A randomized phase III trial of erlotinib versus docetaxel in patients with advanced squamous cell non-small cell lung cancer who failed first line platinum based doublet chemotherapy stratified by VeriStrat Good vs VeriStrat Poor (EMPHASIS, NVALT13, ETOP 3-12)

Standard treatment of non-small cell lung cancer (NSCLC) is platinum-containing
chemotherapy. After failure of this treatment docetaxel en erlotinib are used
as monotherapy, because of the favorable results in comparison with best
supportive care.
Currently there are no accepted baseline criteria to allow choosing between
docetaxel or erlotinib, except for the presence of an activating epidermal
growth factor receptor (EGFR) mutation, provided patients did not receive an
EGFR-tyrosine kinase inhibitor (TKI) as first line therapy. In fact, the
INTEREST trial that randomized NSCLC patients with all histologies between
gefitinib and docetaxel in the second line setting, showed no difference in PFS
and OS in the EGFR wild-type (WT) population. In a subgroup analysis, patients
with squamous cell carcinomas did not present any difference in PFS or OS
between both treatment groups.
Recently, a blood-based proteomic test, VeriStrat®, that appears to be both
predictive and prognostic for outcome in patients with NSCLC, has become
available. VeriStrat assigns each sample a *good* (VSG) or *poor* (VSP) label.
In approximately 2% of cases, an unequivocal label cannot be assigned and an
indeterminate classification is reported. The test has been validated in a
study with De gefitinib and erlotinib. These studies confirmed that patients
classified as VSG had better PFS and OS outcome than patients classified as
VSP. VeriStrat demonstrated outstanding reproducibility. Retrospective analysis
of VeriStrat performed on available serum samples of patients from a trial of
erlotinib versus placebo confirmed the above results for the treatment arms. De
resultaten van de VeriStrat test bij het gevorderde plaveiselcelcarcinoom in de
populatie met een uitslag *goed* waren onverwacht positief na behandeling
gefitinib. In the initial evaluation of VeriStrat it was found that patients
with relapsed squamous cell lung carcinoma and designated to the VSG population
had an unexpectedly favorable outcome following treatment with gefitinib. The
test does not seem to discriminate between patients who receive cytotoxic
chemotherapy, including docetaxel.
Thus, one rational approach for using the VeriStrat test is a trial design
where patients with relapsed squamous cell lung cancer in both strata (VSG and
VSP) are randomized between an EGFR-TKI and chemotherapy. As both erlotinib and
docetaxel are currently approved for this indication, these drugs will be used
in the proposed trial.

Primary: Explore the predictive ability of the VeriStrat signature, by testing
for interaction between treatment arms (Arm A: erlotinib vs Arm B: docetaxel)
and VeriStrat status (VSG vs VSP) using as outcome progression free survival.
Secondary Objectives: Objective response rate (ORR) and disease control rate
(DCR), Duration of response, OS, Safety.
Secondary: Explore whether treatment with erlotinib provides progression free
survival benefit as compared to docetaxel in the VSG group. Compare progression
free survival in the two treatment arms (Arm A: erlotinib vs Arm B: docetaxel)
in the VSP group. Explore the prognostic ability of the VeriStrat signature by
testing for an overall difference in progression free survival between the two
VeriStrat groups (in case of no significant interaction). Effects on OS,
response rate and disease control rate. Assess the safety and the tolerability
of the two treatments separately in each VeriStrat group and overall.

Multicenter randomized open phase III parallel group study.
Testing of VeriStrat status (good/poor). Only patients with a definite
VeriStrat status will be included.
Patient will be randomly allocated to either:
* Docetaxel IV infusions every 3 weeks, 75 mg/m2.
* Erlotinib tablets 150 mg daily.
Stratification for VeriStrat status.
Study duration: till disease progression.
Approx. 500 patients.

Treatment with docetaxel or erlotinib.

Risk: Adverse events of study treatment.
Burden: The study follows the standard treatment for medication (docetaxel or
erlotinib), hospital visits, safety blood tests and imaging.
Extra test:
Blood test VeriStrat 3,5 ml blood once.