Also older patients with previously untreated unresectable hepatocellular carcinoma derive more clinical benefit from atezolizumab-bevacizumab compared to sorafenib
Exploratory subgroup analyses of the phase III IMbrave150 trial showed that also older patients with previously untreated, unresectable hepatocellular carcinoma (HCC) derive a clinical benefit of atezolizumab plus bevacizumab compared to sorafenib. In fact, a consistent benefit in overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and patient-reported outcome was reported with the atezolizumab-bevacizumab combination across all ages. Importantly, no significant added risks or toxicities were observed in the older adults, despite higher rates of baseline comorbid medical conditions.
Background
For older patients with hepatocellular carcinoma (HCC), data regarding safety and efficacy of systemic therapies are scarce. The IMbrave150 study was the first randomised phase III study in over a decade to demonstrate a statistically significant and clinically meaningful improvement in OS compared to the long-standing first-line standard of care. In fact, in this trial atezolizumab plus bevacizumab reduced the risk of death by 42% and the risk of progression or death by 41% compared to sorafenib. In addition, clinically meaningful delays in deterioration or patient-reported functioning and quality of life (QoL) vs. sorafenib were reported. At the 2020 ESMO World Congress on Gastrointestinal cancers exploratory subgroup analyses of efficacy, patient-reported outcomes and safety results for older adults (at least 65 years old) enrolled in the IMbrave150 trial were presented.
The IMbrave150 study is a phase III randomised, open-label study enrolling patients with locally advanced or metastatic and/or unresectable HCC who did not received prior systemic therapy. Study participants were randomly allocated (2:1) to atezolizumab (1200 mg intravenously once every three weeks [Q3W]) plus bevacizumab (15 mg/kg Q3W) or sorafenib (400 mg twice daily) until loss of clinical benefit or unacceptable toxicity. For this analysis, patients receiving treatment with either atezolizumab plus bevacizumab or sorafenib were divided into two major categorical age groups (younger patients < 65 years; older patients ≥ 65 years).
Results
Overall baseline characteristics were consistent between patients receiving atezolizumab plus bevacizumab or sorafenib within each age group. In total, about 50% of the patients in IMbrave150 were of older adult age with a median age of 71 years. As compared to the younger patients, older adults were more likely to be female and more patients in this age group had a non-viral etiology. In contrast, the frequency of Asian patients was lower in the older age group. Not-surprisingly, the older patients also had a higher incidence of comorbid medical conditions (hypertension, diabetes mellitus, constipation, gastroesophageal reflux disease, benign prostatic hyperplasia and hyperlipidaemia) and concomitant medications.
Consistent with the intention to treat population, a clinically meaningful improvement in OS was observed with atezolizumab plus bevacizumab in both younger patients and older adults. The unstratified hazard ratio’s [95%CI] were 0.59[0.38-0.91] and 0.58[0.36-0.92] for younger patients and older adults, respectively. Kaplan-Meier curves begin to separate early in the course of treatment in both age groups and after a median survival follow-up of 8.6 months, the median OS in the atezolizumab-bevacizumab arm had not been reached in either age group. In addition, also a clinically meaningful improvement in PFS was observed for atezolizumab plus bevacizumab in both age groups: 6.7 months vs. 2.9 months (HR[95%CI]: 0.50[0.36-0.71] for patients < 65 years and 7.7 vs. 4.8 months (HR[95%CI]: 0.63[0.45-0.89]) for patients ≥ 65 years old. In the response-evaluable population of older age, the ORR was doubled with atezolizumab plus bevacizumab compared to sorafenib (26% vs. 13%), with 5% of the patients achieving a complete response.
Patient-reported outcomes with respect to time to deterioration for physical functioning, role functioning, QoL and key disease-related symptoms were consistently in favour of atezolizumab plus bevacizumab across both age groups. Median treatment duration in the atezolizumab plus bevacizumab arm was comparable in both age groups with a slightly longer time on treatment in the older age group. Treatment-related adverse events (TRAEs) of the atezolizumab plus bevacizumab combination were not influenced by age group and indicated that this regimen was well tolerated in the older age population. Hypertension (32%), fatigue (27%), diarrhoea (22%), decreased appetite (20%), pyrexia (19%), pruritus (18%), proteinuria 17%), and increased aspartate aminotransferase (16%) were the most commonly reported all-cause adverse events.
Conclusions
Similar to the IMbrave150 intent to treat population, older adults with previously untreated, unresectable HCC derived a clinically meaningful benefit from atezolizumab plus bevacizumab versus sorafenib. In addition, the safety of atezolizumab plus bevacizumab in older adults is generally consistent with what is seen in younger patients, with no significant added risks or toxicities, despite higher rates of baseline comorbid medical conditions. As such, atezolizumab plus bevacizumab should be considered as a practice-changing treatment for previously untreated patients with unresectable HCC, irrespective of age.
Reference
Li D, Toh HC, Merle P, et al. Atezolizumab + bevacizumab vs sorafenib for unresectable hepatocellular carcinoma (HCC): results from older adults enrolled in IMbrave 150. Presented at ESMO World GI 2020; Abstract Oral-8.
