Immunotherapy Combinations Show Promise in Advanced HCC

Following a series of negative phase III single-agent trials in hepatocellular carcinoma, investigators are finding better results with immunotherapy combination regimens.

Anthony El-Khoueiry, MD

Following a series of negative phase III single-agent trials in hepatocellular carcinoma (HCC), investigators are finding better results with immunotherapy combination regimens, Anthony El-Khoueiry, MD, said during the 2020 HCC-TAG conference.

El-Khoueiry, associate professor of medicine at USC Norris Comprehensive Cancer Center, said there are several reasons why those monotherapy trials might have failed, including that single agent therapy might not be sufficient.

“So how do we move forward? There are many ways. One is to use smart combinations to address the various mechanisms of immune resistance, whether primary or secondary.”

El-Khoueiry said there is a strong rationale for anti-VEGF agents and tyrosine kinase inhibitors (TKIs). There is “ample preclinical evidence” showing that targeting the VEGF axis leads to decreases in the activity of inhibitory cells, increased PD-L1 expression, and enhanced T cell tumor infiltration and activation.

In data from the multiarm, phase Ib GO30140 trial, the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) demonstrated strong efficacy as first-line therapy in 2 groups of patients with unresectable or metastatic HCC.1

In Arm A of the trial (n = 104), patients were assigned to cycles of 1200 mg of atezolizumab plus 15 mg of bevacizumab every 3 weeks. The median follow-up was 12.4 months.

The confirmed objective response rate (ORR) was 36% (95% CI, 26-46) according to central review per RECIST v1.1 including a complete response (CR) rate of 12%. ORR was 39% per mRECIST with a CR rate of 15%. The median duration of response was not reached. Sixty-eight percent to 76% of patients had ongoing response.

In Arm F, 60 patients were assigned to the same atezolizumab/bevacizumab regimen while 59 were assigned to 1200 mg of atezolizumab monotherapy. Median follow-up was 6.6 months.

The combination reduced the risk of disease progression or death by 45% compared with atezolizumab monotherapy (HR, 0.55; 80% CI, 0.40-0.74; P=.0108). The median PFS was 5.6 months (95% CI, 3.6-7.4) in the combination arm compared with 3.4 months (95% CI, 1.9-5.2) in the monotherapy arm.

The efficacy of the atezolizumab/bevacizumab combination was further validated in results from the phase III IMbrave150 trial.2 In the trial, 501 patients with unresectable HCC were randomly assigned in the frontline setting to 1200 mg of IV atezolizumab plus 15mg/kg IV bevacizumab every three 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% decreased risk of death (HR, 0.58; 95% CI, 0.42-0.79; P = .0006) and a 41% decreased 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. 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 more than double than in the combination arm (27% vs 12%; P <.0001) based on independent assessment using RECIST 1.1 criteria. The ORR was nearly 3 times for the combination using HCC mRECIST criteria (33% vs 13%, P <.0001).

El-Khoueiry noted that investigators were concerned about toxicity with the combination because, in other tumor types, bevacizumab is known to increase the risk for bleeding and arterial events. These safety results showed that the combination did not appear to increase risk for treatment-related adverse events (TRAEs). “The safety profile looked quite manageable and comparable across both arms,” El-Khoueiry said.

In the combination arm, 36% of patients experienced grade 3/4 TRAEs compared with 46% in the sorafenib group. Overall, 57% and 55% of patients, respectively, experienced grade 3/4 AEs of any cause.

In July 2019, the FDA granted a breakthrough therapy designation to the combination of pembrolizumab (Keytruda) and lenvatinib (Lenvima) in the first-line settings for patients with advanced unresectable HCC that is not amenable to locoregional therapy, based on findings from the phase Ib KEYNOTE-524/Study 116 trial.3 In the multicenter, open-label, single-arm, phase Ib trial, patients were assigned to 200 mg of pembrolizumab every 3 weeks and lenvatinib at 12 mg daily for patients weighing ≥60 kg, and 8 mg/day for patients weighing <60 kg.

Eligible patients had Barcelona Clinic Liver Cancer stage B that was ineligible for transarterial chemoembolization or C, Child-Pugh class A, and an ECOG performance status of 0 or 1.

At a median follow-up of 9.7 months (95% CI, 7.6-12.2), the ORR was 36.7% by mRECIST per investigator, 50.0% by mRECIST per independent imaging review (IIR), and 36.7% per RECIST 1.1 per IIR. The stable disease rate was 60.0%, 43.3%, and 53.3%, respectively.

Based on these positive data, the trial protocol was amended to enroll up to 100 total patients to part 2 of the trial. Moreover, the ongoing phase III LEAP-002 trial (NCT03713593) is evaluating the combination of lenvatinib and pembrolizumab versus lenvatinib alone as a first-line treatment for patients with advanced HCC.

Nonetheless, safety remains a concern with these combinations. “Again, we do pay a price with some of these combinations: 73% grade 3 or higher toxicities, 50% serious AEs, and there were 4 fatal AEs in [KEYNOTE-524],” El-Khoueiry said. “So we look forward to seeing more details in the management related to [AEs].”

Investigators also observed promising results with the triplet of cabozantinib (Cabometyx), nivolumab (Opdivo), and ipilimumab (Yervoy) compared with the doublet of nivolumab/cabozantinib in the phase I/II CheckMate-040 trial. Findings were first presented at the 2020 Gastrointestinal Cancers Symposium.

The median PFS by investigator assessment was 6.8 months (95% CI, 4.0-14.3) in the triplet arm (n = 35) versus 5.4 months (95% CI, 3.2-10.9) with the doublet (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%).4

However, the triplet was associated with a higher rate of TRAEs. Twenty-five (71%) patients in the triplet arm experienced grade 3/4 TRAEs 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%).

“Combinations with anti—PD-1 agents are likely to dominate, especially in the first line,” El-Khoueiry said. “However, we do have to weigh the risk/benefit ratio [and decide]: Is it for all patients?”


  1. Lee M, Ryoo B, Hsu C, et al. Randomised efficacy and safety results for atezolizumab (atezo) + bevacizumab (bev) in patients (pts) with previously untreated, unresectable hepatocellular carcinoma (hcc). Presented at: ESMO Congress 2019; September 27-October 1, 2019; Barcelona, Spain. Abstract LBA39.
  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. Ikeda M, Sung MW, Kudo M, et al. Abstract CT061: a phase Ib trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) in unresectable hepatocellular carcinoma (uHCC): updated results. Cancer Res. 2019;79(13). doi: 10.1158/1538-7445.SABCS18-CT061.
  4. 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 GI Cancers Symposium; January 23-25, 2020; San Francisco, CA. Abstract 478.

<<< View more from the 2020 HCC-TAG Conference