Conditions: Non-small Cell Lung Cancer Non-small Cell Lung Cancer Metastatic Non-small Cell Lung Cancer Recurrent
Keywords: RET-rearrangement advanced NSCLC
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 14
Healthy volunteers: no

Brief summary:
A research study to evaluate the activity of alectinib for the Treatment of pretreated patients with advanced NSCLC that have confirmed RETrearrangement.

Detailed description:
The trial is investigating the efficacy of alectinib in patients with advanced stage RET-rearranged NSCLC, treated with at least one platinum based systemic chemotherapy regimen. Preclinical studies have shown that alectinib, a highly selective next generation ALK inhibitor, has potent anti-tumour activity in RET-rearranged NSCLC. Therapeutically, several multiple kinases inhibitors, are potentially able to inhibit RET kinase function, which has been tested in several unselected NCSLC trials. However, those result were negative and none of the tested drugs was approved for lung cancer treatment.

The ALERT-lung trial is a single arm, phase II trial with the primary objective to assess the efficacy of alectinib in terms of best overall response (OR) assessed by RECIST v1.1 in selected NSCLC patients with RET rearrangement. The secondary objectives are to evaluate secondary measures of clinical efficacy including disease control, progression-free survival (PFS), and overall survival (OS) as well as to assess safety and tolerability of the treatment and to describe the association of primary and secondary outcomes with tumour characteristics.

Alectinib is administered orally, 600 mg, twice per day, until progression, refusal or unacceptable toxicity. Trial treatment may also continue beyond progression, with physician and patient agreement, for as long as the patient may still derive clinical benefit. A total sample size of 44 patients is required.

Arms:
arm 1: Alectinib is administered orally, 600 mg, twice per day (1200 mg per day) until progression, refusal or unacceptable toxicity.

Trial treatment may also continue beyond progression, with physician and patient agreement, for as long as the patient may still derive clinical benefit as per investigator decision.

Interventions: intervention 1: Alectinib
Intervention descriptions: intervention 1: Alectinib is administered orally 600mg (4x150mg capsules), twice per day (8 capsules, total 1200mg daily). The appropriate number of alectinib capsules will be provided to patients to be self-administered at home.

Alectinib capsules must be taken at the same time each day with food. If a planned dose of alectinib is missed, patients can take the missed dose up until 6 hours before the next dose.

Protocol document:
Prot_000.pdf: 
ETOP 12-17 ALERT-lung protocol v1.2 20180306  
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ETOP 12-17 ALERT-lung 
A single arm phase II trial evaluating the activity of alectinib for the 
treatment of pretreated RET-rearranged advanced NSCLC 
ALERT-lung: ALEctinib for the treatment of pretreated RET-rearranged  
advanced non-small cell lung cancer 
Sponsor and Coordinating Group: 
European Thoracic Oncology Platform (ETOP) 
Collaborative Group: 
Lung Cancer Group Cologne 
EudraCT number: 2017-002063-17 
Roche Number: MO30176 
ETOP c/o IBCSG Coordinating Centre, Effingerstrasse 40, CH- 3008 Bern 
Phone: +41 31 511 94 00 
Fax: +41 31 511 94 01 
Version 1.2 
06 March 2018 
 


 
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Contacts 
Trial Chair 
Enriqueta Felip, MD-
PhD 
Address 
 
 
Tel: 
Fax: 
Email:  
Vall d'Hebron University Hospital 
Passeig de la Vall d'Hebron, 119-129 
08035 Barcelona, Spain 
+34 629 125 392 
+34 932 746 059 
efelip@vhebron.net 
Trial Chair 
Jürgen Wolf, MD-
PhD 
Address 
 
 
Tel: 
Fax: 
Email:  
University Hospital Cologne 
Kerpenerstr 62 
50924 Cologne, Germany 
+49 221 478 890 50 
+49 221 478 890 51 
juergen.wolf@uk-koeln.de 
Trial Co-Chair 
Egbert F. Smit, MD-
PhD 
Address 
 
 
 
Tel: 
Fax: 
Email:  
The Netherlands Cancer Institute 
Amsterdam (NKI-AVL) 
Plesmanlaan 121 
1066 CX Amsterdam, the Netherlands 
+31 20 512 90 98 
+31 20 512 25 72 
e.smit@nki.nl 
ETOP Chairman 
Rolf Stahel, MD 
Address 
 
 
 
Tel: 
Fax: 
Email:  
Clinic of Oncology 
University Hospital Zuerich  
Raemistrasse 91 
CH-8091 Zürich, Switzerland  
+41 44 255 22 19 
+41 44 255 9780 
rolf.stahel@usz.ch 
ETOP Scientific 
Coordinator 
Solange Peters, MD-
PhD 
 
 
 
 
Address 
 
 
Tel:  
Fax: 
Email: 
Département d'Oncologie 
Centre Hospitalier Universitaire Vaudois  
1011 Lausanne, Switzerland 
+41 79 556 01 92 
+41 21 314 07 37 
solange.peters@chuv.ch 
SAKK Trial 
Coordinator  
Christian Britschgi, 
MD-PhD 
Address 
 
 
 
Tel: 
Fax: 
Email:  
Clinic of Oncology 
University Hospital Zuerich  
Raemistrasse 91 
CH-8091 Zürich, Switzerland  
+41 44 255 22 14 
+41 44 255 45 48 
Christian.Britschgi@usz.ch 
Translational Research 
Coordinator 
Rosita Kammler 
Address 
 
 
 
Tel: 
Fax: 
Email:  
ETOP Coordinating Office 
c/o IBCSG Coordinating Centre 
Effingerstrasse 40 
3008 Bern, Switzerland 
+41 31 511 94 28 
+41 31 511 94 01 
rosita.kammler@ibcsg.org 
Central Laboratory 
Sabine Merkelbach-
Bruse 
Address 
Institute for Pathology 
University Hospital Cologne 
Kerpenerstr 62 
50924 Cologne, Germany 
+49 221 478 6369 
+49 221 478 6183 


 
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Statistics 
Urania Dafni, ScD 
 
 
 
 
 
Zoi Tsourti, PhD 
Address 
 
 
Tel:  
Fax: 
Email: 
Email: 
Frontier Science Foundation – Hellas 
116 Papadiamantopoulou Str. 
15773, Zografou, Athens, Greece 
+302107710902 
+302107710903 
udafni@frontier-science.gr 
ztsourti@frontier-science.gr 
Project Manager 
 
 
 
 
 
 
Viktor Zsuffa 
 
 
 
 
 
 
Address 
 
 
 
Tel: 
Fax: 
Email: 
ETOP Coordinating Office 
c/o IBCSG Coordinating Centre 
Effingerstrasse 40 
3008 Bern, Switzerland 
+41 31 511 94 48 
+41 31 511 94 01 
ALERT-lung@etop-eu.org 
Data Management 
Anne-Christine 
Piguet, PhD 
Tel: 
Fax: 
Email: 
+41 31 511 94 21 
+41 31 511 94 01 
ETOPDataManagement@etop-eu.org 
Drug Supply 
Barbara Ruepp, 
PharmD 
Address 
 
 
 
Tel:  
Fax: 
Email:  
ETOP Drug Supply Office 
c/o IBCSG Coordinating Centre 
Effingerstrasse 40 
3008 Bern, Switzerland 
+41 31 511 94 16 
+41 31 389 92 29 
drugsupply@etop-eu.org 
Safety and Regulatory 
Affairs 
Barbara Ruepp, 
PharmD 
Address 
 
 
 
Tel:  
Fax: 
Email: 
ETOP Safety and Regulatory Office 
c/o IBCSG Coordinating Centre 
Effingerstrasse 40 
3008 Bern, Switzerland 
+41 31 511 94 16 
+41 31 389 92 29 
regulatoryoffice@etop-eu.org 
ETOP Medical Affairs 
 
 
 
 
 
Manuela Rabaglio, 
MD 
Address 
 
 
 
Tel: 
Fax : 
Email : 
ETOP Medical Affairs 
c/o IBCSG Coordinating Centre 
Effingerstrasse 40 
3008 Bern, Switzerland 
+41 31 511 94 20 
+41 31 511 94 01 
medical.affairs@ibcsg.org 
ETOP Coordinating 
Office 
Anita Hiltbrunner 
 
 
 
 
 
 
Heidi Roschitzki-
Voser, PhD 
 
Address 
 
 
Tel:  
Fax: 
Email: 
 
Tel: 
Fax: 
Email: 
c/o IBCSG Coordinating Centre 
Effingerstrasse 40 
3008 Bern, Switzerland 
+41 31 511 94 42 
+41 31 511 94 01 
anita.hiltbrunner@etop-eu.org 
 
+41 31 511 94 18 
+41 31 511 94 01 
heidi.roschitzki@etop-eu.org 
Remote Data Entry 
System 
Anne-Christine 
Piguet, PhD 
 
Technical assistance 
 
Email: 
 
Email: 
 
ETOPDataManagement@etop-eu.org 
 
richard.king@etop-eu.org 
 
In collaboration with F. Hoffmann-La Roche Ltd. 
 
 


 
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Protocol Signature Page 
 
ETOP 12-17 ALERT-lung 
A single arm phase II trial evaluating the activity of alectinib for the 
treatment of pretreated RET-rearranged advanced NSCLC 
Approved by: 
Enriqueta Felip 
Trial Chair 
 
 
 
 
 
Date 
Jürgen Wolf 
Trial Chair 
 
 
 
 
 
Date 
Rolf Stahel 
ETOP Chairman 
 
 
 
 
 
 
Date 
Urania Dafni 
Biostatistician 
 
 
 
 
 
Date 
Anita Hiltbrunner 
ETOP Director 
 
 
 
 
 
 
Date 


 
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Principal Investigator Protocol Signature Page 
ETOP 12-17 ALERT-lung 
A single arm phase II trial evaluating the activity of alectinib for the 
treatment of pretreated RET-rearranged advanced NSCLC 
I have read the protocol and agree that it contains all necessary details for conducting this trial. 
I will conduct the trial as outlined in the following protocol and in compliance with GCP, and 
will apply due diligence to avoid protocol deviations. I will provide copies of the protocol and 
all drug information relating to pre-clinical and prior clinical experience furnished to me by 
ETOP, to all physicians responsible to me who participate in this trial. I will discuss this 
material with them to assure that they are fully informed regarding the drug and the conduct 
of the trial. I agree to keep accurate records on all patient information including patient's 
informed consent statement, drug shipment and return forms, and all other information 
collected during the trial for a minimum period of 15 years. 
Name of Principal Investigator:  
 
Institution’s name and place: 
 
 
 
 
 
 
Signature 
Date 
 
 
 


 
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TABLE OF CONTENTS  
Section 
Page 
1. 
Protocol summary ...................................................................................................... 9 
2. 
List of abbreviations ................................................................................................ 15 
3. 
Trial schedule ........................................................................................................... 17 
4. 
Background and rationale ........................................................................................ 20 
4.1. 
NSCLC targeted treatment strategies .................................................................. 20 
4.2. 
RET fusion in NSCLC ......................................................................................... 20 
4.3. 
Alectinib .............................................................................................................. 21 
4.4. 
Overall risk / benefit assessment ......................................................................... 22 
4.5. 
Rationale for trial design and alectinib dose ....................................................... 22 
5. 
Objectives and endpoints ......................................................................................... 23 
5.1. 
Primary objective ................................................................................................. 23 
5.2. 
Secondary objectives ........................................................................................... 23 
5.3. 
Primary endpoint ................................................................................................. 23 
5.4. 
Secondary endpoints ............................................................................................ 24 
5.5. 
Correlative studies ............................................................................................... 24 
6. 
Trial design, duration and termination ..................................................................... 24 
6.1. 
Trial design .......................................................................................................... 24 
6.2. 
Sample size and trial duration ............................................................................. 25 
7. 
Patient selection ....................................................................................................... 26 
7.1. 
Inclusion criteria .................................................................................................. 26 
7.2. 
Exclusion criteria ................................................................................................. 27 
8. 
Investigational medicinal products .......................................................................... 28 
8.1. 
Alectinib .............................................................................................................. 28 
8.2. 
Formulation ......................................................................................................... 28 
8.3. 
Packaging and labelling ....................................................................................... 28 
8.4. 
Storage and handling ........................................................................................... 28 
9. 
Trial treatments ........................................................................................................ 29 
9.1. 
Alectinib administration ...................................................................................... 29 
9.2. 
Patient compliance ............................................................................................... 29 
9.3. 
Treatment duration .............................................................................................. 30 
10. 
Safety of alectinib .................................................................................................... 30 
10.1. 
Summary of the safety profile ............................................................................. 30 
10.2. 
Description of selected adverse events ................................................................ 30 
10.3. 
Management of alectinib related toxicities .......................................................... 34 
10.4. 
Contraindications ................................................................................................. 38 
10.5. 
Effects of other medicinal products on alectinib ................................................. 39 
10.6. 
Contraception, nursing, pregnancy ...................................................................... 40 
11. 
Adverse event and serious adverse event reporting ................................................. 41 
11.1. 
Adverse event (AE) ............................................................................................. 41 
11.2. 
Adverse reaction (AR) ......................................................................................... 42 
11.3. 
Unexpected adverse reaction (UAR) ................................................................... 42 
11.4. 
Serious adverse events (SAE) .............................................................................. 42 
11.5. 
Pregnancy ............................................................................................................ 43 
11.6. 
Exceptions to the SAE definition ........................................................................ 44 
11.7. 
Adverse events of special interest (AESI) ........................................................... 45 
11.8. 
Severity / intensity of (serious) adverse events ................................................... 46 


 
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11.9. 
Causality of adverse events ................................................................................. 46 
11.10. Duration of adverse events .................................................................................. 47 
11.11. Action taken ......................................................................................................... 47 
11.12. Reporting of adverse events ................................................................................ 47 
11.13. Reference safety information............................................................................... 48 
12. 
Response evaluation ................................................................................................ 48 
12.1. 
CT schedule for response evaluation ................................................................... 48 
12.2. 
Storage of images for central review ................................................................... 49 
12.3. 
Response evaluation criteria in solid tumours (RECIST version 1.1) ................. 49 
13. 
Endpoints definition ................................................................................................. 54 
13.1. 
Overall response .................................................................................................. 54 
13.2. 
Disease control .................................................................................................... 54 
13.3. 
Progression-free survival ..................................................................................... 54 
13.4. 
Overall survival ................................................................................................... 54 
13.5. 
Toxicity ................................................................................................................ 54 
14. 
Biological material and translational research ......................................................... 56 
14.1. 
Biomarker program .............................................................................................. 56 
14.2. 
Biobank ................................................................................................................ 56 
14.3. 
Central RET confirmation ................................................................................... 56 
14.4. 
Diagnostic assay development ............................................................................. 56 
14.5. 
Mandatory biomaterial ........................................................................................ 57 
14.6. 
Biomaterial at progression ................................................................................... 57 
14.7. 
Submission of biomaterial ................................................................................... 58 
15. 
Trial procedures ....................................................................................................... 59 
15.1. 
Tumour assessment.............................................................................................. 59 
15.2. 
Baseline evaluations ............................................................................................ 59 
15.3. 
Evaluations at every treatment visit ..................................................................... 60 
15.4. 
Evaluations at disease progression ...................................................................... 61 
15.5. 
Evaluations under treatment beyond progression ................................................ 61 
15.6. 
Evaluations at the end of treatment visit ............................................................. 62 
15.7. 
Evaluations in the follow-up phase (post treatment) before progression ............ 63 
15.8. 
Evaluations in the follow-up phase beyond progression of disease .................... 63 
16. 
Case report forms and documentation ..................................................................... 64 
16.1. 
Case report forms schedule .................................................................................. 64 
17. 
Statistical considerations ......................................................................................... 66 
17.1. 
Primary objective ................................................................................................. 66 
17.2. 
Sample size determination ................................................................................... 66 
17.3. 
Trial duration ....................................................................................................... 66 
17.4. 
Analysis populations............................................................................................ 67 
17.5. 
Evaluation of primary and secondary objectives ................................................. 67 
17.6. 
Safety evaluation ................................................................................................. 67 
17.7. 
Interim efficacy analysis ...................................................................................... 68 
18. 
Criteria for termination of the trial .......................................................................... 68 
18.1. 
General criteria for termination of the trial ......................................................... 68 
18.2. 
Discontinuation of protocol treatment for individual patients ............................. 68 
18.3. 
Withdrawal of consent ......................................................................................... 68 
19. 
Ethics aspects, regulatory approval, and patient informed consent ......................... 69 
19.1. 
Ethical Review Board/Ethics Committee ............................................................ 69 
19.2. 
Regulatory approval procedures .......................................................................... 69 
19.3. 
Informed consent ................................................................................................. 69 


 
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20. 
Governance and administrative issues ..................................................................... 70 
20.1. 
Final report .......................................................................................................... 70 
20.2. 
Steering Committee ............................................................................................. 70 
20.3. 
Independent Data Monitoring Committee ........................................................... 70 
20.4. 
Publication ........................................................................................................... 71 
20.5. 
Clinical trial insurance ......................................................................................... 71 
20.6. 
Quality assurance ................................................................................................. 71 
20.7. 
Protocol adherence .............................................................................................. 71 
20.8. 
Data protection .................................................................................................... 71 
20.9. 
Record retention .................................................................................................. 72 
21. 
References ................................................................................................................ 73 
 
Appendices: 
1. Template for patient information and informed consent form 
2. ETOP publication guidelines  
Index of tables 
Table 1 Dose reduction schedule ........................................................................................... 34 
Table 2 Dose modification advice for specified adverse events ............................................ 34 
Table 3: Measurable Disease - Overall Response.................................................................. 53 
Table 4: Non-measurable Disease - Overall Response .......................................................... 53 
Table 5: Case report forms: .................................................................................................... 64 
 
 


 
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1. 
Protocol summary  
ETOP 12-17 ALERT-lung 
A single arm phase II trial evaluating the activity of alectinib for the 
treatment of pretreated RET-rearranged advanced NSCLC 
ALERT-lung: ALEctinib for the treatment of pretreated RET-rearranged  
advanced non-small cell lung cancer 
Sponsor:  
European Thoracic Oncology Platform (ETOP) 
Coordinating group: 
ETOP 
Collaborative group: 
Lung Cancer Group Cologne 
Pharma Partner: 
Roche 
Population:  
Patients with advanced stage RET-rearranged NSCLC, treated 
with at least one platinum based systemic chemotherapy 
regimen. 
Design: 
Single arm, phase II, multicentre trial 
 
Sample size: 44 patients 
A total of 44 enroled patients are required and based on the low incidence of RET 
rearrangement in NSCLC (1-2%) approximately 4500 patients are expected to be screened in 
order to find enough eligible patients. The patients will be recruited from approximately 30 
centres in eight different European countries. 
 
