T-cell receptor pharmacodynamics associated with survival and response to tremelimumab (T) in combination with durvalumab (D) in patients (pts) with unresectable hepatocellular carcinoma (uHCC).

Abstract

4087 Background: Study 22, a phase 2 clinical study (NCT02519348) evaluating T (anti-CTLA-4) and D (anti-PD-L1) as monotherapies and in combination indicated the best efficacy-safety profile with a novel combination regimen containing a single, priming dose of T (T300+D). Additionally, an expansion of proliferative CD8+ lymphocytes at Day 15 was observed with T300+D that was associated with improved response. Here, an exploratory molecular analysis of peripheral blood T cell receptors is presented. Methods: Immune-checkpoint inhibitor-naïve pts were randomized to 1 of 2 T+D combinations: T300+D (T 300 mg [1 dose] + D 1500 mg, then D every 4 weeks [Q4W]) or T75+D (T 75 mg Q4W + D 1500 mg Q4W [4 doses], then D Q4W); or single agent D (1500 mg Q4W) or T (750 mg Q4W [7 doses] then Q12W). DNA was isolated from PAXgene-preserved whole blood collected at baseline and on Day 29 during the first cycle of Q4W dosing, and then underwent CDR3 sequencing of T-cell receptor β using the immunoSEQ Assay (Adaptive Biotechnologies, Seattle, WA). Associations with objective response rate (ORR) and overall survival (OS) were evaluated. Results: The number of evaluable pts, samples, and overall ORR and OS are provided (Table). Immunosequencing analysis did not reveal significant differences in baseline T-cell clonality across arms. Increased T-cell clonal expansion at Day 29 appeared to be T dose dependent (Table), with no significant difference in the median expansion between the D and T75+D arms. Across all arms, responders had a larger median number of expanded T-cell clones on Day 29 than nonresponders (77.5 vs 40), and this greater expansion trended with longer OS (Table). Further evaluation by arm demonstrated an increase in T-cell clonal expansion in responders vs nonresponders in the T300+D arm. Pts with T-cell expansion above the median in the T300+D and T75+D arms also exhibited longer OS. Both newly expanded and total expanded clones on Day 29 vs Day 1 were associated with improved OS. Conclusions: The observed T dose-dependent increase in T-cell clonal expansion trended with improved ORR and longer OS, with the greatest overall benefit seen with T300+D vs T75+D, D and T. This is consistent with the previously reported observation that T300+D led to the highest median proliferating CD8+ T-cell counts and radiographic response. Further work is needed to differentiate the relative contributions of CD4 and CD8 clonal expansion to increased efficacy. T300+D and D are being evaluated in the phase 3 HIMALAYA study (NCT03298451) in uHCC vs sorafenib. Funding: AstraZeneca. Clinical trial information: NCT02519348. [Table: see text]

Immune-Based Combination Therapies for Advanced Hepatocellular Carcinoma

“…67,68 Interestingly, also tremelimumab treatment is associated with an increased median proliferating CD8+ T-cell counts, compared to durvalumab treatment, with a tremelimumab dose-dependent increase in T-cell clonal expansion which is associated with improved ORR and OS. 69,70 These data provide a rationale for combining lenvatinib with anti-PD-1 plus anti-CTLA-4 and by hypothesizing a possible synergistic effect. Lenvatinib plus durvalumab and tremelimumab is now under investigation in the phase III EMERALD-3 trial in association with TACE, while MK-1308A (a coformulation of pembrolizumab and the anti-CTLA-4 antibody quavonlimab) is under evaluation in association with lenvatinib as first-line treatment in advanced HCC.…”

New Challenges Facing Systemic Therapies of Advanced HCC in the Era of Different First-Line Immunotherapy-Based Combinations

“…While the study of patients treated with anti-PD-1 single-agents has already shown some potential biomarkers of response [ 35 , 36 , 37 ], it would also be interesting to define predictive factors that might favor the use of antiangiogenics or anti-CTLA-4. Indeed, the biomarker study of the Study-22 suggested that the proportion of proliferative CD8+ cells in the blood was associated with response; also, the expansion of clonality was associated with response and survival, and more clearly so in the CTLA-4-containing arms [ 29 , 38 ]. In renal cell carcinoma, in a phase 2 study, the benefit of adding bevacizumab to atezolizumab seemed limited to the population of patients with both high effector T cells and high myeloid cells in the tumors [ 39 ].…”