Nivolumab has recently been approved both in combination with fluoropyrimidine- and platinum-based combination chemotherapy and in combination with ipilimumab for the first-line treatment of adults with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma with PD-L1 expression of at least one percent. The German Institute for Quality and Efficiency in Health Care (IQWiG) now examined in two early benefit assessments whether these two combinations have an added benefit for patients in comparison with chemotherapy alone.

According to the findings, both combinations show clear advantages in overall survival, which outweigh disadvantages in individual other outcomes. The data on morbidity and health-related quality of life provided by the drug manufacturer cannot be interpreted in a meaningful way, so that the result in each case is: indication of non-quantifiable added benefit in comparison with the appropriate comparator therapy.

The same three-arm study in both dossiers

In its dossiers, the manufacturer presented data from the CheckMate 648 study. This ongoing randomized controlled trial has three arms: nivolumab in combination with chemotherapy (5-fluorouracil and cisplatin), nivolumab in combination with ipilimumab, and, as control arm, chemotherapy alone (again 5-fluorouracil and cisplatin). The study participants were no longer amenable to curative treatment approaches and in good general condition. The benefit assessments used results of the second data cut-off, and only from the subpopulation with tumor cell PD-L1 expression of at least one percent.

Both combinations led to major prolongation of overall survival

In comparison with chemotherapy alone, both combinations were associated with longer overall survival. In each case, this is an indication of a major added benefit. In the combination of nivolumab with ipilimumab, however, this only became apparent after about six months; before that, even more patients died than in the comparator arm. Chemotherapy is therefore probably more suitable for certain patients, but no characteristics can be inferred from the available data on the basis of which physicians could recognize these patients before making a treatment decision. The European regulatory authority EMA included a corresponding warning in the Summary of Product Characteristics, according to which physicians should consider the delayed onset of effect of nivolumab in combination with ipilimumab before initiating treatment in patients with poorer prognostic features or aggressive disease.

Data on morbidity and quality of life cannot be interpreted in a meaningful way

The observation periods for all outcomes except overall survival were shortened because they were not observed over the total course of the study, but, for example in case of the patient-reported outcomes on morbidity and health-related quality of life, only until about four months after the end of treatment. The manufacturer's dossiers do not contain exact information on the observation periods, but it can be estimated that the observation periods were also different in the treatment arms so that the presented analyses on sustained deterioration cannot be interpreted in a meaningful way. The analyses on the mean change under treatment presented by the manufacturer are also not usable because not all recorded data were included in the analyses. Thus, there are no usable analyses on patient-reported outcomes.

Conclusion: added benefit for both combinations is non-quantifiable

Besides the major survival advantages, both combinations show positive and also negative effects for side effects, which do not outweigh the advantage in overall survival, however. Since no usable data are available for health status and health-related quality of life, the extent of the advantage cannot be quantified. The conclusion in both dossier assessments is therefore: There is an indication of non-quantifiable added benefit in comparison with the appropriate comparator therapy.

G‑BA decides on the extent of added benefit

The dossier assessments are 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 assessments, the G-BA conducts commenting procedures and makes final decisions on the extent of the added benefit.