Oesophageal Cancer
Keytruda® in combination with any platinum & fluoropyrimidine based chemotherapy*
KEYTRUDA® is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic carcinoma of the oesophagus or HER-2 negative gastroesophageal junction adenocarcinoma in adults whose tumours express PD-L1 with a CPS ≥ 10.1
Abbreviations: CPS: combined positive score; HER-2: Human epidermal growth factor receptor 2; PD-L1: programmed death ligand 1.
Reimbursement wording – French:2
Le traitement de première ligne des bénéficiaires adultes atteints d’un cancer de l’oesophage ou d’un adénocarcinome de la jonction gastro-oesophagienne HER-2 négatif, localement avancés non résécables ou métastatiques, dont les tumeurs expriment PD-L1 avec un CPS ≥ 10, en association à une chimiothérapie à base de sels de platine et de fluoropyrimidine (attention : les spécialités pharmaceutiques sur base de capecitabine et la spécialité pharmaceutique Teysuno ne sont pas remboursées dans cette indication).2
Reimbursement wording – Dutch:3
De eerstelijnsbehandeling van lokaal gevorderd inoperabel of gemetastaseerd carcinoom van de slokdarm, of HER-2-negatief adenocarcinoom van maag-slokdarm-overgang bij volwassen rechthebbenden bij wie de tumoren PD-L1-expressie vertonen met een CPS ≥ 10, in combinatie met platinum- en fluoropyrimidinebevattende chemotherapie (let op: de farmaceutische specialiteiten op basis van capecitabine en de farmaceutische specialiteit Teysuno worden niet vergoed in deze indicatie).3
*Platinum and fluoropyrimidine based chemotherapy, capecitabine-based pharmaceutical specialties and Teysuno® are not reimbursed in this indication.
Regardless of squamous cell carcinoma or adenocarcinoma histology, the expression of PD-L1 with a CPS* ≥10 based on the PD L1 IHC 22C3 clone is required for treatment with KEYTRUDA® + chemotherapy.1†
*A minimum of 100 viable tumour cells in the PD-L1–stained slide is required for the specimen to be considered adequate for PD-L1 evaluation.4
†Platinum and fluoropyrimidine based chemotherapy, capecitabine-based pharmaceutical specialties and Teysuno® are not reimbursed in this indication.
Abbreviations: CPS: combined positive score; PD-L1: programmed death-ligand 1; 5-FU: fluorouracil.
Study of KEYTRUDA® + cisplatin/5-FU vs. placebo + cisplatin/5-FU
aPD-L1 status was determined in a central laboratory with the PD-L1 IHC 22C3 pharmDX kit
b5-FU 800 mg/m2/day i.v. on Days 1–5 Q3W for ≤35 cycles + cisplatin 80 mg/m2 i.v. Q3W for ≤6 cycles
cPatients taking KEYTRUDA® permitted to continue beyond the first RECIST v1.1-defined disease progression if clinically stable until the first radiographic evidence of disease progression was confirmed at least 4 weeks later with repeat imaging.
*Or a disease that required immunosuppression.
Abbreviations: CPS: combined positive score; ECOG: Eastern Cooperative Oncology Group; ESCC: oesophageal squamous-cell carcinomas; GEJ: gastroesophageal junction; HER-2: Human epidermal growth factor receptor 2; n: number; ORR: objective response rate; OS: overall survival; PD-L1: programmed death ligand 1; PFS: progression-free survival; Q3W: Every 3 weeks; 5-FU: fluorouracil.
| Pembrolizumab plus chemotherapy group (n=373) | Placebo plus chemotherapy group (n=376) | |
|---|---|---|
| Age, years | ||
| Median (range) | 64 (28–94) | 62 (27–89) |
| ≥65 | 172 (46%) | 150 (40%) |
| Sex | ||
| Female | 67 (18%) | 57 (15%) |
| Male | 306 (82%) | 319 (85%) |
| Asia region* | 196 (53%) | 197 (52%) |
| Race | ||
| Asian | 201 (54%) | 199 (53%) |
| White | 139 (37%) | 139 (37%) |
| Missing | 14 (4%) | 15 (4%) |
| Native American | 9 (2%) | 12 (3%-) |
| African American | 5 (1%) | 2 (1%) |
| Other† | 5 (1%) | 9 (2%) |
| ECOG performance status | ||
| 0 | 149 (40%) | 150 (40%) |
| 1 | 223 (60%) | 225 (60%) |
| 2 | 1 (<1%) | 1 (<1%) |
| Oesophageal squamous cell carcinoma | 274 (73%) | 274 (73%) |
| Adenocarcinoma | 99 (27%) | 102 (27%) |
| Oesophageal adenocarcinoma | 58 (16%) | 52 (14%) |
| Siewert type 1 gastro-oesophageal junction adenocarcinoma‡ | 41 (11%) | 50 (13%) |
| Disease status | ||
| Metastatic | 344 (92%) | 339 (90%) |
| Unresectable locally advanced | 29 (8%) | 37 (10%) |
| PD-L1 CPS ≥10 | 186 (50% | 197 (52%) |
| Oesophageal squamous cell carcinoma | 143 (38%) | 143 (38%) |
| Adenocarcinoma | 43 (12%) | 54 (14%-) |
| PD-L1 CPS <10 | 175 (47%) | 172 (46%) |
| Oesophageal squamous cell carcinoma | 121 (32%) | 126 (34%) |
| Adenocarcinoma | 54 (14%) | 46 (12%) |
| PD-L1 status not evaluable or missing | 12 (3%) | 7 (2%) |
Adapted from Sun JM et al 2021.
