Efficacy and Safety Study of BIBW 2992 to Treat Lung Cancer Patients (TIMELY)

• Progression free survival [ Time Frame: At 6 months ] [ Designated as safety issue: Yes ]
  Progression free survival will be determined by measurement of tumour size using RECIST version 1.1 at progression or date of patient death.
  
  

• Overall response [ Time Frame: CT scan of chest & abdomen 4 weeks after registartion, then every 8 calender weeks until disease progression. CT scans every 12 weeks if patient is still on BIBW 2992 after 1 year of treatment. ] [ Designated as safety issue: Yes ]
  
• Overall survival [ Time Frame: This will be measured in days, from the first day of treatment to the day of death. ] [ Designated as safety issue: Yes ]
  
• Change in performance status [ Time Frame: At 1 month ] [ Designated as safety issue: Yes ]
  
• Safety [ Time Frame: To be assessed at every timepoint i.e. baseline, fortnightly for the first 2 cycles and then monthly for 12 months and 2 monthly thereafter ] [ Designated as safety issue: Yes ]
  For each type of adverse event, the maximum toxicity grade will be obtained for each patient using CTCAE version 4.0 to closely monitor tolerability to BIBW 2992. Focus will be on those with a grade 3 or 4 BIBW 2992 related toxicities. The proportion of patients with any grade 3 or 4 event will also be examined.
  
  
• Progression free survival in patients aged 70 and over [ Time Frame: At progression or patient death ] [ Designated as safety issue: Yes ]
  
• Treatment compliance [ Time Frame: Compliance will be examined based on the time between starting treatment and stopping it completely ] [ Designated as safety issue: Yes ]
  

Drug: BIBW 2992
All patients will be given daily oral BIBW 2992 (40mg) administered every 28 days until disease progression/toxicity/clinician decision to stop.

Lung cancer is most common cause of death from cancer, of which non-small cell lung cancer (NSCLC) accounts for ~80% of all cases with most patients presenting with advanced disease. Patients medically unfit to receive radical or platinum-doublet palliative systemic therapy, because of poor performance status or comorbidity, account for at least 45% of newly diagnosed cases and have poor survival. Many oncologists have interpreted single-agent chemotherapy data as not clinically meaningful when balanced against toxicities, non-significant improvements in quality of life and comorbidity. Hence, in the UK, this group of patients are predominantly treated by best-supportive care (BSC).

This study aims to examine the efficacy and safety of using an irreversible EGFR inhibitor drug BIBW 2992 to treat patients with non-small cell lung cancer and suspected Epidermal Growth Factor Receptor (EGFR) mutation who are considered unfit for chemotherapy. This drug is currently unlicensed.

There has been only one small prospective study of medically unfit patients with EGFR mutation, but it demonstrated good efficacy with a TKI17. This phase II study of East Asian patients (n=30) with performance status 2-4 and treated with gefitinib demonstrated a rapid improvement in performance status at 1 month, an overall response rate of 66% and median survival of 17.8 months. Whilst gefitinib is licensed for EGFR mutant NSCLC, no prospective studies have yet been performed on medically unfit patients from Western countries. Despite dramatic initial responses, EGFR mutant NSCLC patients treated with gefitinib/erlotinib ultimately relapse. In ~50% of cases this is due to the gefitinib/erlotinib-resistant T790M genotype acquired through either secondary somatic mutation or clonal expansion. There is therefore a need to improve the outcomes of medically unfit patients with suspected EGFR mutation, who would otherwise be treated with best supportive care, and in proven EGFR mutation cases by using an effective EGFR-directed therapy that inhibits EGFRT790M.

Prospective data on medically unfit Western NSCLC patients with EGFR mutation are required to assess the efficacy of EGFR-TKIs. Additionally, given that 50% of such patients will become TKI-resistant through EGFRT790M, new therapies are required to overcome this resistance mechanism.

We aim to recruit patients with clinical characteristics likely to harbour EGFR mutation but with EGFR genotype unknown either due to no tissue suitable for genotyping, failed genotype; these will be patients with adenocarcinoma who are never- or ex-light smokers.