In the Phase III IMbrave150 trial, atezolizumab in combination with bevacizumab demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) and progression-free survival (PFS) vs sorafenib in patients with unresectable hepatocellular carcinoma (HCC).

At ESMO 2020, the incidence and management of AESIs related to atezolizumab and bevacizumab in IMbrave150 were reported. AEs of special interest (AESIs) were pre-defined based on the immune-related risks of atezolizumab and other PD-L1/ PD-1 inhibitors and the bleeding risks of bevacizumab and other vascular endothelial growth factor (VEGF) inhibitors.

With regard to commonly reported AESIs defined for atezolizumab by medical concept, post infusion-related reactions were mostly grade 1-2 and manageable. Hepatic events were consistent with the underlying disease, with the rate of all-grade immune-related hepatitis being comparable between the atezolizumab + bevacizumab (43.2%) and sorafenib arms (39.7%). More than 50% of AESIs defined for atezolizumab were resolved.

The most commonly reported AESIs defined for bevacizumab by medical concept in both the atezolizumab + bevacizumab and sorafenib arms were hypertension, bleeding/haemorrhage events and proteinuria. The proportion of patients experiencing grade 3-4 bleeding/ haemorrhage was comparable between the 2 treatment arms (6.4% with atezolizumab + bevacizumab vs 5.8% with sorafenib). All-grade GI haemorrhage, oesophageal varices haemorrhage and upper GI haemorrhage were 2.4%, 2.4% and 1.2%. Grade 3-4: 1.8%, 1.2% and 0.6%.

In conclusion, the AESIs in IMbrave150 were manageable, contributing to the favourable risk profile of atezolizumab + bevacizumab as compared with sorafenib. The nature and severity of these AESIs were consistent with the known safety profiles of the individual agents and the underlying disease. Of note, the proportions of grade 3-4 special interest bleeding events were comparable between treatment arms. With its positive benefit-risk profile, atezolizumab in combination with bevacizumab now becomes the new standard care for patients with unresectable HCC who have not received prior systemic treatment.

Atezolizumab (anti-programmed death-ligand 1 [PD-L1]) in combination with bevacizumab (anti-vascular endothelial growth factor) has recently been approved in 16 countries, including the US, for patients with unresectable or metastatic HCC who have not received prior systemic therapy. These approvals are based on the data from the phase 3 IMbrave150 study.

The efficacy and safety data from the phase Ib GO30140 study support the positive benefit-risk profile demonstrated by the atezolizumab + bevacizumab combination in IMbrave150. In Group F of GO30140, patients who had been randomised to receive atezolizumab monotherapy had the option to cross over to receive atezolizumab + bevacizumab after investigator (INV)-assessed disease progression (PD). At ESMO 2020, the authors presented the efficacy data from these patients who crossed over to atezolizumab + bevacizumab following progression on atezolizumab monotherapy.

Among the 26 patients who crossed over, one patient had a PR (ORR, 3.8%) and 13 patients (50%) had SD with atezolizumab + bevacizumab after crossover; hence, the DCR was 53.8%, compared with an ORR of 0% and a DCR of 30.8% with atezolizumab monotherapy before crossover.

In the patients who crossed over to the combination, the median PFS in the post-crossover period (5.4 months) was numerically longer than the median PFS in pre-crossover atezolizumab monotherapy period (1.9 months). This was similar to the median PFS of 5.7 months in patients in Group F1 who received atezolizumab + bevacizumab from the start of the study.

In conclusion, although this exploratory post hoc analysis has limitations, it suggests that a subset of patients with unresectable HCC that does not respond to atezolizumab monotherapy may benefit from the addition of bevacizumab. These and other data from the phase Ib GO301402 and phase III IMbrave1501 studies support the use of combination therapy with atezolizumab + bevacizumab in patients with unresectable systemic treatment-naive HCC and suggest that atezolizumab + bevacizumab should be the first systemic therapy in this setting.

TACE is the current standard of care for patients with unresectable intermediate-stage HCC. At ESMO 2020, results of a randomized, open-label, multi-center, phase 3 trial conducted in China found that HAIC with FOLFOX significantly improved OS compared with TACE in patients with unresectable HCC.

This study recruited adults (≥18 years) with a primary unresectable HCC tumour with a largest diameter ≥7 cm, without macrovascular invasion or extrahepatic spread, with a total of 315 patients. Hepatitis B infection was present in majority of patients (90%), while 60% had confirmed liver cirrhosis and about half had more than 3 lesions. The study author noted that patient demographics between both arms were similar and was representative of the Chinese intermediate-staged HCC population.

