For regulatory and clinical affairs professionals working in oncology, accurate knowledge of approved lines of therapy is essential for label interpretation, clinical trial eligibility design, and reimbursement strategy. In hepatocellular carcinoma (HCC), the second-line treatment landscape has expanded considerably over the past decade, with multiple agents receiving FDA approval following progression on sorafenib—making precise delineation of on-label indications a practical regulatory priority.
The analysis below examines each FDA-approved agent with an explicit second-line or post-sorafenib HCC indication, drawing on current prescribing information and Drugs@FDA application records. It addresses the approved indication wording, any biomarker eligibility requirements, monotherapy versus combination status, and the approval chronology, while also contextualizing agents whose HCC approvals are limited to first-line use.
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FDA-approved second-line therapies for hepatocellular carcinoma (HCC)
Direct answer
Four agents carry an FDA indication explicitly for HCC patients previously treated with sorafenib, and a fifth (nivolumab) now covers the previously-treated setting only as part of a combination regimen:
| Drug (brand) | Class / mechanism | Second-line indication wording | Biomarker | Regimen | Application |
|---|---|---|---|---|---|
| Regorafenib (Stivarga) | Multikinase (VEGFR/TIE2) inhibitor | HCC "previously treated with sorafenib" 30 | None 30 | Monotherapy (studied with best supportive care) 21 | NDA 203085 231 |
| Cabozantinib (Cabometyx) | Multikinase (MET/VEGFR/AXL) inhibitor | HCC "previously treated with sorafenib" 91 | None 91 | Monotherapy, 60 mg once daily 91103 | NDA 208692 197 |
| Ramucirumab (Cyramza) | Anti-VEGFR2 monoclonal antibody | HCC with elevated AFP "treated with sorafenib" 4950 | AFP >=400 ng/mL (OCR "2400 ng/mL") 4950 | Single agent 49 | BLA 125477 180 |
| Pembrolizumab (Keytruda) | Anti-PD-1 monoclonal antibody | HCC "previously treated with sorafenib" 58 | None 58 | Monotherapy 58 | Accelerated approval; KEYNOTE-394 252 |
| Nivolumab (Opdivo) + ipilimumab | Anti-PD-1 + anti-CTLA-4 | HCC "previously treated with sorafenib" 1204 | None | Combination (nivolumab + ipilimumab) 204206 | BLA — see note below |
Detail by agent
Regorafenib (Stivarga)
The label indicates Stivarga for HCC patients "who have been previously treated with sorafenib," an explicitly second-line/previously-treated indication with no biomarker requirement 30. The pivotal HCC study (RESORCE) administered regorafenib 160 mg once daily plus best supportive care versus placebo plus BSC, so it is used as a single oral agent rather than a biomarker-selected combination 21. The HCC efficacy supplement under NDA 203085 was approved on 2017-04-27, and the product remains marketed (prescription) 232231.
Cabozantinib (Cabometyx)
Cabometyx is indicated "for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib," again a previously-treated/second-line setting with no biomarker requirement 91. It is used as monotherapy at 60 mg once daily 91103. The HCC efficacy supplement under NDA 208692 was approved on 2019-01-14 (CELESTIAL) and the product remains marketed 197.
Ramucirumab (Cyramza)
Cyramza is the only biomarker-selected second-line HCC agent. The label indicates it "as a single agent" for HCC patients "who have an alpha fetoprotein (AFP) of [>=400] ng/mL and have been treated with sorafenib" 4950. This is the second-line setting restricted to AFP-high patients, based on the REACH-2 trial. The HCC efficacy supplement under BLA 125477 was approved on 2019-05-10 and the product remains marketed 180.
Pembrolizumab (Keytruda)
Keytruda is indicated for HCC patients "who have been previously treated with sorafenib," as monotherapy with no stated biomarker requirement 58. This indication originated as an accelerated approval and its confirmatory evidence is described in the label via the KEYNOTE-394 study 252. (The specific accelerated-approval/continued-approval contingency sentence was not captured verbatim in the label pages retrieved, so that language should be confirmed against the current full label 252.)
Nivolumab (Opdivo) plus ipilimumab
The nivolumab program illustrates how the second-line HCC landscape has shifted. Nivolumab originally held a monotherapy accelerated approval for HCC after sorafenib; the current label no longer presents nivolumab monotherapy as an active HCC indication and instead frames that as historical study evidence 211217. Current labeled use is nivolumab in combination with ipilimumab, both for first-line unresectable/metastatic HCC (CHECKMATE-9DW) 210212 and for previously treated patients who progressed on or were intolerant to sorafenib 1204206. So in the previously-treated (second-line) setting, nivolumab is now available only as the nivolumab + ipilimumab combination, not as single-agent nivolumab 211217.
First-line agents (excluded, for context)
The following systemic HCC agents are labeled for the first-line setting (no prior systemic therapy) and therefore are not second-line therapies:
- Sorafenib (Nexavar): indicated for unresectable HCC; the label does not require prior systemic therapy and it is the historical first-line comparator 119120.
- Lenvatinib (Lenvima): "first-line treatment of adult patients with unresectable HCC"; the pivotal study enrolled patients with no prior systemic therapy 161142.
- Atezolizumab (Tecentriq) + bevacizumab: for patients "who have not received prior systemic therapy" (IMbrave150), a first-line combination 125141.
- Durvalumab (Imfinzi) + tremelimumab: for patients who "had not received prior systemic treatment for HCC" (HIMALAYA), a first-line combination 76.
Practical notes for RA reviewers
- The classic second-line oral TKIs (regorafenib, cabozantinib) and the AFP-selected antibody (ramucirumab) were all approved as post-sorafenib options in 2017 to 2019 and remain on the market 232197180.
- Ramucirumab is the only second-line agent with an on-label biomarker gate (AFP), which matters for eligibility and companion-diagnostic considerations 4950.
- The checkpoint-inhibitor second-line indications were built on post-sorafenib populations, but the field is moving toward first-line immunotherapy combinations (atezolizumab+bevacizumab, durvalumab+tremelimumab, nivolumab+ipilimumab), which reshapes what "second-line" means once a patient has already received an IO-based first-line regimen 21012576.
- "Previously treated with sorafenib" is the exact label anchor for the second-line indications; none of these labels define second-line after first-line immunotherapy, so post-IO sequencing is off-label and a reasonable follow-up question to research further.