Clinical Edge Journal Scan

Commentary: Combination therapies and immunotherapy in HCC, December 2022

Dr. Damjanov scans the journals, so you don’t have to!

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Nevena Damjanov, MD

Immunotherapy remains the first-line treatment of choice for unresectable hepatocellular carcinoma (uHCC). This month we will review articles that evaluate the efficacy of immunotherapy in these patients.

Hatanaka and colleagues investigated whether the etiology of the underlying liver disease affected the efficacy of atezolizumab and bevacizumab (A/B). They reported the results of a retrospective cohort study of 323 patients with Barcelona Clinic Liver Cancer (BCLC) stage B or C hepatocellular carcinoma and Child-Pugh class A cirrhosis who started A/B between September 2020 and December 2021. Patients with viral infection were defined as those who were either serum anti–hepatitis C antibody (anti-HCV Ab)- or hepatitis B surface antigen (HBs-Ag)-positive, while patients with nonviral infection was defined as those who were both serum anti-HCV Ab- and HBs-Ag-negative. After propensity matching, no significant difference in response rate ([RR] 20.6% vs 24.6% in viral and nonviral patients), disease control rate (68.3% vs 69.0%), progression-free survival ([PFS] 7.0 months vs 6.2 months), or 12-month overall survival ([OS] 65.5% vs 71.7%) was seen. The authors concluded that the underlying etiology of liver disease in patients with HCC does not affect the response to treatment with A/B.

Scheiner and colleagues evaluated the efficacy of immunotherapy in patients with HCC who had already received immune checkpoint inhibitors (ICI) in a previous line of therapy. The authors reported the results of an international, retrospective multicenter study of 58 patients with HCC who received at least two lines of ICI-based therapies. The first ICI was discontinued due to disease progression in 90%. Nonetheless, the RR to the second ICI was 26% (compared with 22% for the first ICI), with a time-to-progression (TTP) of 5.4 months (95% CI, 3.0-7.7) for the first ICI and 5.2 months (95% CI, 3.3-7.0) for the second ICI. Grade 3/4 treatment-related adverse events were observed in 16% and 17% of patients with the first and second ICI, respectively. Therefore, the authors believe that ICI rechallenge is safe and results in a treatment benefit for a similar proportion of HCC patients, as is seen with the first ICI treatment. They suggest that ICI-based regimens should be studied in prospective trials of patients who progressed on first-line immunotherapy.

Finally, Kim and colleagues reported outcomes of patients who developed anti-drug antibodies (ADA) against atezolizumab while on A/B. In this prospective cohort study, 174 patients with advanced HCC who were treated with first-line A/B were tested for serum ADA levels prior to treatment and at 3 weeks (cycle 2 day 1 [C2D1]). Clinically, patients with progressive disease exhibited higher ADA levels (median 65.2 [0-520.4] ng/mL) at C2D1 than responders (0-117.5 ng/mL). Patients with high ADA levels at C2D1 had a reduced response rate (29%-34% vs 7-11%) and worse PFS and OS. The investigators found that very high ADA levels (≥ 1000 ng/mL) at 3 weeks were consistently associated with poor clinical outcomes due to reduced systemic exposure to atezolizumab and impaired proliferation and activation of peripheral CD8-positive T cells. They suggested future validation and standardization of ADA assays to optimize treatment with atezolizumab in patients with uHCC.

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