Crizotinib (2) – Xalkori®

• Clinical trials
  • The PROFILE 1014 trial is a randomised, controlled trial directly comparing crizotinib with platinum-based chemotherapy.

Patients with an ECOG performance status of 0, 1 or 2

• mortality
  • overall survival
  • No statistically significant difference in overall survival was observed between the treatment groups (hazard ratio: 0.82 [0.54; 1.26], p-value = 0.180). An additional benefit of crizotinib in terms of overall survival is therefore not proven.
  • This result is based on an interim analysis using early-stage data on survival times and should therefore be regarded as preliminary; the median survival time has not yet been reached in either treatment group.
  • The assessment takes into account that, at the time of the analysis, 70% of patients had switched from the control arm to treatment with crizotinib (‘crossover’), meaning that the result for overall survival is subject to potentially significant bias.
• morbidity
  • Progression-free survival
  • Progression-free survival (PFS) was statistically significantly prolonged in the crizotinib treatment group compared with the control group: 10.9 months vs. 7.0 months median (hazard ratio: 0.45 [0.35; 0.6], p-value < 0.001).
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity.
  • The morbidity component was not assessed on the basis of symptoms, but exclusively by means of imaging procedures.
  • 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 for assessing the effects of treatment on symptoms.
  • Time-to-event analysesare used for this assessment, based on the time to the first deterioration of at least 10 points from the baseline value.
  • For the symptoms of dyspnoea, cough, pain, chest pain and fatigue, there is a statistically significant advantage of treatment with crizotinib compared with platinum-based chemotherapy.
  • Furthermore, crizotinib shows statistically significantly better outcomes for insomnia, loss of appetite, hair loss and mouth pain.
  • The only statistically significant disadvantage of crizotinib compared with platinum-based chemotherapy was observed in relation to the worsening of diarrhoea.
  • No statistically significant difference between the treatment groups was observed for the symptoms of haemoptysis, pain (arm/shoulder) / pain (other), as well as nausea and vomiting, constipation, peripheral neuropathy and dysphagia.
  • In the overall assessment of the results regarding the symptoms reported by patients in the PROFILE 1014 study, the positive effects of crizotinib clearly predominate, demonstrating a significant overall improvement in symptoms with crizotinib treatment compared with platinum-based chemotherapy, particularly with regard to the symptoms characteristic of advanced lung cancer – dyspnoea, cough and pain – which are of significant importance to patients.
• quality of life
  • Health-related quality of life was assessed in the PROFILE 1014 study using the functional scales of the cancer-specific EORTC QLQ-C30 questionnaire.
  • The time-to-event analyses used for the evaluation show a statistically significant positive effect for crizotinib across all functional scales: global health status, physical functioning, role functioning, emotional functioning, cognitive functioning and social functioning.
  • Thus, across all parameters of the questionnaire used to assess health-related quality of life, treatment with crizotinib demonstrates advantages which, overall, are assessed as a marked improvement in health-related quality of life compared with platinum-based chemotherapy.
• Side effects
  • Almost every patient in the PROFILE1014 study experienced adverse events at least once, including both those treated with crizotinib and those treated with platinum-based chemotherapy.
  • With regard to serious adverse events (SAEs) occurring under both treatments, the available results show no statistically significant difference.
  • For severe adverse events of CTCAE grade 3 or 4, there was a statistically significant advantage for the crizotinib treatment group.
  • Furthermore, a statistically significant reduction in therapy discontinuations due to adverse events was observed in the crizotinib treatment group compared with the control group receiving platinum-based chemotherapy.
  • With regard to the specific adverse events presented, the comparison of the treatment groups reveals both disadvantages and advantages in some cases, though neither clearly predominates.
  • In summary, the endpoints relating to side effects indicate an advantage for treatment with crizotinib compared with platinum-based chemotherapy.
• Overall assessment
  • For the present assessment of the additional benefit of crizotinib in the first-line treatment of anaplastic lymphoma kinase (ALK)-positive, advanced non-small cell lung cancer, the PROFILE 1014 study provides results on mortality (overall survival), morbidity, health-related quality of life and side effects.
  • For overall survival, which is a key endpoint in this indication, no additional benefit has been proven for treatment with crizotinib.
  • These interim results on overall survival are subject to potentially significant bias due to the high number of patients who switched from the control arm of the study to treatment with crizotinib.
  • There is a marked improvement in disease-specific symptoms, particularly those characteristic of advanced lung cancer and of significant importance to patients.
  • Taken together with the consistently positive effects on health-related quality of life and the advantages in terms of side effects, the overall conclusion is that crizotinib offers considerable additional benefit compared with platinum-based chemotherapy (cisplatin + pemetrexed or carboplatin + pemetrexed).

Courtesy translation only, please refer to the German original.