Background

ORIENT-15 is a global, randomized, double-blind study to evaluate the efficacy and safety of sintilimab + chemo (S+C) vs chemo (C) as first-line (1L) treatment in patients (pts) with unresectable locally advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC).

Methods

Eligible pts were randomized 1:1 to sintilimab/placebo 200 mg Q3W for up to 24 months +chemo (TP: paclitaxel 175 mg/m² Q3W + cisplatin 75 mg/m² Q3W or CF: cisplatin 75 mg/m² Q3W+5-FU 800 mg/m² on d1-5 Q3W). Randomization was stratified by ECOG PS (0 vs 1), liver metastasis (presence vs absence), chemo regimen (TP vs CF). Treatment continued until progression, unacceptable toxicity or withdrawal. No crossover was permitted. The primary end points were OS in the pts with PD-L1 combined positive score (CPS) ≥10 and all pts. The secondary endpoints were PFS and ORR (RECIST v1.1; by investigator) in the pts with PD-L1 CPS ≥10 and all pts. Data cutoff for interim analysis was Apr 9, 2021.

Results

At data cutoff, 659 pts (86% male, 97% Chinese, 87% metastatic) were randomized (327 S+C, 332 C). Median follow-up was 11.4 months. Sintilimab + chemo vs chemo was superior for OS in all pts (median 16.7 vs 12.5 mo, HR 0.628, 95% CI 0.508-0.777, P < 0.0001) and CPS ≥10 pts (median 17.2 vs 13.6 mo, HR 0.638, 95% CI 0.480-0.848, P =0.0018). PFS was superior with S+C vs C in all pts (median 7.2 vs 5.7 mo, HR 0.558, 95% CI 0.461-0.676, P <0.0001) and CPS ≥10 pts (median 8.3 vs 6.4 mo, HR 0.580, 95% CI 0.449-0.749, P <0.0001). ORR was 75.5 vs 56.9% in all pts, with median DOR of 8.3 vs 5.6 mo. ORR was 78.7 vs 57.5% in CPS ≥10 pts, with median DOR of 8.5 vs 5.5 mo. Of pts receiving at least one drug dose, treatment-related adverse events (TRAEs) rates were 98.2% vs 98.2%. Grade ≥3 TRAEs rates were 59.9% vs 54.5%. Discontinuation rates from TRAEs were 20.8% vs 12.3%. Death rates from TRAEs were 2.8% vs 1.8%.

Conclusions

OS, PFS and ORR are all significantly improved in S+C vs C, with a manageable safety profile in the pts with PD-L1 CPS ≥10 and all pts. Especially the HR of OS is less than 0.7 in all pts. The results demonstrate that the combination of sintilimab and chemo can be considered as a new 1L treatment in patients with advanced or metastatic ESCC.

Clinical trial identification

NCT03748134.

Legal entity responsible for the study

Innovent Biologics, Inc., China.

Funding

Innovent Biologics, Inc., China & Eli Lilly and Company, US.

Disclosure

L. Shen: Non-Financial Interests, Institutional, Principal Investigator: Innovent Biologics, Inc.Z. Lu: Non-Financial Interests, Institutional, Principal Investigator: Innovent Biologics, Inc. J. Wang: Non-Financial Interests, Institutional, Principal Investigator: Innovent Biologics, Inc. Y. Shu: Non-Financial Interests, Institutional, Principal Investigator: Innovent Biologics, Inc. L. Kong: Non-Financial Interests, Institutional, Principal Investigator: Innovent Biologics, Inc. L. Yang: Non-Financial Interests, Institutional, Principal Investigator: Innovent Biologics, Inc. B. Wang: Non-Financial Interests, Institutional, Principal Investigator: Innovent Biologics, Inc. Z. Wang: Non-Financial Interests, Institutional, Principal Investigator: Innovent Biologics, Inc. Y. Ji: Non-Financial Interests, Institutional, Principal Investigator: Innovent Biologics, Inc. G. Cao: Non-Financial Interests, Institutional, Principal Investigator: Innovent Biologics, Inc. H. Liu: Non-Financial Interests, Institutional, Principal Investigator: Innovent Biologics, Inc. T. Cui: Non-Financial Interests, Institutional, Principal Investigator: Innovent Biologics, Inc. N. Li: Non-Financial Interests, Institutional, Principal Investigator: Innovent Biologics, Inc. W. Qiu: Non-Financial Interests, Institutional, Principal Investigator: Innovent Biologics, Inc. Z. Ma: Financial Interests, Personal and Institutional, Full or part-time Employment: Innovent Biologics, Inc. Y. Chen: Financial Interests, Personal and Institutional, Full or part-time Employment: Innovent Biologics, Inc. H. Li: Financial Interests, Personal and Institutional, Full or part-time Employment: Innovent Biologics, Inc. X. Sun: Financial Interests, Personal, Full or part-time Employment: Innovent Biologics, Inc. Y. Wang: Financial Interests, Personal, Full or part-time Employment: Innovent Biologics, Inc. H. Zhou: Financial Interests, Personal, Full or part-time Employment: Innovent Biologics, Inc.