RET rearrangement
Trial treatment
Screening, eligibility
Alectinib 600 mg twice daily p.o.
until PD or unacceptable toxicity#
For 6 months 
after enrolment 
of last patient
Follow up
Enrolment
Brain MRI or CT
Mandatory
FFPE
CT every 8 weeks until PD
CT
Advanced pre-treated
NSCLC
Plasma
# treatment may continue beyond progression if there is clinical benefit
Plasma
FF re-biopsy and 
whole blood


 
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Treatment: 
Alectinib is administered orally, 600 mg, twice per day (1200 mg per day) until progression, 
refusal or unacceptable toxicity. 
Trial treatment may also continue beyond progression, with physician and patient agreement, 
for as long as the patient may still derive clinical benefit as per investigator decision. 
Treatment has to start as soon as possible after enrolment, ideally within 7 days. Treatment 
visits are planned at treatment start (week 0) and then every 2 weeks (±3 days) for the first 12 
weeks and every 4 weeks (±3 days) thereafter. 
Rationale: 
Despite advances in the treatment of non-small cell lung cancer (NSCLC) over the past several 
decades, only small incremental overall survival benefits have been demonstrated and 
treatments beyond first-line remain limited in unselected NSCLC.  
In 2004 the discovery of the Epidermal Growth Factor Receptor (EGFR) mutations in NSCLC 
and their predictive value for therapy with EGFR tyrosine kinase inhibitors (TKIs) opened the 
way to an intense program of research on lung cancer, aiming at identifying other genomic or 
protein alterations that could be used as target for treatment. Subsequently, genetic 
rearrangements of the anaplastic lymphoma kinase (ALK) gene in lung cancer and its 
oncogenic features were discovered in 2007. The impressive clinical results obtained with the 
inhibition of ALK and EGFR kinases compared to classical chemotherapy further supported 
the hypothesis that targeting signaling pathways aberrantly active in cancer cells, might lead 
to a better outcome of therapy for molecularly selected lung cancer patients. However, EGFR 
mutations and ALK translocations cover only 15-20% of NSCLC in Western populations, 
calling for discovery and development of novel targets. Studies on molecular alterations of 
lung tumours highlighted specific differences of biomarkers expression and role in the several 
histotypes of lung cancer. Adenocarcinoma (ADC) is the most prevalent histologic subtype 
among lung tumours and certainly the most characterized for its molecular features. To date, 
a targetable alteration may be recognized in 20-30% of adenocarcinomas in Caucasian 
patients.  
RET fusion in NSCLC 
After the discovery of ALK fusions, other genes have been to be found genetically rearranged 
in lung cancer. Gene fusions may occur as consequence of chromosomal translocation, 
inversion or interstitial deletion. Oncogenic rearrangements may cause the expression of new 
proteins or of a protein with different activity than the native one. Fusion can bring a gene 
under the control of a strong promoter, causing aberrant expression of a protein in cells where 
usually the protein has no or low expression.  
The RET gene is located on chromosome 10 and encodes for a transmembrane receptor with 
tyrosine kinase activity. It is involved in cell proliferation, migration, differentiation, and in 
neuronal navigation. Germline and somatic mutations of RET are known to cause the multiple 
endocrine neoplasia type 2 (MEN2) syndrome and are involved in the tumourigenesis of 
sporadic medullary thyroid cancer. Furthermore, RET rearrangements are involved in 
sporadic and radiation induced papillary thyroid carcinoma. RET fusions are transforming in 


 
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vitro and in vivo, and inhibition of RET in RET-rearranged lung cancer cells leads to 
suppressed viability.1 
RET rearrangements have been identified in lung ADC as well, with a prevalence of 1-2%.2-
4 Several genes, such as KIF5B, CCDC6, NCO4 and TRIMM33,2,3,5 can act as fusion partners. 
RET-positive lung carcinomas are more common in poorly differentiated tumours and in 
never-smokers. Therapeutically, several multiple kinases inhibitors, such as vandetanib 
(Astrazeneca, London, England), cabozantinib (Exelis Inc. USA), ponatinib (Ariad, USA), 
axitinib (Pfizer, USA), sunitinib (Pfizer, USA), sorafenib (Bayer Healthcare, Germany), and 
alectinib (Roche, Switzerland) are potentially able to inhibit RET kinase function. Phase III 
trials data in biologically unselected NSCLC are available for some of these agents both as 
monotherapy and in combination. However, all the results from these studies were negative 
and none of the drugs was approved for lung cancer treatment, probably due to the absence 
of genotypic selection. On the other hand, some case reports describe anecdotal responses to 
treatment with vandetanib and cabozantinib in RET-positive lung cancer patients.5-11 
Alectinib 
Alectinib (RO5424802, Alecensa®) is a highly selective next generation ALK inhibitor. In 
preclinical in vitro enzyme inhibition assays alectinib has been shown to selectively inhibit 
ALK, but also RET.12 The compound also showed high antitumour activity both in vitro and 
in vivo against tumour cell lines with some type of ALK gene alteration, including NSCLC 
and anaplastic large cell lymphoma lines harbouring an ALK translocation and a 
neuroblastoma line harbouring amplified ALK gene.12 
The clinical development program for alectinib, comprises several phase I-III studies in 
patients with ALK-positive NSCLC:13 
Two phase I/II studies (NP28761/AF-002JG and NP28673) evaluating alectinib in crizotinib-
failed ALK-positive NSCLC patients are being conducted in North America, Europe, and 
other countries. One hundred and thirty four patients are enroled in study NP28761 (data cut-
off date: 22 January 2016) and 149 patients are enroled in study NP28673 (data cut-off date: 
01 February 2016), both of which are ongoing.14 
The first in human phase I/II study in ALK-positive crizotinib-naïve NSCLC, AF-001JP, is 
being conducted in Japan. The AF-001JP study is ongoing, with 70 patients enroled. Study 
WP29158 is a phase 1b study of the safety and pharmacology of atezolizumab administered 
with erlotinib or alectinib in patients with advanced NSCLC.15 
Clinical pharmacology studies have also been conducted in healthy subjects and patients. A 
study (NP29783) to evaluate the pharmacokinetics of alectinib in subjects with moderate to 
severe hepatic impairment is currently ongoing. 
The global phase III study (BO28984) to evaluate alectinib versus crizotinib in patients with 
treatment-naïve advanced ALK-positive NSCLC is ongoing. A separate phase III study 
(JO28928) with a design similar to the BO28984 study in patients with ALK-positive NSCLC 
who are treatment-naïve or have received one line of standard chemotherapy is ongoing in 
Japan. 


 
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A phase III study (MO29750) was started in October 2015 to evaluate alectinib versus 
pemetrexed or docetaxel in patients with ALK-positive advanced NSCLC, previously treated 
with platinum-based chemotherapy and crizotinib.  
A phase III study (YO29449) was started in June 2016 to evaluate the efficacy and safety of 
alectinib versus crizotinib and to evaluate the pharmacokinetics of alectinib in Asian 
participants with treatment-naive ALK-positive advanced NSCLC. 
In addition, there is an ongoing post marketing drug use surveillance (ALC1401) study in 
Japan. 
Alectinib for RET-rearranged NSCLC 
Preclinical studies have recently shown that alectinib has potent anti-tumour activity in RET-
rearranged NSCLC. In a kinase inhibitory assay, alectinib inhibited RET kinase activity with 
an IC50 of 4.8 nM, and in an ATP-competitive binding assay, alectinib bound to RET at a 
dissociation constant value of 7.6 nM. The IC50 for alectinib for RET kinase appears to be 
higher than for ALK kinase (1.9 nM), which may indicate a need for a higher dose of alectinib 
than currently approved for ALK+ NSCLC (600 mg orally twice a day) to ensure 
efficacious/therapeutic concentrations are achieved in this population.12 
To date, a unique small clinical report of alectinib activity in RET-rearranged NSCLC is 
available. Recently, in the Journal of Thoracic Oncology, the Massachusetts General Lung 
Group reported on four RET-rearranged advanced NSCLC patients who were treated with 
alectinib (600 mg twice daily, N=3; 900 mg twice daily, N=1) as part of single-patient, 
compassionate use protocols or off-label use of the commercially available drug. Three of the 
four had received prior RET TKIs including cabozantinib and experimental RET inhibitors. 
In total, they describe two (50%) objective radiographic responses following treatment with 
alectinib (one confirmed and one  unconfirmed), with durations of therapy of 6 months and 
5+ months (treatment ongoing), respectively. Notably, one of these two patients was dose-
escalated to alectinib 900 mg twice daily and had clinical improvement in central nervous 
system metastases. In addition, one patient (25%) experienced a best response of stable 
disease lasting ~6 weeks (drug discontinued for toxicity). A fourth patient who was  RET-
TKI-naïve had primary progression on alectinib. Therefore, alectinib demonstrated 
preliminary antitumour activity in advanced RET-rearranged NSCLC patients.10 
 
 


 
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Objectives and endpoints:  
The primary objective is to assess the efficacy of alectinib in terms of best overall response 
(OR) assessed by RECIST v1.1. The secondary objectives are to evaluate secondary measures 
of clinical efficacy including disease control, progression-free survival (PFS), and overall 
survival (OS) as well as to assess safety and tolerability of the treatment and to describe the 
association of primary and secondary outcomes with tumour characteristics. 
Primary endpoint: 
Best overall response (OR = CR or PR), per investigator assessment, according to 
RECIST 1.1., from the start of trial treatment across all time points until the end of trial 
treatment. 
Secondary endpoints: 
 
Best overall response per independent review 
 
Disease control at 24-weeks: best overall response of CR or PR, or SD (or non-
CR/non-PD in the case of non-measurable disease only) 
 
Progression-free survival defined as the time from the date of enrolment until 
documented progression or death, if progression is not documented 
 
Overall survival defined as time from the date of enrolment until death from any cause 
 
Safety and tolerability (see Section 13.5) 
Most important eligibility criteria (see Section 7 for complete list):  
Inclusion criteria 
 Histologically or cytologically-documented non-small cell lung carcinoma  
 Advanced disease defined as recurrent stage IV (according to 8th TNM classification) or 
recurrent or progressive disease following multimodal therapy (radiation therapy, surgical 
resection, or definitive chemo-radiation therapy for locally advanced disease) 
 RET rearrangement detected by FISH, Nanostring or by parallel-sequencing on FFPE 
tumour tissue (biopsy, resection or cytoblock) assessed locally.  
 Availability of FFPE tumour material for central confirmation of RET-rearrangement 
 At least one prior platinum-based systemic regimen: Adjuvant or neoadjuvant or definitive 
platinum-based chemo-radiotherapy treatments are considered as a line of treatment only 
if completed less than 6 months before enrolment. Maintenance therapy following 
platinum doublet-based chemotherapy is not considered a separate regimen of therapy. 
 Measurable or non-measurable, but radiologically evaluable (except for skin lesions) 
disease according to RECIST v1.1 criteria  
 Adequate haematological, renal and liver function 
 ECOG Performance Status 0-2 


 
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Exclusion criteria 
 Untreated, active CNS metastases 
 Carcinomatous meningitis 
 Baseline symptomatic bradycardia 
 Prior treatment with any RET TKI or RET targeted therapy 
 Known EGFR, ALK, ROS, and BRAF mutation (in addition to RET rearrangement) 
 Any GI disorder that may affect absorption of oral medications, such as malabsorption 
syndrome or status post-major bowel resection 
 History of hypersensitivity to any of the additives in the alectinib drug formulation 
 Pregnant or lactating women 
 Known HIV positivity or AIDS-related illness 
 Any concurrent systemic anticancer therapy 
Statistical considerations: 
The trial targets a best OR rate of 35% and considers an OR rate of 15% as too low. 
Based on a one-sided exact test for proportions, the trial is designed to test the following 
hypotheses: 
H0: p0 ≤0.15 vs HA: pA>0.35, where p is the rate of best OR (ORR) at a one-sided 
significance level of 0.025 and a power of at least 0.80.  
A significance level of 0.015 and power of 0.82 are achieved with a sample size of 41 
evaluable patients. The null hypothesis will be rejected and the alternative hypothesis 
accepted if at least 12 patients achieve OR. 
The total sample size of 44 patients allows for up to 3 patients to be replaced if a patient is 
ineligible (retrospective review), has not started the experimental treatment or is lost to 
follow-up before evaluation of response.  
Total trial duration:  
Clinical visits are expected to span approximately 44 months after enrolment of the first 
patient. Assuming an accrual rate of approximately 1 patients per month and a start-up period 
of 6 months as the trial is activated by participating centres, the final trial report is expected 
to be available approximately 5 years after the enrolment of the first patient. 
 
 


 
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2. 
List of abbreviations  
ADC 
Adenocarcinoma 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
AIDS 
Acquired Immune Deficiency Syndrome 
ALK 
Anaplastic Lymphoma Kinase 
ALT 
Alanine Transaminase 
ANC 
Absolute Neutrophil count 
AP 
Alkaline Phosphatase 
AST 
Aspartate Transaminase 
AUC 
Area Under the Curve 
BCRP 
Breast Cancer Resistance Protein 
CI 
Confidence Interval 
CNS 
Central Nervous System 
CPK 
Creatinine Phosphokinase 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DC 
Disease Control 
DCR 
Disease Control Rate 
DLTs 
Dose-limiting toxicities 
EC 
Ethics Committee 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EEA 
European Economic Area 
eGFR 
Estimated Glomerular Filtration Rate 
EGFR 
Epidermal Growth Factor Receptor 
ERB 
Ethical Review Board 
ETOP 
European Thoracic Oncology Platform 
FDG-PET 
Fluorodeoxyglucose Positron Emission Tomography 
FFPE 
Formalin Fixed, Paraffin Embedded 
FISH 
Fluorescent In-Situ Hybridization 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl Transpeptidase 
GI 
Gastrointestinal 
HCG 
Human Chorionic Gonadotropin 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator's Brochure 
IC 
Informed Consent 
ICH GCP 
International Conference on Harmonisation’s Good Clinical Practice 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 


 
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ILD 
Interstitial Lung Disease 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
ITT 
Intention-To-Treat 
i.v. 
Intra-venous 
LDH 
Lactate Dehydrogenase 
LFU 
Lost to Follow-up 
MEN2 
Multiple Endocrine Neoplasia Type 2 
MRI 
Magnetic Resonance Imaging 
NE 
Not Evaluable 
NGS 
Next Generation Sequencing 
NSCLC 
Non-Small Cell Lung Carcinoma 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PIS 
Patient Information Sheet 
PK 
Pharmacokinetics 
p.o. 
Orally / per os 
PR 
Partial Response 
RBC 
Red Blood Cell 
RECIST 
Response Evaluation Criteria in Solid Tumours 
RET 
Receptor Tyrosine Kinase 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SmPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TKI 
Tyrosine Kinase Inhibitor 
TNM 
Tumour, Node, Metastases 
ULN 
Upper Limit of Normal Lab Value 
WBC 
White Blood Cell Count 
WC 
Withdrawal of Consent 
WES 
Whole-Exome Sequencing 
 
 
 


 
 
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3. 
Trial schedule  
 
Baseline evaluation 
within 28 days prior 
to enrolment 
At every treatment visit(13) 
At PD 
End of treatment 
visit(14) 
Follow-up 
Before PD 
Beyond PD(11) 
Before PD(15)  
After PD(16) 
Written informed consent for trial participation(1)  
(within 6 weeks  
prior to enrolment) 
 
 
 
 
 
 
Medical history (smoking history, comorbidities, 
allergies) 
 
 
 
 
 
 
 
Patient diary 
 
 
 
 
 
 
 
Physical exam(2) 
 
 
 
 
 
 
 
Baseline symptoms(3) 
 
 
 
 
 
 
 
Adverse events(3) 
 
 
 
 
 
 
 
Survival 
 
 
 
 
 
 
 
Biological material, central laboratory and pathology 
FFPE block for central confirmation of RET 
rearragement(4) 
 
 
 
 
 
 
 
Plasma sample for translational research(6) 
 
 
 
 
 
 
 
Rebiopsy, fresh frozen(5)(6) 
 
 
 
 
 
 
 
Whole blood for reference DNA(6) 
 
 
 
 
 
 
 
Laboratory tests 
Haematology: WBC, haemoglobin, platelets, neutrophils 
 
(17) 
(17) 
 
 
 
 
 
 


 
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Baseline evaluation 
within 28 days prior 
to enrolment 
At every treatment visit(13) 
At PD 
End of treatment 
visit(14) 
Follow-up 
Before PD 
Beyond PD(11) 
Before PD(15)  
After PD(16) 
Hepatic function(7): ALT, AST, AP, bilirubin, GGT, 
LDH 
 
(7) 
(7) 
 
(7) 
 
 
Renal function: serum creatinine, calculated creatinine 
clearance 
 
(17) 
(17) 
 
(17) 
 
 
Urine analysis (microscopic urine analysis or dipstick): 
pH, proteins, glucose, blood(8) 
 
(17) 
(17) 
 
(17) 
 
 
Chemistry: CPK(9), sodium, potassium, calcium, 
magnesium, phosphate, glucose  
 
(17) 
(17) 
 
(17) 
 
 
Pregnancy test if applicable(10) 
 
 
 
 
 
 
 
Treatment 
Alectinib 600 mg p.o. twice daily until PD(11) 
 
 
 
 
 
 
 
Concomitant medication 
 
 
 
 
 
 
 
Further lines of treatment 
 
 
 
 
 
 
 
Disease evaluation 
Electrocardiogram 
 
 
 
 
 
 
 
Brain MRI or contrast enhanced CT 
(within 6 weeks prior 
to enrolment) 
 
 
 
 
 
 
CT thorax and upper abdomen(12) 
 
Every 
8 weeks 
(±4 days) 
 
 
(18) 
(19) 
 
 
 
 
 
 
 
 
 
 
Mandatory 
evaluations 
 
 
 
 
 
 
 
 


 
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(1) 
Before any trial-specific evaluations and intervention. 
(2) 
Physical exam according to local standards, including performance status, heart rate, temperature, blood pressure and body weight. 
(3) 
Adverse events have to be reported on the adverse event form, from the date of signature of informed consent until 30 days after trial treatment discontinuation. Symptoms 
present at baseline will be recorded on the adverse event form as well from date of informed consent (see Section 11.12).  
(4) 
FFPE-block containing sufficient tumour-material for central confirmation of RET-rearrangement. Suitable material encompasses any biopsy material, resection material and 
cytoblocks.  
(5) 
Upon progression, a re-biopsy of a progressive lesion is strongly encouraged. The biopsy material should be fresh-frozen upon extraction.  
(6) 
Plasma samples, re-biopsy sample and whole blood will be locally stored until shipment to the central laboratory. 
(7) 
ALT, AST, bilirubin, ALP should be measured at every treatment visit (week 0 and then every 2 weeks (±3 days) for the first 12 weeks and every 4 weeks thereafter. GGT and 
LDH will be repeated if clinically indicated according to local standards. 
(8) 
Urine samples will be collected as follows: first morning urine sample for baseline and end of treatment visit, spot urine for rest of visits. 
(9) 
CPK to be measured at treatment visit 1, 2 and 3 (week 0, 2 and 4) and then repeated if clinically indicated. 
(10) 
Women of childbearing potential, including women who had their last menstrual period in the last 2 years, must have a negative serum or urine beta HCG pregnancy test within 
7 days before enrolment into the trial and within 3 days before alectinib treatment start. Pregnancy testing has to be repeated during the duration of the trial treatment according 
to local standard. 
Female patients of child-bearing potential, or women of child-bearing potential who are partners of male patients receiving alectinib, must use highly effective contraceptive 
methods during treatment and for at least 3 months following the last dose of alectinib. Any pregnancy occurring during treatment or within 3 months following the last dose of 
alectinib must be reported including its outcome. 
(11) 
Trial treatment may also continue beyond progression, with physician and patient agreement, for as long as the patient may still derive clinical benefit as per investigator decision. 
(12) 
All patients must have a contrast enhanced CT thorax and upper abdomen (from top of thorax until adrenal glands and full liver and kidney included) at baseline during screening 
within 6 weeks before enrolment. CT scan will be repeated 8 weeks (±4 days) after first dose of alectinib and then every 8 weeks (±4 days) until disease progression. The same 
imaging technique, acquisition, and processing parameters should be used in a patient throughout the trial. In the case that a CT scan had to be done earlier or later than scheduled, 
effort should be made to return to the original CT schedule. 
(13) 
Treatment visits are planned at treatment start (week 0) and then every 2 weeks (±3 days) for the first 12 weeks and every 4 weeks (±3 days) thereafter. Patient diary should be 
checked and capsules returned should be counted. 
(14) 
Within 30 days following the decision to stop trial treatment or within 30 days after planned treatment start if treatment never started. 
(15) 
Follow-up visits after treatment stop. Before progression: every 8 weeks (±4 days), coinciding with imaging visits. 
(16) 
Patients with progression that ends trial treatment will be followed up every 12 weeks (±2 weeks) starting from date of progression until trial end (e.g. until 6 months after 
inclusion of the last patient). 
(17) 
Evaluations will also be repeated if clinically indicated according to local standards. 
(18) 
CT to be repeated if not done within 6 weeks prior to end of treatment visit. 
(19) 
In case of treatment stop for reason other than progressive disease, CT needs to be repeated every 8 weeks until progression. 
.


