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Study of Pembrolizumab (MK-3475) Versus Investigator's Choice of Chemotherapy for Participants With Advanced Esophageal/Esophagogastric Junction Carcinoma That Progressed After First-Line Therapy (MK-3475-181/KEYNOTE-181)-China Extension Study
Phase 3 trial testing pembrolizumab in Esophageal Carcinoma in 123 participants. Completed in 14 March 2022.
| Lead sponsor | Merck Sharp & Dohme LLC |
|---|---|
| Phase | Phase 3 |
| Status | Completed |
| Study type | INTERVENTIONAL |
| Allocation | randomized |
| Design | parallel |
| Masking | none |
| Primary purpose | treatment |
| Enrollment | 123 |
| Start date | 29 December 2016 |
| Primary completion | 13 February 2019 |
| Estimated completion | 14 March 2022 |
| Sites | 23 locations across China |
Merck Sharp & Dohme LLC — full company profile →
18 and older, any sex, with Esophageal Carcinoma or Esophagogastric Junction Carcinoma. Patients with the condition only — healthy volunteers not accepted.
Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.
OS was defined as the time from randomization to death due to any cause. Median OS for the first pembrolizumab course in all participants is presented.
| Group | Value | 95% CI |
|---|---|---|
| Pembrolizumab | 8.4 | 5.8 – 10.9 |
| Chemotherapy | 5.6 | 4.5 – 7.3 |
OS was defined as the time from randomization to death due to any cause. Median OS for the first pembrolizumab course in participants with a PD-L1 CPS ≥10 is presented.
| Group | Value | 95% CI |
|---|---|---|
| Pembrolizumab | 12.0 | 6.6 – NA |
| Chemotherapy | 5.3 | 4.1 – 8.2 |
OS was defined as the time from randomization to death due to any cause. Median OS for the first pembrolizumab course in participants with SCC of the esophagus is presented.
| Group | Value | 95% CI |
|---|---|---|
| Pembrolizumab | 8.4 | 5.8 – 10.9 |
| Chemotherapy | 5.6 | 4.5 – 7.3 |
ORR was defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) as assessed using RECIST 1.1 by central imaging vendor review. The percentage of all participants who experienced a CR or PR for the first pembrolizumab course is presented.
| Group | Value | 95% CI |
|---|---|---|
| Pembrolizumab | 16.1 | 8.0 – 27.7 |
| Chemotherapy | 3.3 | 0.4 – 11.3 |
ORR was defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) as assessed using RECIST 1.1 by central imaging vendor review. The percentage of participants with a PD-L1 CPS ≥10 who experienced a CR or PR for the first pembrolizumab course is presented.
| Group | Value | 95% CI |
|---|---|---|
| Pembrolizumab | 24.0 | 9.4 – 45.1 |
| Chemotherapy | 6.9 | 0.8 – 22.8 |
ORR was defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) as assessed using RECIST 1.1 by central imaging vendor review. The percentage of participants with SCC of the esophagus who experienced a CR or PR for the first pembrolizumab course is presented.
| Group | Value | 95% CI |
|---|---|---|
| Pembrolizumab | 16.7 | 8.3 – 28.5 |
| Chemotherapy | 3.4 | 0.4 – 11.7 |
PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. Median PFS for the first pembrolizumab course as assessed by central imaging vendor review per RECIST 1.1 in all participants is presented.
| Group | Value | 95% CI |
|---|---|---|
| Pembrolizumab | 2.5 | 2.1 – 4.1 |
| Chemotherapy | 2.8 | 2.0 – 4.2 |
PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. Median PFS for the first pembrolizumab course as assessed by central imaging vendor review per RECIST 1.1 is presented for participants with a PD-L1 CPS ≥10.
| Group | Value | 95% CI |
|---|---|---|
| Pembrolizumab | 4.0 | 2.1 – 6.1 |
| Chemotherapy | 4.0 | 2.0 – 5.3 |
PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. Median PFS for the first pembrolizumab course as assessed by central imaging vendor review per RECIST 1.1 is presented for participants with SCC of the esophagus.
| Group | Value | 95% CI |
|---|---|---|
| Pembrolizumab | 2.3 | 2.1 – 4.1 |
| Chemotherapy | 2.8 | 2.0 – 4.2 |
An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. The number of participants who experienced ≥1 AE for the first pembrolizumab course are presented.
| Group | Value | 95% CI |
|---|---|---|
| Pembrolizumab | 62 | |
| Chemotherapy | 56 |
An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. The number of participants who discontinued study treatment due to an AE for the first pembrolizumab course are presented.
| Group | Value | 95% CI |
|---|---|---|
| Pembrolizumab | 10 | |
| Chemotherapy | 9 |
Time frame: From randomization through end-of-trial analysis data cutoff date of 14-March-2022 (Up to ~52 months). Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.
