Background

The global, randomized, double-blind, Ph3 LEAP-002 study (NCT03713593) evaluated the efficacy and safety of lenvatinib + pembrolizumab (lenva + pembro) vs lenvatinib (lenva) + placebo as 1L therapy for aHCC.

Methods

Eligible pts with aHCC were randomized 1:1 to lenva (8 mg/day if BW<60 kg or 12 mg/day if BW≥60 kg) plus pembro (200 mg IV Q3W) or lenva plus placebo. Dual primary endpoints OS and PFS (per RECIST 1.1 by BICR) were assessed using the stratified log-rank test. ORR (per RECIST 1.1 by BICR) was a key secondary endpoint. The protocol specified 2 interim analyses (IAs) and a final analysis (FA) for OS. Prespecified efficacy boundaries were one-sided P = 0.002 for PFS at IA1 (prespecified final PFS analysis) and 0.0185 for OS at FA.

Results

794 pts were randomized (lenva + pembro, 395; lenva, 399). At FA (data cutoff 21 June 2022; median follow-up 32.1 mo), 534 OS events had occurred and 36 pts (9.1%) in the lenva + pembro arm and 24 pts (6.1%) in the lenva arm remained on study treatment. The median OS with lenva + pembro was 21.2 mo vs 19.0 mo with lenva, and the HR was 0.840 (95% CI: 0.708-0.997, P=0.0227, Table). HR for PFS at IA1 (data cutoff 5 April 2021) was 0.867 (95% CI: 0.734-1.024, P=0.0466, Table). ORR at FA was 26.1% for lenva + pembro vs 17.5% for lenva. Grade 3-5 treatment-related adverse events (TRAEs) were 62.5% in the lenva + pembro arm and 57.5% in the lenva arm (grade 5 TRAEs, 1.0% vs 0.8%). Post-study systemic anti-cancer treatments were used in 44.1% vs 52.1% of pts, in each arm, respectively. Table: LBA34

Conclusions

LEAP-002 primary endpoints of OS (at FA) and PFS (at IA1) did not meet pre-specified statistical significance. The combination of lenva + pembro achieved the longest median OS ever reported in 1L HCC Ph3 studies (21.2 mo) with no new safety signals observed. The median OS of 19.0 mo with lenva monotherapy supports its role as a standard of care in 1L aHCC.

Clinical trial identification

NCT03713593.

Editorial acknowledgement

Medical writing assistance was provided by Yue Liu of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Legal entity responsible for the study

Eisai Inc., Nutley, NJ, USA, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Funding

Eisai Inc., Nutley, NJ, USA, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Disclosure