 
 
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4. 
Background and rationale 
4.1. 
NSCLC targeted treatment strategies 
Despite advances in the treatment of non-small cell lung cancer (NSCLC) over the past several 
decades, only small incremental overall survival benefits have been demonstrated and 
treatments beyond first-line remain limited in unselected NSCLC.  
In 2004 the discovery of the Epidermal Growth Factor Receptor (EGFR) mutations in NSCLC 
and their predictive value for therapy with EGFR tyrosine kinase inhibitors (TKIs) opened the 
way to an intense program of research on lung cancer, aiming at identifying other genomic or 
protein alterations that could be used as targets for treatment. Subsequently, genetic 
rearrangements of the anaplastic lymphoma kinase (ALK) gene in lung cancer and its 
oncogenic features were discovered in 2007. The impressive clinical results obtained with the 
inhibition of ALK and EGFR kinases compared to classical chemotherapy further supported 
the hypothesis that targeting signaling pathways aberrantly active in cancer cells, might lead 
to a better outcome of therapy for molecularly selected lung cancer patients. However, EGFR 
mutations and ALK translocations cover only 15-20% of NSCLC in Western populations, 
calling for discovery and development of novel targets. Studies on molecular alterations of 
lung tumours highlighted peculiar differences of biomarkers expression and role in the several 
histotypes of lung cancer. Adenocarcinoma (ADC) is the most prevalent histologic subtype 
among lung tumours and certainly the most characterized for its molecular features. To date, 
a targetable alteration may be recognized in 20-30% of adenocarcinomas in Caucasian 
patients.  
4.2. 
RET fusion in NSCLC 
After the discovery of ALK fusions, other genes have been found genetically rearranged in 
lung cancer. Gene fusions may occur as consequence of chromosomal translocation, inversion 
or interstitial deletion. Oncogenic rearrangements may cause the expression of new proteins 
or of a protein with different activity than the native one. Fusion can bring a gene under the 
control of a strong promoter, causing aberrant expression of a protein in cells where usually 
the protein has no or low expression.  
The RET gene is located on chromosome 10 and encodes for a transmembrane receptor with 
tyrosine kinase activity. It is involved in cell proliferation, migration, differentiation, and in 
neuronal navigation. Germline and somatic mutations of RET are known to cause the multiple 
endocrine neoplasia type 2 (MEN2) syndrome and are involved in the tumourigenesis of 
sporadic medullary thyroid cancer. Furthermore, RET rearrangements are involved in 
sporadic and radiation induced papillary thyroid carcinoma. RET fusions are transforming in 
vitro and in vivo, and inhibition of RET in RET-rearranged lung cancer cells leads to 
suppressed viability.1 
RET rearrangements have been identified in lung ADC as well, with an incidence of 1-2%.2-
4 Several genes, such as KIF5B, CCDC6, NCO4 and TRIMM33,2,3,5 can act as fusion partners. 
RET-positive lung carcinomas are more common in poorly differentiated tumours and in 
never-smokers. Therapeutically, several multiple kinases inhibitors, such as vandetanib 
(Astrazeneca, England), cabozantinib (Exelis Inc. USA), ponatinib (Ariad, USA), axitinib 


 
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(Pfizer, USA), sunitinib (Pfizer, USA), sorafenib (Bayer Healthcare, Germany), and alectinib 
(Roche, Switzerland) are potentially able to inhibit RET kinase function. Phase III trials data 
in biologically unselected NSCLC are available for some of these agents both as monotherapy 
and in combination. However, all the results from these studies were negative and none of the 
drugs was approved for lung cancer treatment, probably due to the absence of genotypic 
selection. On the other hand, some case reports describe anecdotal responses to treatment with 
vandetanib and cabozantinib in RET-positive lung cancer patients.5-11 
4.3. 
Alectinib 
Alectinib (RO5424802, Alecensa®) is a highly selective next generation ALK inhibitor. In 
preclinical in vitro enzyme inhibition assays alectinib has been shown to selectively inhibit 
ALK, but also RET.12 The compound also showed high antitumour activity both in vitro and 
in vivo against tumour cell lines with some type of ALK gene alteration, including NSCLC 
and anaplastic large cell lymphoma lines harbouring an ALK translocation and a 
neuroblastoma line harbouring amplified ALK gene.12 
The clinical development program for alectinib, comprises several phase I-III studies in 
patients with ALK-positive NSCLC:13 Two phase I/II studies (NP28761/AF-002JG and 
NP28673) evaluating alectinib in crizotinib-failed ALK-positive NSCLC patients are being 
conducted in North America, Europe, and other countries. One hundred and thirty four 
patients are enroled in study NP28761 (data cut-off date: 22 January 2016) and 149 patients 
are enroled in study NP28673 (data cut-off date: 01 February 2016), both of which are 
ongoing. 
The first in human phase I/II study in ALK-positive crizotinib-naïve NSCLC, AF-001JP, is 
being conducted in Japan. The AF-001JP study is ongoing, with 70 patients enroled. Study 
WP29158 is a phase 1b study of the safety and pharmacology of atezolizumab administered 
with erlotinib or alectinib in patients with advanced NSCLC.15 
Clinical pharmacology studies have also been conducted in healthy subjects and patients. A 
study (NP29783) to evaluate the pharmacokinetics of alectinib in subjects with moderate to 
severe hepatic impairment is currently ongoing. 
The global phase III study (BO28984) to evaluate alectinib versus crizotinib in patients with 
treatment-naïve advanced ALK-positive NSCLC is ongoing. A separate phase III study 
(JO28928) with a design similar to the BO28984 study in patients with ALK-positive NSCLC 
who are treatment-naïve or have received one line of standard chemotherapy is ongoing in 
Japan. 
A phase III study (MO29750) was started in October 2015 to evaluate alectinib versus 
pemetrexed or docetaxel in patients with ALK-positive advanced NSCLC, previously treated 
with platinum-based chemotherapy and crizotinib.  
A phase III study (YO29449) was started in June 2016 to evaluate the efficacy and safety of 
alectinib versus crizotinib and to evaluate the pharmacokinetics of alectinib in Asian 
participants with treatment-naive ALK-positive advanced NSCLC. 
In addition, there is an ongoing post marketing drug use surveillance (ALC1401) study in 
Japan. 
 
 


 
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4.3.1. 
Alectinib for RET-rearranged NSCLC 
Preclinical studies have recently shown that alectinib has potent anti-tumour activity in RET-
rearranged NSCLC. In a kinase inhibitory assay, alectinib inhibited RET kinase activity with 
an IC50 of 4.8 nM, and in an ATP-competitive binding assay, alectinib bound to RET at a 
dissociation constant value of 7.6 nM. The IC50 for alectinib for RET kinase appears to be 
higher than for ALK kinase (1.9 nM), which may indicate a need for a higher dose of alectinib 
than currently approved for ALK+ NSCLC (600 mg orally twice a day) to ensure 
efficacious/therapeutic concentrations are achieved in this population.12 
To date, a unique small clinical report of alectinib activity in RET-rearranged NSCLC is 
available. Recently, in the Journal of Thoracic Oncology’, the Massachusetts General Lung 
Group reported on four RET-rearranged advanced NSCLC patients who were treated with 
alectinib (600 mg twice daily, N=3; 900 mg twice daily, N=1) as part of single-patient, 
compassionate use protocols or off-label use of the commercially available drug. Three of the 
four had received prior RET TKIs including cabozantinib and experimental RET inhibitors. 
In total, they describe two (50%) objective radiographic responses following treatment with 
alectinib (one confirmed and one  unconfirmed), with durations of therapy of 6 months and 
5+ months (treatment ongoing), respectively. Notably, one of these two patients was dose-
escalated to alectinib 900 mg twice daily and had clinical improvement in central nervous 
system metastases. In addition, one patient (25%) experienced a best response of stable 
disease lasting ~6 weeks (drug discontinued for toxicity). A fourth patient who was  RET-
TKI-naïve had primary progression on alectinib. Therefore, alectinib demonstrated 
preliminary antitumour activity in advanced RET-rearranged NSCLC patients.10 
4.4. 
Overall risk / benefit assessment 
Distinct subtypes of NSCLC are driven by a specific genetic alteration and are known to be 
sensitive to inhibition of the corresponding activated oncogenic pathway. RET 
rearrangements have been identified in lung ADC with an incidence of 1-2% and several 
multiple kinases inhibitors are potentially able to inhibit RET kinase function. 
Alectinib has been administered in several clinical trials and it has been shown that it was 
generally well tolerated and had an acceptable safety profile. Section 10 of this protocol 
summarizes potential risks based upon non-clinical toxicity and clinical patient studies with 
alectinib with further detailed information available in the IB for alectinib. 
4.5. 
Rationale for trial design and alectinib dose 
4.5.1. 
Rationale for patient selection 
To ensure an appropriate and standardised patient population, all patients must have 
histologically or cytologically documented advanced NSCLC (recurrent stage IV) with 
locally tested RET rearrangement after at least one previous line of platinum-based systemic 
therapy. RET rearrangement will later be centrally confirmed. 
 
 


 
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4.5.2. 
Rationale for alectinib dose 
Based on the total, current, safety, pharmacokinetic and preliminary efficacy data, 600 mg 
alectinib twice daily was selected as the recommended dose. Please refer to the latest version 
of the Alectinib IB for additional details. 
Dose finding studies 
In study NP28761/AF-002JG, no dose-limiting toxicities (DLTs) were observed in the dose-
escalation cohorts, up to a dose of 900 mg twice daily. However, 2 patients in the subsequent 
900 mg twice daily bridging cohort experienced a DLT, one a Grade 3 headache and the other 
a Grade 3 neutrophil count decreased, and both patients continued study treatment at reduced 
dose of 600 mg twice daily. On the basis of efficacy, safety, and PK data, the recommended 
phase II Dose is 600 mg twice daily. No DLT for this dose was observed in the AF-001JP 
study. 
Further dose-finding for alectinib in RET-rearranged NSCLC is currently conducted in two 
separate studies: 
A phase I/II study of alectinib in RET-rearranged NSCLC or RET-mutated thyroid cancer 
(NCT03131206) and a multicenter phase II/III study (NCT03178552) evaluating the efficacy 
and safety of multiple targeted therapies as treatments for patients with advanced or metastatic 
NSCLC harboring actionable somatic mutations detected in blood (B-FAST: Blood-First 
Assay Screening Trial). The B-FAST trial includes a dose finding phase for alectinib. 
Participants in the RET+ NSCLC cohort receive a starting dose of 900 mg orally BID of 
alectinib, with one additional dose-escalation group to 1200 mg orally if the recommended 
phase II dose is not established in any other clinical study. 
As soon as the 900 mg alectinib twice daily has proven to be safe in any of these dose finding 
studies, the ETOP 12-17 ALERT-lung protocol will be amended to this higher dose. 
5. 
Objectives and endpoints 
5.1. 
Primary objective 
The primary objective is to assess the efficacy of alectinib in terms of best overall response 
(OR) assessed by RECIST 1.1., from the start of trial treatment across all time points until the 
end of trial treatment. 
5.2. 
Secondary objectives 
5.2.1. 
To evaluate secondary measures of clinical efficacy including disease control, 
progression-free survival (PFS), and overall survival (OS).  
5.2.2. 
To assess the safety and tolerability of the treatment. 
5.3. 
Primary endpoint 
5.3.1. 
Best overall response (OR = CR or PR), per investigator assessment, according to 
RECIST 1.1. 


 
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5.4. 
Secondary endpoints 
5.4.1. 
Best overall response per independent review. 
5.4.2. 
Disease control at 24-weeks: best overall response of CR or PR, or SD (or non-
CR/non-PD in the case of non-measurable disease only) 
5.4.3. 
PFS defined as the time from the date of enrolment until documented progression or 
death, if progression is not documented 
5.4.4. 
OS defined as time from the date of enrolment until death from any cause 
5.4.5. 
Safety and tolerability (see Section 13.5) 
5.5. 
Correlative studies 
Further exploratory analyses include description of primary and secondary outcomes for 
patient subgroups of interest, as defined by patient or tumour characteristics or different levels 
of biomarkers examined. 
6. 
Trial design, duration and termination  
6.1. 
Trial design 
ALERT-lung is a single arm, multicentre phase II trial evaluating the activity of alectinib as 
second-line treatment of pretreated RET-rearranged advanced NSCLC. 
 
 
RET rearrangement
Trial treatment
Screening, eligibility
Alectinib 600 mg twice daily p.o.
until PD or unacceptable toxicity#
For 6 months 
after enrolment 
of last patient
Follow up
Enrolment
Brain MRI or CT
Mandatory
FFPE
CT every 8 weeks until PD
CT
Advanced pre-treated
NSCLC
Plasma
# treatment may continue beyond progression if there is clinical benefit
Plasma
FF re-biopsy and 
whole blood


 
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6.2. 
Sample size and trial duration 
A total of 44 enroled patients are required and based on the low incidence of RET 
rearrangement in NSCLC (1-2%) approximately 4500 patients are expected to be screened in 
order to find enough eligible patients. 
The patients will be recruited from approximately 30 centres in eight different countries in 
Europe. 
Clinical visits are expected to span approximately 44 months after enrolment of the first 
patient. Assuming an accrual rate of approximately 1 patient per month and a start-up period 
of 6 months as the trial is activated by participating centres, the final trial report is expected 
to be available approximately 5 years after the enrolment of the first patient. 
 
 


 
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7. 
Patient selection 
Written informed consent (IC) must be signed and dated by the patient and the investigator 
prior to any trial-related intervention and biomaterial submission for central review to confirm 
RET-rearrangement. 
7.1. 
Inclusion criteria 
7.1.1. 
Histologically or cytologically documented non-small cell lung carcinoma  
7.1.2. 
Advanced disease defined as recurrent stage IV (according to 8th TNM 
classification) or recurrent or progressive disease following multimodal therapy 
(radiation therapy, surgical resection, or definitive chemo-radiation therapy for 
locally advanced disease) 
7.1.3. 
At least one prior platinum-based systemic regimen: Adjuvant or neoadjuvant or 
definitive platinum-based chemo-radiotherapy treatments are considered as a line of 
treatment only if completed less than 6 months before enrolment. Maintenance 
therapy following platinum doublet-based chemotherapy is not considered a separate 
regimen of therapy. 
7.1.4. 
RET rearrangement detected by FISH, Nanostring or by parallel-sequencing on 
FFPE tumour tissue assessed locally. 
7.1.5. 
Availability of FFPE tumour material for central confirmation of RET-
rearrangement 
7.1.6. 
Measurable or non-measurable, but radiologically evaluable (except for skin lesions) 
disease according to RECIST v1.1 criteria 
7.1.7. 
Age ≥18 years 
7.1.8. 
Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2 
7.1.9. 
Life expectancy >3 months 
7.1.10. Adequate haematological function:  
– Haemoglobin ≥9 g/dL 
– Neutrophil count ≥1.5 ×109/L 
– Platelet count ≥100 × 109/L 
– WBC ≥2 ×109/L 
7.1.11. Adequate renal function: Calculated creatinine clearance ≥45 mL/min (according to 
Cockcroft-Gault formula below). 
 
Cockcroft-Gault formula 
mL
min = (140-age[years])×actual body weight [kg]
72×Creatinineserum (mg
dL)
(×0.85 if female) 


 
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7.1.12. Adequate liver function: 
– Total bilirubin ≤2× ULN (except patients with Gilbert Syndrome, who can have 
total bilirubin ≤3.0 mg/dL) 
– ALT and AST ≤3 ULN (≤5 ULN for patients with concurrent liver metastasis) 
7.1.13. Patient capable of proper therapeutic compliance, and accessible to correct follow-
up. 
7.1.14. Women of childbearing potential, including women who had their last menstrual 
period in the last 2 years, must have a negative serum or urine beta HCG pregnancy 
test within 7 days before enrolment into the trial and within 3 days before alectinib 
treatment start. 
7.1.15. Sexually active men and women of childbearing potential must use an effective 
contraceptive method (intrauterine devices without hormones, bilateral tubal 
occlusion, vasectomized partner or total abstinence) during the trial treatment and 
for a period of at least 3 months following the last dose of alectinib (see Section 
10.6.1. for effective contraceptive methods). 
7.1.16. Recovered from any previous therapy related toxicity to Grade ≤1 at date of 
enrolment (except for recovery to Grade ≤2 of alopecia, fatigue, creatinine increased, 
lack of appetite or peripheral neuropathy)  
7.1.17. Written Informed Consent (IC) for trial treatment must be signed and dated by the 
patient and the investigator prior to any trial-related intervention.  
7.2. 
Exclusion criteria 
7.2.1. 
Untreated, active CNS metastases 
7.2.2. 
Carcinomatous meningitis 
7.2.3. 
Any previous (in the past 3 years) or concomitant malignancy EXCEPT adequately 
treated basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix 
or bladder, in situ ductal carcinoma of the breast 
7.2.4. 
Any serious diseases or clinical conditions, including but not limited to uncontrolled 
active infection and any other serious underlying medical processes, that could affect 
the patient's capacity to participate in the trial 
7.2.5. 
Liver disease characterized by: 
- ALT or AST >3 × ULN (>5 × ULN for patients with concurrent liver metastasis) 
confirmed on two consecutive measurements or  
- Impaired excretory function (e.g., hyperbilirubinaemia) or synthetic function or 
other conditions of decompensated liver disease such as coagulopathy, hepatic 
encephalopathy, hypoalbuminaemia, ascites, and bleeding from oesophageal 
varices or 
- Acute viral or active autoimmune, alcoholic, or other types of acute hepatitis 


 
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7.2.6. 
Patients with baseline symptomatic bradycardia 
7.2.7. 
Previous treatment with any RET TKI or RET targeted therapy 
7.2.8. 
Known EGFR, ALK, ROS, and BRAF mutation (in addition to RET rearrangement) 
7.2.9. 
Any concurrent systemic anticancer therapy 
7.2.10. Any GI disorder that may affect absorption of oral medications, such as 
malabsorption syndrome or status post major bowel resection 
7.2.11. History of hypersensitivity to any of the additives in the alectinib drug formulation 
7.2.12. Known HIV positivity or AIDS-related illness 
7.2.13. Women who are pregnant or in the period of lactation. 
8. 
Investigational medicinal products 
Alectinib is the investigational medicinal products (IMPs) in this trial. 
Complete details of the IMP logistics, distribution, packaging, labelling and handling as well 
as accountability are described in the ALERT-lung Drug Supply Manual. 
8.1. 
Alectinib 
Alectinib (also RO5424802 or CH5424802) is a small molecule, highly selective, and potent 
oral next generation ALK inhibitor with a benzo[b]carbazole scaffold. In enzyme inhibition 
assays performed in vitro, this compound has been shown to selectively inhibit ALK, but also 
RET. 
8.2. 
Formulation 
Please refer to the current version of the Alectinib IB for pharmaceutical formulation 
information. 
Clinical supplies will be provided by Roche. For details please refer to the ALERT-lung Drug 
Supply Manual. 
8.3. 
Packaging and labelling 
Clinical supplies will be affixed with a clinical trial label in accordance with regulatory 
requirements.  
8.4. 
Storage and handling 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label. Clinical supplies must be stored in the original container in 
order to protect from moisture. The Principal Investigator shall take responsibility for and shall 
take all steps to maintain appropriate records and ensure appropriate supply, storage, handling, 
distribution and usage of investigational product in accordance with the protocol and any 


 
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applicable laws and regulations. See the ALERT-lung Drug Supply Manual for complete 
details. 
9. 
Trial treatments 
9.1. 
Alectinib administration 
Alectinib is administered orally, 600 mg, twice per day (1200 mg per day) until progression, 
refusal or unacceptable toxicity. 
Trial treatment may also continue beyond progression, with physician and patient agreement, 
for as long as the patient may still derive clinical benefit as per investigator decision. 
9.1.1. 
Missed dose of alectinib 
If a planned dose of alectinib is missed, patients can take the missed dose up until 6 hours 
before the next dose. Patients should not take two doses at the same time to make up for a 
missed dose. If vomiting occurs after taking a dose of alectinib, patients should take the next 
dose at the scheduled time. Alectinib treatment should be permanently discontinued if the 
treatment interruption exceeds 21 consecutive days. 
Guidelines for dose modifications and treatment interruptions or discontinuation due to 
specified adverse events are provided in Section 10.3. 
9.2. 
Patient compliance 
9.2.1. 
Treatment compliance 
Alectinib will be given in accordance with the protocol and the instructions of a site 
investigator or pharmacist.  
The appropriate number of alectinib capsules will be provided to patients to be self-
administered at home. Patients should be instructed to use the patient diary to record every 
self-administration as well as any symptoms and to bring the patient diary to every visit at the 
clinic. 
Patients will be asked to return the remaining trial medication at each treatment visit for a 
compliance check. The remaining capsules will be counted by the investigator/site staff and 
recorded at the investigator site. Discrepancies between the number of capsules remaining 
and the calculated number of capsules the patients should have taken as well as the 
information recorded in the patient diary must be documented and explained. 
The investigator and/or ETOP can withdraw a patient from the trial in the event of serious 
and persistent non-compliance, which jeopardizes the patient’s safety or renders trial results 
for this patient unacceptable.  
Patients who do not take a minimum 50% of the daily dose of alectinib, unless due to 
exceptional circumstances, should be discussed with ETOP and be evaluated for compliance. 
9.2.2. 
Visit compliance 
Patients who do not attend a minimum of 75% of scheduled trial visits, unless due to 
exceptional circumstances, should be discussed with ETOP and evaluated for compliance. 


