Table 6.

Overall benefit‐risk assessment

Dimension	Evidence and uncertainties	Conclusions and reasons
Analysis of condition	The overall estimated 5‐year survival rate for patients with HCC is 18.4%; 5‐year survival rates are 33% in those diagnosed with localized disease, 11% in those with regional (nodal) involvement, and 2.4% for those with metastatic disease at diagnosis.	Advanced HCC is a serious disease with a poor prognosis.
Current treatment options	Five drugs (regorafenib, cabozantinib, ramucirumab [for those with AFP ≥400 ng/mL], nivolumab, and pembrolizumab) are approved for the treatment of unresectable or metastatic Child‐Pugh A HCC, following treatment with sorafenib in the first‐line setting. Of these, regorafenib, cabozantinib, and ramucirumab are the only ones with regular approval and demonstrate a modest survival advantage of 1.2 to 2.8 months over placebo and have low ORRs at 4%–7%. Nivolumab and pembrolizumab were approved under the accelerated approval pathway, and these agents had an ORR of 14%–17% with a durable response lasting ≥12 months in 55%–56% of responders.	The efficacy of the treatment options for patients who progressed on first‐line treatment for advanced HCC is limited, and more second‐line treatment options are needed for patients with advanced HCC.
Benefit	The N1I3 Q3 dosage regimen demonstrated an ORR of 33% (95% CI: 20–48) with 56% of responses durable for ≥12 months and 31% of responses durable for ≥24 months. Supportive data was provided by the N3I1 Q3 and N3I1 Q6 dosage regimens, which demonstrated similar ORRs and durability of responses.	The magnitude and durability of the ORR observed in patients with advanced HCC who received second‐line treatment of nivolumab in combination with ipilimumab far exceeded the ORR of available therapy (cabozantinib and regorafenib), was clinically meaningful, and represented a significant increase over the response rates that supported the accelerated approval of nivolumab and pembrolizumab as single agents.
Risk and risk management	The observed safety profile was generally consistent with the known safety profile of combination nivolumab and ipilimumab. The most common adverse reactions (occurring in at least 20% of patients) were rash, pruritus, musculoskeletal pain, diarrhea, cough, decreased appetite, fatigue, pyrexia, headache, abdominal pain, nausea, dizziness, hypothyroidism, and decreased weight. The most common severe adverse reactions (occurring in at least 3% of patients) were rash, abdominal pain, ascites, pruritis, and anemia.	The toxicity profile of nivolumab in combination with ipilimumab was acceptable when assessed in the context of the life‐threatening nature of unresectable HCC that progressed following first‐line treatment with sorafenib. No new significant safety concerned were identified. Significant and serious adverse reactions were primarily immune‐mediated and were adequately addressed by product labeling for nivolumab.

Abbreviations: AFP, alpha‐feto protein; CI, confidence interval; HCC, hepatocellular carcinoma; N1I3 Q3, nivolumab 1 mg/kg i.v. plus ipilimumab 3 mg/kg i.v. every 3 weeks for four cycles, followed by nivolumab 240 mg i.v. every 2 weeks; ORR, overall response rate; N3I1 Q3, nivolumab 3 mg/kg i.v. plus ipilimumab 1 mg/kg i.v. every 3 weeks for four cycles, followed by nivolumab 240 mg i.v. every 2 weeks; N3I1 Q6, nivolumab 3 mg/kg i.v. every 2 weeks plus ipilimumab 1 mg/kg i.v. every 6 weeks.