Single tremelimumab regular interval durvalumab (STRIDE) plus lenvatinib plus transarterial chemoembolization (TACE)—a standard treatment for embolization-eligible hepatocellular carcinoma (HCC) that induces tumour immune responses—has demonstrated statistically significant progression free survival improvement versus TACE alone.
Published in The Lancet Oncology, these were the findings of the global, randomised, open label, phase 3 EMERALD-3 trial in which the efficacy and safety of STRIDE, with or without lenvatinib, plus TACE for HCC was assessed.
Led by Masatoshi Kudo (Kindai University, Osaka, Japan), EMERALD-3 was conducted across 177 sites in 21 countries. Eligible participants were aged 18 years or older (21 years or older in Egypt or Singapore) at screening and had confirmed HCC unsuitable for curative surgery, ablation or transplantation, but suitable for TACE. Included patients had Child-Pugh class A liver function, an Eastern Cooperative Oncology Group performance status of 0–1, and at least one measurable target intrahepatic lesion per modified Response Evaluation Criteria in Solid Tumors (mRECIST).
Patients were randomly allocated in a 1:1:1 ratio to receive STRIDE plus lenvatinib plus TACE, STRIDE plus TACE, or TACE until each group reached its preplanned enrolment target of 175 participants. Once the STRIDE plus TACE group reached its enrolment target, randomisation was adjusted to continue as 1:1 between the STRIDE plus lenvatinib plus TACE group and TACE group until approximately 275 participants were enrolled in each, Kudo and colleagues detail.
From 28 March 2022 to 20 November 2024, 1,124 participants were screened. The analysis included 760 patients who were randomly allocated to STRIDE plus lenvatinib plus TACE (n=293), STRIDE plus TACE (n=175), or TACE (n=292). Kudo and colleagues report that 633 (83%) of participants were male and 548 (72%) were Asian.
Kudo et al describe that, in the STRIDE plus lenvatinib plus TACE group, patients initially received 300mg tremelimumab and 1500mg durvalumab intravenously, followed by 1500mg durvalumab every four weeks. The authors write that the technique and number of TACE procedures were at the investigators’ discretion, with the first procedure administered at least seven days after the first dose of durvalumab in the two investigation treatment groups, and within seven days of random allocation in the TACE group.
At the first data cutoff point (2 September, 2025), the overall median follow-up for progression-free survival was 10 months. Median follow-up for progression-free survival was 11 months for STRIDE plus lenvatinib plus TACE and 8.3 months for TACE. Median progression-free survival was 13 months (95% CI [confidence interval] 12.2–16.7) for STRIDE plus lenvatinib plus TACE versus 9.8 months (8–11.4) for TACE (HR [hazard ratio] 0.70 [95% CI 0.57–0.86]; p=0.0007).
At the second data cutoff (23 February, 2026), median overall survival was reported as 24.6 months for STRIDE plus lenvatinib plus TACE, and 22.9 months for TACE. Additionally, median overall survival was 39.5 months (95% 34.1–not reached) for STRIDE plus lenvatinib plus TACE and 34.7 months (28.8–not reached) for TACE (HR 0.84 [95% CI 0.65–1.09]; p=0.18).
Kude et al describe that, at the second data cutoff, median progression-free survival was 12.9 months (95% CI 10.2–15.9) for STRIDE plus TACE and 8.1 months (6.5–10.2) for the first 175 participants randomised to TACE (HR 0.71 [95% CI 0.56–0.91]), with median follow-up of 10.3 months (4.6−23.7) for STRIDE plus TACE and 7.7 months (3−18.5) for TACE.
Kudo and colleagues state that a maximum of grade 3 or 4 adverse events were recorded across enrolled participants. Among the most common was hypertension (34 [12%] of 287) for STRIDE plus lenvatinib plus TACE; post-embolization syndrome and anaemia (10 [6%] of 175) for STRIDE plus TACE; and post-embolization syndrome (17 [6%] of 290) for TACE. The authors go on to state that 184 (64%) participants receiving STRIDE plus lenvatinib plus TACE, 89 (51%) receiving STRIDE plus lenvatinib plus TACE, and 68 (23%) receiving TACE had serious adverse events.
Treatment-related adverse events with an outcome of death during the treatment-emergent period occurred in seven (2%) of patients receiving STRIDE plus lenvatinib plus TACE—causes included myocarditis (2), hepatic failure (1), haemophagocytic lymphohistiocytosis (1), septic shock (1), cardiac failure (1), and unknown cause (1); none of the 175 participants who received STRIDE plus TACE, and two (1%) of 290 participants who received TACE (one each for acute myocardial infarction and unknown cause).
“STRIDE plus lenvatinib plus TACE showed a statistically significant progression-free survival improvement versus TACE”, write the authors. “These findings support a STRIDE-based regimen as a potential new treatment option for people with embolization-eligible HCC.” Kudo et al state that additional follow-up is being conducted for final analysis of overall survival across treatment groups which will be published in the coming months.
Speaking to Interventional News following the release of these data, investigator Ghassan Abou-Alfa (Memorial Sloan Kettering Cancer Center, New York, USA) shares: “The EMERALD-3 is a monumental study that is the first to prove the value of combining systemic immunotherapy with local chemoembolization for the treatment of locally advanced HCC. The essential element or secret key that led to the positive outcome of the study is the addition of the anti-CTLA4 tremelimumab.”
Abou-Alfa also credits the “gigantic collaborative effort” led by Memorial Sloan Kettering Cancer Center, Kindai University, and Fudan University in Shanghai, China.