Background

ORIENT-16 is a randomized, double-blind, phase 3 trial to evaluate the efficacy and safety of sintilimab in combination with chemo (S+C) vs chemo (C) as the first-line treatment for patients (pts) with advanced G/GEJ adenocarcinoma. We report the first results from a pre-specified interim analysis.

Methods

Eligible pts were adults (≥18 years) with untreated, unresectable locally advanced or metastatic G/GEJ adenocarcinoma, regardless of PD-L1 expression. Pts were randomized 1:1 to receive sintilimab (3mg/kg and 200 mg, respectively, for body weights <60kg and ≥60kg, IV Q3W) or placebo plus chemo (CapeOX: oxaliplatin 130 mg/m² IV Q3W, up to 6 cycles, capecitabine 1000 mg/m² PO Bid d1-14 Q3W) for up to 24 months. The primary endpoints were OS in the pts with CPS ≥5 and all randomized pts. Data cutoff date for interim analysis was June 20, 2021.

Results

As of the cutoff date, 650 pts were randomized (327 in S+C and 323 in C), including 397 (61.1%) pts with CPS≥5. Median follow-up was 18.8 months (range 0.0-29.1). S+C showed a significant improvement in OS vs C in pts with CPS≥5 (median 18.4 vs 12.9 mo; HR 0.660; 95%CI 0.505-0.864; P =0.0023) and all pts (median 15.2 vs 12.3 mo; HR 0.766; 95%CI 0.626-0.936; P =0.0090). OS benefits were consistently observed at all pre-specified CPS cutoffs (CPS ≥1, 5, and 10). PFS was superior with S+C vs C in pts with CPS≥5 (HR 0.628; 95%CI 0.489-0.805; P =0.0002) and all pts (HR 0.636; 95%CI 0.525-0.771; p<0.0001). Unconfirmed ORR were 72.8% vs 59.6% in pts with CPS≥5 and 65.1% vs 58.7% in all pts with measurable disease, with a median DOR of 8.4 vs 5.5 and 8.6 vs 5.5 months, respectively. Among all treated pts, 196 (59.8%) of 328 in S+C and 168 (52.5%) of 320 in C experienced grade ≥3 treatment-related adverse events (TRAEs). TRAE leading to death were occurred in 6 (1.8%) pts in S+C and 2 (0.6%) in C.

Conclusions

Sintilimab is the first PD-1 inhibitor that demonstrated superior OS and PFS with an acceptable safety profile, in combination with chemo, in Chinese pts with G/GEJ cancer regardless of PD-L1 expressions. Sintilimab plus chemo provides a new standard first-line treatment option for these pts.

Clinical trial identification

NCT03745170. First posted November 19, 2018.

Legal entity responsible for the study

Innovent Biologics (Suzhou) Co., Ltd.

Funding

Innovent Biologics (Suzhou) Co., Ltd.

Disclosure

Y. Guo: Financial Interests, Personal, Full or part-time Employment: Innovent Biologics Co., Ltd. Z. Li: Financial Interests, Personal, Full or part-time Employment: Innovent Biologics Co., Ltd. Y. Liu: Financial Interests, Personal, Full or part-time Employment: Innovent Biologics Co., Ltd. Y. Wang: Financial Interests, Personal, Full or part-time Employment: Innovent Biologics Co., Ltd. H. Zhou: Financial Interests, Personal, Full or part-time Employment: Innovent Biologics Co., Ltd. All other authors have declared no conflicts of interest.

Background

In 1^st line EGA, the addition of PD-1 inhibitors to chemotherapy improved outcome in selected patient populations. The INTEGA trial compared different immunotherapy regimens in 1^st line HER2+ EGA.

Methods

INTEGA is a randomized exploratory phase II investigator initiated trial with two experimental arms. Patients (pts) with previously untreated (for advanced disease) HER2+ (local status - IHC3+ or 2+/ISH+) EGA were randomized to receive trastuzumab (trast) and nivolumab (nivo) (240mg or 1mg/kg with ipi) in combination with either ipilimumab (ipi) (4x 3mg/kg every 3 weeks) (arm A) or mFOLFOX6 (arm B) for up to 12 months. The 1° endpoint was to increase the 12month overall survival rate (OSR@12) from 55% (trast/chemo - ToGA regimen) to 70% in each arm.

