Dacomitinib (1) – Vizimpro®

• Clinical trials
  • ARCHER 1050 is a multicentre, open-label, randomised controlled trial comparing dacomitinib with gefitinib.

a) Adult patients receiving first-line treatment for locally advanced or metastatic NSCLC with the activating EGFR mutations L858R or del 19

• An additional benefit is not proven for the treatment of adult patients receiving first-line treatment for locally advanced or metastatic NSCLC with the activating EGFR mutations L858R or del 19.
• mortality
  • In the ARCHER 1050 trial, overall survival was defined as the time from randomisation to death, regardless of the underlying cause of death.
  • A statistically significant difference in favour of dacomitinib was observed between the two treatment arms in terms of overall survival (hazard ratio (HR): 0.76 [95% confidence interval (CI): 0.58; 0.99]; p-value = 0.044). Median overall survival was prolonged by 7.3 months in the intervention arm compared with the control arm (median 34.1 vs. 26.8 months).
  • When interpreting the present results regarding the difference in median overall survival, it should be noted that the corresponding Kaplan–Meier curves for overall survival in both study arms show a high number of censored observations around the median. Consequently, there are significant uncertainties in the interpretation of the overall survival results. The results show a statistically significant effect, the extent of which, however, cannot be conclusively assessed due to these uncertainties. Furthermore, it should be noted that the Kaplan-Meier curves intersect at month twelve.
• Morbidity – Progression-free survival (PFS)
  • Progression-free survival was the primary endpoint in the ARCHER 1050 study and is defined as the time from randomisation to disease progression (determined by a blinded, independent radiological committee (IRC) using the RECIST criteria version 1.1) or death, regardless of the underlying cause of death.
  • PFS was statistically significantly prolonged by a median of 5.5 months in the intervention arm compared with the control arm (median 14.7 vs. 9.2 months; HR: 0.59 [95% CI: 0.47; 0.74]; p < 0.0001).
  • The results for the progression-free survival endpoint are not included in this review.
• quality of life
  • To assess health-related quality of life, the ARCHER 1050 study utilised the functional scales of the disease-specific EORTC QLQ-C30 questionnaire.
  • For the endpoints of global health status, role functioning, cognitive functioning and social functioning, a statistically significant disadvantage was observed in favor of dacomitinib compared with gefitinib. For the endpoints of physical functioning and emotional functioning, no statistically significant difference was observed between the study arms.
  • Overall, treatment with dacomitinib is associated with a clear disadvantage in terms of health-related quality of life compared with treatment with gefitinib.
• Side effects – Adverse events (AEs)
  • In ARCHER 1050, an adverse event occurred in 99.6% of patients in the intervention arm, compared with 98.2% of patients in the control arm.
• Overall assessment
  • In the mortality endpoint category, the available results for the overall survival endpoint show a statistically significant effect in favour of dacomitinib compared with gefitinib. However, due to a high number of censorings in the Kaplan-Meier curves around the median, there are significant uncertainties in the interpretation of the overall survival results, meaning that the extent of this effect cannot be conclusively assessed. Furthermore, it should be noted that the Kaplan-Meier curves intersect.
  • The advantage observed for the endpoint of overall survival is offset by a number of disadvantages in the categories of morbidity, health-related quality of life and side effects.
  • Specifically, the results for the morbidity category, in terms of symptoms, show exclusively negative effects from treatment with dacomitinib compared with gefitinib. These are evident in the patient-reported symptoms of pain, loss of appetite, diarrhoea, mouth ulcers, dysphagia, peripheral neuropathy, alopecia and other types of pain. Overall, there is a clear disadvantage in terms of symptoms. Dacomitinib also shows an adverse effect compared with gefitinib for the endpoint of general health status (assessed using the EQ-5D VAS).
  • With regard to health-related quality of life, the treatment with dacomitinib also showed exclusively adverse effects, which were observed for the patient-reported endpoints of global health status, role functioning, cognitive functioning and social functioning. In the category of health-related quality of life, therefore, dacomitinib also shows a clear disadvantage compared with gefitinib.
  • With regard to side effects, a clear disadvantage of dacomitinib compared with gefitinib is evident for the endpoint of severe adverse events (CTCAE grade 3 or 4). No differences were observed for the endpoints of serious AEs and treatment discontinuation due to AEs. In the case of specific AEs, however, adverse effects clearly predominate. In the category of side effects, therefore, relevant side effects of dacomitinib compared with gefitinib are observed overall.
  • On balance, the positive effect of dacomitinib on overall survival – the extent of which cannot be conclusively assessed – is offset by a multitude of disadvantages, some of which are significant. These are evident across the endpoint categories of morbidity, health-related quality of life and side effects. The G-BA has therefore concluded, following a balancing assessment, that the negative effects of dacomitinib outweigh the positive effect on overall survival. It is therefore concluded that additional benefit is not proven from dacomitinib compared with gefitinib in the first-line treatment of locally advanced or metastatic NSCLC with the activating EGFR mutations L858R or del 19.

b) Adult patients receiving first-line treatment for locally advanced or metastatic NSCLC with activating EGFR mutations other than L858R or del 19

• No additional benefit is proven for the treatment of adult patients receiving first-line treatment for locally advanced or metastatic NSCLC with activating EGFR mutations other than L858R or del 19.
• No data were submitted for the assessment of the additional benefit of dacominitib compared with the appropriate comparator therapy in adult patients receiving first-line treatment for locally advanced or metastatic NSCLC with activating EGFR mutations other than L858R or del 19. The ARCHER 1050 study submitted for assessment exclusively investigated patients with the activating EGFR mutations L858R or del 19.

Courtesy translation only, please refer to the German original.