R.S. Finn: Financial Interests, Personal and Institutional, Advisory Board: AstraZeneca, CStone, Bayer, BMS, Exelixis, Eli Lilly, Eisai, Hengrui, Merck, Pfizer, Roche/ Genenentech; Financial Interests, Institutional, Research Grant: Adaptimmune, Bayer, BMS, Eli Lilly, Eisai, Merck, Pfizer, Roche/ Genentech; Non-Financial Interests, Principal Investigator: Eisai, Merck, BMS, Pfizer, Roche/Genentech. M. Kudo: Financial Interests, Personal, Invited Speaker: Eisai, Chugai, Eli Liiy, Bayer, Takeda, MSD; Financial Interests, Institutional, Research Grant: Otsuka, Sumitomo Dainippon Pharma, EA Pharma, Taiho, Eisai, AbbVie, Gilead Sciences, Takeda, GE Healthcare, Chugai. P. Merle: Financial Interests, Personal and Institutional, Advisory Board: Roche, BMS, MSD, EISAI, AstraZeneca, BAYER, IPSEN; Financial Interests, Institutional, Research Grant: Ipsen. T. Meyer: Financial Interests, Personal, Advisory Board: Ipsen, AstraZeneca, Eisai, Bayer, Roche, Adaptimmune, Boston Scientific; Financial Interests, Institutional, Research Grant: Bayer, BTG. S. Qin: Non-Financial Interests, Personal and Institutional, Principal Investigator: Cina . M. Ikeda: Financial Interests, Personal, Advisory Board: AstraZeneca, Chugai, Eli Lilly Japan, Eisai, NIHON SERVIER, Novartis, Ono, Takeda, GlaxoSmithKline; Financial Interests, Personal, Invited Speaker: AstraZeneca, Bayer, Bristol-Myers Squibb, Chugai, Eli Lilly Japan, Eisai, Nihon Servier, Novartis, Taiho, Yakult, Teijin Pharma, AbbVie, Abbott Japan, Fujifilm Toyama Chemical, Incyte Biosciences Japan, ASLAN, Chugai, Nihon Servier, Takeda; Financial Interests, Institutional, Invited Speaker: Bayer, Bristol-Myers Squibb, Eisai, AstraZeneca, Eli Lilly Japan, Chugai Pharmaceutical, Merck Serono, MSD, Ono, Yakult, Novartis, Takeda, J-Pharma, Pfizer, Chiome Bioscience, Nihon Servier, Delta-Fly Pharma, Syneos Health, Merus.N.V.. J. Edeline: Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, MSD, Bayer, Boston Scientific, Eisai, Ipsen, Servier, MSD; Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, MSD, Bayer, Merck Serono, Eisai, Ipsen, BMS, Basilea, Servier, Incyte, Beigene; Financial Interests, Institutional, Invited Speaker: BMS, Beigene, BMS, MSD, Roche, Beigene, Bayer, Novartis, Taiho, Servier, Agios; Non-Financial Interests, Principal Investigator: Unicancer. Z. Ren: Financial Interests, Personal, Advisory Board: AstraZeneca Roche Merch Sharp & Dohme. A. Cheng: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Bayer Healthcare, AstraZeneca, Genentech/Roche, Merck Sharp Dohme, BeiGene, Ltd., Exelixis Ltd., Ipsen Innovation, F. Hoffmanna-La Roche Ltd; Financial Interests, Personal, Invited Speaker: Eisai, Ono Pharmaceutical, Bayer Yakuhin Ltd., Novartis, Amgen Taiwan, Chugai Pharmaceutical; Financial Interests, Personal, Other, Travel: IQVIA. P.R. Galle: Financial Interests, Personal, Invited Speaker: Bayer, Boston Scientific, Adaptimmune, Eisai, MSD, Sirtex, Lilly, Roche, Ipsen.; Financial Interests, Personal, Writing Engagements: BMS, Roche, AstraZeneca; Financial Interests, Personal, Expert Testimony: BMS, Roche; Financial Interests, Personal, Speaker’s Bureau: Bayer, Boston Scientific, Adaptimmune, Eisai, MSD, Sirtex, Lilly, Roche, Ipsen; Financial Interests, Personal, Advisory Board: Bayer, Boston Scientific, AstraZeneca, Adaptimmune, BMS, Eisai, MSD, Sirtex, Lilly, Roche, Guerbet, Ipsen.; Financial Interests, Institutional, Research Grant: Bayer, Roche; Financial Interests, Personal and Institutional, Principal Investigator: Bayer, Roche. S. Kaneko: Financial Interests, Personal, Invited Speaker: Bayer Eisai Avi pharma Sumitomo pharma Takeda Eli lily; Financial Interests, Personal, Advisory Board: Bayer Eisai Eli lily; Financial Interests, Personal and Institutional, Research Grant: Bayer Eisai Avi pharma Sumitomo pharma Takeda Eli lily Pfizer Otuka. H. Kumada: Financial Interests, Personal, Invited Speaker: AbbVie Eisai Gilead Sciences Sumitomo Dainippon Pharma; Financial Interests, Personal, Full or part-time Employment: Toranomon Hospital. A. Wang: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co. Inc.. K. Mody: Financial Interests, Personal, Full or part-time Employment: Eisai Inc.. L. Dubrovsky: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc.. A.B. Siegel: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc.. J. Llovet: Non-Financial Interests, Personal and Institutional, Invited Speaker: ESMO, ASCO, AASLD, ILCA, AACR, AEEH, EASL; Financial Interests, Personal and Institutional, Advisory Board: BMS MINA Therapeutics Merck Medscape Eversana; Financial Interests, Personal and Institutional, Full or part-time Employment: ICREA Universitat de Barcelona ICAHN Mount Sinai School Of Medicine; Financial Interests, Personal and Institutional, Research Grant: R01 - NIH, R01 – NIDDK, Samuel Waxman Cancer Research, Eisai INC, Alex’s Lemonade StandFoundation For Childhood Cancer, Bayer Pharmaceuticals, Accelerator Award Cancer Research UKAECC- AIRC, Ipsen Pharma, National Health Institute (SPAIN); Non-Financial Interests, Personal and Institutional, Member: EASL, AACR, ASCO, AEEH, AASLD, ILCA, ESMO; Financial Interests, Personal and Institutional, Advisory Role: Eli Lilly, Bayer Healthcare Pharmaceutical, Eisai Inc, Merck, Bristol Myers-Squibb, Ipsen, Glycotest, Nucleix, Genentech, Roche, AstraZeneca, Omega Therapeutics, Iylon., Mina Alpha, Boston Scientific. All other authors have declared no conflicts of interest.