Results

Between March 2018 and May 2020 a total of 97 pts were enrolled and 88 randomized (44 per arm) in 21 German sites. Baseline characteristics were female/male 18/70, median age 61 (range 41-80), ECOG 0/1 54/34, GEJ/stomach 66/22, prior surgery for primary tumor in 24 patients and were well balanced between groups. Central posthoc biomarker analysis (ongoing) yet showed PD-L1 CPS>1 in 55 and >5 in 41 pts and HER2 positivity in 76 pts while 8 were negative (incl. one failed ISH). The 1° endpoint of 70% OSR@12 was reached in arm B, but not in arm A (57%) (Table). Treatment related grade 3/4 AE/SAE occurred in 29/15 pts in arm B and in 20/17 pts in arm A. Liquid biopsy analyses showed strong correlation of high ctDNA load with shorter PFS/OS and emergence of truncating HER2 mutations on trast. Table: LBA54

Conclusions

Trast/nivo/FOLFOX showed increased efficacy compared to the ToGA regimen, whereas trast/nivo/ipi did not improve OS over trast/chemo. Subgroupanalyses are ongoing and will be presented.

Clinical trial identification

NCT03409848.

Legal entity responsible for the study

AIO Studien gGmbH.

Funding

Bristol Myers-Squibb.

Disclosure

A. Stein: Financial Interests, Institutional, Research Grant: BMS; Financial Interests, Personal and Institutional, Invited Speaker: BMS; Financial Interests, Personal and Institutional, Advisory Board: BMS. All other authors have declared no conflicts of interest.

Background

Overexpression and/or amplification of HER2 occurs in ∼20% of gastric or GEJ cancers. In DESTINY-Gastric01, the HER2-targeted antibody-drug conjugate T-DXd improved response and overall survival vs physician’s choice irinotecan/paclitaxel in pts from Japan/Korea with locally advanced or metastatic HER2+ gastric/GEJ cancer who progressed on ≥2L therapy including trastuzumab. Here, we report data from the single-arm, phase 2 DESTINY-Gastric02 trial, the first 2L study of T-DXd in Western pts with HER2+ gastric/GEJ cancer.

Methods

Pts with centrally confirmed HER2+ (IHC3+ or IHC2+/ISH+ biopsy after trastuzumab-based therapy) unresectable/metastatic gastric/GEJ cancer who progressed on or after trastuzumab-containing 1L therapy were treated with T-DXd 6.4 mg/kg intravenously every 3 weeks. The primary endpoint was confirmed objective response rate (ORR) per RECIST v1.1 by independent central review (ICR). Progression-free survival (PFS), duration of response (DoR) by ICR, and safety were secondary endpoints.

Results

Between Dec 2019 and Apr 2021, 79 pts from the US/EU with a median 1.0 (range 1-2) prior therapies were treated with T-DXd for a median of 4.3 mo (range 0.7-15.9). Median duration of follow-up was 5.7 mo (range 0.7-15.2). Median age was 61 years (range 20-78). Confirmed ORR, median PFS, median DoR, and treatment emergent adverse events (TEAEs) are shown (Table). The most common TEAEs were nausea (66%), vomiting (42%) and fatigue (41%). Adjudicated drug-related interstitial lung disease occurred in 6 (7.6%) pts (grade 1-2, 5 pts; grade 5, 1 pt). Table: LBA55

T-DXd in pts with HER2+ gastric/GEJ adenocarcinoma

Conclusions

T-DXd demonstrated clinical efficacy and a manageable safety profile in 2L treatment of Western patients with HER2+ unresectable/metastatic gastric/GEJ cancer.

Clinical trial identification

NCT04014075.

Editorial acknowledgement

Under the guidance of authors, assistance in medical writing and editorial support was provided by Sara Duggan, PhD, of ApotheCom and was funded by Daiichi Sankyo, Inc.

Legal entity responsible for the study

Daiichi Sankyo, Inc., and AstraZeneca.

Funding

This study was funded by Daiichi Sankyo, Inc., and AstraZeneca.

