Crizotinib (3) – Xalkori®

• Clinical trials
  • The PROFILE 1007 trial is an open-label, randomised controlled trial comparing crizotinib with chemotherapy (docetaxel or pemetrexed) in the treatment of patients with ALK-positive, locally advanced or metastatic NSCLC.

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 therefore not proven for overall survival.
  • The results on overall survival are based on the first data cut-off (30 March 2012) from the PROFILE 1007 study.
  • By this point, a high proportion of patients (62%) from the control group had already switched to crizotinib treatment (‘cross-over’).
• morbidity
  • Symptoms
  • Data from the symptom scales of the cancer-specific EORTC QLQ-C30 questionnaire and the lung cancer-specific EORTC QLQ-LC13 questionnaire are available to assess the effects of treatment on symptoms.
  • For the symptoms of breathlessness, pain, cough, fatigue and loss of appetite, there was a statistically significant improvement in symptoms with crizotinib treatment compared with chemotherapy.
  • With regard to symptom deterioration, the combined endpoint comprising shortness of breath, pain and cough also shows a statistically significant advantage for crizotinib.
  • Taken together, this results in an additional benefit with regard to the symptoms of breathlessness, pain and cough, which is quantified as ‘considerable’.
  • As baseline scores of 33 on the EORTC QLQ-C30 and QLQ-LC13 symptom scales 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.
  • Progression-free survival
  • Progression-free survival (PFS) was statistically significantly prolonged in the crizotinib treatment group compared with the chemotherapy treatment group: a median of 7.7 versus 3.0 months (hazard ratio: 0.487 [0.371; 0.638], p < 0.0001).
  • This endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity.
  • Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint.
• quality of life
  • Data from the functional scales of the cancer-specific EORTC QLQ-C30 questionnaire are available to assess the effects of the treatment on health-related quality of life.
  • The responder analyses, using a validated response criterion, show a statistically significant result in favour of treatment with crizotinib for 5 out of 6 scales.
  • Given the effect sizes, which – although varying between the individual scales – 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 of crizotinib over the appropriate comparator therapy at the endpoint level for health-related quality of life, which is quantified as ‘considerable’.
• Side effects
  • The endpoint ‘Adverse events (total)’ shows that almost every patient experienced at least one adverse event, both whilst receiving crizotinib and whilst undergoing chemotherapy with docetaxel or pemetrexed.
  • With regard to serious adverse events (SAEs), significantly more SAEs occurred under crizotinib when considering event rates without time adjustment (absolute difference: +13.8%).
  • This significant difference persists even after excluding fatal SAE due to disease progression.
  • In contrast, the time-adjusted analysis showed no significant difference for the endpoint ‘SAEs – excluding fatal SAEs due to disease progression’.
  • There is no significant difference for the endpoint ‘SAEs – excluding fatal SAEs’.
  • With regard to severe adverse events (severe AEs) of CTCAE grades 3 and 4, there is a statistically significant difference, with an absolute difference of 10.8% more events, to the detriment of treatment with crizotinib.
  • In the time-adjusted analysis, there is no statistically significant difference for this endpoint.
  • The significantly increased incidence of visual disturbances under crizotinib (absolute difference: +50.5 per cent) should be highlighted here.
  • However, these are predominantly visual disturbances of grades 1 and 2 (CTCAE classification).
  • The results on adverse events from the PROFILE 1007 study, particularly due to the differing treatment and follow-up periods between the treatment groups, must be regarded as highly biased.
• Conclusion
  • Taking the results on mortality, morbidity, quality of life and side effects into account as a whole, there is a marked improvement in quality of life as well as a significant reduction in non-serious but significant symptoms.
  • No proof of an additional benefit for treatment with crizotinib has been found in terms of overall survival.
  • The result for this endpoint, taking into account the high proportion of patients who switched to the crizotinib treatment group following tumour progression (‘crossover’), with the possible consequence that differences in survival time between the treatment groups are not captured, does not alter the overall assessment.
  • Against the background of the improvements achieved in quality of life and the severity of the disease, the results regarding side effects are not considered serious; consequently, a downgrading of the extent of the additional benefit would not be justified.
  • Consequently, the overall assessment concludes that crizotinib offers additional benefit over chemotherapy with docetaxel or pemetrexed, the extent of which is classified as ‘considerable’.
  • A classification of the extent as ‘major’ is not justified, as, in particular, long-term freedom from serious symptoms and the largely successful avoidance of serious side effects are not achieved.

b) Patients for whom chemotherapy is not indicated

• For patients for whom chemotherapy is not indicated, an additional benefit is not proven.

Courtesy translation only, please refer to the German original.