Background: Immunotherapy, targeted therapy and their combination has been developed as first-line treatment for advanced HCC.The combination therapy has improved the antitumor effects compared with targeted therapy,but tended to have higher incidence of adverse reactions.This study aims to assess the efficacy and safety of Cadonilimab, a humanized, tetravalent, bispecific antibody targeting PD-1 and CTLA-4,with lenvatinib(len) in first-line treatment of HCC.

Pts with advanced HCC have poor prognosis, with 5-year survival of 18%. Coinhibition of programmed death ligand-1 (PD-L1) and VEGF provides survival benefit in 1st line (1L) HCC. In preclinical studies of HCC and clinical studies of other tumors, coinhibition of T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) and PD-1 enhances antitumor activity of anti-PD-1. AdvanTIG-206 (NCT04948697) is investigating the efficacy/safety of adding OCI (anti-TIGIT) to TIS (anti-PD-1) + BAT1706 backbone as 1L therapy in advanced HCC pts. Eligible adults had histologically confirmed HCC that is BCLC Stage B or C, not amenable to or progressed after loco-regional therapy, and with no prior systemic therapy. Pts were randomized 2:1 to OCI 900 mg + TIS 200 mg + BAT1706 15 mg/kg (O+T+B) or T+B every 3 weeks until loss of clinical benefit at investigator (INV) discretion. Primary endpoint was INV-assessed objective response rate (ORR). Secondary endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). As of 27 Feb 2023, 94 pts (median age 58.5 years) were randomized to O+T+B (n=62) and T+B (n=32). INV-assessed ORR was 35.5% with O+T+B vs. 37.5% with T+B (Table). For O+T+B and T+B, respectively, Grade ≥3 treatment-related adverse events (TRAEs) were 50.0% and 25.8%, most common (≥5% incidence) TRAEs were hypertension (14.5% and 6.5%) and proteinuria (both 6.5%); TRAEs that led to any treatment discontinuation were 16.1% and 6.5%. Three (4.8%) treatment-related deaths occurred with O+T+B vs. none with T+B.Table: 945MOEfficacyBest overall responsea, n (%)O+T+B (n=62)T+B (n=32)Complete response00Partial response22 (35.5)12 (37.5)Stable disease26 (41.9)11 (34.4)Progressive disease10 (16.1)7 (21.9)Not evaluable4 (6.5)2 (6.3)ORRa, % (95% CI)35.5 (23.7, 48.7)37.5 (21.1, 56.3)2-sided P=0.8350DORb(months), median (95% CI)12.6 (7.0, NE)10.6 (4.2, NE)PFS (months), median (95% CI)8.3 (5.5, 10.0)6.9 (4.1, NE)Hazard ratio = 1.08 (0.59, 1.96) 1-sided P=0.4056Median follow-up was 9.2 months P-value is for descriptive purpose only. NE, not estimable aINV-confirmed per RECIST v1.1 bOnly includes pts with confirmed complete/partial response Open table in a new tab Median follow-up was 9.2 months P-value is for descriptive purpose only. NE, not estimable aINV-confirmed per RECIST v1.1 bOnly includes pts with confirmed complete/partial response In pts with advanced HCC, TIS + BAT1706 demonstrated promising ORR, while adding OCI to the doublet was not associated with improved anticancer activity. No new safety signals were identified in either arm. The OS data are premature and need further follow-up.

