LDK378 in Adult Patients With ALK-activated NSCLC Previously Treated With Chemotherapy and Crizotinib

This is a single-arm, open-label, multicenter, phase II study in which the efficacy and
safety of LDK378 will be evaluated in patients with stage IIIB or IV NSCLC harboring a
confirmed ALK rearrangement, defined as 15% or more positive tumor cells as assessed by the
FDA-approved FISH test (Abbott Molecular Inc.) using Vysis break-apart probes. If
documentation of ALK rearrangement by the FDA-approved FISH test is available, no further
ALK test is required for inclusion in the study. If such documentation is not available, a
new test to assess ALK status by the FDA-approved Vysis ALK break-apart FISH test should be
performed.

Patients must have been pretreated with cytotoxic chemotherapy (1 to 3 prior lines, of which
1 must have been a platinum doublet) and then with crizotinib. Patients may also have
received first line treatment with crizotinib followed by cytotoxic chemotherapy and,
subsequently, a rechallenge treatment with crizotinib. Patients must have demonstrated
progression (regardless of initial response) on the last crizotinib treatment, i.e. the
crizotinib regimen received as the last therapy prior to study entry.

The study begins with a screening period to assess eligibility, up to and including 28 days
prior to the first dose of LDK378.

The treatment period begins on Day 1 of Cycle 1. All patients will be treated with LDK378,
administered orally, at a starting dose of 750 mg. A total of approximately 137 patients
will be enrolled in the study. Patients will take LDK378 once daily, at approximately the
same time each day. On days when a PK sample is obtained, the patient will take LDK378
during the clinic visit as instructed by the study staff. Treatment with LDK378 will
continue until the patient experiences unacceptable toxicity that precludes further
treatment, discontinues treatment at the discretion of the patient or investigator, starts a
new anti-cancer therapy or dies. If the patient experiences RECIST-defined progressive
disease (PD) on LDK378 as assessed by the investigator, treatment with the study drug may be
continued if, in the judgment of the investigator, there is still evidence of clinical
benefit. These patients will be counted as PD for ORR, DOR, DCR and PFS calculations.

Assessments of tumor response and progression will be performed every 8 weeks (i.e. every 2
cycles), starting from the first day of treatment with LDK378. This schedule of tumor
assessment must continue regardless of dose interruptions. Tumor assessment should continue
until:

- For patients who experience PD as assessed by the investigator, tumor assessments
should continue every 8 weeks until LDK378 is permanently discontinued (i.e. if the
patient continues treatment with LDK378 after PD, tumor assessments should continue
until LDK378 is permanently discontinued).

- For patients who discontinue treatment in the absence of PD, tumor assessments should
continue every 8 weeks from the EOT visit until PD is assessed by the investigator.

Tumor evaluations will always cease if the patient starts a new anti-cancer therapy,
withdraws consent (unless the patient agrees to continue efficacy assessments in absence of
dosing with LDK378), or dies.

All tumor imaging assessments will be submitted for independent radiological assessment of
response by a Blinded Independent Review Committee (BIRC).

Clinical and laboratory assessments will be performed.

When the patient discontinues from study treatment an End of Treatment (EOT) visit must be
performed as soon as possible and within 7 days of the last dose of LDK378. Patients will be
contacted for the safety follow-up 30 days after their last dose of LDK378 to determine if
they have experienced any new AEs and/or to follow resolution of ongoing AEs.

Following the end of tumor assessments, the Study Phase Completion Disposition eCRF must be
completed. Patients will be contacted every 3 months to obtain information pertaining to
survival status until death, loss to follow-up, withdrawal of consent to survival follow-up,
or the end of the study. Patients do not need to visit the clinic during the survival
follow-up.

Inclusion critieria:

- Histologically or cytologically confirmed diagnosis of stage IIIB or IV NSCLC that
carries an ALK rearrangement, as per the FDA-approved FISH assay (Abbott Molecular
Inc.).

- Age 18 years or older at the time of informed consent.

- Patients must have NSCLC that has progressed during therapy with crizotinib or within
30 days of the last dose

- Patients must have received 1-3 lines of cytotoxic chemotherapy (of which 1 must have
been a platinum doublet) to treat their locally advanced or metastatic NSCLC

- Patients must have a tumor tissue sample available, collected either at the time of
diagnosis of NSCLC or any time since.

- Patients must have recovered from all toxicities related to prior anticancer
therapies to grade ≤ 2, except for patients with grade 2 nausea/vomiting and/or grade
2 diarrhea despite optimal supportive therapy who will not be allowed to participate
in the study.

Exclusion criteria:

- Patients with known hypersensitivity to any of the excipients of LDK378.

- Patients with symptomatic central nervous system (CNS) metastases who are
neurologically unstable or have required increasing doses of steroids within the 2
weeks prior to study entry to manage CNS symptoms.

- History of carcinomatous meningitis.

- Presence or history of a malignant disease other than NSCLC that has been diagnosed
and/or required therapy within the past 3 years.

- Clinically significant, uncontrolled heart disease

- Systemic anti-cancer therapy given after the last dose of crizotinib and prior to
starting study drug.