Data are n(%) unless otherwise stated.
*Countries in the Asia region include China, Hong Kong, Japan, South Korea and Taiwan.
†Other includes multiple patients with ethnicities.
‡58 patients were HER2-negative, 1 patient was HER2-positive, and 32 had unknown HER2 status.
Abbreviations: CPS: combined positive score; ECOG PS: Eastern Cooperative Oncology Group Performance Status; GEJ: gastroesophageal junction; PD-L1: programmed death ligand 1; SCC: squamous cell carcinoma.
Primary endpoint: OS results showed a 38% reduction in the risk of death with KEYTRUDA® + cisplatin/5-FU vs. cisplatin/5-FU alone in patients with PD-L1 CPS ≥10 (HR=0.62; 95% CI, 0.49–0.78; p<0.0001)1
Abbreviations: CI: confidence interval; CPS: combined positive score; HR: hazard ratio; PD-L1: programmed death ligand 1; OS: overall survival; 5-FU: fluorouracil.
Primary endpoint: PFS results showed a 49% reduction in the risk of disease progression or death with KEYTRUDA® + cisplatin/5-FU vs. cisplatin/5-FU alone in patients with PD-L1 CPS ≥10 (HR-0.51; 95% CI, 0.41–0.65; p<0.0001)1
Abbreviations: CI: confidence interval; CPS: combined positive score; HR: hazard ratio; OS: overall survival; PD-L1: programmed death ligand 1; PFS: progression-free survival; 5-FU: fluorouracil.
Secondary endpoint: ORR in advanced oesophageal carcinoma or HER-2 -ve GEJ (PD-L1 CPS ≥10)1
Secondary endpoint: DoR in advanced oesophageal carcinoma or HER-2 -ve GEJ (PD-L1 CPS ≥10)1
| Endpoint response duration (DoR) | KEYTRUDA® + cisplatin/5-FU (n=186) | Cisplatin/5-FU alone (n=197) |
|---|---|---|
| Median in months (range) | 10.4 (1.9, 28.9+) | 5.6 (1.5+, 25.0+) |
| % with duration ≥6 months† | 80.2% | 47.7% |
| % with duration ≥18 months† | 33.4% | 10.4% |
†Based on Kaplan-Meier estimation.
Abbreviations: -ve: negative; CI: confidence interval; CPS: combined positive score; CR: complete response; DOR: duration of response; GEJ: gastroesophageal junction; HER-2: Human epidermal growth factor receptor 2; ORR: objective response rate; PD-L1: programmed death ligand 1; PR: partial response; 5-FU: fluorouracil.
Oesophageal squamous cell carcinoma (ESCC) CPS ≥10
| Overall survival (OS) | KEYTRUDA® + cisplatin/5-FU (n=143) | Cisplatin/5-FU alone (n=143) |
| – Primary endpoint | ||
| Median OS* (95% CI) | 13.9 (11.1–17.7) | 8.8 (7.8–10.5) |
| Hazard ratio (95% CI)† | 0.57 (0.43–0.75); P <0.0001 | |
| Progression-free survival (PFS) | KEYTRUDA® + cisplatin/5-FU (n=143) | Cisplatin/5-FU alone (n=143) |
| – Exploratory endpoint | ||
| Median PFS* (95% CI) | 7.3 (6.2–8.2) | 5.4 (4.2–6.0) |
| Hazard ratio (95% CI)† | 0.53 (0.40–0.69) |
Adapted from Sun JM et al 2021.
Adenocarcinoma CPS ≥10
| Overall survival (OS) | KEYTRUDA® + cisplatin/5-FU (n=43) | Cisplatin/5-FU alone (n=54) |
| – Exploratory endpoint | ||
| Median OS* (95% CI) | 12.1 (9.6–18.7) | 10.7 (8.2–15.3) |
| Hazard ratio (95% CI)† | 0.83 (0.52–1.34) | |
| Progression-free survival (PFS) | KEYTRUDA® + cisplatin/5-FU (n=43) | Cisplatin/5-FU alone (n=54) |
| – Exploratory endpoint | ||
| Median PFS* (95% CI) | 8.0 (6.0–8.3) | 6.0 (4.1–6.2) |
| Hazard ratio (95% CI)† | 0.49 (0.30–0.81) |
Adapted from Sun JM et al 2021.
*Based on Kaplan-Meier method for censored data.
†Based on Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by geographic region and ECOG performance status.
