Nivolumab plus ipilimumab vs lenvatinib or sorafenib as first-line treatment for unresectable hepatocellular carcinoma (HCC): 4-year follow-up of CheckMate 9DW.

LBA479 Background: At a preplanned interim analysis of CheckMate 9DW (NCT04039607), with 35.2 months of median follow-up, nivolumab plus ipilimumab (NIVO + IPI) demonstrated significant overall survival (OS) benefit vs lenvatinib or sorafenib (LEN/SOR) (hazard ratio HR 0.79 95% CI, 0.65–0.96; P = 0.0180), higher objective response rate (ORR; 36% vs 13%, P < 0.0001) with durable responses, and manageable safety in patients (pts) with previously untreated unresectable HCC (Yau T et al. Lancet 2025;405:1851–64). Based on these results, NIVO + IPI combination was approved as a first-line (1L) treatment for unresectable HCC by the US FDA, European Commission, and in other countries. We report updated efficacy and safety results at a median follow-up of 4 years. Methods: Adults with previously untreated histologically confirmed advanced HCC, either ineligible for or having progressed after curative surgical/locoregional therapies, ≤ 1 measurable untreated lesion per RECIST v1.1, Child–Pugh score 5 or 6, and ECOG performance status 0 or 1 were included. Pts were randomized 1:1 to receive NIVO 1 mg/kg + IPI 3 mg/kg Q3W (up to 4 cycles) followed by NIVO 480 mg Q4W or investigator’s choice of SOR 400 mg BID or LEN 8 mg or 12 mg QD until disease progression or unacceptable toxicity. NIVO was given for a maximum of 2 years. The primary endpoint was OS; secondary endpoints included ORR and duration of response (DOR) per blinded independent central review (BICR). Results: A total of 668 pts were randomized to NIVO + IPI (n = 335) or LEN/SOR (n = 333); among 325 pts treated in the LEN/SOR arm, 275 (85%) received LEN. After a median (range) follow-up of 52.5 (44.0–66.1) months, NIVO + IPI continued to show OS benefit vs LEN/SOR (HR, 0.78; 95% CI, 0.65–0.93), with higher 48-month OS rates (31% vs 18%; Table). ORR was higher with NIVO + IPI vs LEN/SOR (36% vs 13%), with higher complete response rates (8% vs 2%, respectively) and durable responses (median DOR, 34.3 vs 12.9 months, respectively; Table). A summary of treatment-related adverse events (TRAEs) is shown in the Table. Conclusions: After 4 years of follow-up, 1L NIVO + IPI continued to show sustained efficacy benefit vs LEN/SOR in unresectable HCC and manageable safety with no new concerns. These results continue to support NIVO + IPI as a standard-of-care treatment in these patients. Clinical trial information: NCT04039607 . Efficacy NIVO + IPI(n = 335) LEN/SOR(n = 333) Median OS (95% CI), mo 23.7 (18.8–29.4) 20.6 (17.7–22.5) HR (95% CI) 0.78 (0.65–0.93) 48-mo OS rate (95% CI), % 31 (26–36) 18 (14–23) ORR, a n (%); (95% CI) 122 (36); 31–42 44 (13); 10–17 Median DOR a,b (95% CI), mo 34.3 (22.6–47.7) 12.9 (10.2–33.9) Safety, n (%) (n = 332) (n = 325) Any-grade/grade 3–4 TRAEs 277 (83)/136 (41) 297 (91)/138 (142) Any-grade/grade 3–4 TRAEs leading to discontinuation 59 (18)/44 (13) 34 (10)/21 (6) a Per BICR. b In responders only.