PFS Improves With Durvalumab, Bevacizumab, and TACE in Embolization-Eligible, Unresectable HCC

PFS Improves With Durvalumab, Bevacizumab, and TACE in Embolization-Eligible, Unresectable HCC

Significant improvement in progression-free survival (PFS) was observed in embolization-eligible patients with unresectable hepatocellular carcinoma (HCC) who were treated with durvalumab (Imfinzi), bevacizumab (Avastin), and transarterial chemoembolization (TACE) compared with TACE alone, as demonstrated into findings from the phase 3 EMERALD-1 trial (NCT03778957) presented at the 2024 Gastrointestinal Cancers Symposium.

At the final PFS analysis, the median PFS was 15.0 months (95% CI, 11.1-18.9) with durvalumab and bevacizumab plus TACE (n = 204) vs 8.2 months (95% CI, 6.9-11.1) with TACE alone (n = 205), resulting in a 23% reduction in the risk of progression or death with the 2 systemic therapies (HR, 0.77; 95% CI, 0.61-0.98; P =.032 [threshold, .0434]). The 12- and 18-month PFS rates were 55.5% and 43.1% with durvalumab and bevacizumab vs 39.8% and 28.3% with TACE alone, respectively. Similar PFS benefit was seen across most prespecified subgroups.

“Durvalumab plus bevacizumab in combination with TACE has the potential to set a new standard of care in unresectable HCC eligible for embolization,” Riccardo Lencioni, MD, lead study author and professor in the Department of Surgery, Medical, Molecular, and Critical Area Pathology at Università di Pisa in Italy, said in a presentation of the data.

For more than 2 decades, TACE has been a standard treatment for patients with embolization-eligible unresectable HCC despite the commonality of disease progression within 1 year of therapy. Given the efficacy of checkpoint inhibitors and VEGF inhibitors in advanced HCC and the resulting proinflammatory tumor microenvironment and increased VEGF signaling following embolization, investigators hypothesized that the addition of durvalumab and/or bevacizumab could lead to prolonged tumor response.

The double-blind, global, placebo-controlled phase 3 trial enrolled patients eligible for embolization with unresectable measurable HCC per modified RECIST criteria, Child-Pugh A to B7 liver function, an ECOG performance status of 0 or 1, and no evidence of extrahepatic disease.

Patients who were candidates for curative therapy with surgical resection, ablation, or transplantation; those who received prior systemic therapy or TACE; and those with grade 3 or 4 portal vein thrombosis were excluded from enrollment.

Eligible patients (n = 616) were randomly assigned 1:1:1 to durvalumab plus bevacizumab and TACE (arm B), durvalumab plus TACE (arm A), or TACE alone (arm C). The protocol allowed investigator’s choice of conventional TACE or TACE with drug-eluting beads. Patients received 1500 mg of durvalumab (arm A and B) or placebo (arm C) every 4 weeks plus TACE, after which they received 1120 mg of durvalumab plus placebo (arm A), 15 mg/kg of bevacizumab (arm B), or placebo for both agents every 3 weeks.

Durvalumab and placebo were administered during the TACE period, which consisted of 1 to 4 TACE procedures within 16 weeks according to the investigator’s discretion. The second phase of therapy began at week 16 and was continued until progressive disease, unacceptable toxicity, consent withdrawal, or other discontinuation criteria were met.

The primary end point was PFS for the durvalumab, bevacizumab, and TACE arm vs the TACE-alone arm. Secondary end points included PFS for durvalumab plus TACE vs TACE alone, overall survival (OS), objective response rate (ORR), time to progression (TTP), safety, and quality of life for durvalumab, bevacizumab, and TACE vs durvalumab and TACE vs TACE alone. PFS, ORR, and TTP were evaluated according to blinded independent central review by RECIST v1.1 criteria.

Patients underwent imaging for tumor assessment at week 12 and every 9 weeks thereafter.

Stratification factors included TACE modality (DEB-TACE vs cTACE), geographical region (Japan vs Asia vs other), and portal vein invasion (Vp1 or Vp2+ / -Vp1 vs none).

Demographic and baseline features were generally balanced across arms. Most patients in the durvalumab and bevacizumab arm had BCLC stage B disease (57.4%) followed by stage A (25.0%) and stage C (17.2%). More than half of patients across arms A, B, and C received cTACE (59.4%; 58.3%; 58.5%). Approximately half of patients received treatment in Asia (52.1%; 52.4%; 52.1%), and most patients did not have portal vein invasion (93.7%; 92.2%; 93.7%).