Disclosure

E. van Cutsem: Financial Interests, Personal, Advisory Role, Advisory/Consultancy: AbbVie, Array, Astellas, Astrazeneca, Bayer, Beigene, Biocartis, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Daiichi, Halozyme, GSK, Helsinn, Incyte, Ipsen, Janssen Research, Lilly, Merck Sharp & Dohme, Merck KGaA, Mirati, Novartis, Pierre Fabr; Financial Interests, Institutional, Research Grant: Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, Servier. M. Di Bartolomeo: Financial Interests, Institutional, Other, Honoraria: Lilly; Financial Interests, Institutional, Research Grant: Lilly; Financial Interests, Personal, Speaker’s Bureau, Speaker Bureau/Expert Testimony: BMS, MSD, Lilly, Servier, Daiichi . E. Smyth: Financial Interests, Personal, Advisory Role, Advisory/Consultancy: Amal Therapeutics, Astellas, AstraZeneca , Beigene, BMS, Celgene, Five Prime, Merck, Roche, Pfizer, Servier, Zymeworks; Financial Interests, Personal, Leadership Role: EORTC Gastric Cancer Taskforce co-lead; ESMO GI Faculty; Financial Interests, Personal, Other, Travel expenses, including accommodations: Astellas, AstraZeneca , BMS, Celgene, Servier, Zymeworks; Financial Interests, Personal, Research Grant: AstraZeneca , Astellas, Basilea, BMS, Daiichi Sankyo, Roche, Macrogenics, MSD. I. Chau: Financial Interests, Personal, Advisory Role: Eli-Lilly, Bristol Meyers Squibb, MSD, Bayer, Roche, Merck-Serono, Five Prime Therapeutics, AstraZeneca, OncXerna, Pierre Fabre, Boehringer Ingelheim, Incyte, Astellas; Financial Interests, Institutional, Research Grant: Eli-Lilly, Janssen-Cilag; Financial Interests, Personal, Other, Honoraria: Eli-Lilly, Eisai. H. Park: Financial Interests, Institutional, Research Grant: Adlai Nortye USA, Alpine Immune Sciences, Ambrx, Amgen, Aprea Therapeutics AB, Array BioPharma, Bayer, BeiGene, BJ Bioscience, Bristol Myers Squibb, Daiichi Pharmaceutical, Eli Lilly, Elicio Therapeutics, EMD Serono, Exelixis, Genentech, Gilead Sciences,; Non-Financial Interests, Personal, Other, Non-remunerated activity: Jacobio; Jounce. S. Siena: Financial Interests, Personal, Advisory Role: Amgen, AstraZeneca, Bayer, BMS, CheckmAb, Daiichi Sankyo, Merck, and Seattle Genetics. S. Lonardi: Financial Interests, Personal, Advisory Role, Advisory/Consultancy: Amgen, Merck Serono, Lilly, AstraZeneca , Incyte, Daiichi Sankyo, Bristol Myers Squibb, Servier, MSD; Financial Interests, Personal, Speaker’s Bureau, Speaker Bureau/Expert Testimony: Roche, Lilly, Bristol Myers Squibb, Servier, Merck Serono, Pierre-Fabre, GSK, Amgen; Financial Interests, Institutional, Research Grant: Amgen, Merck Serono, Bayer, Roche, Lilly, AstraZeneca , Bristol Myers Squibb. Z.A. Wainberg: Financial Interests, Personal, Advisory Role, Advisory/Consultancy: Merck, Ibsen, Lilly, Five prime, QED, Molecular Templates, Daiichi, AstraZeneca; Other, Personal, Other, Travel expenses, including accommodations: Lilly, Merck, Novartis, Daiichi. J.A. Ajani: Financial Interests, Personal, Other, Honoraria: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Daiichi Sankyo; Financial Interests, Personal, Other, Travel/Accommodations/Expenses: Daiichi Sankyo. J. Chao: Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Advisory Board: Astellas; Financial Interests, Personal, Other, Consulting: AstraZeneca; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Other, Consulting: Lilly; Financial Interests, Personal, Advisory Board: Macrogenics; Financial Interests, Personal, Invited Speaker: Merck; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Other, Consulting: Ono Pharmaceuticals; Financial Interests, Personal, Other, Consulting: Roche; Financial Interests, Personal, Advisory Board: Turning Point Therapeutics; Financial Interests, Institutional, Research Grant: Brooklyn Immunotherapeutics; Financial Interests, Institutional, Research Grant: Merck. J. Seraj: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. Y. Kawaguchi: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo, Inc.; Financial Interests, Personal, Stocks/Shares: Daiichi Sankyo, Inc. A. Qin: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo Inc. J. Singh: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. G. Meinhardt: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo; Financial Interests, Personal, Stocks/Shares: Daiichi Sankyo. G. Ku: Financial Interests, Personal, Advisory Role, Advisory/Consultancy: Apexigen, BMS, Eli Lilly, Merck, Pieris, Zymeworks; Financial Interests, Institutional, Research Grant: Arog, AstraZeneca, BMS, Daiichi Sankyo, Merck, Oncolys, Pieris, Zymeworks.

Background

Platinum-based chemotherapy is the standard first-line treatment for advanced or metastatic ESCC. Toripalimab, a humanized monoclonal antibody against PD-1, showed promising efficacy results as first-line treatment for ESCC in combination with paclitaxel plus cisplatin (TP) in a phase Ib trial. Here, we report the results of JUPITER-06 (NCT03829969), a randomized, double-blind phase III trial of toripalimab in combination with TP for advanced or metastatic ESCC.

