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The combination of atezolizumab and bevacizumab demonstrated comparable clinical activity and safety versus sorafenib in older and younger patients with previously untreated, unresectable hepatocellular carcinoma.
The combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) demonstrated comparable clinical activity and safety versus sorafenib (Nexavar) in older and younger patients with previously untreated, unresectable hepatocellular carcinoma (HCC), according to findings from exploratory subgroup analyses of the phase 3 IMbrave150 trial that were presented at the 2020 World Congress on Gastrointestinal Cancer.1
At a median follow-up of 8.6 months, the median overall survival (OS) with the combination was not evaluable in older patients (65 years or older; n = 161) compared with 14.9 months with sorafenib (HR, 0.58; 95% CI, 0.36-0.92), or younger patients (younger than 65 years; n = 175) versus sorafenib (HR, 0.59; 95% CI, 0.38-0.91), translating to a 42% and 41% reduction in the risk of death, respectively.
“The results support the use of atezolizumab and bevacizumab as a practice-changing treatment even amongst older adults with unresectable HCC who have not received prior systemic treatment,” Daneng Li, MD, an assistant clinical professor in the Department of Medical Oncology and Therapeutics Research at City of Hope, said in a presentation during the Congress.
IMbrave150 is the first randomized phase 3 trial in over a decade to demonstrate a statistically significant and clinically meaningful improvement in OS versus sorafenib in previously untreated patients with unresectable HCC, Li explained.
In the trial, patients were randomized 2:1 to 1200 mg of intravenous atezolizumab plus 15 mg/kg of bevacizumab every 3 weeks versus 400 mg of sorafenib twice daily. Treatment was administered until loss of clinical benefit or unacceptable toxicity.
The primary results from the trial showed that the combination led to a 41% reduction in the risk of disease progression or death (HR, 0.59; 95% CI, 0.47-0.76; P <.001), and a 42% reduction in the risk of death versus sorafenib in this setting (HR, 0.58; 95% CI, 0.42-0.79; P <.001). Clinically meaningful delays in deterioration of patient-reported functioning and quality of life (QOL) were also reported with the combination.
Findings from the trial served as the basis for the May 2020 FDA approval of the combination for the treatment of patients with unresectable or metastatic HCC who have not received prior systemic therapy.2
However, data regarding the efficacy and safety of systemic therapies in older patients with HCC are limited, said Li. To that end, investigators conducted exploratory subgroup analyses to assess the efficacy, safety, and patient-reported outcome (PRO) results in older patients enrolled in the trial.
Baseline characteristics were generally well balanced between arms within each age group. A total of 50% of all patients were older and had a median age of 71 (range, 65-88). The older cohort had a greater proportion of female patients from the rest of the world, and with non-viral etiology as cause of their HCC compared with the younger cohort.
Forty-six perfect and 28% of patients, younger than 65 years and 65 years and older, respectively, who received the combination had an alpha-fetoprotein (AFP) level that was greater than or equal to 400 ng/mL. Additionally, a majority of older patients had extrahepatic spread (57%) and/or macrovascular invasion (31%), although the latter was lower compared with younger patients at 69% and 45%, respectively.
Older patients had a higher incidence of comorbid medical conditions, including hypertension, diabetes, constipation, gastroesophageal reflux disease, benign prostatic hyperplasia, and hyperlipidemia. Investigators found a lower incidence of hepatitis B and hepatic cirrhosis among older patients despite a similar frequency of esophageal varices across the 2 age groups.
Regarding concomitant medications, older patients used antihypertensive agents more commonly than younger patients, which is consistent with the overall comorbid index of this population.
In addition to comparable OS, investigators showed that the progression-free survival (PFS) benefit was consistent across age groups. The median PFS in older patients was 7.7 months in the combination arm versus 4.8 months in the sorafenib arm (HR, 0.63; 95% CI, 0.45-0.89). In younger patients, the median PFS was 6.7 months versus 2.9 months, respectively (HR, 0.50; 95% CI, 0.36-0.71).
The ORR also favored the combination arm, irrespective of age. In older patients, the ORR was 26% in the combination arm versus 13% in the sorafenib arm. In younger patients, the ORRs were 29% and 10%, respectively. Notably, the combination led to complete response rates of 5% and 6%, respectively, versus 0% in both age groups in the sorafenib arm.
The median treatment duration was 7.5 months in older patients and 6.75 months in younger patients. In general, the frequency and severity of adverse events (AEs) were similar between the 2 age groups and consistent with the known safety profiles of atezolizumab and bevacizumab. Notably, no additional risks or toxicities were reported in older patients.
The most common all-grade AEs in older patients were hypertension (32%), fatigue (27%), and diarrhea (22%) versus hypertension (27%), proteinuria (23%), and aspartate aminotransferase increase (23%) in younger patients.
Overall, the incidence of all-grade treatment-related AEs (TRAEs; 82% vs 85%), grade 3/4 TRAEs (39% vs 32%), serious TRAEs (18% vs 16%), and grade 5 TRAEs (3% vs 1%) were consistent in older and younger patients, respectively.
AEs leading to withdrawal from the combination occurred in 9% of older patients and 5% of younger patients. AEs leading to dose interruptions were reported in 55% and 44% of patients, respectively.
“It is especially noteworthy to see the benefit in favor of the combination treatment among older adults despite these patients having more comorbid medical conditions at baseline,” said Li.
An analysis of PROs indicated that the combination also lengthened the time to deterioration of physical and role functioning, QoL, abdominal swelling, appetite loss, diarrhea, fatigue, jaundice, nutrition, and pain in both age groups.
“Similar to the IMbrave150 intention-to-treat population, older adults with previously untreated, unresectable HCC derived a clinically meaningful benefit from atezolizumab plus bevacizumab versus sorafenib,” concluded Li.