| Reaction | System | Pembrolizumab First Course | Chemotherapy | Pembrolizumab Second Course |
|---|---|---|---|---|
| Pneumonia | Infections and infestations | — | — | — |
| Myelosuppression | Blood and lymphatic system disorders | — | — | — |
| Diarrhoea | Gastrointestinal disorders | — | — | — |
| Dysphagia | Gastrointestinal disorders | — | — | — |
| Gastrointestinal haemorrhage | Gastrointestinal disorders | — | — | — |
| Oesophageal fistula | Gastrointestinal disorders | — | — | — |
| Oesophageal obstruction | Gastrointestinal disorders | — | — | — |
| Death | General disorders | — | — | — |
| Upper respiratory tract infection | Infections and infestations | — | — | — |
| White blood cell count decreased | Investigations | — | — | — |
| Suicide attempt | Psychiatric disorders | — | — | — |
| Haemoptysis | Respiratory, thoracic and mediastinal disorders | — | — | — |
| Febrile neutropenia | Blood and lymphatic system disorders | — | — | — |
| Cardiopulmonary failure | Cardiac disorders | — | — | — |
| Ventricular extrasystoles | Cardiac disorders | — | — | — |
| Tracheo-oesophageal fistula | Congenital, familial and genetic disorders | — | — | — |
| Abdominal pain upper | Gastrointestinal disorders | — | — | — |
| Constipation | Gastrointestinal disorders | — | — | — |
| Gastrointestinal disorder | Gastrointestinal disorders | — | — | — |
| Upper gastrointestinal haemorrhage | Gastrointestinal disorders | — | — | — |
| Vomiting | Gastrointestinal disorders | — | — | — |
| Chest discomfort | General disorders | — | — | — |
| Pyrexia | General disorders | — | — | — |
| Autoimmune hepatitis | Hepatobiliary disorders | — | — | — |
| Liver injury | Hepatobiliary disorders | — | — | — |
| Reaction | System | Pembrolizumab First Course | Chemotherapy | Pembrolizumab Second Course |
|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | — | — | — |
| White blood cell count decreased | Investigations | — | — | — |
| Vomiting | Gastrointestinal disorders | — | — | — |
| Diarrhoea | Gastrointestinal disorders | — | — | — |
| Neutrophil count decreased | Investigations | — | — | — |
| Nausea | Gastrointestinal disorders | — | — | — |
| Weight decreased | Investigations | — | — | — |
| Hypoalbuminaemia | Metabolism and nutrition disorders | — | — | — |
| Cough | Respiratory, thoracic and mediastinal disorders | — | — | — |
| Hypothyroidism | Endocrine disorders | — | — | — |
| Asthenia | General disorders | — | — | — |
| Alanine aminotransferase increased | Investigations | — | — | — |
| Decreased appetite | Metabolism and nutrition disorders | — | — | — |
| Hypokalaemia | Metabolism and nutrition disorders | — | — | — |
| Constipation | Gastrointestinal disorders | — | — | — |
| Fatigue | General disorders | — | — | — |
| Pyrexia | General disorders | — | — | — |
| Pneumonia | Infections and infestations | — | — | — |
| Gamma-glutamyltransferase increased | Investigations | — | — | — |
| Lymphocyte count decreased | Investigations | — | — | — |
| Leukopenia | Blood and lymphatic system disorders | — | — | — |
| Back pain | Musculoskeletal and connective tissue disorders | — | — | — |
| Productive cough | Respiratory, thoracic and mediastinal disorders | — | — | — |
| Alopecia | Skin and subcutaneous tissue disorders | — | — | — |
| Gastrooesophageal reflux disease | Gastrointestinal disorders | — | — | — |
| Malaise | General disorders | — | — | — |
| Aspartate aminotransferase increased | Investigations | — | — | — |
| Hyperglycaemia | Metabolism and nutrition disorders | — | — | — |
| Proteinuria | Renal and urinary disorders | — | — | — |
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | — | — | — |
| Neutropenia | Blood and lymphatic system disorders | — | — | — |
| Abdominal pain upper | Gastrointestinal disorders | — | — | — |
| Dysphagia | Gastrointestinal disorders | — | — | — |
| Chest pain | General disorders | — | — | — |
| Platelet count decreased | Investigations | — | — | — |
| Hyponatraemia | Metabolism and nutrition disorders | — | — | — |
| Cancer pain | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | — | — | — |
| Abdominal distension | Gastrointestinal disorders | — | — | — |
| Hepatic function abnormal | Hepatobiliary disorders | — | — | — |
| Upper respiratory tract infection | Infections and infestations | — | — | — |
Most-reported serious reactions: Pneumonia, Myelosuppression, Diarrhoea, Dysphagia, Gastrointestinal haemorrhage, Oesophageal fistula, Oesophageal obstruction, Death.
Data from ClinicalTrials.gov NCT03933449 adverse events section.
In the China extension study, Chinese participants with advanced or metastatic adenocarcinoma or squamous cell carcinoma of the esophagus or Siewert type I adenocarcinoma of the esophagogastric junction (EGJ) that has progressed after first-line standard therapy will be randomized to receive either single agent pembrolizumab or the Investigator's choice of chemotherapy with paclitaxel, docetaxel, or irinotecan. The primary extension study hypothesis is that treatment with pembrolizumab will prolong overall survival (OS) as compared to treatment with chemotherapy.
6 peer-reviewed publications reference this trial (live from Europe PMC):
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