How “second-line” was determined (FDA-label based)

For this summary, FDA-approved second-line therapy for HCC means the labeled indication explicitly requires prior systemic therapy (most commonly prior sorafenib)—e.g., “previously treated with sorafenib” or similar prior-therapy language. Agents whose HCC indication specifies no prior systemic therapy were treated as first-line and are not included as second-line here (e.g., atezolizumab + bevacizumab; durvalumab + tremelimumab; lenvatinib) ^{32954140811537529}.

FDA-approved second-line (previously treated) systemic therapies for HCC (from the provided FDA-label extracts)

Stivarga (regorafenib) — post-sorafenib

Labeled indication (HCC): “Stivarga is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.” ^158797795799
Second-line status: Yes (explicitly post-sorafenib) ^{1588382757884}.
Key practical constraints reflected in label/trial context: pivotal RESORCE population was largely Child‑Pugh A (98%) and required prior sorafenib tolerance in the trial design ^8038221618.
Regulatory note: described as a regular/traditional approval based on OS benefit in RESORCE (no accelerated-approval conditionality described in these excerpts) ^9171213.

Cabometyx (cabozantinib) — post-sorafenib

Labeled indication (HCC): “CABOMETYX is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.” ^18891374
Second-line status: Yes (explicitly post-sorafenib) ^896914901.
Key practical constraints reflected in label/trial context: CELESTIAL enrolled patients previously treated with sorafenib and Child‑Pugh Class A liver impairment ^1896893895.
Regulatory note: the 2019 supplement approval letter is framed as a Prior Approval supplement “approved, effective on the date of this letter,” without accelerated-approval language in the cited excerpt ⁹¹⁴.

Cyramza (ramucirumab) — biomarker-selected post-sorafenib (AFP threshold)

Labeled indication (HCC): “CYRAMZA, as a single agent, is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have an alpha fetoprotein (AFP) of 2400 ng/mL and have been treated with sorafenib.” ^1465470
Second-line status: Yes (requires prior sorafenib) ^14654761218.
Key constraints: AFP requirement is part of the indication; additionally, the 2019 supplement approval letter describes the new indication as AFP >400 ng/mL with prior sorafenib ¹⁴⁷⁵. Trial population described as Child‑Pugh A and advanced disease (BCLC B not amenable to locoregional therapy, or BCLC C) ^1476521.
Regulatory note: 2019 supplement approval letter indicates approval effective on the letter date and does not describe accelerated approval in that letter excerpt ⁴⁷⁵.

Keytruda (pembrolizumab IV) — post-sorafenib (Accelerated Approval in provided documents)

Labeled indication (HCC): “KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.” ^1500504
Second-line status: Yes (explicitly post-sorafenib) ^1485141166.
Regulatory note: the HCC indication is described as approved under accelerated approval based on response rate/durability, with continued approval contingent on confirmatory trials ^{5005055071875511}. The provided extracts do not state conversion to regular approval or withdrawal for this HCC indication ^{1531116515311165}.
Clinical context in label: KEYNOTE‑224 enrolled patients with progression on/after sorafenib or sorafenib intolerance and required Child‑Pugh A in the study description ^{1851415391166}.

Opdivo (nivolumab) + Yervoy (ipilimumab) — post-sorafenib (Accelerated Approval in provided documents)

Labeled indication (combination): “OPDIVO, in combination with ipilimumab, is indicated for the treatment of adult patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.” ²⁴⁸
Second-line status: Yes (explicitly post-sorafenib) ^12431113.
Regulatory note: described as Accelerated Approval, with a postmarketing requirement to verify clinical benefit (overall survival) ^{1803182124618151808}. The provided extracts do not state conversion to regular approval or withdrawal for this HCC indication ^18211815246.
Clinical context in label: CHECKMATE‑040 enrolled patients who progressed on or were intolerant to sorafenib; label describes Child‑Pugh Class A in eligibility (with limited early-cohort exceptions) ^{12471115111814941497}.

