Abou-Alfa Hails "Positive and Disruptive" Impact of Novel Combinations in HCC

Findings from the phase III IMbrave 150 trial represented the first time a treatment outperformed sorafenib for overall survival and progression-free survival in patients with unresectable hepatocellular carcinoma (HCC), and the HCC world was understandably excited, said Ghassan K. Abou-Alfa, MD.

Ghassan K. Abou-Alfa, MD

The phase III IMbrave 150 trial showed the combination of atezolizumab (Tecentriq) plus bevacizumab (Avastin) improved overall survival (OS) versus sorafenib (Nexavar) in patients with unresectable hepatocellular carcinoma (HCC). These findings represented the first time a treatment outperformed sorafenib for OS and progression-free survival (PFS) in this setting, and the HCC world was understandably excited, said Ghassan K. Abou-Alfa, MD.1

Abou-Alfa, a medical oncologist at Memorial Sloan Kettering Cancer Center, said the combination will likely overtake sorafenib as the standard of care in the first-line setting at some point. However, he cautioned his audience at the 2020 HCC-TAG Conference about making too much of the data pending further validation.

“This is positive data, but I'm always cautious...waiting to see the full data,” he said. “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 took his audience on a recap of the triumphs and challenges of 2019 in HCC—with IMbrave 150 being the most significant development—and set the stage for the year ahead.

In IMbrave 150, 501 patients with unresectable HCC were randomly assigned to 1200 mg of IV atezolizumab plus 15mg/kg of IV bevacizumab every 3 weeks or 400 mg of sorafenib twice daily. Patients stayed on 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% decrease in the risk of disease progression or death (HR, 0.59; 95% CI, 0.47-0.76; P <.0001) in the atezolizumab/bevacizumab arm versus the sorafenib arm.2 The median PFS was 6.8 months in the experimental arm and 4.3 months in the control arm. The median OS was not reached 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

While sorafenib and lenvatinib (Lenvima) remain the only approved agents for HCC in the upfront setting, Abou-Alfa said combinations—anti-VEGF agents plus checkpoint inhibitors, TKIs 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 doublet of nivolumab (Opdivo) plus cabozantinib (Cabometyx), and the triplet regimen combining nivolumab with ipilimumab (Yervoy) and cabozantinib.

Previous data from another cohort from the 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.4 Moreover, 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 presented at the 2020 Gastrointestinal Cancers Symposium, 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 to not reached) with the doublet and not reached with the triplet (95% CI, 15.1 to not reached). 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. Twenty-five (71%) patients in the triplet arm experienced grade 3/4 treatment-related adverse events 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 adverse events (11% vs 6%).

“The one thing that caught our attention quite a bit was the adverse events—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.

References

  1. Abou-Alfa GK. The Year in Review — Triumphs and Challenges. Presented at: 2020 HCC-TAG Conference. February 27-March 1, 2020; Park City, Utah.
  2. Cheng A-L, Qin S, Ikeda M, et al. IMbrave150: Efficacy and Safety Results From a Ph 3 Study Evaluating Atezolizumab (atezo) + Bevacizumab (bev) vs Sorafenib (Sor) as First Treatment (tx) for Patients (pts) With Unresectable Hepatocellular Carcinoma (HCC). Presented at ESMO Asia 2019 Congress; November 22-24, 2019; Singapore. Abstract LBA3.
  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). Presented at GI Cancers Symposium; January 23-25, 2020; San Francisco, CA. Abstract 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): Abstract 412.
  5. Abou-Alfa GK, Meyer T, Cheng AL, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379:54-63.
  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. Presented at the 2020 Gastroinstinal Cancers Symposium; January 23-25, 2020; San Francisco, CA. Abstract 478.

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