Pembrolizumab (17) – Keytruda®
Carcinoma of the esophagus or gastroesophageal junction, PD-L1 expression ≥ 10 (CPS), first-line, combination with platinum- and fluoropyrimidine-based chemotherapy.
Characteristics
| Start date | 15.11.2021 – Marketing authorisation: 24.06.2021 |
|---|---|
| Resolution | 05.05.2022 |
| INN | Pembrolizumab |
| Brand name | Keytruda® |
| Pharm. company | MSD Sharp & Dohme GmbH |
| G-BA Procedure ID | D-751 |
| ATC code | L01FF02 PD-1/PDL-1 inhibitors (L01FF) |
| ICD-10 codes (AIS) | C15.0, C15.1, C15.2, C15.3Malignant neoplasm of upper third of esophagus, C15.4Malignant neoplasm of middle third of esophagus, C15.5Malignant neoplasm of lower third of esophagus, C15.8Malignant neoplasm of overlapping sites of esophagus, C16.0Malignant neoplasm of cardiac orifice, C16.0Malignant neoplasm of cardiac orifice |
| Alpha-ID codes (AIS) | I103100Malignant neoplasm of the gastroesophageal junction, I25397Malignant neoplasm of the cervical esophagus, I25398Malignant neoplasm of the thoracic esophagus, I25399Malignant neoplasm of the abdominal esophagus, I29934Malignant neoplasm of the upper third of the esophagus, I29935Malignant neoplasm of the middle third of the esophagus, I29936Malignant neoplasm of the lower third of the esophagus, I29936Malignant neoplasm of the lower third of the esophagus |
| DDD | 9.5 mg P |
| Therapeutic area | Oncological diseases Adenocarcinoma (AC), Squamous cell carcinoma |
| Reason for procedure | New therapeutic indication |
| Specialty | Bundling Special practice conditions |
| Therapeutic indication of the resolution |
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KEYTRUDA, in combination with platinum and fluoropyrimidine-based chemotherapy, is indicated for the first-line treatment of 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 |
| Subpopulation | Indication | Comparator |
|---|---|---|
| A) | Adults with locally advanced or metastatic, non-curable squamous cell carcinoma of the oesophagus with PD-L1 expressing tumours (Combined Positive Score (CPS) ≥ 10); first-line therapy. | Therapy according to physician's choice |
| B1) | Adults with locally advanced or metastatic, non-curable, HER2-negative adenocarcinoma of the oesophagus or gastro-oesophageal junction with PD-L1 expressing tumours (Combined Positive Score (CPS) ≥ 10); first-line therapy. | Therapy according to physician's choice |
| B2) | Adults with locally advanced or metastatic, non-curable, HER2-positive adenocarcinoma of the oesophagus with PD-L1 expressing tumours (Combined Positive Score (CPS) ≥ 10); first-line therapy. | HER2-targeted therapy according to the physician's choice |
Studies and Results
|
No. of studies
(best subpopulation) |
1 (KEYNOTE 590) |
|---|---|
|
Study design
(best subpopulation) |
H2H vs. ACT |
|
Meta analysis
(best subpopulation) |
no |
| Reason for dividing into subpopulations (G-BA) | Gene/mutation specifics |
- Clinical trials
- KEYNOTE 590 is an ongoing, double-blind, randomised, multicentre trial comparing pembrolizumab in combination with cisplatin and 5-fluorouracil with placebo in combination with cisplatin and 5-fluorouracil.
- KEYNOTE 062 is a three-arm, partially blinded, randomised, multicentre trial which is double-blinded in the arms used for the benefit assessment. In the intervention arm, patients were treated with pembrolizumab in combination with cisplatin and 5-fluorouracil or capecitabine, whilst in the comparison arm they were treated with placebo in combination with cisplatin and 5-fluorouracil or capecitabine.
a) Adults with locally advanced or metastatic, non-curable squamous cell carcinoma of the oesophagus with PD-L1-expressing tumours (Combined Positive Score (CPS) ≥ 10); first-line treatment
- Consequently, the G-BA has approved pembrolizumab in combination with platinum- and fluoropyrimidine--based chemotherapy for the first-line treatment of adults with locally advanced, unresectable or metastatic squamous cell carcinoma of the oesophagus with PD-L1-expressing tumours (CPS ≥ 10).
- Consequently, the certainty of evidence for the established additional benefit is classified as ‘indication’.
- mortality
- Overall survival is defined in the KEYNOTE 590 trial as the time from randomisation to death from any cause.
- For the endpoint of overall survival, a statistically significant difference was observed between the treatment groups in favour of pembrolizumab in combination with cisplatin and 5-fluorouracil compared with cisplatin in combination with 5-fluorouracil.
- The extent of the prolongation in overall survival achieved is assessed as a significant improvement.
- Morbidity – Progression-free survival (PFS)
- In the KEYNOTE 590 trial, PFS is defined as the period from randomisation to the first documented instance of disease progression or death from any cause, whichever occurs first.