Patients were randomised 1:1 to HAIC (oxaliplatin 130 mg/m², leucovorin 400 mg/m², fluorouracil bolus 400 mg/m² on day 1, and fluorouracil infusion 2400 mg/m² for 24 hours, every 3 weeks via repeated catheterization) or TACE (50 mg of epirubicin, 50 mg of lobaplatin, and lipiodol and polyvinyl alcohol particles). The primary endpoint of the study was overall survival (OS) and secondary endpoints included objective response rate (ORR), progression-free survival (PFS) and safety.

Median OS was higher for patients receiving HAIC vs TACE: 23.1 months vs 16.07 months; with a HR of 0.58 (95% CI, 0.45−0.75; P <0.001). Hence this translated to a 42% reduction in the risk of death in patients receiving HAIC vs TACE. Patients receiving HAIC also demonstrated a higher ORR (45.9% vs. 17.9%) and had a longer median PFS (9.63 vs. 5.40 months). There were also more patients in the HAIC group that underwent subsequent resection as compared to those who received TACE (23.8 vs 11.5%). In terms of the safety profile, the incidence of serious adverse events was higher in the TACE group versus the HAIC group (30 vs 19%).

In the phase III RESORCE trial, regorafenib improved overall survival (OS) vs placebo in patients with uHCC who progressed on sorafenib.

REFINE is an international, prospective observational study that recruited patients with uHCC. The primary aim is to assess treatment-emergent adverse events (TEAEs). Secondary endpoints include OS, progression-free survival, and tumor response. At ESMO 2020, the authors presented interim results for 182 patients who enrolled in REFINE from Korea (70%), China (26%), and Taiwan (4%).

The median age was 60 years and 80% of them were male. Majority of these patients had ECOG 0 (37%) or 1 (49%) and a Child-Pugh A (70%) or B (5%). The initial daily regorafenib dose was 160 mg (70%), 120 mg (14%) and 80 mg (15%) respectively. Median treatment duration was 3.2 months.

TEAEs reported among Asian patients were consistent with those reported in the phase III RESORCE trial, with grade 3 or higher AEs seen in 11% of the patients, which include diarrhea (2%), limb syndrome (1%), hypertension (1%) and fatigue (1%). There were no grade 4/5 adverse events observed. Notably, incidence rates of some TEAEs were lower than in RESORCE.

The study results also showed that the median overall survival (OS) for the 182 patients was 16.3 months, a 52% increase compared to 10.6 months seen in the RESORCE study. This median OS was also longer than 13.2 months shown in the total cohort of the REFINE study.

The first-line treatment with sorafenib for advanced hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) shows limited survival benefit. Previous reports have suggested the application of hepatic arterial infusion chemotherapy (HAIC) for these patients. At ESMO 2020, results from a single-centre, randomized phase II trial investigating the efficacy and safety of sorafenib plus HAIC compared with sorafenib for advanced HCC with major PVTT (Vp3/4) was reported.

The study recruited patients with unresectable advanced HCC and main (Vp3) or first branch PVTT (Vp4) who were previously untreated with chemotherapy or radiotherapy, with a total of 64 patients recruited. They were randomly assigned in a 1:1 ratio to receive sorafenib (400 mg, twice daily) plus HAIC (oxaliplatin 35 mg/m² for 2 h, and 5-fluorouracil 600 mg/m² for 22 h on days 1-3) or sorafenib (400 mg, twice daily) every four weeks. Percutaneously port catheter system was used for HAIC. The primary endpoint was overall survival (OS). Secondary endpoints included objective response rate (ORR) according to mRECIST, progression-free survival (PFS) and safety.

The median OS was 23.5 months in the sorafenib + HAIC group and 6.8 months in the sorafenib group (P<0.001). In addition, patients receiving sorafenib + HAIC also demonstrated higher ORR (57.1% vs 4.0%) and longer median PFS (10.7 vs 2.5 months) vs patients who received only sorafenib. However, a higher incidence of grade 3/4 treatment-related AEs were noted in the patients receiving sorafenib + HAIC vs sorafenib alone. These include the following: gastrointestinal reaction (21.9% vs.18.8%), hand-foot syndrome (18.8% vs. 6.2%), hematological abnormalities (12.5% vs. 0%) and liver dysfunction (6.3% vs. 3.1%). Nevertheless, there were no treatment-related death.

The authors concluded that sorafenib plus HAIC with oxaliplatin and 5-fluorouracil significantly improved survival compared with sorafenib in patients with HCC and major PVTT, with acceptable safety profile.

Editors: David Tai and Choo Su Pin