 
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9.3. 
Treatment duration 
Patients remain on treatment until one of the following events, whichever occurs first: 
 Documented progression according to RECIST v1.1 (except if the patient may still 
derive clinical benefit as per investigator’s decision). 
 Unacceptable toxicity to alectinib 
 Medical condition that prevents further treatment 
 Patient withdraws consent 
 Patient becomes pregnant 
 Trial termination (approximately 6 months after inclusion of the last patient) 
10. 
Safety of alectinib 
Alectinib has minor influence on the ability to drive and use machines. Caution should be 
exercised when driving or operating machines as patients may experience symptomatic 
bradycardia (e.g., syncope, dizziness, and hypotension) or vision disorders while taking 
alectinib. 
10.1. 
Summary of the safety profile 
The safety of alectinib has been evaluated in 253 patients in pivotal phase II clinical trials 
(NP28761, NP28673) with ALK-positive non-small cell lung cancer (NSCLC) treated with 
the recommended dose of 600 mg twice daily. The median duration of exposure to alectinib 
was 11 months.  
The most common adverse drug reactions (ADRs) (≥20%) were constipation (36%), oedema 
(34%, including oedema peripheral, oedema, generalised oedema, eyelid oedema, periorbital 
oedema), myalgia (31%, including myalgia and musculoskeletal pain) and nausea (22%).  
A detailed safety profile of alectinib is provided in the most recent version of the alectinib 
Investigator's Brochure. 
10.2. 
Description of selected adverse events  
Events described below will be closely monitored and represent selected AEs for this trial.  
10.2.1. Abnormal renal function and acute kidney injury 
In the 2-week non-human primate study at 60 mg/kg alectinib, an increase in creatinine was 
observed but no changes were observed in histopathology. In all other non-human primate 
studies, no changes in creatinine were observed. Serum creatinine increases and/or decreases 
in GFR have been reported for other ALK inhibitors (crizotinib, ceritinib). In the pooled 
analysis of the pivotal studies NP28761 and NP28673, serum creatinine increases have been 
reported in 17/253 patients (6.7%) treated with 600 mg alectinib twice daily. All but one event 
were of Grade 1 or 2 severity. A low rate of dose modification (including dose reduction, 
treatment interruption and withdrawal) due to these events was observed in approximately 2% 
of the patients. No cases of renal failure have been reported in the patients treated with 600 mg 
alectinib twice daily. In the evaluation of the safety laboratory tests, blood creatinine 


 
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displayed an increase in median values which remained within the normal range. In study AF-
001JP, a total of 19/58 patients (32.8%) treated with 300 mg alectinib twice daily reported 
blood creatinine increased, all of Grade 1 or 2 severity. Blood creatinine tended to increase 
slightly after treatment start but then generally remained at around 1.5-fold the site upper limit 
of baseline. For 3/58 patients (5.2%), renal impairment (not serious, Grade 1) was reported. 
See Section 10.3 for the management of abnormal renal function. 
10.2.2. Anaemia 
Haematologic findings were observed in both the rat and monkey 4-week and 13-week 
toxicity studies and findings in the 13-week studies were similar to those of the 4-week 
studies. Findings were at or close to clinically relevant exposures. Findings in the 13-week rat 
study 
included 
abnormal 
RBC 
morphology, 
large 
platelets 
in 
blood, 
macrophage/erythrophagy/blood absorption in lymph nodes, decreased lymphocyte in 
lymphoid tissues, and prolongation of prothrombin time. Findings in the 13-week monkey 
study included decreased RBCs with or without decreased haemoglobin concentration and 
haematocrit. In the 13-week toxicity study in rats, but not in monkeys, ileal haemorrhage 
accompanied by prolongation of the clotting time was noted. Haematologic adverse effects 
such as anaemia, thrombocytopenia, leukopenia and neutropenia have been observed with 
ALK inhibitors, including crizotinib and ceritinib. In the pooled analysis of the pivotal studies 
NP28761 and NP28673, anaemia was observed for 40/253 (15.8%; 1 serious) of the patients 
treated with 600 mg alectinib BID. The majority of events were Grade 1 or 2; four patients 
(1.6%) experienced a Grade 3 event, which did not require changes to study drug dosing, and 
one patient (0.4%) experienced a serious Grade 4 event, which was assessed by the 
Investigator to be unrelated to alectinib. A generally mild decrease of median haemoglobin 
levels was observed during the first month of treatment with alectinib, with median levels 
stabilizing at a level slightly below the normal range.  
In Study AF-001JP, 3/58 (5.2%) patients treated with 300 mg alectinib BID experienced 
anaemia (with 1 case [1.7%] reported as Grade 3) and 2/58 (3.4%) patients had haemoglobin 
decreased. Haematologic parameters including RBC, neutrophil, lymphocyte, and platelet 
counts will be monitored routinely in clinical trials. Study-specific inclusion, exclusion and 
withdrawal criteria are included in study protocols. 
10.2.3. Bradycardia  
Cases of bradycardia (7.9%) of Grade 1 or 2 have been reported in patients treated with 
alectinib in pivotal phase II clinical trials (NP28761, NP28673). There were 44 of 221 patients 
(20%) treated with alectinib who had post-dose heart rate values below 50 beats per minute. 
Patients who develop symptomatic bradycardia should be managed as recommended in 
Section 10.3. No case of bradycardia led to withdrawal from alectinib treatment. 
10.2.4. Gastrointestinal effects  
Constipation (36%), nausea (22%), diarrhoea (18%) and vomiting (13%) were the most 
commonly reported gastrointestinal (GI) reactions. Most of these events were of mild or 
moderate severity; Grade 3 events were reported for diarrhoea (1.2%), nausea (0.4%), and 
vomiting (0.4%). These events did not lead to withdrawal from alectinib treatment. Median 
time to onset for constipation, nausea, diarrhoea, and/or vomiting events was 18 days. The 


 
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events declined in frequency after the first month of treatment. See Section 10.3 for 
management of gastrointestinal events. 
10.2.5. Hepatotoxicity  
The finding of an elevated ALT or AST (≥3× baseline value) in combination with either an 
elevated total bilirubin (≥2× ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as defined 
by Hy's Law), see Section 11.7.1. 
Patients should be monitored for liver function and investigators must report as an adverse 
event of special interest (AESI) the occurrence of either of the following: 
 Treatment-emergent ALT or AST (≥3× baseline value in combination with total 
bilirubin ≥2× ULN (of which ≥35% is direct bilirubin) 
 Treatment-emergent ALT or AST ≥3× baseline value in combination with clinical 
jaundice 
See also Section 10.3 for the management of hepatotoxicity events. 
In the pivotal phase II clinical trials (NP28761, NP28673) two patients with Grade 3-4 
AST/ALT elevations had documented drug induced liver injury by liver biopsy. One of these 
cases led to withdrawal from alectinib treatment. Adverse reactions of increased AST and 
ALT levels (16% and 14% respectively) were reported in patients treated with alectinib in 
pivotal phase II clinical trials (NP28761, NP28673). The majority of these events were of 
Grade 1 and 2 intensity, and events of Grade ≥3 were reported in 2.8% and 3.2% of the patients, 
respectively. The events generally occurred during the first 3 months of treatment, were 
usually transient and resolved upon temporary interruption of alectinib treatment (reported 
for 1.2% and 3.2% of the patients, respectively) or dose reduction (1.6% and 0.8%, 
respectively). In 1.2% and 1.6% of the patients, AST and ALT elevations, respectively, led to 
withdrawal from alectinib treatment.  
Adverse reactions of bilirubin elevations were reported in 17% of the patients treated with 
alectinib in pivotal phase II clinical trials (NP28761, NP28673). The majority of the events 
were of Grade 1 and 2 intensity; Grade 3 events were reported in 3.2% of the patients. The 
events generally occurred during the first 3 months of treatment, were usually transient and 
resolved upon temporary interruption of alectinib treatment (4.7% of the patients) or dose 
reduction (2.8%). In 4 patients (1.6%), bilirubin elevations led to withdrawal from alectinib 
treatment.  
Concurrent elevations in ALT or AST greater than or equal to three times the ULN and total 
bilirubin greater than or equal to two times the ULN, with normal alkaline phosphatase, 
occurred in one patient (0.2%) treated in alectinib clinical trials.  
10.2.6. Interstitial lung disease (ILD) / pneumonitis  
Severe ILD/pneumonitis occurred in patients treated with alectinib. In the pivotal phase II 
clinical trials (NP28761, NP28673), 1 out of 253 patients treated with alectinib (0.4%) had a 
Grade 3 ILD. This event led to withdrawal from alectinib treatment. There were no fatal cases 
of ILD. Patients should be monitored for pulmonary symptoms indicative of pneumonitis. See 
Section 10.3 for the management of ILD events. 


 
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10.2.7. Oedema 
Most tyrosine kinase inhibitors have been associated with oedema, including ALK inhibitors, 
such as crizotinib and ceritinib. In the pooled analysis of the pivotal studies NP28761 and 
NP28673, oedema was observed in 85/253 (33.6%; 2/253 Grade ≥3) patients treated with 
600 mg alectinib twice daily. None of the events were reported as serious, and none required 
withdrawal from or interruption of treatment. Three patients (1.2%) required a dose reduction 
due to oedema. In study AF-001JP, 6 events of oedema were reported in 58 patients who 
received treatment with 300 mg twice daily. See Section 10.3 for the management oedema 
events. 
10.2.8. Photosensitivity 
Results of an in vitro phototoxicity study indicated that alectinib may have a phototoxic 
potential. Photosensitivity has been reported also with ALK-inhibitor (ceritinib). In the pooled 
analysis of the pivotal studies NP28761 and NP28673, photosensitivity reactions 
(photosensitivity and sunburn) were observed for 30/253 (11.9%) patients treated with 
600 mg alectinib twice daily. All of these events were Grade 1 or 2 and none were serious. 
Frequency of dose interruptions (0.4%) due to these events was low; there were no such events 
leading to withdrawal from treatment. No cases of photosensitivity were reported in study 
AF-001JP. See Section 10.3 for the management of photosensitivity. 
10.2.9. Rash 
Skin rash has been reported with ALK inhibitors (ceritinib and crizotinib). In the pooled 
analysis of the pivotal studies NP28761 and NP28673, rash (generalized rash, rash 
maculopapular, dermatitis acneiform, erythema, rash papular, rash pruritic, and rash macular) 
was observed for 51/253 (20.2%) patients treated with 600 mg alectinib twice daily. All 
except 1 of these events were Grade 1 or 2 and none were serious. Frequency of dose 
reductions (0.8%) and interruptions (1.2%) due to these events was low; there were no such 
events leading to withdrawal from treatment. In study AF-001JP, rash, dermatitis acneiform 
and maculo-papular rash were reported in 22/58 (37.9%), 1/58 (1.7%) and 3/58 (5.2%) 
patients treated with 300 mg twice daily, respectively, mostly of Grade 1 or 2. One case of 
skin exfoliation (Grade 2) and two cases of palmarplantar erythrodysaesthesia syndrome (one 
Grade 1 and one Grade 2) were reported. No case required any dose modification. See Section 
10.3 for the management of skin disorders. 
10.2.10. Severe myalgia and CPK elevations  
Cases of myalgia (31%) including myalgia events (25%) and musculoskeletal pain (7.5%) 
have been reported in patients treated with alectinib in pivotal phase II clinical trials 
(NP28761, NP28673). The majority of events were Grades 1 or 2 and three patients (1.2%) 
had a Grade 3 event. Dose modifications of alectinib treatment due to these adverse events 
were only required for two patients (0.8%); alectinib treatment was not withdrawn due to 
these events of myalgia. Elevations of CPK occurred in 46% of 219 patients with CPK 
laboratory data available in pivotal phase II clinical trials (NP28761, NP28673) with alectinib. 
The incidence of Grade 3 elevations of CPK was 5.0%. Median time to Grade 3 CPK elevation 
was 14 days. Dose modifications for elevation of CPK occurred in 4.0% of patients; 
withdrawal from alectinib treatment did not occur due to CPK elevations. See Section 10.3 
for the management of myalgia and CPK elevation. 


 
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10.2.11. Vision disorders 
In the rat QWBA study, tissue radioactivity disappeared over time, following a time course 
comparable to that of plasma radioactivity, except for melanin-containing tissues such as 
uveal tract of eyes which had much higher and more sustained exposure in pigmented rats. 
This is consistent with what is commonly observed for lipophilic basic drugs. Vision disorders, 
including diplopia, photopsia, vision blurred, visual impairment, and vitreous floaters have 
been reported with several ALK inhibitors (ceritinib, crizotinib). 
In the pooled analysis of the pivotal studies NP28761 and NP28673, vision disorders were 
observed for 29/253 patients (11.5%) treated with 600 mg alectinib twice daily. These 
included blurred vision (4.0%), visual impairment and vitreous floaters (each 2.4%), reduced 
visual acuity (1.6%), diplopia (1.2%) and asthenopia (0.8%). All of these events were Grade 
1 or 2 and none were serious. In study AF-001JP, 17 out of the 58 patients (29.3%) treated 
with 300 mg twice daily had vision disorder events, including dry eye (6/58 [10.3%]), 
conjunctivitis (5/58 [8.6%]), increased lacrimation, blepharitis and cataract (2/58 [3.4%] each) 
as well as single cases of conjunctivitis allergic, vision blurred, visual impairment, 
maculopathy, foreign body sensation in eyes, and vitreous haemorrhage. The majority were 
Grade 1 or 2, except for a case of maculopathy of Grade 3, reported as an SAE, and requiring 
dose modification of alectinib therapy. Investigators should consider referring the patients for 
ophthalmological evaluation according to local clinical practice guidelines, if vision disorders 
persist or worsen in severity. See Section 10.3 for the management of vision disorders. 
10.3. 
Management of alectinib related toxicities 
Management of adverse events may require dose reduction, temporary interruption, or 
discontinuation of treatment with alectinib. The dose of alectinib should be reduced in steps 
of 150 mg twice daily based on tolerability. Alectinib treatment should be permanently 
discontinued if patients are unable to tolerate the 300 mg twice daily dose. 
Dose modification advice is provided in Table 1 and Table 2 below. 
Table 1 Dose reduction schedule 
Reduction schedule  
Dose level  
Total daily dose 
Starting dose  
600 mg twice daily  
1200 mg 
First dose reduction  
450 mg twice daily  
900 mg 
Second dose reduction  
300 mg twice daily  
600 mg 
Table 2 Dose modification advice for specified adverse events  
Event 
Action to be taken 
Abnormal kidney function AEs 
Kidney function laboratory abnormalities 
are to be reported as AEs: 
 If, at any time during the trial treatment, 
eGFR decreases by >50% of the 
baseline visit value, the patient has to be 
carefully 
monitored. 
All 
of 
the 
underlying factors that may have 


 
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acutely impacted serum creatinine 
levels need to be evaluated and 
corrected (e.g., dehydration, recent 
exposure to contrast media, increased 
amount of cooked meat in diet, 
concomitant 
medications 
affecting 
renal function as appropriate, etc.).  
 Any eGFR decrease by >50% of the 
baseline visit value requires repeat 
testing. 
– If, at the repeat test, the eGFR 
decrease is still >50% of the baseline 
visit value, the treatment with 
alectinib should be interrupted. 
 Alectinib treatment may be resumed 
with caution if the eGFR value has 
increased to approximately the baseline 
visit value. 
GI tract AEs (e.g., nausea, vomiting, 
diarrhoea) 
Diarrhoea, nausea, and vomiting should 
be handled with best supportive care first 
before considering dose modification.  
GI events are expected to be minimized by 
taking the study drug with a meal. In case GI 
events occur, appropriate measures should 
be taken in accordance with local clinical 
practice guidelines. If GI toxicities are 
observed and not tolerable, treatment with 
study drug should be temporarily interrupted 
until recovery to Grade 1 or lower. 
Hepatotoxicity 
Liver test laboratory abnormalities are to be 
reported as AEs: 
 If ALT or AST >3× baseline, repeat 
testing of ALT, AST, ALP, and total 
bilirubin within 48 –72 hours, with 
inquiry about symptoms. If upon repeat 
testing the transaminases remain >3× 
baseline, but are not >5× baseline, or 
not 
accompanied 
with 
bilirubin 
increases, or do not match any other 
rule for permanent discontinuation, 
then monitoring can continue as per 
investigator 
judgment, 
and 
dose 
modification is not necessary.  
 At any time during the trial treatment, 
if symptoms compatible with liver 
injury are observed, liver enzymes 
should be measured as soon as possible. 


 
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 Study drug treatment has to be 
permanently discontinued if any of the 
following occurs: 
– First observation of ALT or AST 
>8× ULN 
– ALT or AST >5× ULN for more than 
2 weeks  
– First observation of ALT or AST 
>3× ULN and total bilirubin >2× 
ULN# 
– First observation of ALT or AST 
>3× ULN and the appearance of 
jaundice 
or 
signs 
of 
hepatic 
dysfunction or other symptoms (such 
as fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, 
fever, rash, or eosinophilia [>5%])# 
 Following 
IMP 
discontinuation, 
weekly monitoring of laboratory values 
should continue until the abnormal 
values 
have 
normalized 
to 
pre-
treatment levels and/or an adequate 
explanation of the abnormal value is 
found.  
 Resumption of study drug is not 
allowed 
in 
patients 
discontinuing 
because of any of the above criteria. 
Interstitial lung disease 
 Patients should be monitored for 
pulmonary symptoms indicative of 
pneumonitis. 
 Study drug should be permanently 
discontinued in patients diagnosed with 
interstitial lung disease. 
Oedema 
Physical examinations will be performed 
routinely in clinical trials. In case oedema 
events occur, appropriate measures should 
be taken in accordance with local clinical 
practice guidelines. 
Skin disorder AEs (e.g., phototoxicity, 
rash) 
Patients should be advised to avoid 
prolonged sun exposure while taking 
alectinib and for at least 7 days after study 
drug discontinuation. Patients should also be 
advised to use a broad-spectrum sunscreen 
and lip balm of at least SPF 50 to help 
protect against potential sunburn. 


