What Comes After Atezolizumab–Bevacizumab in HCC: JHEP Reports | September 2026

Introduction:

Immunotherapy-based combinations have transformed first-line treatment of unresectable HCC, but the optimal strategy after progression remains uncertain because no phase III trial has yet defined a standard second-line sequence after atezolizumab–bevacizumab. The French CHIEF/STRETCH cohort provides important real-world evidence on what happens after first-line immunotherapy.

Why was this study needed?

Most historical second-line HCC trials were conducted after sorafenib, not after atezolizumab–bevacizumab.

Progression in HCC is often accompanied by worsening liver function or performance status, limiting access to further therapy.

Clinicians need practical data on whether TKIs remain effective after prior immunotherapy.

The role of immunotherapy rechallenge remains particularly uncertain.

Results:

1,103 patients were included: 899 received atezolizumab–bevacizumab and 204 sorafenib as first-line treatment.

First-line median OS was 22.3 months with atezolizumab–bevacizumab vs 9.4 months with sorafenib.

After first-line discontinuation, only 42.1% of patients previously treated with atezolizumab–bevacizumab reached second-line therapy, compared with 60% after sorafenib.

Preserved liver function strongly influenced second-line access; patients receiving further therapy more often had ALBI grade 1, better albumin, lower bilirubin, less macrovascular invasion, and less advanced disease at progression.

After atezolizumab–bevacizumab, approximately 73% received a TKI.

Median OS from second-line TKI initiation after atezolizumab–bevacizumab was 13.0 months, with median PFS 3.4 months.

Outcomes did not significantly differ among sorafenib, lenvatinib, regorafenib, or cabozantinib, although lenvatinib showed a numerically longer PFS.

Second-line TKI outcomes were broadly similar whether patients had previously received atezolizumab–bevacizumab or sorafenib.

Selected patients receiving immunotherapy rechallenge had encouraging outcomes, but this group was highly selected and often had interval locoregional therapy.

Clinical Impact:

The most clinically useful finding is that TKI activity appears to be preserved after atezolizumab–bevacizumab.

A practical sequence therefore remains:

Atezolizumab–bevacizumab → preserve liver function → TKI at progression

The study also highlights that the biggest challenge may not be choosing among TKIs, but getting patients to second-line therapy at all. Maintaining Child–Pugh A/ALBI 1–2 status and avoiding unnecessary deterioration during first-line treatment may be crucial to preserving subsequent treatment options.

Immunotherapy rechallenge is intriguing, particularly in patients who previously responded and discontinued for reasons other than progression, but these observational data do not establish rechallenge as standard care.

Bottom Line:

After atezolizumab–bevacizumab failure in unresectable HCC, TKIs remain the most reliable second-line option, with real-world survival around 13 months from second-line initiation. No individual TKI clearly emerged as superior. The major determinant of successful sequencing is preservation of liver function and performance status, while immunotherapy rechallenge should remain highly selective pending prospective evidence.