Methods

Patients with treatment-naïve, advanced or metastatic ESCC were randomized (1:1) to receive 240 mg toripalimab or placebo in combination with TP Q3W up to 6 cycles, followed by toripalimab or placebo maintenance. Stratification factors were ECOG performance score and prior radiotherapy. The primary endpoints were progression-free survival (PFS) by a blinded independent central review (BICR) per RECIST v1.1 and overall survival (OS).

Results

A total of 514 ESCC patients were randomized; 257 in each arm. At a prespecified interim analysis on March 22, 2021, with median follow-up of 7.4 and 7.3 months in the two arms, there was a significant improvement in OS for toripalimab over placebo (HR=0.58 [95% CI: 0.43-0.78], P=0.00037) with median OS of 17.0 vs. 11.0 months. One-year OS rates were 66.0% vs. 43.7%. A significant improvement in PFS by BICR was also detected for toripalimab over placebo (HR=0.58 [95% CI: 0.46-0.74], P<0.00001). The OS and PFS benefits were observed across key subgroups, including all PD-L1 expression subgroups. The incidence of Grade ≥3 adverse events (AEs) (73.2% vs 70.0%) and fatal AEs (8.2% vs 8.2%) were similar between the two arms; however, AEs leading to discontinuation of toripalimab/placebo (11.7% vs 6.2%); immune-related AEs (irAEs) (37.0% vs. 26.5%) and Grade ≥3 irAEs (6.6% vs. 1.6%) were more frequent in the toripalimab arm.

Conclusions

The addition of toripalimab to standard first-line chemotherapy in patients with ESCC showed superior PFS and OS over chemotherapy alone with a manageable safety profile. These results support the use of toripalimab with TP chemotherapy as a new first-line treatment for advanced or metastatic ESCC.

Legal entity responsible for the study

Shanghai Junshi Biosciences and Coherus Biosciences.

Funding

Shanghai Junshi Biosciences and Coherus Biosciences.

Disclosure

R. Xu: Financial Interests, Personal, Advisory Role: Bristol-Myers Squibb; Financial Interests, Personal, Advisory Role: Merk Serono; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: Astellas; Financial Interests, Personal, Advisory Role: AstraZeneca. All other authors have declared no conflicts of interest.

Background

Survival and treatment options in advanced biliary tract cancer (BTC) are limited with the current standard of care gemcitabine/cisplatin. The NIFE study examined nanoliposomal-irinotecan (nal-IRI)/5-FU/leucovorin (LV) as an alternative 1^st-line treatment option in advanced BTC.

Methods

NIFE is a prospective, randomized, two-sided, phase II study. Advanced BTC patients were randomized (1:1) to receive either nal-IRI/5-FU/LV (arm A) or gemcitabine/cisplatin (arm B) with a stratification for tumor site (intrahepatic vs. extrahepatic), sex and ECOG (0 vs. 1). Arm A was planned as a Simon’s optimal two-stage design and arm B served as an internal control for selection bias. As primary endpoint a 4 months (mo) progression free survival (PFS) rate ≥50% in the ITT-population was defined.

Results

Between 01/2018-09/2020 93 patients were randomly assigned in 21 German centers. Two patients violating inclusion criteria had to be excluded from the ITT population (n=91) due to inappropriate randomization. The NIFE trial met its primary endpoint with a PFS-rate of 51% at 4mo in the ITT population (arm A). Median PFS in arm A was 5.98mo (2.37-9.59) and in arm B 6.87mo (2.46-7.82). Provisional median overall survival (mOS) was 15.9mo (10.58-21.85) in arm A and 13.63mo (6.51-17.68) in arm B with ongoing follow-up at data closesure. Median PFS in intrahepatic (ICCA) vs. extrahepatic (ECCA) cholangiocarcinoma was 3.45mo (2.10-6.05) vs. 9.59mo (1.94-15.67) in arm A and 7.72mo (6.05-9.46) vs. 1.76mo (0.16-6.87) in arm B. Corresponding mOS times were ICCA 14.19/ECCA 18.23mo in arm A and ICCA 16.36/ECCA 6.34mo in arm B. Table: LBA10

Conclusions

In the phase II NIFE trial nal-IRI/5-FU/LV showed efficacy as 1^st-line treatment of advanced BTC with no new safety findings. ECCA and ICCA responded differently to drug interventions, with a clear benefit for nal-IRI/5-FU/LV in ECCA.

Clinical trial identification

AIO-YMO HEP-0315 (NIFE); EudraCT 2016-002467-34; NCT03044587.

Legal entity responsible for the study

AIO-Studien GmbH.

Funding

Servier.

