The combination of tremelimumab and durvalumab improved overall response rate and median overall survival in patients with unresectable hepatocellular carcinoma previously treated with sorafenib.
Robin Kate Kelley, MD
The combination of tremelimumab and durvalumab (Imfinzi) improved overall response rate (ORR) and median overall survival (OS) in patients with unresectable hepatocellular carcinoma (HCC) previously treated with sorafenib (Nexavar), according to findings presented during the International Liver Cancer Association 2020 Virtual Conference.
Principal investigator Robin Kate Kelley, MD, said results from the 4-armed, phase 1/2 Study 22 (NCT02519348) showed that combining the anti–CTLA-4 monoclonal antibody tremelimumab with the anti–PD-L1 monoclonal antibody durvalumab demonstrated efficacy and a tolerable safety profile among patients who were refractory to sorafenib, who had progressed during treatment with the kinase inhibitor, or who had refused sorafenib.
“A single priming dose of tremelimumab combined with monthly durvalumab showed promising clinical activity in a predominately second-line advanced HCC population” said Kelley, a gastrointestinal oncologist and associate professor of clinical medicine at University of California San Francisco Helen Diller Family Comprehensive Cancer Center.
In part 3 of the 3-part Study 22, patients were assigned to a 1-time dose of 300 mg of tremelimumab followed by 1500 mg of durvalumab monthly (T300 plus D; n = 65), the same dose of durvalumab monotherapy (D; n = 64), once-monthly 750 mg tremelimumab monotherapy for 7 doses, then once ever 12 weeks thereafter (T; n = 33), or 4 doses of 75 mg tremelimumab plus 1500 mg of durvalumab monthly (T75 pluse D; n = 45).
In the T300 plus D group, 43 (57.3%) patients had progressed on sorafenib, 12 (16.0%) were refractory, and 20 (26.7%) refused the drug. In the T75 plus D group, those numbers were 47 (56.0%), 10 (11.9%), and 27 (32.1%), respectively. In the D arm, 52 (50.0%) patients progressed, 15 (14.4%) were refractory, and 37 (35.6%) refused treatment. In the T arm, those numbers were 30 (43.5%), 14 (20.3%), and 25 (36.2%), respectively.
Kelley noted that the Kaplan-Meier survival curves for patients receiving the highest tremelimumab doses, the T300 and tremelimumab monotherapy arms, separated early. The survival advantage in those arms remained consistent through the study period. “The T300 plus D arm had the best performance at the median,” she added.
Median OS in the T300 plus D group was 18.7 months (95% CI, 10.8-27.3), followed by tremelimumab alone (15.1 months; 95% CI, 11.3-20.5), durvalumab alone (13.6 months; 95% CI, 8.7-17.6), and the T75+D group (11.3 months; 95% CI, 8.4-15.0).
Similarly, 18-month survival was greatest in the T300 plus D group (52.0%; (95% CI, 38.9%-63.6%), followed by the T arm (45.7 months; 95% CI, 32.8%-57.7%). The 18-month survival rate was lowest in the D group (35.3%; 95% CI, 25.0%-45.8%) and the T75 plus D group (34.7%; 95% CI, 24.4%-45.2%).
In the T300 plus D arm, ORR was 24.0% (95% CI, 14.9%-35.3%) with 1 (1.3%) complete response (CR) and 17 (22.7%) partial responses (PR). The median duration of response has not been reached and the median progression-free survival is 2.17 months (1.91-5.42).
The ORR in the D arm was 10.6% (95% CI, 5.4%-18.1%), followed by 9.5% (95% CI, 4.2%-17.9%) in the T75 plus D arm and 7.2% (95% CI, 2.4%-16.1%) in the T arm. Median duration of response was 11.2 months, 13.2 months, and 24.0 months, respectively. Investigators observed 2 (2.4%) CRs in the T75 plus D arm and none in the other 2 arms.
A total of 332 patients were included in the safety analysis. Kelley said investigators did not observe any adverse events (AEs) beyond the established safety profile for any agent. Grade 3/4 treatment-related (TR) AEs were most common in the T arm at 43.5%, followed by the T300 plus D arm at 35.1%, the T75 plus D arm at 23.2%, and the D arm at 17.8%.
There were 17 (24.6%) serious TRAEs, including death, in the T arm, 13 (17.6%) in the T300 plus D arm, 12 (14.6%) in the T75 plus D arm, and 11 (10.9%) in the D arm. Investigators observed 3 (3.0%) deaths due to TRAEs in the D arm, 2 (2.7%) in the T300 plus D arm, and 1 (1.2%) in the T75 plus D arm. There were no deaths due to TRAEs in the T arm.
A total of 30 patients discontinued treatment due to TRAEs, 9 in the T arm, 8 each in the T300 plus D and D arms, and 5 in the T75 plus D arm.
“In sum, these data show that the T300 plus D regimen provides the best benefit-to-risk profile across arms,” Kelley said. “Furthermore, the unique association of the T300 plus D regimen with proliferative CD8-positive T cells provides a strong biologic rationale for the observed treatment response, which warrants further study.”
She added that the T300 plus D and D alone regimens are being evaluated versus sorafenib for the treatment of HCC in first-line in the ongoing phase 3 HIMALAYA trial (NCT03298451). AstraZeneca hopes to present findings from HIMALAYA later this year.
Kelly RK, Kudo M, Harris W, et al. The novel regimen of tremelimumab in combination with durvalumab provides a favorable safety profile and clinical activity for patients with advanced hepatocellular carcinoma. Presented at: International Liver Cancer Association 2020 Virtual Conference; September 11-13, 2020; virtual. Abstract 0-22.