and 15 mg/kg of bevacizumab IV every 3 weeks until unacceptable toxicity or loss of clinical benefit. The median age among the 23 patients in the efficacy-evaluable population was 62 years (range, 35-78). The majority of patients were male (n = 18) and 5 were female. Patients were from either United States or Japan (n = 14), and areas in Asia outside of Japan (n = 9). Ten patients had an ECOG performance status of 0 and the remaining 13 patients had a status of 1.

The Child Pugh class for the 23 patients was A5 (n = 17), A6 (n = 5), or B7 (n = 1). Ten patients had the hepatitis B virus (HBV), 9 had the hepatitis C virus (HCV), and 4 had non-viral disease. Ten patients had TNM stage IVb disease and 11 patients had extrahepatic spread. Baseline AFP levels were measured at <200 ng/mL (n = 11), 200 to 400 ng/mL (n = 2), and ≥400 ng/mL (n = 9). The baseline AFP value was missing for 1 patient in the efficacy population.

At a median follow-up of 10.3 months, results from independent reviewers determined that atezolizumab/bevacizumab elicited an ORR of 65% (n = 15) among the 23 evaluable patients. Additionally, the responses were observed across patient subgroups defined by etiology, geography, baseline AFP levels, and extrahepatic spread.

The 65% ORR comprised a complete response (CR) rate of 4% (n = 1) and a partial response rate of 61% (n = 14). 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.

The ORR was 60% in HBV-positive patients, 78% in HCV-positive patients, and 50% in non-viral patients. In US/Japanese and Asian (non-Japanese) patients, the ORRs were 65% and 67%, respectively. Among the patients with low, intermediate, and high AFP levels, the ORRs were 55%, 100%, and 78%, respectively. Patients with and without extrahepatic spread had ORRs of 73% and 75%, respectively.

The safety population included all 43 patients who received any amount of study treatment. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 28% (n = 12) of patients, with the most common being hypertension (n = 7); there were no treatment-related deaths.

Data of two small clinical trials of the combination as a frontline treatment in this population were presented at the 2019 ESMO Congress.³ In the first trial, which was an update from the ongoing phase Ib trial, investigators in the United States, Japan, South Korea, and Taiwan involved 104 patients with no prior systemic therapy. All of the patients received atezolizumab at 1200 mg every 3 weeks plus bevacizumab at 15 mg/kg every 3 weeks. In the second study, investigators randomized 119 patients with untreated HCC to the same combination or to atezolizumab monotherapy.

The first study had primary endpoints of safety and objective response by independent review. In the randomized study, PFS by independent review and safety were the primary endpoints.

In the single-arm trial, updated results showed that 37 (36%) patients had confirmed responses, including a CR rate of 12%. An additional 37 patients had stable disease, which led to a 71% disease control rate (DCR). At a median follow-up of 12.5 months, 28 of 37 responses were ongoing. The median DOR had yet to be reached, and response duration ranged from 1.6 to 31 months. Responses persisted ≥9 months in 20 (54%) cases and ≥12 months in 11 (30%).

The median PFS was 7.3 months, 54% remained alive and free of progression at 6 months, and 35% had not progressed at 12 months. The median OS was 17.1 months, the 6-month OS rate was 82%, and the 12-month OS rate was 63%.

In the randomized and second study, and after a median follow-up of 6.6 months, 35 (58%) PFS events had occurred in the combination arm as compared with 39 (66%) among patients randomized to single-agent atezolizumab, which favored the combination (HR, 0.55; P = .0108). The combination arm had a median PFS of 5.6 months versus 3.4 months for the atezolizumab-alone group.

Twelve (20%) patients had confirmed responses with the combination and 10 (17%) with atezolizumab alone. An additional 28 (47%) in the combination arm had stable disease compared with 19 (32%) in the control group; the DCR rate 67% with the combination and 49% with atezolizumab alone.

Grade 3/4 adverse events (AEs) occurred in 37% of those on the combination arm and 14% of patients in the atezolizumab-alone group. AEs were considered treatment related in 20% and 5% of patients, respectively. Serious AEs occurred in 25% of the combination group and 10% of the monotherapy group and were considered treatment related in 12% and 3% of cases, respectively.

References

1. Genentech’s Tecentriq in Combination With Avastin Increased Overall Survival and Progression-Free Survival in People With Unresectable Hepatocellular Carcinoma. Genentech. Published October 20, 2019. https://bit.ly/2Mwd9Au. Accessed October 20, 2019.
2. Stein S, Pishvaian MJ, Lee MS, et al. Safety and clinical activity of 1L atezolizumab + bevacizumab in a phase Ib study in hepatocellular carcinoma (HCC). J Clin Oncol. 2018;36(suppl; abstr 4074). doi: 10.1200/JCO.2018.36.15_suppl.4074.
3. Lee M, Ryoo B-Y, Hsu C-H, et al. Randomised efficacy and safety results for atezolizumab (Atezo) + bevacizumab (Bev) in patients (pts) with previously untreated, unresectable hepatocellular carcinoma (HCC). Presented at 2019 ESMO Congress; September 27 to October 1, 2019; Barcelona, Spain. Abstract LBA39.