The benefits of immunotherapy plus an anti-angiogenic TKI in uHCC are unclear. This study aimed to assess C (Camrelizumab; anti-PD-1 IgG4 monoclonal antibody) + R (Rivoceranib, Apatinib; VEGFR2-TKI) vs. S (Sorafenib) as first-line treatment for uHCC. In this international, randomized, open-label, phase III trial, eligible patients (pts) were randomized 1:1 to receive C (200 mg, iv, q2w) + R (250 mg, po, qd) or S (400 mg, po, bid). Pts were stratified by macrovascular invasion and/or extrahepatic metastases, geographical region (Asia vs. non-Asia), and baseline serum AFP (<400 vs. ≥ 400 ng/mL). The primary endpoints were PFS per RECIST v1.1 criteria by BIRC as well as OS. The primary analysis for PFS was done after 339 PFS events occurred (May 10, 2021) and the planned interim analysis of OS was done after 262 deaths occurred (Feb 8, 2022). A total of 543 pts (ITT population) were randomized to receive C+R (N=272) or S (N=271) respectively. With a median follow-up time of 7.8 mo, PFS was significantly improved with C+R vs. S (median 5.6 mo [95% CI 5.5-6.3] vs. 3.7 mo [2.8-3.7]; HR 0.52 [95% CI 0.41-0.65]); 1-sided p<0.0001). With a median follow-up of 14.5 mo, OS was significantly prolonged with C+R vs. S (median 22.1 mo [95% CI 19.1-27.2] vs. 15.2 mo [13.0-18.5]; HR 0.62 [95% CI 0.49-0.80]; 1-sided p<0.0001). ORR, DCR and DoR were also better with C+R vs. S (Table). A pre-specified subgroup analysis showed that HRs of PFS and OS obviously favored C+R in the majority of the subgroups. Grade ≥3 TRAEs occurred in 80.9% with C+R and 52.4% with S. TRAE led to discontinuation of any treatment in 24.3% (of both agents in 3.7%) with C+R and 4.5% with S. Fatal TRAE occurred in 1 pt in each arm.Table: LBA35Summary of efficacy outcomesC+R (N=272)S (N=271)1-sided p-valueMedian OS (95% CI), mo22.1 (19.1-27.2)15.2 (13.0-18.5)-HR (95% CI)0.62 (0.49-0.80)<0.0001*Median PFS (95% CI), mo5.6 (5.5-6.3)3.7 (2.8-3.7)-HR (95% CI)0.52 (0.41-0.65)<0.0001*Confirmed ORR (95% CI), %25.4 (20.3-31.0)5.9 (3.4-9.4)<0.0001†Median DoR (95% CI), mo14.8 (8.4-NR)9.2 (5.3-NR)-DCR (95% CI), %78.3 (72.9-83.1)53.9 (47.7-59.9)-Median TTP (95% CI), mo7.2 (5.6-8.2)3.7 (3.6-3.7)-All assessed by BIRC per RECIST v1.1 except for OS. Data cutoff was May. 10, 2021 for PFS and Feb. 8, 2022 for other outcomes. * Stratified log-rank test. † Stratified Cochran-Mantel-Haenszel test. NR=not reached. Open table in a new tab All assessed by BIRC per RECIST v1.1 except for OS. Data cutoff was May. 10, 2021 for PFS and Feb. 8, 2022 for other outcomes. * Stratified log-rank test. † Stratified Cochran-Mantel-Haenszel test. NR=not reached. C+R significantly prolonged PFS and OS and improved ORR vs. S, and presents as a new first-line treatment option for uHCC. This is the first positive pivotal trial to show survival benefits with a PD-1/PD-L1 inhibitor plus an anti-angiogenic TKI for uHCC.

Tislelizumab (TIS), an anti-PD-1 monoclonal antibody, has demonstrated durable responses and was well tolerated as monotherapy in 2L+ treatment in patients (pts) previously treated systemically for unresectable HCC (Ducreux et al, 2021). TIS has been further evaluated against sorafenib (SOR) in a global randomized Phase 3 study (RATIONALE-301; NCT03412773) as 1L treatment in adult pts with unresectable HCC. Systemic therapy-naïve adults with histologically confirmed HCC BCLC Stage B/C who were not amenable to or progressed after loco-regional therapy, Child-Pugh A, with ≥1 measurable lesion per RECIST v1.1, and an ECOG PS ≤1 were eligible. Pts were randomized 1:1 to receive TIS (200 mg IV Q3W) or SOR (400 mg PO BID) until disease progression, intolerable toxicity, withdrawal, or no longer benefiting from therapy. The primary endpoint was OS; secondary endpoints included ORR, PFS, and DOR by blinded independent review committee, and safety. Non-inferiority of OS between TIS and SOR was tested against the non-inferiority margin of 1.08. A total of 674 pts were randomized (n=342, TIS; n=332, SOR); at data cutoff (11 Jul 2022) minimum study follow up was 33 months (mo). In this final analysis, RATIONALE-301 met its primary endpoint of OS non-inferiority (mOS: 15.9 mo [TIS] vs 14.1 mo [SOR]; stratified HR: 0.85 [95.003% CI: 0.712, 1.019]). TIS was associated with higher ORR (14.3% vs 5.4%) and more durable responses (mDoR: 36.1 mo vs 11.0 mo) compared with SOR. Median PFS with TIS was 2.2 mo and 3.6 mo with SOR (HR: 1.1 [95% CI: 0.92, 1.33]). Median treatment duration was longer with TIS vs SOR (4.1 mo vs 2.7 mo). The safety profiles for both treatments were consistent with prior reports. Incidence rates of grade ≥3 AEs (48.2% vs 65.4%) and AEs leading to discontinuation (10.9% vs 18.5%) were lower with TIS compared with SOR; AEs leading to death were low across both treatments (4.4%, TIS; 5.2%, SOR). Immune-mediated AEs occurring in ≥5% TIS-treated pts were hepatitis (5.3%) and hypothyroidism (5.3%). Single-agent TIS demonstrated clinically meaningful OS benefit that was non-inferior to SOR with a favorable safety profile as a 1L treatment option for pts with unresectable HCC.

