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NCT04696055

Regorafenib Plus Pembrolizumab in Patients With Advanced or Spreading Liver Cancer Who Have Been Previously Treated With PD-1/PD-L1 Immune Checkpoint Inhibitors

Completed Phase 2 Results posted Last updated 13 May 2025
What this trial tests

Phase 2 trial testing Pembrolizumab in Hepatocellular Carcinoma in 95 participants. Completed in 23 April 2024.

Timeline
3 February 2021
Primary endpoint
5 May 2022
23 April 2024

Quick facts

Lead sponsorBayer
PhasePhase 2
StatusCompleted
Study typeINTERVENTIONAL
Allocationna
Designsequential
Maskingnone
Primary purposetreatment
Enrollment95
Start date3 February 2021
Primary completion5 May 2022
Estimated completion23 April 2024
Sites39 locations across France, Italy, Japan, Israel, Germany, South Korea, United States, Spain

Drugs / interventions tested

Conditions studied

Sponsor

Bayer — full company profile →

Who can join

18 and older, any sex, with Hepatocellular Carcinoma. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Overall Response Rate (ORR) Per RECIST 1.1 by Central Assessment Primary · Up to 15 months. Data up to 38 months are now available and are also reported for full transparency.

Overall response rate (ORR) is defined as the percentage of participants with best overall response of confirmed complete response (CR) or partial response (PR). ORR per RECIST 1.1 by independent central assessment is reported). RECIST 1.1: response evaluation criteria in solid tumors version 1.1

Up to 15 months (primary outcome as previously reported)
GroupValue95% CI
Cohort 1 (Regorafenib + Pembrolizumab [1L: Atezolizumab + Bevacizumab])5.91.6 – 14.4
Cohort 2 (Regorafenib + Pembrolizumab [1L: Any Other IO Containing Treatment])11.12.4 – 29.2
Up to 38 months (as of study completion)
GroupValue95% CI
Cohort 1 (Regorafenib + Pembrolizumab [1L: Atezolizumab + Bevacizumab])7.42.4 – 16.3
Cohort 2 (Regorafenib + Pembrolizumab [1L: Any Other IO Containing Treatment])14.84.2 – 33.7
Overall Response Rate (ORR) Per RECIST 1.1 by Investigator Assessment Secondary · Up to 38 months

Overall response rate (ORR) is defined as the percentage of participants with best overall response of confirmed complete response (CR) or partial response (PR). ORR by RECIST 1.1 investigator review is reported. RECIST 1.1: response evaluation criteria in solid tumors version 1.1

GroupValue95% CI
Cohort 1 (Regorafenib + Pembrolizumab [1L: Atezolizumab + Bevacizumab])7.42.4 – 16.3
Cohort 2 (Regorafenib + Pembrolizumab [1L: Any Other IO Containing Treatment])18.56.3 – 38.1
Duration of Response (DOR) Per RECIST 1.1 by Central Assessment and Investigator Assessment Secondary · Up to 38 months

Duration of response (DOR) for partial response (PR) and complete response (CR) was defined as the time from the first documented objective response of PR or CR, whichever noted earlier, to disease progression or death (if death occurs before progression was documented). DOR was defined for confirmed responders only, i.e., participants with a CR or PR. RECIST 1.1: response evaluation criteria in solid tumors version 1.1

Central assessment
GroupValue95% CI
Cohort 1 (Regorafenib + Pembrolizumab [1L: Atezolizumab + Bevacizumab])210158 – 937
Cohort 2 (Regorafenib + Pembrolizumab [1L: Any Other IO Containing Treatment])19583 – 280
Investigator assessment
GroupValue95% CI
Cohort 1 (Regorafenib + Pembrolizumab [1L: Atezolizumab + Bevacizumab])43182 – 893
Cohort 2 (Regorafenib + Pembrolizumab [1L: Any Other IO Containing Treatment])364117 – 839
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) Secondary · Up to 38 months

An AE was considered as treatment-emergent (TEAE) if arising or worsening after start of first study intervention administration until 30 days after administration of any study intervention. In addition, any AEs qualifying as a serious adverse event (SAE) were collected for 90 days after the last dose of pembrolizumab, unless a new anti-cancer therapy had been initiated.

Any TEAE
GroupValue95% CI
Cohort 1 (Regorafenib + Pembrolizumab [1L: Atezolizumab + Bevacizumab])68
Cohort 2 (Regorafenib + Pembrolizumab [1L: Any Other IO Containing Treatment])27
Any SAE
GroupValue95% CI
Cohort 1 (Regorafenib + Pembrolizumab [1L: Atezolizumab + Bevacizumab])37
Cohort 2 (Regorafenib + Pembrolizumab [1L: Any Other IO Containing Treatment])11
Number of Participants With Safety-relevant Changes in Clinical Parameters Secondary · Up to 38 months

Number of participants with clinically relevant trends observed in laboratory data, ECG data, or ECOG performance status is reported.