Background

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.

Methods

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).

Results

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: LBA35

Summary of efficacy outcomes

Conclusions

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.

Clinical trial identification

NCT03764293.

Editorial acknowledgement

Editorial assistance was provided by Xiuzhi Wu, PhD (Hengrui Pharmaceuticals).

Legal entity responsible for the study

Jiangsu Hengrui Pharmaceuticals & Elevar Therapeutics Inc.

Funding

Jiangsu Hengrui Pharmaceuticals Co.Ltd & Elevar Therapeutics Inc.

Disclosure

X. Liang: Financial Interests, Personal, Full or part-time Employment: Hengrui Pharmaceuticals. C. Chen: Financial Interests, Personal, Full or part-time Employment: Hengrui Pharmaceuticals. Z. Nie: Financial Interests, Personal, Full or part-time Employment: Hengrui Pharmaceuticals. L. Wang: Financial Interests, Personal, Full or part-time Employment: Hengrui Pharmaceuticals. All other authors have declared no conflicts of interest.

Background

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.

Methods

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.

Results

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%).

Conclusions

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.

Clinical trial identification

NCT03412773.

Editorial acknowledgement

This study was sponsored by BeiGene, Ltd. Medical writing support, under the direction of the authors, was provided by Arezou Seyed Hossein, MPharm, of Ashfield MedComms, an Ashfield Health company, and was funded by BeiGene, Ltd.

Legal entity responsible for the study

BeiGene, Ltd.

Funding

BeiGene, Ltd.

Disclosure

M. Kudo: Financial Interests, Invited Speaker: Eli Lilly, Bayer, Eisai, Chugai, Takeda; Financial Interests, Research Grant: Gilead Sciences, Taiho, Sumitomo Dainippon Pharma, Takeda, Otsuka, EA Pharma, AbbVie, Eisai. T. Meyer: Financial Interests, Advisory Board: MSD, Ipsen, AstraZeneca, Eisai, Roche, Adaptimmune; Financial Interests, Institutional, Funding, Grant to institution: MSD, BTG. R.S. Finn: Financial Interests, Personal and Institutional, Advisory Board: AstraZeneca, CStone, Bayer, BMS, Exelixis, Eli Lilly, Eisai,Hengrui, Merck, Pfizer, Roche/ Genenentech; Financial Interests, Institutional, Research Grant: Adaptimmune, Bayer, BMS, Eli Lilly, Eisai,Merck, Pfizer, Roche/ Genentech; Non-Financial Interests, Principal Investigator: Eisai, Merck, Roche/Genentech, BMS, Pfizer. A. Vogel: Financial Interests, Invited Speaker: Roche, Bayer, BMS, Lilly, EISAI, AstraZeneca, Ipsen, MSD, Sirtex, BTG, Servier, Terumo, Imaging Equipment Ltd (AAA); Financial Interests, Advisory Board: Roche, Bayer, BMS, Lilly, EISAI, AstraZeneca, Ipsen, MSD, Sirtex, BTG, Servier, Terumo, Imaging Equipment Ltd (AAA). A. Hiraoka: Non-Financial Interests, Speaker’s Bureau: Chugai Pharma., Lilly, Beyer. D. Marino: Financial Interests, Advisory Board: Roche, MSD; Financial Interests, Sponsor/Funding, Travel and meeting expenses: Pierre-Fabre. E. Assenat: Financial Interests, Advisory Board: Roche, Astra Zeneca, Servier,Ipsen. M. Calvo Campos: Financial Interests, Advisory Role: Roche/Eisai/Bayer/MSD. K. Hsing-Tao: Financial Interests, Principal Investigator: BeiGene Ltd. F. Boisserie: Financial Interests, Full or part-time Employment: BeiGene; Financial Interests, Stocks/Shares: BeiGene. S. Li: Financial Interests, Full or part-time Employment: BeiGene, Ltd. Y. Chen: Financial Interests, Full or part-time Employment: BeiGene, Ltd. A.X. Zhu: Financial Interests, Advisory Role, Consulting fee: Merck, Roche, Sanofi, Eisai, Exelixis, Bayer, Lilly. All other authors have declared no conflicts of interest.