TIS is a humanized monoclonal antibody with high affinity and binding specificity to programmed cell death protein 1 receptor. In the phase 3 trial RATIONALE-301 (NCT03412773), TIS showed non-inferior overall survival (OS) vs SOR (hazard ratio 0.85, 95% confidence interval [CI]: 0.71, 1.02), and was well tolerated in 1L treatment of patients (pts) with unresectable HCC. This analysis assessed and compared efficacy and safety of TIS in the Chinese subgroup with the overall population of RATIONALE-301. This open-label trial enrolled systemic therapy-naïve adults with histologically confirmed Barcelona Clinic Liver Cancer Stage C or B HCC. Pts were randomized (1:1) to receive TIS (200 mg IV every 3 weeks [TIS Arm]) or SOR (400 mg orally twice daily [SOR Arm]) until disease progression, intolerable toxicity, or treatment discontinuation due to other reasons. The primary endpoint was OS. Secondary endpoints included objective response rate (ORR), duration of response (DoR), and progression-free survival, all by blinded independent review committee, and safety. Of 674 randomized pts, 425 were from China. In the Chinese subgroup, median follow-up was 13.8 months (mo, 95%CI: 0.1, 50.8) in TIS arm vs 13.1 mo (95%CI: 0.1, 49.4) in SOR arm, similar to the overall population. Efficacy data in the Chinese subgroup were similar to the overall population and characterised by higher ORR and longer DoR in the TIS arm vs the SOR arm (Table). In the Chinese subgroup, 53 pts (24.9%) had grade ≥3 treatment-related adverse events in TIS arm vs 112 pts (54.6%) in SOR arm, similar to the overall population (22.2% and 53.4%, respectively)Table: LBA2Chinese subgroupOverall populationTIS (n=215)SOR (n=210)TIS (N=342)SOR (N=332)mOS, mo (95%CI)14.2 (11.6, 18.1)13.4 (11.4, 15.4)15.9 (13.2, 19.7)14.1 (12.6, 17.4)ORR, % (95%CI)12.6 (8.4, 17.7)6.2 (3.3, 10.4)14.3 (10.8, 18.5)5.4 (3.2, 8.4)mDoR, mo (95%CI)42.9 (9.7, NE)11.0 (6.2, 19.6)36.1 (16.8, NE)11.0 (6.2, 14.7)mPFS, mo (95%CI)2.1 (2.1, 2.1)2.4 (2.1, 4.1)2.1 (2.1, 3.5)3.4 (2.2, 4.1)ITT Analysis Set; Data cutoff: Jul 11, 2022.CI, confidence interval; ITT, intent-to-treat; mo, months; m, median; DoR, duration of response; NE, not evaluable; ORR, confirmed objective response rate; OS, overall survival; PFS, progression-free survival; SOR, sorafenib; TIS, tislelizumab. Open table in a new tab . ITT Analysis Set; Data cutoff: Jul 11, 2022. CI, confidence interval; ITT, intent-to-treat; mo, months; m, median; DoR, duration of response; NE, not evaluable; ORR, confirmed objective response rate; OS, overall survival; PFS, progression-free survival; SOR, sorafenib; TIS, tislelizumab. TIS demonstrated a numerically longer OS, higher ORR, more durable responses, and a favorable safety profile vs SOR in the Chinese subgroup, consistent with the overall population representing a potential 1L treatment option for Chinese pts with unresectable HCC.