Nivolumab has recently been approved both in combination with fluoropyrimidine-platinum combination chemotherapy and in combination with ipilimumab for the first-line treatment of adults with unresectable, advanced, recurrent, or metastatic squamous cell carcinoma of the esophagus with PD-L1 expression of at least one. per cent. The German Institute for Quality and Efficiency in Healthcare (IQWiG) now examined in two early benefit assessments whether these two combinations have an added benefit for patients compared to chemotherapy alone.
According to the results, both combinations show clear advantages in overall survival, which outweigh disadvantages in other individual outcomes. Morbidity and health-related quality of life data provided by the drug manufacturer cannot be meaningfully interpreted, so the result in each case is: indication of unquantifiable added benefit compared with the appropriate comparator therapy.
In its filings, 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 an arm control, chemotherapy alone (again 5-fluorouracil and cisplatin). Study participants were no longer amenable to curative treatment approaches and in good general health. Benefit assessments used results from the second data cutoff and only the subpopulation with PD-L1 tumor cell expression of at least one percent.
Compared with chemotherapy alone, both combinations were associated with longer overall survival. In each case, this is an indication of a large added benefit. In the combination of nivolumab with ipilimumab, however, this only became apparent after about six months; before that, more patients still died than in the comparator arm. Therefore, chemotherapy is probably more appropriate for certain patients, but no characteristics can be inferred from the available data on the basis of which clinicians 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 clinicians should consider the delayed onset of effect of nivolumab in combination with ipilimumab before starting treatment in patients with poorer prognostic characteristics or aggressive disease.
The observation periods for all outcomes, except overall survival, were shortened because they were not observed throughout the study, but, for example, in the case of patient-reported outcomes of morbidity and quality of health-related life, only up to 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 analyzes of sustained deterioration cannot be interpreted a significant way. Analyzes of mean change under treatment reported by the manufacturer also cannot be used because not all recorded data were included in the analyses. Therefore, there are no usable analyzes of patient-reported outcomes.
In addition to the main survival advantages, both combinations show positive and also negative effects for side effects, which do not, however, exceed the advantage in overall survival. Because useful data on health status and health-related quality of life are not available, the extent of the benefit cannot be quantified. Therefore, the conclusion of both case reviews is: there is an indication of unquantifiable added benefit compared to the appropriate comparator therapy.
Dossier evaluations are part of the Advance Benefit Evaluation under the Drug Market Reform Act (AMNOG) overseen by the Federal Joint Committee (G-BA). After the dossier evaluations are published, the G-BA conducts comment procedures and makes final decisions on the scope of the added benefit.
Source:
Institute for Quality and Efficiency in Health Care