Abbreviations: CI: confidence interval; CPS: combined positive score; n: number; OS, overall survival; PFS, progression-free survival; 5-FU: fluorouracil.
Safety data full analysis set median follow-up 12.6 months*
| KEYTRUDA® + cisplatin/5-FU (n=370) | Placebo + cisplatin/5-FU (n=370) | |
|---|---|---|
| All AEs | 100% | 99.5% |
| Treatment-related | 98.4% | 97.3% |
| Grade ≥ 3 | 71.9% | 67.6% |
| Discontinued therapy due to treatment-related AE | 19.5% | 11.6% |
| Death due to treatment-related AE | 2.4% | 1.4% |
| Immune-mediated Adverse Events and Infusion Reactions | 25.7% | 11.6% |
| Grade ≥ 3 | 7.0% | 2.2% |
Adapted from CHMP Assessment Report. EMA/331504/2021.
No major relevant differences are observed between KEYTRUDA® + cisplatin/5-FU vs. placebo + cisplatin/5-FU after adjusting for exposure.
The noted exceptions are that more patients discontinued any drug due to drug-related AEs (19.5% vs. 11.6%) in the KEYTRUDA® combination arm.
In addition, the observed incidence of drug-related Grade 3-5 AEs (71.9% vs. 67.6%) was higher for the KEYTRUDA® cisplatin/5-FU combo with more deaths due to drug-related AEs also observed (9 vs. 5 deaths, i.e. 2.4% vs. 1.4%).
Data are n (%). The as-treated population included all patients who were randomly assigned to a treatment group and received at least one dose of study treatment.
*Safety data from participants with locally advanced unresectable or metastatic carcinoma of the oesophagus and gastroesophageal junction adenocarcinoma (Siewert type 1) who received at least one dose of KEYTRUDA® in combination with chemotherapy in KEYNOTE-590. Data cut-off July 2020.
Abbreviations: 5-FU: 5-fluorouracil; AEs: adverse event.
Adverse events with ≥15% incidence median follow-up 12.6 months†
†Data cut-off July 2020.
- Comparable safety profile between the two treatment groups
- No new safety signals detected
Abbreviations: AEs: adverse event; ITT: intention-to-treat; n: number; 5-FU: fluorouracil.
KEYTRUDA® plus cisplatin/5-FU vs. cisplatin/5-FU alone in patients with PD-L1 CPS ≥10 provides:
SUPERIOR OS AND PFS1
- OS: 38% reduction in the risk of death (HR=0.62; 95% CI: 0.48-0.78, P<0.0001)
- PFS: 49% reduction in the risk of progression or death (HR=0.51; 95% CI: 0.41-0.65, P<0.0001)
NEAR DOUBLING OF ORR AND LONGER DOR1
- ORR: 51.1% vs. 26.9% (P<0.0001)
- DoR 10.4 (1.9–28.9+) vs. 5.6 (1.5+–25.0+) months (median)
CONSISTENT SAFETY PROFILE5
- Comparable safety profile between the two treatment groups
- No new safety signals detected
FLEXIBILITY OF USE
KEYTRUDA® is approved to be combined with platinum/fluoropyrimidine* based chemotherapies of your choice and given 200 mg every 3 weeks or 400 mg every 6 weeks.1
*Platinum and fluoropyrimidine based chemotherapy, capecitabine-based pharmaceutical specialties and Teysuno® are not reimbursed in this indication.
Abbreviations: CI: confidence interval; CPS: combined positive score; DOR: duration of response; HR: hazard ratio; ORR: objective response rate; OS: overall survival; PFS: progression-free survival; 5-FU: fluorouracil.
- KEYTRUDA® must not be given as an intravenous pressure or bolus injection when used in combination, the technical information for the respective accompanying therapeutic agents must be taken into account
- When KEYTRUDA® is given as part of a combination therapy with intravenous chemotherapy, KEYTRUDA® should be given first
- Other drugs must not be given through the same infusion set
- SmPC KEYTRUDA®
- Institut national d’assurance maladie-invalidité (INAMI) / Rijksinstituut voor ziekte-en invaliditeitsverzekering (RIZIV): Keytruda® (https://ondpanon.riziv.fgov.be/SSPWebApplicationPublic/fr/Public/ProductSearch / https://ondpanon.riziv.fgov.be/SSPWebApplicationPublic/nl/Public/ProductSearch, last accessed on 01/02/2022).
- Website RIZIV: geneesmiddelen –KEYTRUDA® (pembrolizumab).
( https://www.riziv.fgov.be/nl/toepassingen/Paginas/farmaceutische-specialiteiten.aspx, last accessed on 01/02/2022). - Agilent Technologies, Inc. Instructions for Use: PD-L1 IHC 22C3 pharmDx.
- Sun JM, Shen L, Shah MA, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. Lancet 2021; 398: 759–71.
- Sun JM, Shen L, Shah MA, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. Lancet 2021(Suppl); 398: 759–71, supplementary appendix.
- Committee for Medicinal Products for Human Use (CHMP) Assessment report. EMA/331504/2021. 01/02/2022