Immunotherapy Combinations Emerge as Likely Standard for Future HCC Management

Targeted Therapies in Oncology, April 2 2020, Volume 9, Issue 6

The combination of PD-L1 and VEGF inhibition suggests promise for the treatment of unresectable hepatocellular carcinoma, according to findings of the phase III IMbrave150 study.

Ghassan K. Abou-Alfa, MD

The combination of PD-L1 and VEGF inhibition suggests promise for the treatment of unresectable hepatocellular carcinoma (HCC), according to findings of the phase III IMbrave150 study. The results of the trial, which compared the combination of atezolizumab (Tecentriq) plus bevacizumab (Avastin) versus standard-of-care sorafenib (Nexavar), was the first to show improvement of overall survival (OS) and progression-free survival (PFS) in this setting, and clinicians who treat this patient population took notice. From these findings, it is likely that the combination will eventually overtake sorafenib as the standard of care in the frontline setting, according to Ghassan K. Abou-Alfa, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York, who spoke about data at HCC-TAG Conference 2020. However, he cautioned his audience not to make too much of the data pending further validation.1

“These are positive data, but I’m always cautious,” he said, noting that he is eagerly awaiting the presentation of the final trial results. “What we are depending on so far is an abstract. We need more data to see the analysis in depth to put it in place and compare it to other agents.”

Abou-Alfa recapped the triumphs and challenges of 2019 in HCC, calling IMbrave150 the most significant development, and set the stage for the year ahead(TABLE).2

In the IMbrave150 trial, 501 patients with unresectable HCC were randomly assigned to 1200 mg of intravenous (IV) atezolizumab plus 15 mg/kg of IV bevacizumab every 3 weeks or 400 mg of sorafenib twice daily. Patients stayed on the study until unacceptable toxicity or loss of clinical benefit. At a median follow-up of 8.6 months, investigators observed a 42% decrease in the risk of death (HR, 0.58; 95% CI, 0.42-0.79;P= .0006) and a 41% reduced risk of disease progression or death (HR, 0.59; 95% CI, 0.470.76; P<.0001) in the atezolizumab/bevacizumab arm versus the sorafenib arm, respectively.2The median PFS was 6.8 months in the experimental arm and 4.3 months in the control arm. The median OS was not reached (NR) versus 13.2 months, respectively.

Compared with the sorafenib arm, the overall response rate (ORR) was higher than in the combination arm (27% vs 12%; P<.0001) based on independent assessment using RECIST 1.1 criteria and similarly increased using HCC mRECIST criteria (33% vs 13%;P<.0001).

Subsequent findings presented at the 2020 Gastrointestinal Cancers Symposium in January showed that atezolizumab/bevacizumab confers benefits in quality of life, functioning, and key symptoms compared with sorafenib.3

Although sorafenib and lenvatinib (Lenvima) remain the only approved agents for HCC in the up-front setting, Abou-Alfa said combinations—anti-VEGF agents plus checkpoint inhibitors, tyrosine kinase inhibitors plus checkpoint inhibitors, and dual checkpoint inhibitors—are “novel, positive, and disruptive.” He pointed to data from the phase I/II CheckMate 040 trial to show the potential impact of the nivolumab (Opdivo) plus cabozantinib (Cabometyx) doublet and the triplet regimen combining nivolumab with ipilimumab (Yervoy) and cabozantinib. Ghassan K. Abou-Alfa, MD.

Previous data from another cohort of this trial showed that nivolumab in combination with ipilimumab demonstrated a high response rate and durable responses in patients with advanced HCC previously treated with sorafenib.4Moreover, a previous pivotal phase III study of cabozantinib in patients with advanced HCC showed a median OS of 10.2 months.5

In findings from CheckMate 040, the median PFS by investigator assessment was 6.8 months (95% CI, 4.0-14.3) with nivolumab/ipilimumab/cabozantinib (n = 35) versus 5.4 months (95% CI, 3.2-10.9) with nivolumab/cabozantinib (n = 36). The median OS was 21.5 months (95% CI, 13.1-NR) with the doublet and NR with the triplet (95% CI, 15.1-NR). The 15-month OS rates also favored the triplet (70% vs 64%).6

However, the triplet was associated with a higher rate of treatment-emergent adverse events (AEs). In the triplet arm, 25 (71%) patients experienced grade 3/4 treatment-related AEs compared with 17 (47%) in the doublet arm. The rate of discontinuation due to toxicity was nearly twice as high in the triplet arm (20% vs 11%), as was discontinuation for immune-related AEs (11% vs 6%).

“The 1 thing that caught our attention quite a bit was the AEs—that high level of grade 3/4 toxicity with the triplet,” Abou-Alfa said. He added that the toxicity profile means that the triplet will require further study before its therapeutic role can be defined.


  1. Abou-Alfa GK. The year in review — triumphs and challenges. Presented at: HCC-TAG Conference 2020; February 27-29, 2020; Park City, Utah.
  2. Cheng A-L, Qin S, Ikeda M, et al. IMbrave150: efficacy and safety results from a ph III study evaluating atezolizumab (atezo) + bevacizumab (bev) vs sorafenib (Sor) as first treatment (tx) for patients (pts) with unresectable hepatocellular carcinoma (HCC).Ann Oncol. 2019;30(suppl 9):ix186-ix187. doi: 10.1093/annonc/mdz446.002.
  3. Galle P, Finn RS, Qin S, et al. Patient-reported outcomes (PROs) from the phase III IMbrave150 trial of atezolizumab (atezo) + bevacizumab (bev) vs sorafenib (sor) as first-line treatment (tx) for patients (pts) with unresectable hepatocellular carcinoma (HCC).J Clin Oncol. 2020;38(suppl 4; abstr 476). doi: 10.1200/JCO.2020.38.4_suppl.476.
  4. Yau T, Kang Y-K, Kim T-Y, et al. Nivolumab (NIVO) + ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): results from CheckMate 040.J Clin Oncol. 2019;37(suppl 15;abstr 4012). doi: 10.1200/JCO.2019.37.15_suppl.4012.
  5. Abou-Alfa GK, Meyer T, Cheng AL, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma.N Engl J Med. 2018;379(1):54-63. doi: 10.1056/NEJMoa1717002.
  6. Yau T, Zagonel V, Santoro A, et al. Nivolumab (NIVO) + ipilimumab (IPI) + cabozantinib (CABO) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): results from CheckMate 040.J Clin Oncol. 2020;38(suppl 4; abstr 478). doi: 10.1200/JCO.2019.38.4_suppl.478.