 
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Severe myalgia and CPK elevations 
CPK laboratory abnormalities are to be 
reported as AEs: 
 Myopathy should be considered in any 
patient with diffuse myalgia, muscle 
tenderness or weakness, and/or marked 
elevations of CPK levels. Patients 
should promptly report unexplained 
muscle pain, tenderness, or weakness, 
particularly if accompanied by malaise 
or fever. CPK levels should be assessed 
in patients reporting these symptoms. 
 At the first occurrence of any of 
asymptomatic CPK values (>10× ULN, 
symptomatic CPK >5× ULN, or in the 
presence of severe muscular symptoms 
with CPK >ULN but ≤5× ULN) at any 
time during the trial treatment, the 
patient requires monitoring of the CPK 
values until they are normalized to pre-
treatment levels or a reasonable 
explanation for the CPK elevation and 
the symptoms is established. 
Vision disorders 
Investigators should consider referring 
patients for an ophthalmological evaluation 
according 
to 
local 
clinical 
practice 
guidelines if vision disorders persist or 
worsen in severity and should advise 
patients to exercise caution when driving or 
operating machinery due to the risk of 
developing a vision disorder. 
Other AEs (including bradycardia and 
anaemia) or laboratory abnormalities: 
Grade 3 or 4: 
 Temporarily interrupt alectinib for a 
maximum of 3 weeks.  
 If improvement to Grade ≤1 or baseline 
does 
not 
occur 
within 
21 days, 
permanently discontinue alectinib. 
 First episode: If improvement to Grade 
≤1 or baseline does not occur within 
21 days, decrease the current dose of 
alectinib by 150 mg (1 capsule) twice 
daily (to a total dose of 450 mg twice 
daily). 
 Second episode: If improvement to 
Grade ≤1 or baseline does not occur 
within 21 days, decrease the current 
dose of alectinib by another 150 mg (1 


 
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capsule) twice daily (to a total dose of 
300 mg twice daily). 
 Third 
episode: 
Permanently 
discontinue alectinib. 
Grade 2 (except any symptoms and signs 
that can be corrected with supportive care): 
 Temporarily interrupt alectinib and 
resume if recovering to Grade ≤1 or 
baseline if. 
 First episode: If improvement to Grade 
≤1 or baseline occurs within 10 days, 
continue same dose of alectinib. If 
improvement occurs after 10 days, 
decrease the current dose of alectinib by 
150 mg (1 capsule) twice daily when 
resuming treatment (to a total dose of 
450 mg twice daily). 
 Second episode: If improvement to 
Grade ≤1 or baseline does not occur 
within 10 days, decrease the current 
dose of alectinib by 150 mg (1 capsule) 
twice daily (to a final dose of 450 mg 
twice daily, or 300 mg twice daily if 
dose was reduced to 450 mg twice daily 
after first episode). If improvement 
occurs after 10 days, decrease the 
current dose of alectinib by 300 mg (2 
capsules) when resuming treatment (to 
a total dose of 300 mg twice daily, or 
150 mg twice daily if dose was reduced 
to 450 mg twice daily after first 
episode). 
 Third 
episode: 
Permanently 
discontinue alectinib. 
Grade 1:  
no action required 
AE: adverse event; twice daily: twice a day; ANC: absolute neutrophil count; eGFR: 
estimated glomerular filtration rate; GI: gastrointestinal. 
Note: Pre-existing pleural effusion will not be considered as an adverse event. 
Note: # refer to Section 11.7 Adverse Events of Special Interest 
10.4. 
Contraindications 
Hypersensitivity to alectinib or to any of the excipients (see the Alectinib IB for details). 


 
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10.5. 
Effects of other medicinal products on alectinib  
Based on in vitro data, CYP3A4 is the primary enzyme mediating the metabolism of both 
alectinib and its major active metabolite M4, and CYP3A contributes to 40% − 50% of total 
hepatic metabolism. M4 has shown similar in vitro potency and activity against ALK. 
10.5.1. CYP3A inducers 
Co-administration of multiple oral doses of 600 mg rifampicin once daily, a strong CYP3A 
inducer, with a single oral dose of 600 mg alectinib reduced alectinib Cmax, and AUCinf by 
51% and 73% respectively and increased M4 Cmax and AUCinf 2.20 and 1.79-fold 
respectively. The effect on the combined exposure of alectinib and M4 was minor, reducing 
Cmax and AUCinf by 4% and 18%, respectively. Based on the effects on the combined 
exposure of alectinib and M4, no dose adjustments are required when alectinib is co-
administered with CYP3A inducers. Appropriate monitoring is recommended for patients 
taking concomitant strong CYP3A inducers (including, but not limited to, carbamazepine, 
phenobarbital, phenytoin, rifabutin, rifampicin and St. John’s Wort [Hypericum perforatum]). 
10.5.2. CYP3A inhibitors 
Co-administration of multiple oral doses of 400 mg posaconazole twice daily, a strong 
CYP3A inhibitor, with a single oral dose of 300 mg alectinib increased alectinib exposure 
Cmax and AUCinf by 1.18 and 1.75-fold respectively, and reduced M4 Cmax and AUCinf 
by 71% and 25% respectively .The effect on the combined exposure of alectinib and M4 was 
minor, reducing Cmax by 7% and increasing AUCinf 1.36-fold. Based on the effects on the 
combined exposure of alectinib and M4, no dose adjustments are required when alectinib is 
co-administered with CYP3A inhibitors. Appropriate monitoring is recommended for patients 
taking concomitant strong CYP3A inhibitors (including, but not limited to, ritonavir, 
saquinavir, 
telithromycin, 
ketoconazole, 
itraconazole, 
voriconazole, 
posaconazole 
nefazodone, grapefruit or Seville oranges). 
10.5.3. Medicinal products that increase gastric pH 
Multiple doses of esomeprazole, a proton pump inhibitor, 40 mg once daily, demonstrated no 
clinically relevant effect on the combined exposure of alectinib and M4. Therefore, no dose 
adjustments are required when alectinib is co-administered with proton pump inhibitors or 
other medicinal products which raise gastric pH (e.g. H2 receptor antagonists or antacids). 
10.5.4. P-gp substrates  
In vitro, alectinib and its major active metabolite M4 are inhibitors of the efflux transporter 
P-glycoprotein (P-gp). Therefore, alectinib and M4 may have the potential to increase plasma 
concentrations of co-administered substrates of P-gp. When alectinib is co-administered with 
P-gp substrates (e.g., digoxin, dabigatran etexilate, topotecan, sirolimus, everolimus, nilotinib 
and lapatinib), appropriate monitoring is recommended.  
10.5.5. BCRP substrates  
In vitro, alectinib and M4 are inhibitors of the efflux transporter Breast Cancer Resistance 
Protein (BCRP). Therefore, alectinib and M4 may have the potential to increase plasma 
concentrations of co-administered substrates of BCRP. When alectinib is co-administered 


 
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with BCRP substrates (e.g., methotrexate, mitoxantrone, topotecan and lapatinib), appropriate 
monitoring is recommended.  
10.5.6. CYP substrates  
In vitro, alectinib and M4 show weak time-dependent inhibition of CYP3A4, and alectinib 
exhibits a weak induction potential of CYP3A4 and CYP2B6 at clinical concentrations.  
Multiple doses of 600 mg alectinib had no influence on the exposure of midazolam (2 mg), a 
sensitive CYP3A substrate. Therefore, no dose adjustment is required for co-administered 
CYP3A substrates.  
A risk for induction of CYP2B6 and PXR regulated enzymes apart from CYP3A4 cannot be 
completely excluded. The effectiveness of concomitant administration of oral contraceptives 
may be reduced. 
10.6. 
Contraception, nursing, pregnancy 
10.6.1. Contraception 
For women who are not postmenopausal (≥12 months of non-therapy-induced amenorrhea) 
or surgically sterile (absence of ovaries and/or uterus): agreement to remain abstinent or use 
single or combined contraceptive methods that result in a failure rate of <1% per year during 
the treatment period and for at least 3 months after the last dose of IMP. 
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the patient. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and 
withdrawal are not acceptable methods of contraception. 
Examples of effective contraceptive methods with a failure rate of <1% per year include tubal 
ligation, male sterilization, hormonal implants, established, proper use of combined oral or 
injected hormonal contraceptives, and certain intrauterine devices. 
Men must agree to remain abstinent or use a condom plus an additional contraceptive method 
that together result in a failure rate of <1% per year during the treatment period and for at 
least 3 months after the last dose of IMP. 
Women who become pregnant while participating in the trial must discontinue trial 
medication immediately. The pregnancy must be reported following procedures detailed in 
Section 11.13. Also any pregnancy that occurs in a female partner of a male trial participant 
must be reported. 
Patients should be informed that taking the trial medication may involve unknown risks to the 
foetus if pregnancy were to occur during the trial. In order to participate in the trial they must 
adhere to the contraception requirement (described above) for the duration of the trial up to 
at least 3 months after the last dose of any alectinib. If there is any doubt whether a patient 
will reliably comply with the requirements for contraception, that patient should not be 
entered into the trial. 
10.6.2. Use in pregnancy 
If a patient inadvertently becomes pregnant while on trial treatment, trial treatment will be 
stopped immediately for the patient and the event must be reported immediately, see 


 
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Section 11.13. The site will contact the patient at least monthly and document the patient’s 
status until the pregnancy has been completed or terminated. The outcome of the pregnancy 
will be reported to ETOP without delay and within 24 hours if the outcome is a serious adverse 
experience (e.g. death, abortion, congenital anomaly, or other disabling or life-threatening 
complication to the mother or newborn). The trial investigator will make every effort to obtain 
permission to follow the outcome of the pregnancy and report the condition of the foetus or 
newborn to ETOP.  
10.6.3. Use in nursing women 
It is unknown whether alectinib and its metabolites are excreted in human milk. A risk to the 
newborn/infant cannot be excluded. Patients who are breast-feeding are not eligible for the 
trial. 
11. 
Adverse event and serious adverse event reporting 
ICH GCP and the EU Directive 2001/20/EC require that both investigators and sponsors 
follow specific procedures when notifying and reporting adverse events/reactions in clinical 
trials. These procedures are described in this section of the protocol. 
The main criterion for tolerability is the occurrence of toxicities and adverse events. The 
severity and causality will be classified according to the CTCAE version 4.0.  
The 
CTCAE 
is 
available 
for 
downloading 
on 
the 
internet 
at 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm. 
Detailed reporting instructions are indicated in Section 11.12. 
11.1. 
Adverse event (AE) 
An adverse event (AE) is defined as any untoward medical occurrence that occurs from the 
date of signature of informed consent until 30 days after all trial treatment discontinuation, 
regardless of whether it is considered related to a medication. 
An AE can therefore be any of the following: 
 Any unfavourable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an IMP, whether considered 
related to the IMP or not. 
 Any new disease or exacerbation of an existing disease (a worsening in the character, 
frequency, or severity of a known condition). 
 Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline. 
 Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in trial treatment or concomitant 
treatment or discontinuation from IMP. 


 
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 AEs that are related to a protocol-mandated intervention, including those that occur 
prior to assignment of trial treatment (e.g., screening invasive procedures such as 
biopsies) 
Any grade of any observed AE should be reported on the AE eCRFs. Please see Section 11.12 
for details. 
11.2. 
Adverse reaction (AR) 
An adverse reaction (AR) is defined as “any noxious and unintended response to an IMP 
related to any dose administered”. 
All adverse events judged by either the reporting investigator or the sponsor (ETOP) as having 
a reasonable causal relationship (see Section 11.9) to an IMP qualify as adverse reactions. 
The expression suspected/related means to convey in general that there is evidence or 
argument to suggest a causal relationship to the trial treatment. 
11.3. 
Unexpected adverse reaction (UAR) 
An unexpected adverse reaction (UAR) is any adverse reaction, the nature, or severity of 
which is not consistent with the applicable product information. 
When the outcome of the adverse reaction is not consistent with the Alectinib IB or summary 
of product characteristics (SmPC) this adverse reaction should be considered as unexpected. 
11.4. 
Serious adverse events (SAE) 
A serious adverse event (SAE) is defined as any undesirable medical occurrence/adverse drug 
experience that at any dose: 
 results in death (any cause, except progression of cancer under study) 
 is life-threatening 
 requires or prolongs inpatient hospitalisation (see 11.4.1 for details) 
 results in persistent or significant disability/incapacity 
 constitutes an important medical event 
 is a congenital anomaly or birth defect (including neonatal deaths and abortions) 
 is a secondary malignancy/second primary malignancy 
11.4.1. Inpatient hospitalisation 
A hospital stay equal to, or greater than, 24 hours. Hospitalisations occurring under the 
following circumstances are not considered to be SAEs:  
 elective surgery, for pre-existing conditions and planned prior to trial entry 
 occur on an outpatient basis and do not result in admission (hospitalisation <24h) 
 are part of the normal treatment or monitoring of the studied treatment 
11.4.2. Important medical events 
Important medical events are defined as those occurrences that may not be immediately life-
threatening or result in death, hospitalisation, or disability, but may jeopardise the patient or 
require medical or surgical intervention to prevent one of the other outcomes listed above. 


 
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Medical and scientific judgment should be exercised in deciding whether such an AE should 
be considered serious. 
11.4.3. Secondary malignancies / second primary malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the previous malignancy. 
A second primary malignancy is one that is unrelated to the treatment of a previous 
malignancy (and is NOT a metastasis from the previous malignancy). 
SAEs are required to be reported to ETOP immediately (i.e., within 24 hours after 
awareness of the event) by completing the SAE eCRF (SAE Initial Reports). See Section 
11.12 for detailed reporting instructions. 
11.5. 
Pregnancy 
Patients who are not of childbearing potential due to being postmenopausal (2 years without 
menstruation) or surgical sterilisation (oophorectomy, hysterectomy and/or tubal ligation) do 
not need to use contraception to be eligible for the trial. All other patients are considered to 
be of childbearing potential and must use adequate contraception throughout the trial. 
Women of childbearing potential and sexually active men must use highly effective 
contraception during trial treatment and until at least 3 months thereafter. Please refer to 
Section 10.6.1 for highly effective contraception methods. 
11.5.1. Abortions 
Any abortion (miscarriage, spontaneous, induced or elective abortion) should be classified as 
an SAE (as the ETOP as the sponsor considers abortions to be medically significant) and 
reported to ETOP immediately (i.e., within 24 hours after awareness of the event) by 
completing the SAE eCRF (SAE Initial and Follow-up Reports). 
11.5.2. Congenital anomalies/birth defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to IMP or the 
female partner of a male patient exposed to the IMP should be classified as an SAE and 
reported to ETOP immediately (i.e., within 24 hours after awareness of the event) by 
completing the SAE eCRF (SAE Initial and Follow-up Reports). 
 
11.5.3. Maternal exposure 
In the case of pregnancy occurring during the course of the trial or within at least 3 months 
after treatment discontinuation, the investigator shall immediately (within 24 hours after 
awareness of pregnancy) notify ETOP by completing the pregnancy eCRF in ETOPdata in 
accordance with the SAE reporting procedures. 
Follow-up information regarding the course of the pregnancy, including perinatal and 
neonatal outcome and, where applicable, offspring information must be reported (within 
14 days) by submitting a second pregnancy eCRF in ETOPdata. All neonatal deaths and 


 
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congenital anomalies/birth defects that occur within 30 days of birth should be reported, 
irrespective of causality, as SAEs. In addition, any infant death after 30 days, irrespective of 
causality should also be reported within 24 hours of the investigator’s knowledge of the event 
using the SAE eCRF. 
11.5.4. Paternal exposure 
Pregnancy that occurs in a female partner of a male trial participant is not considered to be an 
adverse event. The pregnant partner will need to sign a “Pregnant Partner ICF” to allow for 
follow-up on her pregnancy. 
The outcome of all pregnancies (spontaneous abortion or miscarriage, induced or elective 
abortion, ectopic pregnancy, normal birth or congenital abnormality) must immediately be 
reported (within 24 hours after awareness of pregnancy) to ETOP by completing the 
pregnancy eCRF in ETOPdata in accordance with the SAE reporting procedures. . 
11.6. 
Exceptions to the SAE definition  
The following situations do not need to be reported as SAEs:  
 Elective hospitalisation for pre-existing conditions that have not been exacerbated by 
trial treatment.  
 A hospitalisation which was planned before the patient consented for trial participation 
and where admission did not take longer than anticipated (see also 11.4.1). 
 A hospitalisation planned for protocol related treatment or protocol related procedure 
as per institutional standard timelines. 
 Social and/or convenience admission to a hospital  
 Medical or surgical procedure (e.g. endoscopy, appendectomy); the condition that 
leads to the procedure is an (serious) AE.  
 Situations where an untoward medical occurrence did not occur (palliative care, 
rehabilitation). 
 Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the trial that do not worsen significantly. 
 Progression or death due to worsening of cancer under study (see Section 11.6.1 for 
details).  
11.6.1. Deaths 
For the ALERT-lung protocol, mortality is a secondary efficacy endpoint. Deaths that occur 
during the protocol-specified adverse events reporting period (e.g. during trial treatment and 
within 30 days following cessation of treatment) that are attributed by the investigator solely 
to progression of the underlying disease should be recorded on the End of Treatment eCRF 
and the Follow-up eCRF. 
All other on-trial deaths, regardless of relationship to IMP, must be recorded on the SAE 
eCRF (SAE Initial and Follow-up Reports) and immediately (within 24 hours) reported to 
ETOP.  
Death should be considered an outcome and not a distinct event. The event or condition that 
caused or contributed to the fatal outcome should be recorded as the single medical concept 
on the SAE eCRF (SAE Initial and Follow-up Reports). Generally, only one such event 


 
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should be reported. The term "sudden death" should be used only for the occurrence of an 
abrupt and unexpected death due to presumed cardiac causes in a patient with or without 
preexisting heart disease, within 1 hour after the onset of acute symptoms or, in the case of an 
unwitnessed death, within 24 hours after the patient was last seen alive and stable.  
If the cause of death is unknown and cannot be ascertained at the time of reporting, 
"unexplained death" should be recorded on the SAE eCRF (SAE Initial and Follow-up 
Reports).  
If the cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death. 
11.7. 
Adverse events of special interest (AESI) 
The following events of special interest (AESI) are not necessarily SAEs, but should be 
reported as such on the SAE eCRFs (SAE Initial Reports) by indicating that this is an 
“adverse event of special interest”. 
AESIs are required to be reported to ETOP immediately (i.e., within 24 hours after awareness 
of the event) by completing the SAE eCRF (SAE Initial Reports). See Section 11.12 for 
detailed reporting instructions. 
AEs of special interest for this trial are the following: 
11.7.1. Drug-induced liver injury 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s law. 
The finding of an elevated ALT or AST (>3× baseline value) in combination with either an 
elevated total bilirubin (>2× ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury. Therefore, 
investigators must report the occurrence of either of the following: 
 
Treatment-emergent ALT or AST >3× baseline value in combination with total 
bilirubin >2× ULN (of which 35% is direct bilirubin) 
 
Treatment-emergent ALT or AST >3× baseline value in combination with clinical 
jaundice 
The most appropriate diagnosis or the abnormal laboratory values, if a diagnosis cannot be 
established, should be recorded. 
11.7.2. Suspected transmission of an infectious agent by the IMP 
Suspected transmission of an infectious agent by the IMP as defined below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting spongiform 
encephalopathy), pathogenic or non-pathogenic, is considered an infectious agent. A 
transmission of an infectious agent may be suspected from clinical symptoms or laboratory 
findings indicating an infection in a patient exposed to a medicinal product. This term applies 
only when a contamination of the study drug is suspected. 
11.7.3. Adverse events associated with an overdose 


 
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An overdose is the accidental or intentional use of a drug in an amount higher than the dose 
being studied. An overdose or incorrect administration of IMP is not itself an AE, but it may 
result in an AE. All AEs associated with an overdose or incorrect administration of the IMP 
are required to be reported to ETOP immediately (i.e., within 24 hours after awareness of the 
event) by completing the SAE eCRF, whether the event fulfils “serious” criteria or not. 
11.8. 
Severity / intensity of (serious) adverse events 
The (serious) AE severity grade provides a qualitative assessment of the extent or intensity of 
a specific event, as determined by the investigator or as reported by the patient. The severity 
grade does not reflect the clinical seriousness of the event, only the degree or extent of the 
affliction or occurrence (e.g. severe nausea, mild seizure), and does not reflect the relationship 
to trial drug. A severe event may be of relatively minor medical significance (such as severe 
headache). The term “severe” is not the same as “serious”, which is based on patient/event 
outcome or action criteria associated with events that pose a threat to a patient’s life or 
functioning. 
Severity grade for other adverse events not covered in the toxicity grading scale: 
 Grade 1 = Mild – transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required 
 Grade 2 = Moderate – mild to moderate limitation in activity, some assistance may 
be needed; no or minimal medical intervention/therapy required 
 Grade 3 = Severe – marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalisation is possible 
 Grade 4 = Life threatening – extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, hospitalisation or hospice 
care probable 
 Grade 5 = Death – the event results in death 
11.9. 
Causality of adverse events 
The investigator must determine the relationship between the administration of trial drug(s) 
and the occurrence of an AE/SAE following the definitions indicated below: 
Not suspected 
The temporal relationship of the adverse event to trial drug(s) 
administration makes a causal relationship unlikely or remote, or 
other medications, therapeutic interventions, or underlying 
conditions provide a sufficient explanation for the observed 
event. 
Suspected 
The temporal relationship of the adverse event to trial drug(s) 
administration makes a causal relationship possible, and other 
medications, therapeutic interventions, or underlying conditions 
do not provide a sufficient explanation for the observed event. 
 
