Crizotinib (1) – Xalkori®

• Clinical trials
  • The PROFILE 1007 trial is an open-label, randomised, controlled trial in which crizotinib is compared directly with the appropriate comparator therapy for patients for whom chemotherapy is indicated, namely chemotherapy with docetaxel or pemetrexed.

a) Patients for whom chemotherapy is indicated

• Mortality (overall survival)
  • There is no statistically significant difference in overall survival between crizotinib and chemotherapy with docetaxel or pemetrexed.
  • An additional benefit of crizotinib over the appropriate comparator therapy is not proven for overall survival.
  • The results on overall survival are based on an interim analysis of the ongoing PROFILE 1007 trial, with data cut-off on 30 March 2012.
  • In the trial, a high proportion of patients (62%) from the control group switched to crizotinib treatment (cross-over) and were included in the analysis of overall survival.
• Morbidity (symptoms)
  • The symptom scales from the EORTC QLQ-C30 and EORTC QLQ-LC13 questionnaires are used to assess symptoms; these were employed in the PROFILE 1007 study to record, in addition to health-related quality of life, general symptoms of cancer and specific symptoms of lung cancer.
  • Improvement in symptoms is described by the proportion of patients showing an improvement of 10 points.
  • The responder analyses show a statistically significant advantage for treatment with crizotinib in terms of symptom improvement for the symptoms of breathlessness, pain, cough, fatigue and loss of appetite.
  • With regard to symptom deterioration, the combined endpoint of shortness of breath, pain and cough also shows a statistically significant advantage in favour of crizotinib.
  • Taken together, this results in an additional benefit with regard to the symptoms of breathlessness, pain and cough, which is quantified as ‘considerable’.
  • Since baseline scores of 33 on the EORTC QLQ-C30 and QLQ-LC13 indicate minor symptoms, and as the observed mean values were consistently below or only slightly above this value, the symptoms recorded via the questionnaires are assessed as non-serious.
  • Nevertheless, against the background of the underlying disease, the symptoms of cough and, in particular, shortness of breath and pain are significant for the patient.
  • The endpoint ‘progression-free survival’ shows a statistically significant prolongation of progression-free survival in favour of crizotinib.
  • In the PROFILE 1007 study, tumour-related symptoms and health-related quality of life were assessed directly. Accordingly, there is no need to use progression-free survival as an auxiliary parameter for assessing symptoms or health-related quality of life.
• Health-related quality of life
  • To assess health-related quality of life, the EORTC QLQ-C30 and EQ-5D questionnaires were used in the PROFILE 1007 study.
  • The results from the EQ-5D questionnaire are not used for the assessment, due to the small number of patients – approximately 40 per cent of those included – who have so far been able to be included in the analysis.
  • With regard to the relevant subscales for health-related quality of life in the EORTC QLQ-C30, various analyses of the results are available.
  • For 5 out of 6 scales or endpoints, there is a statistically significant result in favour of treatment with crizotinib.
  • Given the effect sizes—which, although varying between endpoints, suggest a marked rather than merely moderate improvement in quality of life— and taking into account the consistent direction of effect across all statistically significant differences, there is an additional benefit for health-related quality of life from crizotinib compared with the appropriate comparator therapy at the endpoint level, which is quantified as ‘considerable’.
• Side effects
  • There is no statistically significant difference between crizotinib and chemotherapy with docetaxel or pemetrexed in terms of the overall rate of adverse events (AEs).
  • For the endpoint ‘selected common AEs’, statistically significant differences in effects were observed both to the detriment and to the benefit of crizotinib.
  • Of particular note here are the visual disturbances, which occurred at a significantly higher rate with crizotinib (absolute difference: +50.5%). However, these were predominantly visual disturbances of grades 1 and 2 (CTCAE classification).
  • For severe adverse events (severe AEs) of CTCAE grades 3 and 4, there is a statistically significant difference, with an absolute difference of 10.8 per cent more events, to the detriment of treatment with crizotinib.
  • When interpreting these results, however, it is important to take into account that progression-free survival was more than twice as long in the crizotinib arm compared with the chemotherapy arm.
  • In the time-adjusted analysis, which takes into account the resulting longer duration of treatment in the crizotinib arm, there is no longer a statistically significant difference for this endpoint.
  • With regard to serious adverse events (SAEs), significantly more SAEs occurred with crizotinib when event rates were considered without time adjustment (absolute difference: +13.8%).
  • The significant difference persists even after excluding fatal SAE due to progression.
  • In the time-adjusted analysis, however, no significant difference is observed for this endpoint.
  • There is no significant difference for the endpoint ‘SAEs excluding fatal SAEs’.
  • Given the rapid disease progression and taking into account that fatal SAEs are already included in the overall survival endpoint, the exclusion of fatal SAEs or fatal SAEs due to disease progression is considered an appropriate approach in the assessment of SAEs.
  • The results on adverse events from the PROFILE 1007 study, particularly due to the differing treatment and observation periods between the treatment groups, are to be regarded as highly biased.

b) Patients for whom chemotherapy is not indicated

• In its dossier, the pharmaceutical manufacturer does not present any studies that allow conclusions to be drawn regarding additional benefit for patients for whom chemotherapy is not indicated.
• An additional benefit for this patient group is therefore not proven.

Courtesy translation only, please refer to the German original.