Pembrolizumab in combination with chemotherapy: Major added benefit in advanced squamous cell carcinoma of the oesophagus

Pembrolizumab in combination with platinum- and fluoropyrimidine-based chemotherapy is approved for the first-line treatment of adults with locally advanced, unresectable or metastatic squamous cell carcinoma or adenocarcinoma of the oesophagus with PD-L1-expressing tumours. The German Institute for Quality and Efficiency in Health Care (IQWiG) has now examined in an early benefit assessment whether and for which patients the new treatment offers an added benefit in comparison with the appropriate comparator therapy. According to this, there is a hint of major added benefit in advanced squamous cell carcinoma of the oesophagus. However, in advanced adenocarcinoma, an added benefit has not been proven.

Large therapeutic demand

Cancers of the oesophagus (oesophageal carcinomas) can be triggered by alcohol, smoking or rising stomach acid (reflux), for example. They often go unnoticed for a long time, so that the cancer is far advanced at the time of diagnosis and may already have formed metastases. In such cases, even the first-line treatment is of a palliative nature: The aim is to fight the distressing symptoms of the typically rapidly progressing disease and to prolong life by a few more months with as high a quality of life as possible. However, the therapies used so far could hardly prolong survival.

Three research questions, two studies

Recently, pembrolizumab has been approved in combination with platinum- and fluoropyrimidine-based chemotherapy for the first-line treatment of locally advanced or metastatic not curatively treatable oesophageal carcinomas, i.e. for three types of oesophageal cancer: squamous cell carcinoma (30 to 40% of all cases), HER2-negative adenocarcinoma, which is the most common one with a good 60% of all cases, and the rare HER2-positive adenocarcinoma. HER2 stands for “human epidermal growth factor receptor 2”. This growth factor receptor inhibits cell death and makes tumours producing it insensitive to chemotherapy alone.

In its dossier, the manufacturer submitted data from the KEYNOTE 590 study for the first patient group, for the second group, it additionally presented data from the KEYNOTE 062 study, and no study data for the third group. At most hints (first group) or indications (second group) of greater or lesser benefit can be derived from the material, since the exact treatment regimen in the studies remains unclear and usable data on certain patient-relevant outcomes are lacking.

Major increase in life expectancy

In HER2-negative adenocarcinoma of the oesophagus, the data of both studies suggest no effect on overall survival and no clinically relevant difference in the other outcomes. And there are no evaluable study data for patients with HER2-positive adenocarcinoma. An added benefit is therefore not proven for these two groups.

The situation was different in squamous cell carcinoma: In the KEYNOTE 590 study, the median survival time of the patients was 13.9 months with the new treatment, compared to 8.8 months in the control arm. Together with lesser harm in some side effect outcomes, this results in a hint of a major advantage that is not challenged by a single hint of a disadvantage in the side effect outcome "immune-related serious adverse events". Due to a lack of usable data, a conclusion on the health-related quality of life cannot be drawn.

Overall, there is a hint of a major added benefit of pembrolizumab in combination with platinum- and fluoropyrimidine-based chemotherapy compared with cisplatin and 5-fluorouracil for the first-line treatment of locally advanced or metastatic not curatively treatable squamous cell carcinoma of the oesophagus. “In ten years of early benefit assessment, this is the first time we have seen a new drug for this indication in the first line," says Volker Vervölgyi, Head of the Oncology Division in IQWiG's Drug Assessment Department. “The clear prolongation of overall survival in oesophageal squamous cell carcinoma is gratifying.”

G‑BA decides on the extent of added benefit

The dossier assessment is part of the early benefit assessment according to the Act on the Reform of the Market for Medicinal Products (AMNOG) supervised by the Federal Joint Committee (G-BA). After publication of the dossier assessment, the G-BA conducts a commenting procedure and makes a final decision on the extent of the added benefit.

More English-language information will be available soon (extract of the dossier assessment). If you would like to be informed when this document is available, please send an e-mail to info@iqwig.de.