A phase II study of erlotinib and sorafenib in patients with locally advanced and/or metastatic (stage IIIB or IV) Non-Small cell lung cancer (NSCLC) who have not received prior chemotherapy

Therapeutic results of standard cytotoxic therapy for advanced non small cell
lung cancer (NSCLC) are far from satisfactory: survival has reached a plateau
at a median of 9-11 months in the recently published phase III trials.
Therefore, clinical research of new treatment strategies is warranted. Several
targeted agents have been introduced into clinical trials in NSCLC. Today, two
agents, notably the EGFR-TKI erlotinib and the anti-VEGF monoclonal antibody
bevacizumab have show clinically relevant activity in NSCLC either as a single
agent in the relapse setting (erlotinib) or in conjuncture with chemotherapy in
first line setting (bevacizumab). There is a strong preclinical rationale to
pursue a strategy combining agents directed against the EGFR axis (including
the RAS-RAF pathway) and the VEGF axis in NSCLC. Indeed, in NSCLC patients
relapsing after platinum based chemotherapy, the combination of erlotinib and
bevacizumab has shown activity comparable to standard chemotherapy in
randomised phase II setting. There are several reasons to replace bevacizumab
for sorafenib in this novel doublet. Sorafenib is a very potent inhibitor of
the RAS-RAF pathway, but also affects several other pathways such as the VEGFR
pathway. Sorafenib may prove to be particularly active against NSCLC because
the proliferation signaling of the RAS/RAF/MAPK/ERK pathway is increased due to
an increase in K-RAS mutations. Sorafenib has shown activity against NSCLC cell
lines and has clinically relevant single agent activity against platinum
pretreated advanced NSCLC patients10. In addition, sorafenib is orally
available and, in contrast to bevacizumab, is labeled for all histologies of
NSCLC.

Primary:
•Efficacy of combination of erlotinib and sorafenib as determined by the rate
of no progression at 6 weeks.
•Determination of the impact of concomitant administration of sorafenib on the
pharmacokinetics (PK) of erlotinib

Secondary:
•Efficacy of erlotinib and sorafenib as determined by
-the objective response rate and disease control rate
-duration of response
-time to disease progression or death
-survival
-safety of erlotinib and sorafenib

An open-label, multicenter, phase II study

All patients will receive Erlotinib 150 mg od and Sorafenib 400 mg bid

Risks asociated with treatment of erlotinib and sorafenib. Phase I trials have
shown no excess with respect to side effects when the two agents are combined.