- A statistically significant difference in PFS was observed between the treatment groups, in favour of pembrolizumab in combination with cisplatin and 5-fluorouracil.
- The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity.
- Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint to patients. The overall conclusion regarding additional benefit remains unaffected.
- Morbidity – Symptoms (EORTC QLQ-C30 and EORTC QLQ-OES18)
- In the KEYNOTE 590 study, disease symptoms are assessed using the symptom scales of the cancer-specific questionnaire EORTC QLQ-C30 and the oesophageal cancer-specific supplementary module EORTC QLQ-OESI18.
- For the endpoints assessed using the EORTC QLQ-C30 – fatigue, nausea and vomiting, insomnia, loss of appetite, constipation and diarrhoea – as well as for the endpoints assessed using the EORTC QLQ-OES18 – eating, reflux, pain, swallowing saliva, dry mouth, sense of taste, cough, speech and dysphagia, there were no statistically significant differences between the treatment arms.
- By contrast, statistically significant differences in favour of pembrolizumab in combination with cisplatin and 5-fluorouracil were observed for the endpoints of pain and dyspnoea (EORTC QLQ-C30) and for the endpoint of swallowing (EORTC QLQ-OES18), there were statistically significant advantages in favour of pembrolizumab in combination with cisplatin and 5-fluorouracil.
- For the endpoint of pain (EORTC QLQ-C30), an effect modification was observed for the characteristic of age. For patients aged ≥ 65 years, there was a statistically significant advantage in favour of pembrolizumab in combination with cisplatin and 5-fluorouracil compared with cisplatin in combination with 5-fluorouracil. For patients < 65 years of age, there is no statistically significant difference between the treatment arms.
- Morbidity – Health status (EQ-5D VAS)
- Health status is assessed using the visual analogue scale (VAS) of the EQ-5D questionnaire.
- None of the analyses presented showed a statistically significant difference between the treatment arms.
- quality of life
- Health-related quality of life is assessed in the KEYNOTE 590 trial using the functional scales of the cancer-specific EORTC QLQ-C30 questionnaire.
- A statistically significant advantage in favour of pembrolizumab in combination with cisplatin and 5-fluorouracil was observed only for emotional functioning. Overall, therefore, no difference between the treatment arms relevant to the benefit assessment was observed for pembrolizumab in combination with cisplatin and 5-fluorouracil in the quality of life endpoint category.
- Side effects – Total adverse events (AEs)
- Adverse events occurred in all study participants. The results are presented here for supplementary information only.
- Side effects – Serious adverse events (SAEs), severe adverse events (CTCAE grade ≥ 3)
- No statistically significant difference was observed between the treatment arms for the endpoints SAE and severe AEs.
- Side effects – Therapy discontinuations due to AEs (≥ 1 active ingredient)
- There is no statistically significant difference between the treatment arms.
- Overall assessment
- Results from the KEYNOTE 590 trial are available for the benefit assessment of pembrolizumab in combination with platinum- and fluoropyrimidine-based chemotherapy as first-line treatment for adults with locally advanced, unresectable or metastatic squamous cell carcinoma of the oesophagus with PD-L1-expressing tumours (Combined Positive Score (CPS) ≥ 10), results from the KEYNOTE 590 trial are available for the endpoint categories of mortality, morbidity, quality of life and side effects.
- In this ongoing study, pembrolizumab in combination with cisplatin and 5-fluorouracil is being compared with the appropriate comparator therapy, cisplatin in combination with 5-fluorouracil.
- A statistically significant advantage was observed for pembrolizumab in combination with cisplatin and 5-fluorouracil in terms of overall survival. The extent of the prolongation in survival is assessed as a significant improvement.
- In the morbidity endpoint category, pembrolizumab in combination with cisplatin and 5-fluorouracil shows advantages in terms of the symptoms of pain, dyspnoea and difficulty swallowing.
- With regard to health-related quality of life, there is no difference between the treatment arms that is relevant to the assessment.
- With regard to side effects, neither an advantage nor a disadvantage can be identified for pembrolizumab in combination with cisplatin and 5-fluorouracil compared with cisplatin in combination with 5-fluorouracil. In detail, there is a disadvantage in terms of severe immune-mediated adverse events, whilst there are predominantly advantages in other specific adverse events.
- When the available results on patient-relevant endpoints are considered as a whole, the clear advantage in overall survival and further advantages in terms of symptoms are not offset by any disadvantages.
b2) Adults with locally advanced or metastatic, non-curably treatable, HER2-positive adenocarcinoma of the oesophagus with PD-L1-expressing tumours (Combined Positive Score (CPS) ≥ 10); first-line treatment
- The additional benefit is not proven.
- The pharmaceutical manufacturer did not submit any data with the dossier to assess the additional benefit of pembrolizumab in combination with platinum- and fluoropyrimidine-based chemotherapy compared with the appropriate comparator therapy.
Courtesy translation only, please refer to the German original.
Associated procedures
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