GroupValue95% CI
Cohort 1 (Regorafenib + Pembrolizumab [1L: Atezolizumab + Bevacizumab])0
Cohort 2 (Regorafenib + Pembrolizumab [1L: Any Other IO Containing Treatment])0
Percentage of Participants With Dose Modification Secondary · Up to 38 months

Dose modification included dose interruption, dose reduction, dose discontinuation.

Regorafenib - drug interruptions or delays
GroupValue95% CI
Cohort 1 (Regorafenib + Pembrolizumab [1L: Atezolizumab + Bevacizumab])63.2
Cohort 2 (Regorafenib + Pembrolizumab [1L: Any Other IO Containing Treatment])70.4
Regorafenib - dose reductions
GroupValue95% CI
Cohort 1 (Regorafenib + Pembrolizumab [1L: Atezolizumab + Bevacizumab])41.2
Cohort 2 (Regorafenib + Pembrolizumab [1L: Any Other IO Containing Treatment])63.0
Regorafenib - drug withdrawal
GroupValue95% CI
Cohort 1 (Regorafenib + Pembrolizumab [1L: Atezolizumab + Bevacizumab])16.2
Cohort 2 (Regorafenib + Pembrolizumab [1L: Any Other IO Containing Treatment])25.9
Pembrolizumab - dose interruptions or delays
GroupValue95% CI
Cohort 1 (Regorafenib + Pembrolizumab [1L: Atezolizumab + Bevacizumab])14.7
Cohort 2 (Regorafenib + Pembrolizumab [1L: Any Other IO Containing Treatment])25.9
Pembrolizumab - drug withdrawal
GroupValue95% CI
Cohort 1 (Regorafenib + Pembrolizumab [1L: Atezolizumab + Bevacizumab])4.4
Cohort 2 (Regorafenib + Pembrolizumab [1L: Any Other IO Containing Treatment])11.1

Adverse events — posted to ClinicalTrials.gov

Time frame: These data extend to the final release date of the clinical database (38 months).. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Regorafenib+Pembrolizumab [1L: Atezolizumab + Bevacizumab]
Serious: 37/68 (54%)
Deaths: 53/68
Regorafenib+Pembrolizumab [Any Other IO Containing Treatment]
Serious: 11/27 (41%)
Deaths: 20/27

Serious adverse events (64 terms)

ReactionSystemRegorafenib+Pembrolizumab …Regorafenib+Pembrolizumab …
SepsisInfections and infestations
AnaemiaBlood and lymphatic system disorders
MelaenaGastrointestinal disorders
Blood bilirubin increasedInvestigations
Acute kidney injuryRenal and urinary disorders
Acute myocardial infarctionCardiac disorders
Atrial fibrillationCardiac disorders
Cardiac arrestCardiac disorders
AscitesGastrointestinal disorders
ColitisGastrointestinal disorders
Gastric ulcer perforationGastrointestinal disorders
Gastritis erosiveGastrointestinal disorders
Gastrointestinal haemorrhageGastrointestinal disorders
HaematocheziaGastrointestinal disorders
HaemoperitoneumGastrointestinal disorders
Oesophageal varices haemorrhageGastrointestinal disorders
Lower gastrointestinal haemorrhageGastrointestinal disorders
AstheniaGeneral disorders
DeathGeneral disorders
FatigueGeneral disorders
Injection site haematomaGeneral disorders
PyrexiaGeneral disorders
General physical health deteriorationGeneral disorders
Systemic inflammatory response syndromeGeneral disorders
CholangitisHepatobiliary disorders
Other adverse events (50 terms — click to expand)