Yervoy (ipilimumab) + Opdivo (nivolumab) — post-sorafenib (conversion documented)

Labeled indication (Yervoy label): “YERVOY, in combination with nivolumab, is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.” ¹⁴⁹
Second-line status: Yes (explicitly post-sorafenib) ^187913451339.
Regulatory note: Accelerated approval granted in 2020 with confirmatory PMR ^{1488020362025}, and conversion to regular approval is documented in 2025 after PMR fulfillment ^{867203920242047}.
Clinical context in label: trial population described as progressed on/intolerant to sorafenib and Child‑Pugh Class A eligibility ^{18708741243032}.

Opdivo Qvantig (nivolumab + hyaluronidase‑nvhy, SC formulation) — previously treated setting after sorafenib and after IV nivolumab+ipilimumab

Labeled indication (previously treated HCC): “OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult patients with unresectable or metastatic hepatocellular carcinoma (HCC) who have been previously treated with sorafenib following treatment with intravenous nivolumab and ipilimumab combination therapy.” ⁶²¹⁸⁶
Second-line status: Yes (requires prior sorafenib; also requires prior IV nivolumab+ipilimumab) ^{11083194200197}.
Regulatory note: initially Accelerated Approval for HCC in 2024 labeling ^1851760, with conversion to regular approval documented in a 2025 supplement approval letter (fulfillment of PMR and conversion) ^1921759.
Important limitation of use: “OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of patients with unresectable or metastatic HCC.” ¹⁸⁵²⁰⁶.

Keytruda Qlex (pembrolizumab + berahyaluronidase alfa, SC formulation) — etiology- and prior-therapy-restricted HCC

Labeled indication (HCC): “for the treatment of adult patients with hepatocellular carcinoma (HCC) secondary to hepatitis B who have received prior systemic therapy other than a PD‑1/PD‑L1‑containing regimen.” ¹²³
Second-line status: Yes (requires prior systemic therapy; excludes prior PD‑1/PD‑L1 regimen) ¹²³.
Key constraints: restricted to HCC secondary to hepatitis B and requires prior systemic therapy other than PD‑1/PD‑L1-containing regimens ¹²³. Trial context required Child‑Pugh A and included prior sorafenib or oxaliplatin-based chemotherapy ²¹²⁰²⁵.
Regulatory note: approved 2025-09-19 ¹²⁶, and FDA review materials characterize HCC under the traditional (regular) approval umbrella for these pembrolizumab SC “solid tumor indications,” with accelerated approval reserved for TMB‑H (not HCC) ³²²⁴.

Not second-line (excluded because FDA label specifies no prior systemic therapy)

Several HCC regimens in the provided extracts are FDA-approved for HCC but not second-line because their labeled population is treatment-naïve for systemic therapy, such as:

• Tecentriq (atezolizumab) + Avastin (bevacizumab): “…who have not received prior systemic therapy” ³²³⁸⁵⁴.
• Imfinzi (durvalumab) + Imjudo (tremelimumab): supported in patients who “had not received prior systemic treatment for HCC” ¹¹⁵³⁷.
• Lenvima (lenvatinib): “For the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC).” ⁵²⁹⁵²⁶.

Practical implication

Across the provided FDA-label extracts, most second-line HCC approvals are defined by prior exposure to sorafenib (regorafenib, cabozantinib, ramucirumab, pembrolizumab IV, nivolumab+ipilimumab) ^{158188914651500248}. A smaller subset uses more specific sequencing/eligibility (e.g., SC nivolumab formulation requiring prior IV nivolumab+ipilimumab plus prior sorafenib ⁶²¹⁸⁶, and SC pembrolizumab restricted to HBV-related HCC and excluding prior PD‑1/PD‑L1 therapy ¹²³), which can materially affect who qualifies under the FDA label.

If you want, I can also provide a “current-as-of 2026-01-21” reconciliation note for any indications in this list that have had accelerated-approval withdrawals/label removals (the provided extracts show conversions for ipilimumab+nivolumab and nivolumab SC, but do not show withdrawal status for pembrolizumab IV or nivolumab+ipilimumab) ^{8672039202419217591531116518211815}.