CIRT Plus Durvalumab/Tremelimumab Is Safe in Advanced HCC With Macrovascular Invasion

The addition of carbon-ion radiotherapy (CIRT) to the combination of durvalumab (Imfinzi) plus tremelimumab (Imjudo; the STRIDE regimen) demonstrated safety in the treatment of patients with advanced hepatocellular carcinoma (HCC) and macrovascular invasion, according to data from the phase 1b DEPARTURE trial (jRCT2031210046).¹

Findings presented at the 2024 ASCO Breakthrough Conference showed that patients treated with the regimen in cohort A (n = 3) and cohort B (n = 12) did not experience any dose-limiting toxicities (DLTs). All patients (n = 15) experienced any-grade treatment-emergent adverse effects (TEAEs), and treatment-related TEAEs were reported in 93.3% of patients. The rates of grade 3, grade 4, and grade 5 TEAEs were 46.7%, 13.3%, and 6.7%, respectively. The respective rates of grade 3, grade 4, and grade 5 treatment-related TEAEs were 26.7%, 6.7%, and 0%.

Serious TEAEs occurred in 33.3% of patients, although none were observed in cohort A. The rate of serious treatment-related AEs was 26.7%.

“The safety of durvalumab plus tremelimumab in combination with particle therapy has been confirmed in advanced HCC with macrovascular invasion,” lead study author Keisuke Koroki, MD, PhD, of the Department of Gastroenterology in the Graduate School of Medicine at Chiba University in Japan, said in a presentation of the data.

In October 2022, the FDA approved the STRIDE regimen for the treatment of patients with unresectable HCC based on data from the phase 3 HIMALAYA trial (NCT03298451).²

Koroki explained that radiotherapy is associated with the release of cancer antigens and antigen presentation. Accordingly, a synergistic effect is anticipated when radiotherapy is combined with immune checkpoint inhibitors.¹

DEPARTURE was a multicenter, open-label, single-arm trial that enrolled patients at least 20 years of age with histologically confirmed HCC and a diagnosis of macrovascular invasion. Patients must have been ineligible for locoregional therapy for unresectable HCC, and a history of at least 1 prior systemic therapy regimen was required for those enrolled onto cohorts A and B. Other inclusion criteria consisted of an ECOG performance status (PS) of 0 or 1, and a Child-Pugh A score.

Enrolled patients in cohort A received 1500 mg of durvalumab alone on day 1, and those in cohort B were given the STRIDE regimen consisting of 1500 mg of durvalumab plus 300 mg of tremelimumab. On day 8, all patients received CIRT for 4 consecutive days. All patients then received 1500 mg of durvalumab once every 4 weeks until disease progression.

Safety, including the incidence of DLTs, served as the trial’s primary end point. Secondary end points included overall survival (OS), 6-month OS rate, objective response rate, 6-month progression-free survival (PFS) rate, and time to progression.

DLTs were defined as the following: grade 4 or higher neutropenia; grade 4 or higher anemia; grade 3 or higher thrombocytopenia with bleeding; grade 4 or higher non-immunological AEs; grade 4 or higher AEs excluding endocrine disorders; grade 3 or higher non-immunological AEs that do not improve within 30 days of onset despite appropriate therapy; and grade 3 or higher immunological AEs that do not improve within 30 days despite appropriate therapy, with some exceptions.

All 15 patients enrolled in cohorts A and B were from Japan. The median age was 69.0 years (range, 25.0-81.0), and the median body weight was 63.1 kg (range, 53.2-88.2). The majority of patients were male (86.7%) and had an ECOG PS of 0 (86.7%). All patients had Barcelona Clinic Liver Cancer stage C disease, and 13.3% of patients were heavy drinkers. Patients had a Child-Pugh score of 5 (66.7%) or 6 (33.3%). The median alpha-fetoprotein was 213.7 ng/kg (range, 3.5-270208.0).

Histologies included HBV surface antigen–positive HCC (20.0%), anti-HCV–positive disease (13.3%), and other (66.7%). The majority of patients (66.7%) had at least 8 tumors, and the median maximum tumor size was 91.1 mm (range, 32-221.8). Portal vein invasion included Vp0 (6.7%), Vp2 (46.7%), Vp3 (20.0%), and Vp4 (26.7%); hepatic vein invasion consisted of Vv0 (86.7%), Vv2 (6.7%), and Vv3 (6.7%). No patients had intrahepatic bile duct invasion. Notably, 26.7% of patients were naive to systemic therapy.

Efficacy data showed that no patients in either cohort experienced responses. Stable disease was reported in 11 patients. Ten patients had progressive disease, 7 of whom had experienced stable disease. Treatment was ongoing for 2 patients in cohort B. One patient withdrew, and 2 patients discontinued treatment due to AEs, including 1 patient who died.

The median PFS was 4.67 months (95% CI, 1.35-6.44) for the overall population, 4.67 months (95% CI, 4.63-4.67) for cohort A, and 3.84 months (95% CI, 1.12-6.64) for cohort B. The median OS was 10.40 months (95% CI, 5.62-15.16) for the overall population, 28.22 months (95% CI, 5.54-50.89) for cohort A, and 10.20 months (95% CI, 4.31-16.09) for cohort B.

Additional safety data showed the most common any-grade TEAEs reported in at least 10% of the overall population included pyrexia (60.0%), rash (33.3%), increased lipase (33.3%), radiation skin injury (33.3%), decreased appetite (26.7%), constipation (20.0%), diarrhea (20.0%), malaise (20.0%), increased alanine aminotransferase (20.0%), increased amylase (20.0%), increased aspartate aminotransferase (20.0%), COVID-19 (13.3%), interstitial lung disease (13.3%), pleural effusion (13.3%), abdominal pain (13.3%), and decreased platelet count (13.3%).

“The [STRIDE plus CIRT] combination, especially the irradiation of tumors with macrovascular invasion using CIRT, hold promise in managing prognostic determinant tumors and potentially enhancing OS,” Koroki concluded.

Disclosures: Dr Koroki did not disclose any relationships.

References

1. Koroki K, Ogasawara S, Makishima H, et al. Phase Ib trial of durvalumab plus tremelimumab in combination with particle therapy in patients with advanced hepatocellular carcinoma with macrovascular invasion: DEPARTURE trial. J Clin Oncol. 2024;42(suppl 23):34. doi:10.1200/JCO.2024.42.23_suppl.34
2. FDA approves tremelimumab in combination with durvalumab for unresectable hepatocellular carcinoma. FDA. October 21, 2022. Accessed August 8, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tremelimumab-combination-durvalumab-unresectable-hepatocellular-carcinoma