Disclosure

M. Sinn: Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Advisory Board: Incyte; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Servier; Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Sanofi. T.O. Goetze: Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Advisory Board: MSD Sharp Dohme; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Advisory Board: Celgene; Financial Interests, Personal, Advisory Board: Servier; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Ipsen; Financial Interests, Personal, Invited Speaker: Lilly; Financial Interests, Personal, Invited Speaker: MCI; Financial Interests, Personal, Invited Speaker: MSD Sharp Dohme; Financial Interests, Personal, Research Grant: AstraZeneca; Financial Interests, Personal, Research Grant: Incyte; Financial Interests, Personal, Research Grant: Lilly. D. Waldschmidt: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Advisory Board: Celgene; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: Incyte; Financial Interests, Personal, Advisory Board: Ipsen; Financial Interests, Personal, Advisory Board: Falk; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Servier; Financial Interests, Personal, Advisory Board: Shire Baxalta; Financial Interests, Personal, Advisory Board: Sirtex. T. Seufferlein: Financial Interests, Personal, Advisory Board: Sanofi; Financial Interests, Personal, Advisory Board: Pierre Fabre; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Baxalta; Financial Interests, Personal, Advisory Board: Servier; Financial Interests, Personal, Speaker’s Bureau: Sanofi; Financial Interests, Personal, Speaker’s Bureau: Pierre Fabre; Financial Interests, Personal, Speaker’s Bureau: Pfizer; Financial Interests, Personal, Speaker’s Bureau: Baxalta; Financial Interests, Personal, Speaker’s Bureau: Servier; Financial Interests, Personal, Research Grant: Boehringer; Financial Interests, Personal, Research Grant: Sanofi; Financial Interests, Personal, Research Grant: Celgene; Financial Interests, Personal, Research Grant: Amgen. T.J. Ettrich: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: Ipsen; Financial Interests, Personal, Invited Speaker: Ipsen; Financial Interests, Personal, Advisory Board: Sanofi Aventis; Financial Interests, Personal, Invited Speaker: Eisai; Financial Interests, Personal, Advisory Board: Pierre-Fabre Pharma; Financial Interests, Personal, Advisory Board: Incyte; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Financial Interests, Institutional, Research Grant: Servier; Financial Interests, Institutional, Research Grant: Sanofi Aventis; Financial Interests, Institutional, Research Grant: Celgene. All other authors have declared no conflicts of interest.

Background

Immunotherapy based combinations recently revolutionized the treatment of patients (pts) with advanced HCC, but its significance in earlier stages remains to be determined. TACE is commonly used as first line treatment in intermediate HCC, but outcome of pts treated with TACE in real-life cohorts is still poor with a median overall survival (OS) below 20 months. The release of neoantigens following local treatments is projected to trigger synergistic effects with anti-PD-1 antibodies, thus providing a rational for the combination of immunotherapy with TACE. The aim of this study was to determine the safety and efficacy of TACE with nivolumab.

Methods

This is a phase II trial, that recruited 59 pts at 10 sites in Germany between 06/2018 and 06/2020. Pts received up to 2 TACE treatments followed by nivolumab (240 mg/ Q2W), initiated on day 2-3 after the first TACE session and continued until progression for a maximum treatment duration of two years. One additional local treatment was allowed upon first progression. Primary endpoint (EP) was ORR (mRECIST; with an ORR exceeding 55% as promising for further investigations). Secondary EPs include PFS, TTFS, OS, QoL, and safety/tolerability. Tumor tissue was obtained at baseline and blood samples were collected longitudinally and subjected to an extensive biomarker analysis.

Results

49 pts (14.3% HCV and 8.2% HBV) were enrolled and received at least one dose of nivolumab. Median tumor size was 3 cm (0.6 – 14.7 cm) and median no. 3 (1 – 12). ORR was 71%. At a median follow-up of 14.6 months, mPFS was 6.14 mo (95% CI; 5.16 – 7.56; 41 events). Provisional mOS was 28.32 mo (95% CI; 20.60 – not estimable; 18 events). Grade ≥3 treatment-related adverse events occurred in 34.7% of pts. Correlative analysis of efficacy with genetic alterations, gene expression signatures and immune cell populations is ongoing.

Conclusions

The study met its primary EP and provides evidence for the efficacy of TACE in combination with nivolumab without new safety signals in pts with intermediate HCC and no prior systemic therapy. Our findings support further evaluation of nivolumab-based combinations for the treatment of intermediate HCC.

Clinical trial identification

NCT03572582; AIO-HEP-0217.

Legal entity responsible for the study

AIO-Studien-gGmbH.

Funding

BMS.