 


 
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Relationship to the protocol treatment 
Not suspected  
Suspected / related to trial treatment 
- 
unrelated 
- 
unlikely 
- 
possible 
- 
probable 
- 
definite 
11.10. Duration of adverse events 
For both AEs and SAEs, the investigator will provide a record of the start and stop dates of 
the event. 
11.11. Action taken 
The investigator will report the action taken with trial drug(s) because of an AE or SAE, as 
applicable (e.g. discontinuation of trial drug(s), medication needed for the treatment of an AE) 
and in case of an SAE report if concomitant and/or additional treatments were given for the 
event. 
11.12. Reporting of adverse events 
11.12.1. Reporting of adverse events 
All AEs, regardless of relationship to IMP, will be reported from the date of signature of 
informed consent until 30 days after the last dose of IMP. After this period, the investigator 
is not required to actively monitor patients for AEs; however, ETOP should be notified if the 
investigator becomes aware of any post-study SAEs or AESIs that are at least possibly related 
to previous trial treatment. 
During trial treatment and until 30 days after the last dose of IMP, investigators should seek 
information on AEs at each patient contact. All AEs, whether reported by the patient or noted 
by trial personnel, will be recorded in the patient’s medical record and on the Adverse Event 
eCRF. 
11.12.2. Reporting of serious adverse events 
Any SAE, whether related to alectinib or not, or any AESI will be reported from the date of 
signature of informed consent until 30 days after the last dose of IMP. Information about all 
such events will be collected and recorded on the SAE eCRFs (SAE Initial and Follow-up 
Reports). 
After completion of trial treatments, report all SAEs beyond 30 days that are considered at 
least possibly related to previous trial treatment. Cases of secondary malignancies and 
congenital abnormalities and neonatal deaths are to be considered as SAEs, regardless of 
whether they occur during or after trial treatment. These events should be reported during the 
whole trial duration on the serious adverse event eCRFs (SAE Initial and Follow-up Reports) 
To ensure patient safety, ETOP must be informed of each SAE using the procedures described 
below: 
 Any SAE must be reported by submitting the completed SAE Initial Reports eCRF in 
English within 24 hours of awareness in the EDC system ETOPdata. 


 
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 Queries may be issued by the ETOP safety office; a timely response by the investigator 
to all SAE-related queries is crucial. 
 The SAE outcome must be reported within 15 days after initial reporting by online 
submitting the SAE Follow-up Report eCRF. In case the SAE is reported as ongoing 
after 15 days, a second follow-up report has to be submitted with the final outcome. 
Submission of SAE is done via the EDC system, or in case of unavailability, by sending the 
SAE form by fax to the ETOP safety office: 
+41 31 389 92 29 
As soon as the EDC system is available again, the SAE eCRF has to be completed and 
submitted by the site. 
The ETOP safety office will inform Roche safety and other appropriate persons about all 
SAEs within 24 hours of receipt at the ETOP safety office.  
The ETOP safety office will review the SAE and prepare a summary report of all SAEs 
received. Listings of SAEs will be prepared as required. 
The ETOP safety office will assess serious adverse events for expectedness. Any unexpected 
serious adverse reactions (SUSARs) occurring in this trial qualify for expedited reporting and 
ETOP will notify the appropriate regulatory authorities within the following timeframes:  
 Fatal or life-threatening SUSARs within 7 calendar days  
 Non-fatal or non-life-threatening SUSARs within 15 calendar days 
11.13. Reference safety information 
For the determination of the expectedness of the serious adverse events of alectinib, Section 6 
of the most recent version of the Alectinib IB serves as reference safety information  
The Sponsor will compare the severity of each event for the trial with the severity in the 
applicable reference document. 
12. 
Response evaluation 
12.1. 
CT schedule for response evaluation 
All patients must have a contrast enhanced CT thorax and upper abdomen (from top of thorax 
until adrenal glands and full liver and kidneys included) at baseline during screening within 
6 weeks before enrolment. CT scan will be repeated 8 weeks (±4 days) after first dose of 
alectinib and then every 8 weeks (±4 days) until disease progression. 
The same imaging technique, acquisition, and processing parameters should be used in a 
patient throughout the trial. 
In the case that a CT scan had to be done earlier or later than scheduled, effort should be made 
to return to the original CT schedule. 


 
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12.2. 
Storage of images for central review 
All CT images must be stored locally in electronic format for later central review, please 
consult the ALERT-lung Procedures Manual for details. 
Any information from which the identity of patients could be deduced must be removed 
before transferring any imaging data for central review (e.g. initials, birth date etc.). 
12.3. 
Response evaluation criteria in solid tumours (RECIST version 1.1) 
12.3.1. Introduction 
All included patients will be evaluated for disease response and progression according to the 
revised response evaluation criteria in solid tumours (RECIST version 1.1)16 
In this trial, patients must have measurable or evaluable disease (see definitions below).  
12.3.2. Methods of assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess 
the antitumour effect of a treatment. 
CT scan is the best currently available and reproducible method to measure lesions selected 
for response assessment. CT scan should generally be performed using a ≤5 mm contiguous 
reconstruction algorithm. MRI is acceptable for certain situations, e.g. body scans. 
Clinical lesions will only be considered measurable when they are superficial (e.g. skin 
nodules) and ≥10 mm. In the case of skin lesions, documentation by colour photography 
including a ruler to estimate the size of the lesion is recommended. 
Lesions on chest X-ray are acceptable as measurable lesions when they are clearly defined 
and surrounded by aerated lung. However, CT scan is preferable. 
Ultrasound is not useful in assessment of lesion size and is not accepted as a method of 
assessment. 
FDG-PET is not foreseen for regular response assessments. It may, however, be used to detect 
or confirm the appearance of new lesions. Attenuation correction CT scans performed as part 
of a PET/CT scan frequently show lower resolution; therefore, dedicated CT scans are 
preferred. However, if the site can demonstrate that the CT scan performed as part of a 
PET/CT is of the same diagnostic quality as a diagnostic CT scan (with i.v. and oral contrast), 
then the CT scan portion of the PET/CT can be used for RECIST measurements. 
12.3.3. Non-measurable disease 
Non-measurable disease is defined as lesions or sites of disease that cannot be measured. Non-
measurable lesions/sites of disease and special considerations:  
 Small non-nodal lesions (longest diameter <10 mm in CT scan) 
 Small lymph nodes (short axis ≥10 and <15 mm). Lymph nodes that have a short axis 
<10 mm are considered non-pathological and should not be recorded or followed as 
measurable or non-measurable disease. 


 
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 Bone lesions. Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft 
tissue components, can be considered as measurable lesions if the soft tissue 
component meets the definition of measurability described above. Blastic bone lesions 
are non-measurable. 
 Leptomeningeal disease 
 Ascites 
 Pleural or pericardial effusion 
 Lymphangitic involvement of skin or lung 
 Cystic lesions. Cystic lesions thought to represent cystic metastases may be considered 
as measurable lesions. However, if non-cystic lesions are present, these are preferred 
as target lesions 
 Tumour lesions situated in a previously irradiated area, or subjected to other 
locoregional therapy. Such lesions may be considered measurable if there has been 
demonstrated progression in the lesion 
 Abdominal masses/abdominal organomegaly identified by physical exam that are not 
measurable by reproducible imaging techniques 
12.3.4. Measurable disease 
Measurable disease is defined as the presence of at least one measurable lesion. 
Measurable lesions: 
 Tumour lesions must be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of: 
- 10 mm by CT scan (CT scan slice thickness no greater than 5mm) 
- 10 mm calliper measurement by clinical exam (lesions which cannot be 
accurately measured with callipers should be recorded as non-measurable) 
- 20 mm by chest X-ray 
Reminder: A lesion in a previously irradiated area is not eligible for measurable 
disease. 
 Malignant lymph nodes: to be considered pathologically enlarged and 
measurable, a lymph node must be ≥15 mm in short axis when assessed by CT 
scan, assuming the slice thickness is ≤5 mm. At baseline and in follow-up, only the 
short axis will be measured. 
12.3.5. Selection of target lesions 
Target lesions should be identified, measured and recorded at baseline. At baseline, there can 
be up to a maximum of 5 lesions representative of all involved organs, and up to 2 per organ. 
Target lesions should be selected on the basis of their size and their suitability for accurate 
repetitive measurements. A sum of diameters for all target lesions will be calculated and 
reported as the baseline sum of diameters. Lymph nodes selected as target lesions should 
always have the short axis recorded. All other lesions should always have their longest 


 
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diameters recorded. The sum of diameters will be used as reference to further characterize 
the objective tumour response of the measurable dimension of the disease. 
12.3.6. Selection of non-target lesions  
All other lesions (or sites of disease) not identified as target lesions should also be recorded 
as non-target lesions at baseline.  
For non-target lesions, measurements are not required, but the presence or absence of each 
should be noted throughout follow-up. It is possible to record multiple non-target lesions as a 
single item on the eCRF. 
12.3.7. Evaluation of target lesions 
All target lesions will be measured at each tumour assessment, and the sum of their diameters 
will be compared to previous assessments in order to assign the response status as specified 
below. 
 Complete Response (CR): Disappearance of all target lesions. Lymph nodes selected 
as target lesions must each have reduction in the short axis to <10 mm in order for the 
response to be considered complete. In this case, the sum of diameters may be >0. 
 Partial Response (PR): At least a 30% decrease in the sum of diameters of target 
lesions taking as reference the baseline sum of diameters. 
 Progression (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum recorded on the trial. In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. 
The appearance of one or more new lesions (see Section 12.3.9) denotes disease 
progression. 
 Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD taking as reference the smallest sum of diameters recorded 
on the trial. 
Note: All target lesions, including lymph nodes, should have their actual measurements 
recorded at each subsequent evaluation, even when very small (e.g. 2 mm). If the radiologist 
does not feel comfortable assigning an exact measure and reports a lesion as "too small to 
measure", a default value of 5 mm should be recorded. If a target lesion is thought likely to 
have disappeared, use "0 mm." 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable (NE) at that time point. If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered NE at that time point, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not 
change the assigned time point response. This would be most likely to happen in the case of 
PD. 
12.3.8. Evaluation of non-target lesions  
 Complete Response (CR): Disappearance of all non-target lesions; lymph nodes 
selected as non-target lesions must be non-pathological in size (<10 mm). 
 Non-CR/non-PD: Persistence of one or more non-target lesions (non-CR). 


 
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 Progression (PD): unequivocal progression of existing non-target lesions. 
Unequivocal means: comparable in magnitude to the increase that would be required 
to declare PD for measurable disease or an overall substantial increase in tumour 
burden that merits treatment discontinuation. 
When no imaging is done at all at a particular time point, the patient is not evaluable (NE) at 
that time point. If only a subset of lesions are evaluated at an assessment, usually the case is 
also considered NE at that time point, unless a convincing argument can be made that the 
contribution of the individual missing lesion(s) would not change the assigned time point 
response. This would be most likely to happen in the case of PD. 
12.3.9. Determination of new lesions 
The appearance of any new malignant lesion denotes disease progression. The finding of a 
new lesion should be unequivocal, i.e. not attributable to differences in scanning technique or 
findings thought to represent something other than tumour. If a new lesion is equivocal, e.g. 
because of its small size, the patient will stay on treatment (if the decision on PD is based on 
this lesion only). If the repeat scans confirm there is definitely a new lesion, then progression 
should be declared using the date of the previous scan when the lesion was discovered. 
Lesions or sites of disease found in a new location not included in the baseline scan (e.g. brain 
metastases) are considered new lesions. The detection of new lesions is not restricted to the 
examination methods used at baseline. 
Note: the "re-appearance" of a previously "disappeared" target or non-target lesion does not 
in itself necessarily qualify as PD; this is the case only if the overall evaluation meets the PD 
criteria, or if the patient was previously in CR. 
12.3.10. Additional considerations 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before 
confirming the complete response status. 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumour has met criteria for response or stable disease 
is mandatory to differentiate between response or stable disease (an effusion may be a side 
effect of the treatment) and progressive disease. 
12.3.11. When the patient has only non-measurable disease 
This circumstance arises in some phase III trials when it is not a criterion of trial entry to have 
measurable disease. The same general concepts apply here as noted above, however, in this 
instance there is no measurable disease assessment to factor into the interpretation of an 
increase in non-measurable disease burden. Worsening in non-target disease cannot be easily 
quantified (by definition: if all lesions are truly non-measurable). 
A useful test that can be applied when assessing patients for unequivocal progression is to 
consider if the increase in overall disease burden based on the change in non-measurable 
disease is comparable in magnitude to the increase that would be required to declare PD for 
measurable disease: i.e.an increase in tumour burden representing an additional 73% increase 
in ‘volume’ (which is equivalent to a 20% increase diameter in a measurable lesion). 


 
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Examples include an increase in a pleural effusion from ‘trace’ to ‘large’ or an increase in 
lymphangitic disease from localised to widespread. Some illustrative examples are shown in 
Figs. 5 and 6 in Appendix II of reference. 16 
If ‘unequivocal progression’ is seen, the patient should be considered to have had overall PD 
at that point. While it would be ideal to have objective criteria to apply to non-measurable 
disease, the very nature of that disease makes it impossible to do so, therefore the increase 
must be substantial. 
12.3.12. Determination of time point response 
Based on the responses of target lesions, non-target lesions, and the presence or absence of 
new lesions, the overall response will be determined at each tumour evaluation time point, 
according to the table below. 
12.3.13. For patients with measurable disease 
Table 3: Measurable Disease - Overall Response 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR / non-PD* 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any  
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes  
PD 
*Non-CR/non-PD should be used rather than SD for categorizing non-target lesions.  
12.3.14. For patients with non-measurable disease 
Table 4: Non-measurable Disease - Overall Response 
Non-target lesions 
New lesions 
Overall response 
CR 
No 
CR 
Non-CR / non-PD* 
No 
Non-CR / non-PD* 
Not evaluated 
No 
NE 
Unequivocal PD 
Yes or no 
PD 
Any  
Yes 
PD 


 
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*Non-CR/non-PD should be used rather than SD for categorizing non-target lesions.  
12.3.15. Determination of best overall response 
Best overall response is defined as best response recorded from the start of trial treatment 
across all time points until the end of trial treatment. 
13. 
Endpoints definition 
13.1. 
Overall response 
Overall response, the primary endpoint, is defined as best overall response (complete response 
(CR) or partial response (PR) according to RECIST criteria v1.1 (see Section 12.3) from the 
start of trial treatment across all time points until the end of trial treatment. 
13.2. 
Disease control 
Disease control (DC) is defined as complete or partial response, or disease stabilisation at 
24 weeks. 
13.3. 
Progression-free survival  
PFS is defined as the time from the date of enrolment until documented progression (based 
on RECIST 1.1 criteria) or death, if progression is not documented. Censoring (for patients 
without a PFS/death event) will occur at the last tumour assessment if patient is lost to follow-
up or refuses further documentation of follow-up. 
13.4. 
Overall survival 
OS is defined as time from the date of enrolment until death from any cause. Censoring will 
occur at the last follow-up date.  
13.5. 
Toxicity 
All safety parameters will be summarised in tables to evaluate the safety profile of patients 
treated with alectinib in terms of: 
 Adverse events including adverse events leading to dose modifications or 
interruptions, study drug withdrawal, and death 
 Severe, serious, and selected adverse events 
 Deaths 
 Laboratory parameters and abnormalities, vital signs and ECGs 
Adverse events will be coded using MedDRA and summarized by mapped term and 
appropriate thesaurus level. All adverse events and routine laboratory parameters will be 
assessed according to the NCI CTCAE v4.0 grading system. For adverse events, the most 
extreme intensity will be used for reporting. Adverse events will be described by individual 
listings and by body system, as well as by severity. In tables showing the overall incidence of 
adverse events, patients who experienced the same event on more than one occasion are 


 
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counted only once in the calculation of the event frequency. Laboratory values will be 
summarized including summary tables for the shifts in grades from baseline to the worst grade 
observed during treatment. Descriptive summary tables of change from baseline over time 
will be provided for vital signs. ECG findings over time will be summarized. Study drug 
administration will be summarized by duration and cumulative dose. In addition, treatment 
exposure will be summarized including the number of doses received, dose intensity, and the 
percentage of planned dose. 
 


 
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14. 
Biological material and translational research 
14.1. 
Biomarker program 
The biomarker program has the following goals:  
 Identification of the translocation-partners of RET 
 Investigation of mechanisms for intrinsic and acquired resistance 
 Identification of co-occurring mutations in the initial FFPE-material by parallel-
sequencing 
 Search for potential mechanisms of resistance upon progression 
 Investigate test characteristics of FISH as current gold-standard compared to parallel-
sequencing or Nanostring technology. 
 Development of diagnostic assays 
14.2. 
Biobank 
A central biobank with all biological material collected from every patient enroled in this trial 
will be established for translational research, which is integral to the trial. The required 
pathology material (described below) is submitted to, catalogued, and maintained at the 
ALERT-lung Central Laboratory, located at the Institute for Pathology, University 
Hospital Cologne, Germany. Formalin-fixed, paraffin-embedded (FFPE) tumour tissue 
blocks (tissue blocks, resection or biopsy specimen) or cytoblocks collected prior to treatment 
with alectinib, will be centrally collected and biobanked at the central laboratory in Cologne. 
The material will undergo central histology review, investigation of RET using FISH and 
parallel-sequencing of cancer-related genes. Upon progression, a re-biopsy of the progressive 
lesion is strongly encouraged to obtain fresh-frozen biopsy material for whole-exome 
sequencing. An EDTA-blood sample at progression, which can be taken in the same setting 
as the biopsy at progression, is required as a matched reference normal DNA sample.  
14.3. 
Central RET confirmation 
RET rearrangement of tumour samples from all enroled patients will be retested by FISH and 
by parallel-sequencing at the Central Laboratory in Cologne. In the routine clinical setting, 
FISH is currently the gold-standard to detect RET-rearrangements. However, the technique 
has limited sensitivity and specificity. Thus, comprehensive parallel-sequencing will be used 
to determine the sequence of the rearrangement and to compare it with the FISH-patterns. 
Parallel-sequencing will also allow the determination of potential co-occurring mutations and 
the translocation-partner of RET, both of which have potential clinical implications.5 
14.4. 
Diagnostic assay development 
In the current age of targeted therapies, advances in biomarker identification and the 
increasing access to biomarker testing have allowed for a more personalised healthcare 
approach and treatment with appropriately targeted therapies. However, these technological 
advances have also helped to uncover some limitations to be overcome in order for truly 
personalised healthcare to become a reality. 


