Prospective Evaluation of Small Molecule EGFR-1 Tyrosine Kinase Inhibition as a First-Line Treatment in Patients With Advanced Non-Small Cell Lung Cancer (NSCLC) Harbouring a Mutant EGFR Gene
Trial Snapshot
- Phase
- Phase 2
- Sponsor
- Enrollment
- 40
- Locations
- 2
- Primary Endpoint
- Establish clinical benefit (progression free survival) of first line RTKI in patients with stage IV and stage IIIB NSCLC not eligible for curative-intent treatment (chemo-radiotherapy) carrying a mutant EGFR-1.
Study Overview
Brief Summary
Current chemotherapy for advanced non-small cell lung cancer, not amenable for curative local treatment (surgery or chemoradiotherapy), has a modest life-prolonging effect and can improve quality of life. There is however no potential for long-term cure for these patients.
Chemotherapy also produces variable and often significant toxicity. Current retrospective evidence suggests that significant clinical responses can be obtained when patients whose cancer cells have an EGFR TKD mutation are treated with an EGFR TKI.
The ease of administration and toxicity profile of TKI compare favourably with that of chemotherapy, even single agents such as for example gemcitabine The present study will establish the clinical benefit rate of TKI as a first line treatment in patients with EGFR mutations and thus estimate the proportion of patients who might benefit for a prolonged period from a treatment with a modest toxicity profile.
Detailed Description
Patients with stage IV NSCLC and some patients with advanced locoregional disease (stage III) are in general incurable and have a low probability for long-term survival.
Current systemic treatment in good PS patients (PS 0-1) consists of a cisplatin doublet (e.g. cisplatin plus a second drug: vinorelbine, gemcitabine, paclitaxel, docetaxel). The median and one year survival obtained with this treatment ranges between 8-10 months and 25 - 35 % respectively (1,2). Progression-free survival is a median of 5 month or less in randomized studies (3). Response rates obtained are less than 25% in metastatic disease and up to 75% in advanced locoregional disease.
Receptor tyrosine kinase inhibitors (RTKI's) are active drugs in patients with NSCLC pre-treated with cisplatin and/or docetaxel containing chemotherapy (2,4). Recently it has been shown that the EGFR1 kinase inhibitor erlotinib added to best supportive care (BSC) prolonged survival compared to BSC alone in patients with advanced NSCLC failing 1st or 2nd line chemotherapy (5).
A small number of preliminary reports have indicated that the objective response rate with these RTKI's as first line treatment in some patient populations with advanced NSCLC could be around 20 % (6), The objective (mainly partial) response in the phase II studies with pre-treated patients ranges from 10 - 15 % according to the level of pre-treatment but the control of the disease (stable disease) and improvement of symptoms without demonstrated objective response has been reported to be as high as 40 to 50 % (2,4). The addition of RTKI's or placebo to the current standard doublets (e.g. cisplatin, gemcitabine or taxol/carboplatin) has not been shown to impact on response rate, time to treatment failure or survival in large phase III randomised trials in advanced NSCLC patients not selected for EGFR expression (7,8).
Recently, mutations in the intracellular EGFR kinase domain that increase sensitivity of the receptor to RTKI's have been discovered (9,10). These studies suggest that the response/resistance to treatment could be strongly correlated to the presence/absence of such mutations. It is presently unclear whether patients who achieve stable disease under RTKI treatment do have receptor mutations, of which nature such mutations could be or what other biological pathways modulate the responsiveness/resistance.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Histological or cytological diagnosis of inoperable, locally advanced, recurrent or metastatic (Stage IIIB or Stage IV) adenocarcinoma of the lung in a patient with a smoking history of < 15 years and quit smoking > 1 year before diagnosis.
- •Evidence of disease but measurable disease is not mandatory.
- •18 years of age or older.
- •ECOG performance status of 0 -
- •Patients not eligible for standard curative-intent treatment with surgery or chemo-radiotherapy.
- •Life expectancy ³ 3 months.
- •Prior therapy for NSCLC allowed for primary disease: surgery and radiotherapy and adjuvant or proto-adjuvant chemotherapy completed > 6 months before inclusion
- •Adequate bone marrow, hepatic and renal function:
- •Granulocyte count > 1.5 x 109/L and platelet count > 100 x 109/L Serum bilirubin must be < 1.5 upper limit of normal (ULN). If alkaline phosphatase is > 2.5 x ULN, SGOT (AST) and SGPT (ALT) must be < 1.5 x ULN.
- •Serum creatinine < 1.5 ULN or creatinine clearance > 60 ml/min.
- •Ability for giving informed consent for participating in the study and filling out FACT-L quality of life scales.
- •Able to comply with study and follow-up procedures.
- •Availability of tumour biopsy sample (fixed in formalin and, if possible, also snap frozen tumour sample). If frozen samples are available, these will be collected by central data management.
- •Signed Informed Consent for performing mutation analysis and subsequent biomarker analysis.
- •Separate signed Informed Consent for participation in the treatment phase of the study.
- •Ability to take oral medication.
- •For all females of childbearing potential a negative pregnancy test must be obtained within 48 hours before starting therapy.
Exclusion Criteria
- •Patients for whom urgent chemotherapy or radiotherapy is deemed necessary (e.g. rapidly progressive disease).
- •Current symptomatic central nervous disorder, brain or leptomeningeal metastasis.
- •Pre-existing symptomatic interstitial lung disease, not related to the current malignancy.
- •Patients with a history of other malignancies, except patients with basal cell carcinoma of the skin or in situ carcinoma of the cervix with a disease free interval of ³ 5 years. Patients with a prior history of other good prognosis malignancies more than 5 years since end of treatment and in un-maintained complete remission also can be considered for inclusion
- •Prior therapy with systemic anti-tumour therapy with HER1/EGFR inhibitors (small molecule or monoclonal antibody) or chemotherapy
- •Significant malabsorption syndrome or disease affecting the gastrointestinal tract function
- •Pregnant or breast-feeding women; for women in reproductive condition, a negative pregnancy test is required.
- •Concomitant food or drug intake which potentially impairs absorption and metabolisation of RTKI's.
- •Participation in another clinical trial with any investigational drug within 30 days prior to study screening.
- •Any unstable systemic disease (including active infection, grade 4 hypertension, unstable angina, congestive heart failure, hepatic, renal or metabolic disease).
- •Any significant ophthalmological abnormality, especially severe dry eye syndrome, keratoconjunctivitis sicca, Sjögren syndrome, severe exposure keratitis or any other disorder likely to increase the risk of corneal epithelial lesions.
Outcomes
Primary Outcomes
Establish clinical benefit (progression free survival) of first line RTKI in patients with stage IV and stage IIIB NSCLC not eligible for curative-intent treatment (chemo-radiotherapy) carrying a mutant EGFR-1.
Secondary Outcomes
- Determine biological correlates for response/resistance in tumour tissues.
- Determine response rate (OR and stable disease) and duration under erlotinib treatment.
- Determine the effect on Quality of Life (QOL) of first-line anti-EGFR-1 treatment.
- Determine the value of positron emission tomography (PET)-scan as an early predictor of response and clinical benefit.
- Overall survival from the time of study entry to the date of death or date of last follow-up.