Disclosure

A. Vogel: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Invited Speaker: Sanofi; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Eisai; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Invited Speaker: Ipsen; Financial Interests, Personal, Advisory Board: Ipsen; Financial Interests, Personal, Invited Speaker: Incyte; Financial Interests, Personal, Advisory Board: Incyte; Financial Interests, Personal, Invited Speaker: PierreFabre; Financial Interests, Personal, Advisory Board: PierreFabre; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Invited Speaker: Lilly; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Beigene; Financial Interests, Personal, Invited Speaker: Jiangsu Hengrui Medicines. A. Saborowski: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: Servier; Financial Interests, Personal, Invited Speaker: BMS. T.J. Ettrich: Financial Interests, Personal, Other, Receipt of honoraria or consultation fees: BMS; Financial Interests, Personal, Other, Performing work in clinical trials / financial support: Servien; Financial Interests, Personal, Other, Performing work in clinical trials / financial support: Celgene; Financial Interests, Personal, Other, Performing work in clinical trials / financial support: Sanofi Aventis. U. Ehmer: Financial Interests, Personal, Other, Receipt of honoraria or consultation fees: AstraZeneca; Financial Interests, Personal, Other, Receipt of honoraria or consultation fees: Bayer; Financial Interests, Personal, Other, Receipt of honoraria or consultation fees: Eisai; Financial Interests, Personal, Other, Receipt of honoraria or consultation fees: Ipsen; Financial Interests, Personal, Other, Receipt of honoraria or consultation fees: Lilly; Financial Interests, Personal, Other, Receipt of honoraria or consultation fees: Roche; Financial Interests, Personal, Other, Performing work in clinical trials / financial support: AstraZeneca; Financial Interests, Personal, Other, Performing work in clinical trials / financial support: Eisai; Financial Interests, Personal, Other, Performing work in clinical trials / financial support: Ipsen; Financial Interests, Personal, Other, Performing work in clinical trials / financial support: MSD; Financial Interests, Personal, Other, Performing work in clinical trials / financial support: Roche; Financial Interests, Personal, Other, Receipt of honoraria or consultation fees: Sirtex. U.M. Martens: Financial Interests, Personal, Other, Receipt of honoraria or consultation fees: BMS; Financial Interests, Personal, Other, Receipt of honoraria or consultation fees: Roche; Financial Interests, Personal, Other, Performing work in clinical trials / financial support: BMS; Financial Interests, Personal, Other, Performing work in clinical trials / financial support: MSD; Financial Interests, Personal, Other, Performing work in clinical trials / financial support: Roche. T. Berg: Financial Interests, Personal, Other, Receipt of grants / research support: AbbVie; Financial Interests, Personal, Other, Receipt of grants / research support: BMS; Financial Interests, Personal, Other, Receipt of grants / research support: Gilead; Financial Interests, Personal, Other, Receipt of grants / research support: MSD/Merck; Financial Interests, Personal, Other, Receipt of grants / research support: Humedics; Financial Interests, Personal, Other, Receipt of grants / research support: Intercept; Financial Interests, Personal, Other, Receipt of grants / research support: Merz; Financial Interests, Personal, Other, Receipt of grants / research support: Novartis; Financial Interests, Personal, Other, Receipt of grants / research support: Sequana Medical; Financial Interests, Personal, Other, Receipt of honoraria or consultaion fees/advisory board: AbbVie; Financial Interests, Personal, Other, Receipt of honoraria or consultaion fees/advisory board: Alexion; Financial Interests, Personal, Other, Receipt of honoraria or consultaion fees/advisory board: Bayer; Financial Interests, Personal, Other, Receipt of honoraria or consultaion fees/advisory board: Gilead; Financial Interests, Personal, Other, Receipt of honoraria or consultaion fees/advisory board: GSK; Financial Interests, Personal, Other, Receipt of honoraria or consultaion fees/advisory board: Eisai; Financial Interests, Personal, Other, Receipt of honoraria or consultaion fees/advisory board: Enyo Pharma; Financial Interests, Personal, Other, Receipt of honoraria or consultaion fees/advisory board: HepaRegeniX GmbH; Financial Interests, Personal, Other, Receipt of honoraria or consultaion fees/advisory board: Humedics; Financial Interests, Personal, Other, Receipt of honoraria or consultaion fees/advisory board: Intercept; Financial Interests, Personal, Other, Receipt of honoraria or consultaion fees/advisory board: Ipsen; Financial Interests, Personal, Other, Receipt of honoraria or consultaion fees/advisory board: Janssen; Financial Interests, Personal, Other, Receipt of honoraria or consultaion fees/advisory board: MSD/Merck; Financial Interests, Personal, Other, Receipt of honoraria or consultaion fees/advisory board: Novartis; Financial Interests, Personal, Other, Receipt of honoraria or consultaion