ReactionSystemRegorafenib+Pembrolizumab …Regorafenib+Pembrolizumab …
Palmar-plantar erythrodysaesthesia syndromeSkin and subcutaneous tissue disorders
DiarrhoeaGastrointestinal disorders
AstheniaGeneral disorders
Decreased appetiteMetabolism and nutrition disorders
Abdominal painGastrointestinal disorders
HypertensionVascular disorders
ConstipationGastrointestinal disorders
FatigueGeneral disorders
NauseaGastrointestinal disorders
PyrexiaGeneral disorders
ArthralgiaMusculoskeletal and connective tissue disorders
DysphoniaRespiratory, thoracic and mediastinal disorders
AnaemiaBlood and lymphatic system disorders
RashSkin and subcutaneous tissue disorders
VomitingGastrointestinal disorders
Mucosal inflammationGeneral disorders
Aspartate aminotransferase increasedInvestigations
Blood bilirubin increasedInvestigations
Oedema peripheralGeneral disorders
MyalgiaMusculoskeletal and connective tissue disorders
Weight decreasedInvestigations
HyponatraemiaMetabolism and nutrition disorders
Back painMusculoskeletal and connective tissue disorders
PruritusSkin and subcutaneous tissue disorders
Dry mouthGastrointestinal disorders
COVID-19Infections and infestations
HypoalbuminaemiaMetabolism and nutrition disorders
InsomniaPsychiatric disorders
CoughRespiratory, thoracic and mediastinal disorders
HypothyroidismEndocrine disorders
AscitesGastrointestinal disorders
StomatitisGastrointestinal disorders
HeadacheNervous system disorders
EpistaxisRespiratory, thoracic and mediastinal disorders
Dry skinSkin and subcutaneous tissue disorders
Abdominal pain upperGastrointestinal disorders
HyperbilirubinaemiaHepatobiliary disorders
Alanine aminotransferase increasedInvestigations
Transaminases increasedInvestigations
Blood alkaline phosphatase increasedInvestigations

Most-reported serious reactions: Sepsis, Anaemia, Melaena, Blood bilirubin increased, Acute kidney injury, Acute myocardial infarction, Atrial fibrillation, Cardiac arrest.

Data from ClinicalTrials.gov NCT04696055 adverse events section.

Sponsor's own description

Researchers are looking for a better way to treat people diagnosed with liver cancer which may have spread to nearby tissue and is unlikely to be cured or controlled with treatment (advanced metastatic hepatocellular carcinoma, HCC). Before a treatment can be approved for people to take, researchers do clinical trials to better understand its safety and how it works. In this trial, the researchers will learn more about the trial treatment, regorafenib, in a small number of participants. They will study the results when the trial treatment is taken with another cancer treatment called pembrolizumab. There will be 2 parts to this trial. The part 1 (pilot phase) will include about 52 men and women. The part 2 (expansion phase) will include about 67 men and women. All of the participants will have HCC and will be aged 18 years or older. All of the participants will have tried other treatments that did not help their HCC. These other treatments (PD-1/PD-L1 Immune Checkpoint Inhibitors) are designed to work by stopping the activity of certain proteins in the immune system thought to play a role in HCC. During both parts of the trial, the participants will take regorafenib and receive pembrolizumab. In the pilot phase, there will be 2 groups of participants. The group that each participant joins will be based on the treatment they already received for their HCC. The researchers will review the results in each group to learn if regorafenib and pembrolizumab are helping one group of participants more than others. Outcome of this review will determine the population to be treated in the expansion phase.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Molecular pathogenesis and systemic therapies for hepatocellular carcinoma.
    Llovet JM, Pinyol R, Kelley RK, El-Khoueiry A, et al · · 2022 · cited 365× · PMID 35484418 · DOI 10.1038/s43018-022-00357-2
  2. Tumor immunotherapies by immune checkpoint inhibitors (ICIs); the pros and cons.
    Naimi A, Mohammed RN, Raji A, Chupradit S, et al · · 2022 · cited 350× · PMID 35392976 · DOI 10.1186/s12964-022-00854-y
  3. Combination therapy with immune checkpoint inhibitors (ICIs); a new frontier.
    Vafaei S, Zekiy AO, Khanamir RA, Zaman BA, et al · · 2022 · cited 190× · PMID 34980128 · DOI 10.1186/s12935-021-02407-8
  4. Immunotherapy for Hepatocellular Carcinoma: Current Status and Future Prospects.
    Liu Z, Liu X, Liang J, Liu Y, et al · · 2021 · cited 109× · PMID 34675942 · DOI 10.3389/fimmu.2021.765101
  5. Experience with regorafenib in the treatment of hepatocellular carcinoma.
    Granito A, Forgione A, Marinelli S, Renzulli M, et al · · 2021 · cited 97× · PMID 34104211 · DOI 10.1177/17562848211016959
  6. Biomarkers and prognostic factors of PD-1/PD-L1 inhibitor-based therapy in patients with advanced hepatocellular carcinoma.
    Zhang N, Yang X, Piao M, Xun Z, et al · · 2024 · cited 69× · PMID 38355603 · DOI 10.1186/s40364-023-00535-z
  7. Advances of Targeted Therapy for Hepatocellular Carcinoma.
    Niu M, Yi M, Li N, Wu K, et al · · 2021 · cited 39× · PMID 34381735 · DOI 10.3389/fonc.2021.719896
  8. Drug Treatment for Advanced Hepatocellular Carcinoma: First-Line and Beyond.
    Feng MY, Chan LL, Chan SL. · · 2022 · cited 37× · PMID 36005172 · DOI 10.3390/curroncol29080434

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