GEfitinib Plus viNOrelbine in Advanced EGFR Mutated NSCLC. GENOA Trial

Randomized, Phase II Study With Gefitinib Plus Vinorelbine Versus Gefitinib Alone in Patients Affected by Non-small Cell Lung Cancer (NSCLC) With Activating Mutations of EGFR

A sub-population of patients affected by non-small cell lung cancer (NSCLC) with activating mutations of the epidermal growth factor receptor (EGFR) do not gain benefit from treatment with tyrosine-kinase inhibitors (TKIs). The hypothesis of this study is that the addition of chemotherapy with oral vinorelbine to first-line TKI might result in improved outcomes in EGFR-mutated patients.

In spite of the dramatic improvements obtained with EGFR-TKIs in patients affected by NSCLC with activating mutations of EGFR, a fraction of these patients (about 30%) do not respond to EGFR-TKIs or achieve a response of short duration. It has been suggested that these patients may be affected by additional mutations that confer resistance to EGFR-TKIs in spite of the presence of activating mutations of the EGFR gene. Pre-clinical studies show that the addition of chemotherapy to gefitinib may result in increased anti-proliferative activity, and subsequent clinical studies suggest that the synergic activity of gefitinib and chemotherapy can depend from the employed schedules (concurrent versus sequential). Additionally, data from phase I trials of gefitinib plus vinorelbine revealed a high incidence of severe hematological toxicity with concurrent administration, while sequential schedules resulted in a more manageable safety profile.

On the basis of the aforementioned data, we hypothesize that the sequential combination of vinorelbine and gefitinib might result in improved outcomes (in terms of response and survival) in EGFR-mutated NSCLC over gefitinib alone with acceptable tolerability. The availability of an oral formulation of vinorelbine makes it possible to offer the patients an exclusively oral treatment.

Inclusion Criteria:

• Signed informed consent
• At least 18 years old
• Histologically confirmed NSCLC
• Stage IV disease
• Evidence of activating mutations of EGFR
• Measurable disease (assessed by RECIST 1.1)
• No previous chemotherapy or biological therapy for NSCLC
• Previous radiation treatment is allowed, unless all the eligible target lesions have been irradiated, and provided that at least 2 weeks have passed from the end of radiation therapy to the start of the treatment in the study
• Eastern Cooperative Oncology Group (ECOG) performance status : 0-1
• Adequate baseline bone marrow, hepatic and renal function
• In presence of central nervous system metastases, the patient has to be asymptomatic for at least 4 weeks before starting treatment in the study
• Patients who had received neoadjuvant or adjuvant chemotherapy, or concurrent chemo-radiation for non-metastatic, radically treated NSCLC are considered eligible, provided that they had not received vinorelbine as part of such treatment
• Female patients must provide a negative pregnancy test (serum or urine) prior to treatment

Exclusion Criteria:

• Other malignancies within the last 3 years, with exclusion of non-melanoma skin neoplasms and in-situ carcinoma of the cervix
• Grade III-IV New York Heart Association (HYHA) cardiac dysfunction
• Acute myocardial infarction or pulmonary embolism in the last 6 months
• Brain metastases or meningeal carcinomatosis or spinal cord compression, unless controlled and asymptomatic for at least 30 days before starting study treatment
• HIV positivity or AIDS requiring pharmacological treatment
• Pregnancy or lactation