Across all 3 arms, most patients had received 1 or 2 TACE procedures. A total of 43.6%, 42.5%, 40.0% of patients in the durvalumab and bevacizumab, durvalumab, and TACE-alone arms remain on study, respectively, and 14.0%, 13.0%, and 13.5% of whom continue to receive durvalumab.

The data cutoff date for the final PFS analysis, presented here with an approximate target maturity of 72%, and the interim OS analysis, was September 11, 2023. At the time of data cutoff, OS was not statistically significant.

Additional results showed that the median PFS with the addition of durvalumab to TACE was 10.0 months (95% CI, 9.0-12.7) vs 8.2 months (95% CI, 6.9-11.1) with TACE alone, failing to meet the secondary end point for PFS (HR, 0.94; 95% CI, 0.75-1.19; P =.638).

The median TTP was improved with the addition of durvalumab and bevacizumab to TACE vs TACE alone but not with durvalumab alone. The median TTP was 22.0 months (95% CI, 16.6-24.9) with durvalumab and bevacizumab vs 10.0 months (95% CI, 7.1-13.6) with TACE alone (HR, 0.63; 95% CI, 0.48-0.82). The median TTP was 11.5 months (95% CI, 9.2-13.9) with durvalumab vs 10.0 months (95% CI, 7.1-13.6) with TACE alone (HR, 0.89; 95% CI, 0.69-1.15).

Regarding responses, the ORR was 43.6% with durvalumab and bevacizumab, 41.0% with durvalumab, and 29.6% with TACE alone, with odds ratios of 1.87 (95% CI, 1.24-2.84) and 1.67 (95% CI, 1.10-2.54) for durvalumab and bevacizumab vs TACE and durvalumab vs TACE, respectively. Notably, complete responses across the 3 arms were rare, with partial responses representing 40.6%, 39.5%, and 27.1% of responses in the durvalumab/bevacizumab, durvalumab, and TACE-alone arms, respectively. Stable disease lasting at least 20 weeks occurred in 22.3%, 20.5%, and 31.0% of patients, respectively.

The median duration of response was 22.1 months (lower quartile-upper quartile [LQ-UQ], 11.2-30.3), 14.0 months (LQ-UQ, 6.9-30.7), and 16.4 months (LQ-UQ, 6.3-26.3) with durvalumab and bevacizumab, durvalumab, and TACE alone, respectively.

“The median time from the start of TACE to the first dose of the combination therapy was similar across the 3 arms [at approximately 3 months],” Lencioni said. “However, the duration of exposure was longer in the post-TACE period as well as across the total study in the durvalumab and bevacizumab arm, consistent with the PFS in these patients.”

Regarding safety, no new signals were identified. Within the safety analysis sets of the durvalumab and bevacizumab (n = 154), durvalumab (n = 232), and TACE alone (n = 200) arms, 45.5%, 27.6%, and 23.0% of patients had grade 3/4 adverse effects (AEs). AEs leading to discontinuation occurred in 24.7%, 12.1%, and 7.0% of patients, respectively. Deaths occurred in the durvalumab and bevacizumab, bevacizumab, and TACE alone arms, at rates of 24.7% (n = 38), 12.1% (n = 28), and 7.0% (n = 14), respectively.

Some of the most common treatment-emergent AEs (TEAEs) of any grade reported in the durvalumab and bevacizumab arm included hypertension (27.3%), post-embolization syndrome (26.6%), hypothyroidism (22.7%), pruritus (21.4%), proteinuria (21.4%), and constipation (18.8%). Grade 3/4 TEAEs in this arm included hypertension (5.8%), anemia (4.5%), acute kidney injury (3.9%), proteinuria (3.9%), post-embolization syndrome (3.2%), hepatic encephalopathy (3.2%), ascites (2.6%), hyponatremia (2.6%), and esophageal varices hemorrhage (2.6%).

“The incidence of AEs was consistent with the duration of treatment exposure and the known safety profiles of durvalumab, bevacizumab, and TACE, and the incidence of maximum grade 3 or 4 AEs was low across all arms,” Lencioni stated.

The study remains blinded to investigators and participants and follow-up will continue for OS.

Reference

Lencioni R, Kudo M, Erinjeri J, et al. EMERALD-1: A phase 3, randomized, placebo-controlled study of transarterial chemoembolization combined with durvalumab with or without bevacizumab in participants with unresectable hepatocellular carcinoma eligible for embolization. J Clin Oncol. 2024;42(suppl 3):LBA432. doi:10.1200/JCO.2024.42.3_suppl.LBA432