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, relapsed or metastatic squamous cell carcinoma of the esophagus with PD-L1 expression of at least one percent. The German Institute for Quality and Efficiency in Healthcare (IQWiG) is now investigating in two early benefit assessments whether these two combinations have an additional benefit for patients compared to chemotherapy alone.
According to the findings, both combinations show clear benefits in overall survival, which outweigh the drawbacks in individual other outcomes. The morbidity and health-related quality of life data provided by the drug manufacturer cannot be meaningfully interpreted, so the result in any case is: indication of unquantifiable added value compared to the appropriate comparative therapy.
Same three-arm study in both files
In its files, 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 a control arm, chemotherapy alone (again 5-fluorouracil and cisplatin). The study participants were no longer amenable to curative treatment methods and were in good general condition. The benefit assessments used the results from the second data cut-off, and only from the subpopulation with tumor cell PD-L1 expression of at least one percent.
Both combinations resulted in a significant prolongation of overall survival
Compared to chemotherapy alone, both combinations were associated with longer overall survival. In any case, this is an indication of a great additional benefit. However, in the combination of nivolumab with ipilimumab, this only became apparent after approximately six months; before that, even more patients died than in the comparison arm. Chemotherapy is therefore likely to be more appropriate for certain patients, but the available data do not allow for any characteristics to be inferred that would allow physicians to identify these patients before making a treatment decision. The European regulatory authority EMA has 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 prognosis or aggressive disease.
Morbidity and quality of life data cannot be meaningfully interpreted
The observation periods for all outcomes except overall survival were shortened because they were not observed over the entire course of the study, but, for example, in the case of patient-reported outcomes on morbidity and health-related quality of life, only up to approximately four years . months after the end of treatment. The manufacturer’s records do not contain exact information about the observation periods, but it can be estimated that the observation periods were also different in the treatment arms, so that the presented analyzes of persistent deterioration cannot be interpreted in a meaningful way. The analyzes of the mean change under treatment presented by the manufacturer are also not usable because not all registered data are included in the analyses. Thus, there are no useful analyzes of patient-reported outcomes.
Conclusion: additional benefit for both combinations is not quantifiable
In addition to the major survival benefits, both combinations show positive and also negative effects for side effects, which, however, do not outweigh the benefit in overall survival. Because no useful data is available on health status and health-related quality of life, the magnitude of the benefit cannot be quantified. The conclusion in both file reviews is therefore: There is an indication of a non-quantifiable added value compared to the appropriate comparative therapy.
G‑BA decides on the amount of the extra benefit
The dossier reviews are part of the early benefit assessment under the Medicines Market Reform Act (AMNOG) under the supervision of the Federal Joint Committee (G-BA). After publication of the dossier evaluations, the G-BA conducts commentary procedures and makes the final decisions on the size of the added benefit.