 
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The first of these limitations is that for many patients with tumours like NSCLC, obtaining 
enough tissue to test for an ever-increasing number of biomarkers is difficult. This in effect 
limits diagnostic testing, the associated targeted drug development, and thus, treatment 
options for patients. 
Further, retesting patients multiple times throughout the course of therapy to guide treatment 
is rarely possible, as the benefit-risk ratio of obtaining more tissue is often not favourable.  
A second limitation is that some tumours considered common, such as NSCLC, are 
increasingly being divided into subgroups based on infrequently or rarely occurring 
biomarkers. A more efficient means to test patients and develop drugs targeted at identified 
mutations or biomarkers is needed in order to provide these patients with access to effective 
and innovative treatment options. 
A multiplex diagnostic test based on easily accessible substrate such as circulating cell-
free DNA (cfDNA) from blood would allow the testing of more samples to determine 
their molecular status and would therefore contribute significantly to providing the most 
appropriate molecularly based treatment option for each patient. 
14.5. 
Mandatory biomaterial  
 FFPE tumour block from a biopsy or resection prior to treatment with alectinib must 
be centrally submitted. Suitable materials are any biopsy or resection specimens as 
well as cytoblocks. 
 Pathology Report from biopsy after disease progression on the most recent treatment 
regimen prior to treatment with alectinib (all information allowing identification of 
the patient, e.g. patient name, day and month of birth, must be removed). 
 2x 5 mL tubes of plasma for diagnostic assay development, from 20 mL whole blood, 
immediately frozen at -80°C in EDTA blood tubes and stored locally at -80°C until 
further notice. Please consult the ALERT-lung Procedures Manual for details. 
14.6. 
Biomaterial at progression 
Upon progression of the disease, the following biomaterial is collected: 
 2x 5 mL tubes plasma for translational research, from 20 mL whole blood, 
immediately frozen at -80°C in EDTA blood tubes and  stored locally at -80°C until 
further notice. 
Patients should also be encouraged to have a re-biopsy of the progressive lesion with the aim 
of performing whole-exome sequencing (WES). If the patient agrees to a re-biopsy procedure, 
a whole blood sample should also be collected and a pathology report submitted: 
 Fresh frozen re-biopsy 
 Whole blood sample (9-10 mL) to be taken at the time of re-biopsy 
 Pathology Report from biopsy at progression (all information allowing identification 
of the patient, e.g. patient name, day and month of birth, must be removed). 


 
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The re-biopsy material should be snap-frozen in liquid nitrogen upon extraction and stored 
locally at (-80°C). The 2x 5 mL plasma and the 9-10 mL whole blood samples should stored 
in EDTA tubes and stored locally at 80°C. 
Both samples will be shipped to the central laboratory at the end of the trial. The re-biopsy 
material will undergo histological review. If sufficient material is available, WES will be 
performed to detect potential mechanisms of resistance. The whole EDTA-blood will be used 
to extract genomic DNA (non-tumour) as reference. This analysis is for scientific purposes 
only and will not be used for clinical-decision making. 
14.7. 
Submission of biomaterial 
All biological samples collected during the conduct of the trial must be marked with the ETOP 
patient identifier issued by the EDC system and registered in the ETOP system. 
Anonymised pathology reports should be uploaded via the EDC system. Please consult the 
ALERT-lung Procedures Manual for specific instructions on how to submit the samples and 
pathology reports.  
 
 


 
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15. 
Trial procedures 
This section gives an overview of procedures, clinical and laboratory evaluations and follow-
up investigations. 
15.1. 
Tumour assessment 
Radiological tumour assessment by CT scans of thorax / upper abdomen (from top of thorax 
until adrenal glands and full liver and kidney included) will be done as indicated in Section 
12.1 until PD. 
15.2. 
Baseline evaluations 
The following examinations should be done within 28 days before enrolment. 
Written informed consent: 
Before any trial specific evaluations or interventions (within 6 weeks prior 
enrolment). 
15.2.1. Medical history: 
Including smoking history, medications, comorbidities, allergies and baseline 
symptoms. Baseline symptoms will be recorded on the adverse events form. 
15.2.2. Physical examination: 
According to local standards, including performance status, heart rate, and 
temperature, blood pressure and body weight. 
15.2.3. Chemistry 
CPK, sodium, potassium, calcium, magnesium, phosphate, glucose. 
15.2.4. Haematology 
WBC, haemoglobin, platelets, neutrophils. 
15.2.5. Hepatic function 
ALT, AST, AP, bilirubin, GGT, LDH. 
15.2.6. Renal function 
Serum creatinine, creatinine clearance (Cockcroft-Gault). 
15.2.7. Urine analysis on first morning urine sample (microscopic urine analysis or dipstick) 
pH, proteins, glucose, blood. 
15.2.8. Electrocardiogram 
15.2.9. Pregnancy test 
Women of childbearing potential, including women who had their last menstrual 
period in the last 2 years, must have a negative serum or urine beta-HCG pregnancy 
test within 7 days before enrolment into the trial and within 3 days before alectinib 


 
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treatment start. Pregnancy testing has to be repeated during the duration of the trial 
treatment according to local standard. 
15.2.10. Brain MRI or contrast enhanced CT, performed within 6 weeks before enrolment. 
15.2.11. Radiological tumour assessment 
By CT scan of thorax / upper abdomen (from top of thorax until adrenal glands and 
full liver and kidney included), performed within 6 weeks before enrolment. 
15.2.12. TNM categories 
15.2.13. FFPE tumour material 
15.2.14. Plasma sample 
15.3. 
Evaluations at every treatment visit 
Treatment has to start as soon as possible after enrolment, ideally within 7 days. Treatment 
visits are planned at treatment start (week 0) and then every 2 weeks (±3 days) for the first 
12 weeks and every 4 weeks (±3 days) thereafter. The following evaluations should be done 
within 24 hours of every treatment visit. 
15.3.1. Patient diary 
Patient diary should be checked and capsules returned should be counted. 
15.3.2. Physical examination: 
According to local standards, including performance status, heart rate, and 
temperature, blood pressure and body weight. 
15.3.3. Recording of symptoms, adverse events and concomitant medications: 
Adverse events have to be reported on the adverse event form, from the date of 
signature of informed consent until 30 days after trial treatment discontinuation. 
15.3.4. Chemistry  
Sodium, potassium, calcium, magnesium, phosphate, glucose will be repeated if 
clinically indicated according to local standards.  
15.3.5. CPK has to be measured only at treatment visit 1, 2 and 3 (week 0, 2 and 4) and then 
repeated if clinically indicated. 
15.3.6. Haematology 
WBC, haemoglobin, platelets, and neutrophils will be repeated if clinically indicated 
according to local standards. 
15.3.7. Hepatic function 
ALT, AST, AP, bilirubin, GGT, LDH 
15.3.8. Renal function 


 
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Serum creatinine, creatinine clearance (Cockcroft-Gault) will be repeated if 
clinically indicated according to local standards. 
15.3.9. Urine analysis on spot urine (microscopic urine analysis or dipstick) 
pH, proteins, glucose, blood will be repeated if clinically indicated according to local 
standards. 
15.3.10. Radiological tumour assessment as indicated in Section 12.1. 
15.4. 
Evaluations at disease progression 
At progression, the following assessments are required: 
15.4.1. Radiological tumour assessment 
By CT scan of thorax / upper abdomen (from top of thorax until adrenal glands and 
full liver and kidney included) 
At progression, collection of the following samples for translational research is encouraged: 
15.4.2. Fresh frozen re-biopsy 
15.4.3. Plasma sample 
15.4.4. Whole blood in EDTA tube 
15.5. 
Evaluations under treatment beyond progression 
In case of clinical benefit, with physician and patient agreement, trial treatment can continue 
beyond confirmed progression for as long as the patient may still derive benefit as per 
investigator decision. The following evaluations should be done within 24 hours of every 
treatment visit. 
15.5.1. Patient diary 
Patient diary should be checked and capsules returned should be counted. 
15.5.2. Physical examination: 
According to local standards, including performance status, heart rate, and 
temperature, blood pressure and body weight. 
15.5.3. Recording of symptoms, adverse events and concomitant medications: 
Adverse events have to be reported on the adverse event form, from the date of 
signature of informed consent until 30 days after trial treatment discontinuation. 
15.5.4. Chemistry  
Sodium, potassium, calcium, magnesium, phosphate, glucose will be repeated if 
clinically indicated according to local standards. 
15.5.5. CPK has to be measured only at treatment visit 1, 2 and 3 (week 0, 2 and 4) and then 
repeated if clinically indicated. 


 
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15.5.6. Haematology 
WBC, haemoglobin, platelets, and neutrophils will be repeated if clinically indicated 
according to local standards. 
15.5.7. Hepatic function 
ALT, AST, AP, bilirubin, GGT, LDH 
15.5.8. Renal function 
Serum creatinine, creatinine clearance (Cockcroft-Gault) will be repeated if 
clinically indicated according to local standards. 
15.5.9. Urine analysis on spot urine (microscopic urine analysis or dipstick) 
pH, proteins, glucose, blood will be repeated if clinically indicated according to local 
standards. 
15.6. 
Evaluations at the end of treatment visit 
At the end of trial treatment and irrespective of the reason for stopping treatment, an end of 
treatment visit at the centre is to be scheduled within 30 days following the decision to stop 
trial treatment or within 30 days after planned treatment start if treatment never started. In 
case treatment was delayed due to AEs and could not be resumed (for example if treatment 
interruption exceeded 21 consecutive days), the end of treatment visit should be performed 
within 8 weeks after the last dose. 
15.6.1. Patient diary 
Patient diary should be checked and capsules returned should be counted. 
15.6.2. Physical examination: 
According to local standards, including performance status, heart rate, and 
temperature, blood pressure and body weight. 
15.6.3. Recording of symptoms, adverse events and concomitant medications: 
Adverse events have to be reported on the adverse event form, from the date of 
signature of informed consent until 30 days after trial treatment discontinuation. 
15.6.4. Chemistry 
Sodium, potassium, calcium, magnesium, phosphate, glucose.  
15.6.5. CPK if clinically indicated. 
15.6.6. Haematology 
WBC, haemoglobin, platelets, neutrophils 
15.6.7. Hepatic function 
ALT, AST, AP, bilirubin, GGT, LDH 
15.6.8. Renal function 
Serum creatinine, creatinine clearance (Cockcroft-Gault). 


 
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15.6.9. Urine analysis on first morning urine sample (microscopic urine analysis or dipstick) 
pH, proteins, glucose, blood 
15.6.10. Electrocardiogram 
15.6.11. Radiological tumour assessment 
By CT scan of thorax / upper abdomen (from top of thorax until adrenal glands and 
full liver and kidney included), repeated if not done within 6 weeks prior to end of 
treatment visit 
15.7. 
Evaluations in the follow-up phase (post treatment) before progression 
Patients who discontinue trial treatment before progression should have the following 
examinations documented every 8 weeks (4 days), aligned with the imaging visits. 
15.7.1. Recording of symptoms, adverse events and concomitant medications: 
Adverse events have to be reported on the adverse event form, from the date of 
signature of informed consent until 30 days after trial treatment discontinuation. 
15.7.2. Radiological tumour assessment 
By CT scan of thorax / upper abdomen (from top of thorax until adrenal glands and 
full liver and kidney included) 
15.7.3. Survival 
15.8. 
Evaluations in the follow-up phase beyond progression of disease 
Patients with progression that ends trial treatment will be followed up every 12 weeks 
(2 weeks) starting from date of progression until trial end (e.g. until 6 months after inclusion 
of the last patient). They should have documented: 
15.8.1. Further lines of treatment 
15.8.2. Survival 
 
 


 
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16. 
Case report forms and documentation 
16.1. 
Case report forms schedule 
eCRFs will only be available on-line at the electronic data capture (EDC) facility ETOPdata. 
No paper forms will be used, with the exception of a paper SAE form and pregnancy form in 
case of system unavailability. 
Table 5: Case report forms: 
eCRF in ETOPdata 
To be completed 
1 - Eligibility Check and 
Enrolment 
Within 28 days of start of baseline evaluations 
2 - Baseline  
Within 14 days after enrolment 
3 - Tumour Assessments  
Baseline before enrolment: within 14 days after enrolment; 
During trial until tumour progression: within 14 days of date 
of each radiological imaging. 
4 - Concomitant 
Medications 
Continuously from date of enrolment to 30 days after end of 
trial treatment; 
- 
within 14 days after enrollment 
- 
within 14 days after each treatment visit 
- 
within 14 days after End of treatment visit 
or within 14 days after Follow-up visits. 
5 – Alectinib Treatment 
Visit 
Within 14 days after each alectinib treatment visit. 
6 - Adverse Events  
Continuously from date of Informed Consent signature to 
30 days after all treatment discontinuation;  
- 
within 14 days of enrolment (baseline symptoms) 
- 
within 14 days of start of each treatment visit 
- 
within 14 days after End of Treatment visit 
or within 14 days of Follow-up visits. 
7 - Serious Adverse Event 
Initial Reports 
Within 24h of awareness of SAE; 
All SAEs and AESIs must be submitted via ETOPdata, 
submission via fax to ETOP safety office only in case of 
unavailability of ETOPdata. 
8 - Serious Adverse Event 
Follow-up Reports 
Within 15 days of completion of initial report. 
If event was not resolved after 15 days, submit an additional 
report within 7 days of resolution of event.  
9 - End of Treatment  
Within 14 days after End of Treatment visit. 


 
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eCRF in ETOPdata 
To be completed 
10 - Follow-up 
Within 14 days of follow-up visits, which take place: 
Before progression: 
every 8 weeks (+/-4 days), coinciding with imaging visits; 
After progression: 
every 12 weeks (+/-2 weeks) from date of progression until 
trial end; 
On death:  
Within 14 days upon awareness of death 
11 - Pregnancy  
Maternal exposure: 
Within 24h of first documentation of pregnancy; 
Within 14 days of end of pregnancy. 
Paternal exposure (pregnancy in a female partner of a male 
trial participant): 
At end of pregnancy. 
12 – WC/LFU 
Within 14 days of awareness of withdrawal of consent or 
loss to follow-up.  
13 - Biological Material 
Tracking  
This eCRF is to be completed incrementally. 
Entries are to be made: 
- 
within 14 days of enrolment: for information pertaining to 
“FFPE Tumour tissue: at enrolment” (prior to treatment 
with alectinib); 
- 
immediately after local storage of blood samples (on same 
day): for information pertaining to “Blood samples: at 
progression”; 
- 
within 14 days of progression: for information pertaining 
to “Fresh-frozen Tumour tissue: at progression” (after trial 
treatment, optional);  
- 
immediately (on same day) after submission of material 
(FFPE, fresh-frozen tumour tissue and blood) for central 
biobanking: for “Date Specimen sent to Central Lab”. 
 
 


 
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17. 
Statistical considerations 
17.1. 
Primary objective 
The primary objective of this single arm phase II trial is to assess the efficacy of alectinib in 
terms of best overall response (OR) assessed by RECIST 1.1, for patients with pretreated 
RET-rearranged advanced NSCLC. 
17.2. 
Sample size determination 
The target population of this trial includes patients with advanced stage RET-rearranged 
NSCLC, treated with at least one platinum based systemic chemotherapy regimen. 
A best OR rate of 35% is targeted, while an OR rate of 15% is considered to be too low. 
Based on a one-sided exact test for proportions, the trial is designed to test the null hypothesis 
H0: p0 ≤0.15 versus the alternative HA: pA >0.35, where p is the rate of OR (ORR) at a one-
sided significance level of 0.025 and a power of at least 0.80.  
The attained alpha of 0.015 and power of 82% are achieved with a sample size of 41 evaluable 
patients. The null hypothesis H0 will be rejected and the alternative hypothesis H1 accepted if 
at least 12 patients achieve OR. 
A total sample size of 44 patients is required, allowing for up to 3 patients to be replaced if a 
patient is ineligible (retrospective review), has not started the experimental treatment or is lost 
to follow-up before the first confirmed response evaluation, according to RECIST 1.1. 
17.3. 
Trial duration 
Clinical visits are expected to span approximately 44 months after enrolment of the first 
patient, assuming an accrual rate of approximately 1 patient per month and a start-up period 
of 6 months as the trial is activated by participating centres. 
The trial ends when both of the following criteria are satisfied: 
 The trial is mature for the analysis of the primary endpoint, according to protocol 
specifications. 
 The cleaning procedure of the database is completed and database is ‘frozen’. 
The total duration of the trial is expected to be 5 years, including a run-in period of 6 months 
and an additional 6 months for the final analysis report. 
 
 


 
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17.4. 
Analysis populations 
17.4.1. Intention-To-Treat Cohort 
The Intention-To-Treat (ITT) cohort will include all patients enroled in the trial. 
17.4.2. Efficacy Cohort 
The efficacy cohort will encompass all evaluable patients, e.g. all enroled patients excluding 
patients that were found to be ineligible (in retrospective review), patients that have never 
started the trial treatment and patients that are lost to follow-up before their first response 
evaluation (by RECIST 1.1). 
17.4.3. Safety Cohort 
The safety cohort will include all patients that have received at least one dose of trial treatment. 
17.5. 
Evaluation of primary and secondary objectives 
The primary analysis of OR will be performed on all the patients included in the efficacy 
cohort. OR rate will be estimated along with the corresponding 95% exact binomial 
confidence interval (CI).  
The secondary time-to-event endpoints (PFS and OS), evaluated on the efficacy cohort, will 
be estimated by the Kaplan-Meier method. Kaplan-Meier plots will be presented, median 
survival estimates and estimates of the event-free rate at fixed time points and 95% CIs will 
also be obtained using the Kaplan-Meier technique.  
Clinical efficacy will be further explored by the estimation of disease control rate (DCR) and 
its corresponding 95% exact binomial confidence interval. 
Median follow-up time will be estimated based on the reverse censoring method. 
A secondary analysis of the efficacy endpoints evaluated for all patients in the ITT cohort will 
also be performed. 
The safety and the tolerability of the trial treatment will be evaluated by the occurrence of 
AEs on all patients that have received at least one dose of trial treatment (safety cohort). 
Classification of severity and causality will be performed according to CTCAE v4.0 and will 
be presented using tables and bar charts. For each subject, each AE will be analysed according 
to the worst grade of toxicity observed over the whole treatment period. 
Further exploratory analyses include description of primary and secondary outcomes for 
patient subgroups of interest, as defined by patient or tumour characteristics or different levels 
of biomarkers examined. 
More detailed description of the statistical analysis for the primary and secondary endpoints 
as well as for the translational research will be provided in the corresponding Statistical 
Analysis Plan (SAP) document. 
17.6. 
Safety evaluation 
Safety evaluations of the trial treatment will be performed twice per year and presented for 
review to the ETOP Independent Data Monitoring Committee (IDMC) at each of their bi-
annual meetings. Recruitment into the trial will continue while safety is being evaluated. 


 
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17.7. 
Interim efficacy analysis 
No formal interim efficacy analysis is planned in the framework of this trial. 
18. 
Criteria for termination of the trial 
18.1. 
General criteria for termination of the trial 
The trial may be discontinued early in parts or completely if the information on the IMPs 
leads to doubt as to the benefit/risk ratio, by decision of the ETOP Foundation Council upon 
recommendation of the ETOP 12-17 ALERT-lung Steering Committee and IDMC. Specific 
considerations will be based on the regular safety reviews by the ETOP IDMC. 
The trial can be terminated at any time if the authorization and approval to conduct the trial 
is withdrawn by ethics committee or regulatory authority decision, insufficient accrual, 
emerging new data impacting the scientific value of the trial or ethical grounds. 
18.2. 
Discontinuation of protocol treatment for individual patients  
Protocol treatment should be stopped in the following situations: 
 Disease progression according to RECIST criteria 1.1. 
 Occurrence of unacceptable toxicities. Stopping protocol treatment is determined by 
medical judgment of the treating physician. 
 Request by the patient. Patients have the right to refuse further trial treatment at any 
time during the trial. Such patients will remain in the trial and will be transferred to 
the follow-up phase. 
 If a patient refuses to have the treatments or follow-up examinations and tests needed 
to determine whether the treatment is safe and effective. 
The decision for discontinuation of protocol treatment of individual patients is taken by the 
treating physician based on her/his medical evaluation and taking into account the patient’s 
individual situation. 
18.3. 
Withdrawal of consent 
Patients have the right to withdraw consent for further trial participation at any time without 
having to specify the reason. The data recorded up to the time point of withdrawal will 
continue to be evaluated in the trial. The investigator should ask the patient for consent to 
continue to collect information on her/his disease and survival status. 
It should be documented in both the medical records and in the eCRF, according to the 
instructions in the ALERT-lung CRF Completion Guidelines, if the patient accepts to be 
contacted for survival status despite withdrawing the trial consent. For the patient’s safety, an 
end of treatment visit should be performed and documented in the eCRF if the patient agrees 
to this. 