fees/advisory board: Roche; Financial Interests, Personal, Other, Receipt of honoraria or consultaion fees/advisory board: Sequana Medical; Financial Interests, Personal, Other, Receipt of honoraria or consultaion fees/advisory board: SIRTEX; Financial Interests, Personal, Other, Receipt of honoraria or consultaion fees/advisory board: SOBI; Financial Interests, Personal, Other, Receipt of honoraria or consultaion fees/advisory board: Shionogi; Financial Interests, Personal, Other, Participation in a company sponsored speakers bureau: AbbVie; Financial Interests, Personal, Other, Participation in a company sponsored speakers bureau: Alexion; Financial Interests, Personal, Other, Participation in a company sponsored speakers bureau: Bayer; Financial Interests, Personal, Other, Participation in a company sponsored speakers bureau: Gilead; Financial Interests, Personal, Other, Participation in a company sponsored speakers bureau: Eisai; Financial Interests, Personal, Other, Participation in a company sponsored speakers bureau: Intercept; Financial Interests, Personal, Other, Participation in a company sponsored speakers bureau: Ipsen; Financial Interests, Personal, Other, Participation in a company sponsored speakers bureau: Janssen; Financial Interests, Personal, Other, Participation in a company sponsored speakers bureau: MedUpdate GmbH; Financial Interests, Personal, Other, Participation in a company sponsored speakers bureau: MSD/Merck; Financial Interests, Personal, Other, Participation in a company sponsored speakers bureau: Novartis; Financial Interests, Personal, Other, Participation in a company sponsored speakers bureau: Sequana Medical; Financial Interests, Personal, Other, Participation in a company sponsored speakers bureau: SIRTEX; Non-Financial Interests, Personal, Other, Non-remunerated membership or affiliation: DGVS; Non-Financial Interests, Personal, Other, Non-remunerated membership or affiliation: EASL; Non-Financial Interests, Personal, Other, Non-remunerated membership or affiliation: AASVD. D. Waldschmidt: Financial Interests, Personal, Other, Receipt of honoria or consultaion fees: AstraZenecaCompany; Financial Interests, Personal, Other, Receipt of honoria or consultaion fees: Bayer Health Pharma; Financial Interests, Personal, Other, Receipt of honoria or consultaion fees: BMS; Financial Interests, Personal, Other, Receipt of honoria or consultaion fees: Celgene; Financial Interests, Personal, Other, Receipt of honoria or consultaion fees: Eisai; Financial Interests, Personal, Other, Receipt of honoria or consultaion fees: Incyte; Financial Interests, Personal, Other, Receipt of honoria or consultaion fees: Ipsen; Financial Interests, Personal, Other, Receipt of honoria or consultaion fees: Falk; Financial Interests, Personal, Other, Receipt of honoria or consultaion fees: MSD; Financial Interests, Personal, Other, Receipt of honoria or consultaion fees: Novartis; Financial Interests, Personal, Other, Receipt of honoria or consultaion fees: Roche Pharma AG; Financial Interests, Personal, Other, Receipt of honoria or consultaion fees: Servier; Financial Interests, Personal, Other, Receipt of honoria or consultaion fees: Shire Baxelta; Financial Interests, Personal, Other, Receipt of honoria or consultaion fees: Sirtex; Financial Interests, Personal, Other, Performing work in clinical trials/financial support: AstraZenecaCompany; Financial Interests, Personal, Other, Performing work in clinical trials/financial support: Bayer Health Pharma; Financial Interests, Personal, Other, Performing work in clinical trials/financial support: BeiGene; Financial Interests, Personal, Other, Performing work in clinical trials/financial support: BMS; Financial Interests, Personal, Other, Performing work in clinical trials/financial support: Celgene; Financial Interests, Personal, Other, Performing work in clinical trials/financial support: Eisai; Financial Interests, Personal, Other, Performing work in clinical trials/financial support: Incyte; Financial Interests, Personal, Other, Performing work in clinical trials/financial support: Ipsen; Financial Interests, Personal, Other, Performing work in clinical trials/financial support: MSD; Financial Interests, Personal, Other, Performing work in clinical trials/financial support: Pharmacyclics; Financial Interests, Personal, Other, Performing work in clinical trials/financial support: Roche Pharma AG; Financial Interests, Personal, Other, Performing work in clinical trials/financial support: Servier; Financial Interests, Personal, Other, Performing work in clinical trials/financial support: Sirtex; Financial Interests, Personal, Other, Non-remunerated membership or affiliation: AIO; Financial Interests, Personal, Other, Non-remunerated membership or affiliation: ASCO; Financial Interests, Personal, Other, Non-remunerated membership or affiliation: DGHO; Financial Interests, Personal, Other, Non-remunerated membership or affiliation: DGIM; Financial Interests, Personal, Other, Non-remunerated membership or affiliation: DGVS; Financial Interests, Personal, Other, Non-remunerated membership or affiliation: DKG. All other authors have declared no conflicts of interest.