A phase III, multicenter, randomized, open-label study of oral LDK378 versus standard chemotherapy in adult patients with ALK-rearranged (ALK-positive) advanced non-small cell lung cancer who have been treated previously with chemotherapy (platinum doublet) and crizotinib

Lung cancer has been among the most common cancers in the world, representing
12.7% of all new cancers worldwide. It was also the most common cause of death
from cancer. NSCLC accounts for more than 85% of all lung cancer cases.
Overall, current treatments are not considered satisfactory for most NSCLC
patients and the prognosis continues to be poor despite chemotherapy treatment,
with a 5-year OS rate of only 15%. During the last few years, improved
knowledge of NSCLC biology has led to the identification of molecular events
crucial for malignant transformation and cancer cell survival and *molecular
subsets* of NSCLC patients who may be candidates for targeted therapy. As a
result, new targeted treatment options have been developed.
ALK is a receptor tyrosine kinase of the insulin receptor superfamily. ALK gene
rearrangements result in aberrant ALK activation, and ALK fusion proteins
possess potent oncogenic activity in both in vitro and in vivo models. This
activity can be effectively blocked by small-molecule inhibitors that target
ALK.
Although ALK gene rearrangement is a relatively uncommon event in NSCLC with a
frequency of 2-8%, tumors driven by the EML4 and ALK translocation have been
identified as a clinically relevant molecular subset of NSCLC. While crizotinib
has impressive activity in patients with ALK-rearranged NSCLC, these cancers
invariably progress, typically within 1 year, with the development of
resistance to crizotinib. For these patients there is no alternative
ALK-targeted therapy. Therefore, the development of ALK TKIs with clinical
activity against ALK-positive NSCLC resistant to crizotinib is crucial.
LDK378 is an orally available ALK inhibitor. LDK378 is an approximately 20-fold
more potent ALK inhibitor than crizotinib, it is more selective for ALK and
does not inhibit MET. In addition, LDK378 shows potent antitumor activity in
crizotinib-resistant animal models, and the efficacy seen in the ongoing Phase
I clinical trial in patients who failed crizotinib has been extremely
encouraging. These features support the hypothesis that LDK378 could be active
in NSCLC patients whose disease has progressed on crizotinib.
In conclusion, the rationale for investigating the anti-cancer activity of
LDK378 in patients with ALK-rearranged NSCLC with disease progression following
treatment with chemotherapy and crizotinib is supported by the following:
* LDK378 is highly active in NSCLC in vitro and in vivo models.
* LDK378 has potent antitumor activity against crizotinib-resistant NSCLC cell
lines.
* Preliminary efficacy data demonstrate that LDK378 has clinically important
anti-tumor activity in the target population.
* Preliminary efficacy data support the premise that ALK oncogene addiction may
continue in NSCLC after crizotinib therapy.
* Preliminary safety data demonstrate that LDK378 is well tolerated by the
target population at the 750 mg daily dose.
* There are limited available therapeutic options and no available ALK-targeted
treatment options for the target population.

The primary objective is to compare the antitumor activity of LDK378 versus
reference chemotherapy.
The key secondary objective is to compare Overall Survival (OS) in patients
treated with LDK378 versus reference chemotherapy (pemetrexed or docetaxel).

This is an open-label, randomized, active-controlled, multi-center, phase III
study to compare the efficacy and safety of LDK378 to standard, second-line,
reference chemotherapy (pemetrexed or docetaxel) in patients with advanced
NSCLC harboring a confirmed ALK rearrangement.
Approximately 236 patients will be randomized in a 1:1 ratio to either LDK378
or reference chemotherapy (pemetrexed or docetaxel at the investigator*s
discretion). Patients will continue LDK378 or reference chemotherapy treatment
until they experience any of the following: disease progression, unacceptable
toxicity that precludes further treatment, start of a new anti-cancer therapy,
treatment is discontinued at the discretion of the investigator or patient, or
death.
Patients in the reference chemotherapy arm will be allowed to crossover to
receive LDK378 therapy.

Investigational Therapy: LDK378 (750 mg po QD)
Reference chemotherapy based on Investigator*s discretion:
pemetrexed (500 mg/m2 IV q 21 days) or
docetaxel (75 mg/m2 IV q 21 days)

There are additional assessments and visits take longer. Some of the tests
would be done during regular treatment (CT and / or MRI scans, blood tests).
Specifically for this study there will be extra assessments: ECGs, blood draws
for PK-sampling, tumor biopsy and filling out questionnaires.
The medication may cause side effects.
The tests to be carried out are generally accepted medical examinations.