Transcript Related Guidelines

Single-Agent Immune-Oncology Options in HCC

Aiwu Ruth He, MD, PhD · Georgetown University


September 21, 2021

Editorial Collaboration

Medscape &

Key Takeaways:

  • Following the phase 1/2 CheckMate 040 trial, nivolumab received US Food and Drug Administration (FDA) approval as a second-line therapy after sorafenib.

  • In the phase 3 CheckMate 459 study of nivolumab, a durable response was achieved in a patient subgroup, but the study’s primary endpoint of overall survival (OS) was not met.

  • In 2018, after the phase 1/2 KEYNOTE-224, pembrolizumab received FDA’s accelerated approval based on durable responses in second-line therapy; however, in the phase 3 KEYNOTE-240 study, the primary endpoint of OS was not met.

  • Oncology Drugs Advisory Committee (ODAC) voted to support pembrolizumab’s indication awaiting phase 3 study data and to remove nivolumab’s indication for hepatocellular carcinoma after sorafenib; the indication was withdrawn in July 2021.

  • Single-agent immunotherapies may provide benefit and should continue to be evaluated.

This transcript has been edited for clarity.

In 2017, nivolumab received accelerated approval by the FDA (US Food and Drug Administration) for durable response rate in patients who received sorafenib treatment. The approval was based on a phase 1/2 study CheckMate 040.[1] An additional cohort in the study evaluated nivolumab treatment in patients with Child-Pugh B liver function and showed nivolumab was safe in a Child-Pugh B patients and induced durable response in the subgroup of patients.

However, when nivolumab was evaluated in a randomized phase 3 study CheckMate 459, durable response was again seen in a subgroup of patients.[2] However, the study did not meet the overall survival primary study endpoint.

In 2018, pembrolizumab received an accelerated approval by the FDA for durable response rate in patients who received prior sorafenib treatment. The approval was based on a phase 1/2 study KEYNOTE-224.[3] However, when pembrolizumab was evaluated in a randomized phase 3 study KEYNOTE-240, the study did not meet the overall survival study primary endpoint.[4]

In the spring meeting, ODAC, which stands for Oncological Drug Advisory Committee for FDA, recommended to continue to support the indication of pembrolizumab, pending the readout of additional phase 3 studies. As far as indication for nivolumab is concerned, there was a heated discussion whether to continue to support this indication.

In a four to five vote, ODAC recommended rescinding the indication for nivolumab for the treatment of patients with HCC (hepatocellular carcinoma) and prior sorafenib treatment. The indication was voluntarily withdrawn in July 2021. The ODAC committee felt this was a very difficult decision.

In summary, pembrolizumab is supported as a single-agent immunotherapy in HCC. Additional single-agent immunotherapies are still being evaluated in this disease. Clearly, there is an unmet need in patients with Child-Pugh B liver function, for whom treatment options are very limited.

Anti-PD-1 (programmed cell death protein 1) monotherapy could provide benefit. Additional studies are needed to investigate single-agent immunotherapies in this patient population.


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