 
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19. 
Ethics aspects, regulatory approval, and patient informed consent 
The investigator will ensure that this trial is conducted in full conformance with the principles 
of the “Declaration of Helsinki” or with the laws and regulations of the country in which the 
research is conducted, whichever affords the greater protection to the individual. The trial 
must fully adhere to the principles outlined in “Guideline for Good Clinical Practice (GCP)” 
ICH Tripartite Guideline (January 1997) or with local law if it affords greater protection to 
the patient. For studies conducted in the EU/EEA countries, the investigator will ensure 
compliance with the EU Clinical Trial Directive (2001/20/EC). 
19.1. 
Ethical Review Board/Ethics Committee 
All protocols and the patient informed consent forms must have the approval of a properly 
constituted committee or committees responsible for approving clinical trials. The ERB/IRB 
decision must contain approval of the designated investigator, the protocol (identifying 
protocol title and version number), and of the patient informed consent. 
The Ethical Review Board/Institutional Review Board (ERB/IRB) written, signed approval 
letter/form must contain approval of the designated investigator, the protocol (identifying 
protocol title and version number), and of the patient informed consent. Documentation of 
Ethics Committee approval must be sent to the ETOP coordinating office prior to enrolment 
of the first patient. 
Any modifications made to the protocol must be submitted to the appropriate ERB/IRB for 
information or approval in accordance with local procedures and regulatory requirements and 
to health authorities if required. 
Once approved or acknowledged by the appropriate ERB/IRB and by the health authorities 
(if required), the investigator shall implement the protocol modifications. Protocol 
modifications for urgent safety matters may be directly implemented following the 
instructions of ETOP. 
19.2. 
Regulatory approval procedures 
If applicable, in addition to the approval of the ethics committee according to national 
legislation, the protocol, protocol related documents including patient information and 
informed consent and other documents as required locally must be submitted to and be 
approved by the health authority. Documentation of health authority approval must be sent to 
the ETOP coordinating office prior to participating centre activation. 
19.3. 
Informed consent 
Informed consent for each patient will be obtained prior to initiating any trial procedures in 
accordance with the “patient information and informed consent" (see Appendix 1). Once 
signed and dated, a copy of the informed consent must be given to each patient and the original 
copy must be retained in the investigator’s trial records. The informed consent form must be 
available in the case of data audits. Verification of signed informed consent and the date 
signed are required for enrolment into this trial. 
The “Declaration of Helsinki” recommends that consent be obtained from each potential 
patient in biomedical research trials after the aims, methods, anticipated benefits, and potential 


 
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hazards of the trial, and discomfort it may entail, are explained to the individual by the 
physician. The potential patient should also be informed of her/his right to not participate or 
to withdraw from the trial at any time. The patient should be told that material from her/his 
tumour and blood and serum samples will be stored and potentially used for additional studies 
not described in this protocol. 
If the patient is in a dependent relationship to the physician or gives consent under duress, the 
informed consent should be obtained by an independent physician. If the patient is legally 
incompetent (i.e. a minor, or mentally incompetent), informed consent must be obtained from 
the parent, legal guardian, or legal representative in accordance with the law of the country in 
which the trial is to take place. By signing this protocol, the investigator agrees to conduct the 
trial in accordance with GCP and the "Declaration of Helsinki". 
ETOP recognises that each institution has its own local, national, and international guidelines 
to follow with regard to informed consent. Therefore, we provide a template information sheet 
and informed consent form (appendix 1), which can be edited to incorporate information 
specific to your institution. The template patient information sheet and informed consent has 
been written according to ICH guidelines which state the informed consent should adhere to 
GCP and to the ethical principles that have origin in the “Declaration of Helsinki”. The final 
version should receive the IRB / local EC approval in advance of its use. Centres should send 
their locally modified PIS/IC to ETOP for review and approval before submitting to their 
ethics committee. 
20. 
Governance and administrative issues 
20.1. 
Final report 
A final clinical trial report will be written and distributed to health authorities as required by 
applicable regulatory requirements. 
20.2. 
Steering Committee 
A Steering Committee will be constituted for this trial. The Steering Committee is responsible 
for maintaining the scientific integrity of the trial, for example, by recommending changes to 
the protocol in light of emerging clinical or scientific data from other trials. Membership will 
include the trial chairs and co-chairs, trial statisticians, ETOP officials, representatives from 
participating institutions and a representative from Roche. 
20.3. 
Independent Data Monitoring Committee 
The ETOP IDMC is a standing committee of independent experts. Its role is the systematic 
review of the accumulating data from all ongoing ETOP sponsored trials including accrual, 
safety and efficacy. The primary mandate of the IDMC is to safeguard the interest and safety 
of the patients in the trial and to ensure the scientific integrity of the trial. Details of the 
particular responsibilities and procedures within the ETOP 12-17 ALERT-lung trial are 
summarised in the ETOP IDMC Guidelines and the trial-specific IDMC charter. 
The trial will be presented for review to the ETOP IDMC at each of their bi-annual meetings. 
Based on this review, the IDMC recommends to the trial Steering Committee whether to 
continue, modify or stop the trial. 


 
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20.4. 
Publication 
The results of the trial will be published according to the ETOP publication guidelines 
(appendix 2). 
20.5. 
Clinical trial insurance 
ETOP will contract the appropriate liability insurance for this trial. Patients who suffer 
injuries due to the trial should report them immediately to their physician. The local 
group/institution should report all alleged claims immediately to the ETOP coordinating 
office. 
20.6. 
Quality assurance 
ETOP conducts trials according to the ICH GCP guidelines. The Trial data manager reviews 
each eCRF as it is received. In addition, the ETOP medical reviewer reviews each case at 
specific time points. ETOP conducts periodic audit visits to ensure proper trial conduct, verify 
compliance with GCP, and perform source data verification. 
The investigator should ensure that source documents are made available to appropriately 
qualified personnel from ETOP or its designees, or to ethics committee and health authority 
inspectors after appropriate notification. 
At regular intervals during the clinical trial, the centre will be contacted, through monitoring 
visits, letters or telephone calls, by a representative of the monitoring team to review trial 
progress, investigator and patient compliance with clinical trial protocol requirements and any 
emergent problems. These monitoring visits will include but not be limited to review of the 
following aspects: patient informed consent, patient recruitment and follow-up, SAE 
documentation and reporting, AEs with pre-specified monitoring documentation and 
reporting, AE documentation, dispensing IMP, compliance with protocol, drug accountability, 
concomitant therapy use, quality of data and storage of blood and serum samples. 
20.7. 
Protocol adherence 
Investigators ascertain that they will apply due diligence to avoid protocol deviations. Under 
no circumstances should the investigator contact ETOP or personnel monitoring the trial to 
request approval of a protocol deviation, as no deviations are permitted. The investigator 
should document and explain any deviations from the approved protocol. The investigator 
should promptly report any deviations to ETOP (sponsor) and to the EC concerned in 
accordance with the applicable EC policies and procedures. If the investigator feels a protocol 
deviation would improve the conduct of the trial this must be considered a protocol 
amendment, and unless such an amendment is developed and activated by ETOP (sponsor) 
and approved by the IRB/IEC/ERB it cannot be implemented. All protocol deviations will be 
recorded. 
20.8. 
Data protection 
The samples and data collected will be coded to protect patient confidentiality. Each patient 
will have a unique identifier assigned by the EDC facility ETOPdata. Sites are responsible to 
keep a patient log locally in order to be able to link the unique identifier to the record of the 
patient.  


 
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Biological material will be assigned the same unique identifier. No identifiable / personal data 
will be stored in the trial database or the tissue repositories in the central labs. 
Biological material will be transferred outside the treating institution for central screening and 
review. Results of the assays will be coded only by the patient identifier. 
Regulatory authorities and pertinent ethics committees (IRB/ERB) may have access to patient 
data on-site. ETOP audit or monitoring personnel will also have access to such data on-site. 
20.9. 
Record retention 
The centre must retain all essential documents according to ICH GCP. This includes copies 
of the patient trial records, which are considered as source data, patient informed consent 
statement, laboratory printouts, drug inventory and destruction logs, and all other information 
collected during the trial. These documents are to be stored until at least 15 years after the 
termination of the trial. ETOP guarantees access and availability of the data entered into 
ETOPdata for at least 15 years after the termination of the trial. 
Longer retention may be required for participating centres according to national regulations. 
In the event that the principal investigator retires or changes employment, custody of the 
records may be transferred to another competent person who will accept responsibility for 
those records. Written notice of such transfer has to be given to ETOP and the local ethics 
committee at least one month in advance. 
 
 


 
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21. 
References 
1. 
Gainor JF, Shaw AT. Novel targets in non-small cell lung cancer: ROS1 and RET 
fusions. Oncologist 2013; 18(7): 865-75. 
2. 
Kohno T, Nakaoku T, Tsuta K, et al. Beyond ALK-RET, ROS1 and other oncogene 
fusions in lung cancer. Transl Lung Cancer Res 2015; 4(2): 156-64. 
3. 
Lipson D, Capelletti M, Yelensky R, et al. Identification of new ALK and RET gene 
fusions from colorectal and lung cancer biopsies. Nat Med 2012; 18(3): 382-4. 
4. 
Takeuchi K, Soda M, Togashi Y, et al. RET, ROS1 and ALK fusions in lung cancer. 
Nat Med 2012; 18(3): 378-81. 
5. 
Takashi S, Kiyotaka Y, Miyako S, et al. A phase II open-label single-arm study of 
vandetanib in patients with advanced RET-rearranged non-small cell lung cancer 
(NSCLC): Luret study. J Clin Oncol 2016; 34 (suppl; abstr 9012). 
6. 
Drilon A, Rekhtman N, Arcila M, et al. Cabozantinib in patients with advanced RET-
rearranged non-small-cell lung cancer: an open-label, single-centre, phase 2, single-
arm trial. Lancet Oncol 2016. 
7. 
Drilon A, Wang L, Hasanovic A, et al. Response to Cabozantinib in patients with RET 
fusion-positive lung adenocarcinomas. Cancer Discov 2013; 3(6): 630-5. 
8. 
Gautschi O, Zander T, Keller FA, et al. A patient with lung adenocarcinoma and RET 
fusion treated with vandetanib. J Thorac Oncol 2013; 8(5): e43-4. 
9. 
Lee S-H, Lee J-K, Ahn M-J, et al. A phase II study of vandetanib in patients with non-
small cell lung cancer harboring RET rearrangement. J Clin Oncol 2016; 34 (suppl; 
abstr 9013). 
10. 
Lin JJ, Kennedy E, Sequist LV, et al. Clinical Activity of Alectinib in Advanced RET-
Rearranged Non-Small Cell Lung Cancer. J Thorac Oncol 2016; 11(11): 2027-32. 
11. 
Gautschi O, Milia J, Filleron T, et al. Targeting RET in Patients With RET-Rearranged 
Lung Cancers: Results From the Global, Multicenter RET Registry. J Clin Oncol 2017; 
35(13): 1403-10. 
12. 
Kodama T, Tsukaguchi T, Satoh Y, et al. Alectinib shows potent antitumor activity 
against RET-rearranged non-small cell lung cancer. Mol Cancer Ther 2014; 13(12): 
2910-8. 
13. 
HOFFMANN-LA ROCHE LTD F. ALK Tyrosine Kinase Inhibitor.  Alectinib Investigator 
Broschure Version 7; 2016. 
14. 
Gadgeel SM, Shaw AT, Govindan R, et al. Pooled Analysis of CNS Response to 
Alectinib in Two Studies of Pretreated Patients With ALK-Positive Non-Small-Cell 
Lung Cancer. J Clin Oncol 2016; 34(34): 4079-85. 
15. 
Tamura T, Kiura K, Seto T, et al. Three-Year Follow-Up of an Alectinib Phase I/II 
Study in ALK-Positive Non-Small-Cell Lung Cancer: AF-001JP. J Clin Oncol 2017; 
35(14): 1515-21. 
16. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in 
solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45(2): 
228-47. 
 

SAP_001.pdf: 
ALERT-lung SAP – Final analysis  
Page 1 of 20 
 
 
 
 
ETOP 12-17 ALERT-lung 
 
 
 
 A single arm phase II trial evaluating the activity of alectinib for the 
treatment of pretreated RET-rearranged advanced NSCLC 
 
 
Statistical Analysis Plan (SAP) for 
Final analysis 
 
 
 
 
A clinical trial of ETOP 
 
 
 
 
 
SAP VERSION 
V1.1 
SAP DATE 
31.03.2021 


ALERT-lung SAP – Final analysis  
Page 2 of 20 
 
Contents 
INTRODUCTION ............................................................................................................................................... 3 
1 
Trial oversight (according to trial protocol) ............................................................................................ 4 
1.1 
Objectives ........................................................................................................................................ 4 
1.2 
Endpoints ........................................................................................................................................ 5 
1.3 
Most important eligibility criteria ................................................................................................... 5 
1.4 
Trial treatment ................................................................................................................................ 6 
1.5 
Statistical design, sample size & power .......................................................................................... 6 
1.6 
Total trial duration .......................................................................................................................... 7 
2 
Statistical considerations for final analysis ............................................................................................. 8 
2.1 
Premature trial closure ................................................................................................................... 8 
2.2 
Study’s endpoints ............................................................................................................................ 8 
2.2.1 
Primary endpoint .................................................................................................................... 8 
2.2.2 
Secondary endpoints ............................................................................................................... 8 
2.2.3 
Exploratory endpoints ............................................................................................................. 9 
(Serious) Adverse Events ....................................................................................................................... 10 
2.3 
Analysis populations ..................................................................................................................... 12 
3 
Primary efficacy analysis of OR ............................................................................................................. 13 
4 
Additional secondary analyses .............................................................................................................. 14 
4.1 
Patient accrual and baseline characteristics ................................................................................. 14 
4.2 
Follow-up information and treatment administration ................................................................. 14 
4.3 
Secondary and exploratory efficacy endpoints ............................................................................. 15 
4.3.1 
Disease control rate .............................................................................................................. 15 
4.3.2 
Progression-free survival....................................................................................................... 15 
4.3.3 
Overall survival ...................................................................................................................... 16 
4.3.4 
Sensitivity efficacy analysis ................................................................................................... 16 
4.3.5 
Safety and tolerability ........................................................................................................... 16 
4.3.6 
Subgroup analysis ................................................................................................................. 17 
5 
Technical details .................................................................................................................................... 19 
5.1 
Data Retrieval Information ........................................................................................................... 19 
5.2 
Missing Data .................................................................................................................................. 19 
5.3 
Reporting conventions .................................................................................................................. 20 
5.4 
Multiple recordings of an event for the same patient .................................................................. 20 
5.5 
Presentation of results .................................................................................................................. 20 


ALERT-lung SAP – Final analysis  
Page 3 of 20 
6 
Listing of tables and figures ..................................................................... Error! Bookmark not defined. 
 
 
INTRODUCTION 
The aim of this Statistical Analysis Plan (SAP) is to describe an analytic and solid framework that 
will be followed in order the final efficacy analysis of the ALERT-lung trial to be implemented. A 
short description of the contents of this statistical analysis plan is provided below: 
1. Trial oversight: trial’s schema, objectives and trial endpoints, eligibility criteria, study 
treatment, statistical design (sample size and power), trial duration  
2. Statistical considerations for final analysis: analysis timing, definition of primary and 
secondary endpoints, (serious) adverse events definition, analysis populations 
3. Primary efficacy analysis of alectinib in terms of best overall response (OR) 
assessed by RECIST v1.1 
4. Additional secondary analysis: accrual and baseline characteristics, follow-up and 
treatment administration, secondary analysis (including analysis of biomarkers available) 
5. Technical issues: data retrieval, testing, handling of missing data, reporting conventions 
 


ALERT-lung SAP – Final analysis  
Page 4 of 20 
1 Trial oversight (according to trial protocol) 
ALERT-lung is a single arm, multicentre phase II trial evaluating the activity of alectinib as 
second-line treatment of pretreated RET-rearranged advanced NSCLC.  
 
SCHEMA 1. Trial design  
1.1 Objectives  
Primary objective 
The primary objective is to assess the efficacy of alectinib in terms of best overall response (OR) 
assessed by RECIST 1.1., from the start of trial treatment across all time points until the end of 
trial treatment.  
Secondary objectives  
The secondary objectives of the study include: 
• 
To evaluate secondary measures of clinical efficacy including disease control, progression-
free survival (PFS), and overall survival (OS).  
• 
To assess the safety and tolerability of the treatment. 
Correlative studies  
RET rearrangement
Trial treatment
Screening, eligibility
Alectinib 600 mg twice daily p.o.
until PD or unacceptable toxicity#
For 6 months 
after enrolment 
of last patient
Follow up
Enrolment
Brain MRI or CT
Mandatory
FFPE
CT every 8 weeks until PD
CT
Advanced pre-treated
NSCLC
Plasma
# treatment may continue beyond progression if there is clinical benefit
Plasma
FF re-biopsy and 
whole blood


ALERT-lung SAP – Final analysis  
Page 5 of 20 
Further exploratory analyses include description of primary and secondary outcomes for patient 
subgroups of interest, as defined by patient or tumour characteristics or different levels of 
biomarkers examined. 
1.2 Endpoints  
Primary endpoint:  
• Best overall response (OR = CR or PR), per investigator assessment, according to RECIST 1.1. 
Secondary endpoints:  
• 
Best overall response per independent review. 
• 
Disease control at 24-weeks: best overall response of CR or PR, or SD (or non-CR/non-PD 
in the case of non-measurable disease only) 
• 
PFS defined as the time from the date of enrolment until documented progression or death, 
if progression is not documented 
• 
OS defined as time from the date of enrolment until death from any cause 
• 
Safety and tolerability 
 
1.3 Most important eligibility criteria  
Inclusion criteria: 
• 
Histologically or cytologically documented non-small cell lung carcinoma. 
• 
Advanced disease defined as recurrent stage IV (according to 8th TNM classification) or 
recurrent or progressive disease following multimodal therapy (radiation therapy, 
surgical resection, or definitive chemo-radiation therapy for locally advanced disease). 
• 
At least one prior platinum-based systemic regimen: Adjuvant or neoadjuvant or 
definitive platinum-based chemo-radiotherapy treatments are considered as a line of 
treatment only if completed less than 6 months before enrolment. Maintenance therapy 
following platinum doublet-based chemotherapy is not considered a separate regimen of 
therapy. 
• 
RET rearrangement detected by FISH, Nanostring or by parallel-sequencing on FFPE 
tumour tissue assessed locally. 
• 
Availability of FFPE tumour material for central confirmation of RET-rearrangement. 
• 
Measurable or non-measurable, but radiologically evaluable (except for skin lesions) 
disease according to RECIST v1.1 criteria. 


ALERT-lung SAP – Final analysis  
Page 6 of 20 
• 
Age ≥18 years. 
• 
Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2. 
• 
Life expectancy >3 months. 
Exclusion criteria:  
• 
Untreated, active CNS metastases. 
• 
Carcinomatous meningitis. 
• 
Any previous (in the past 3 years) or concomitant malignancy EXCEPT adequately 
treated basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix or 
bladder, in situ ductal carcinoma of the breast. 
• 
Any serious diseases or clinical conditions, including but not limited to uncontrolled 
active infection and any other serious underlying medical processes, that could affect the 
patient's capacity to participate in the trial. 
• 
Previous treatment with any RET TKI or RET targeted therapy. 
• 
Patient with locally detected EGFR, ROS or ALK mutation (in addition to RET 
rearrangement). 
• 
Any concurrent systemic anticancer therapy. 
• 
Women who are pregnant or in the period of lactation. 
 
1.4 Trial treatment 
Alectinib is administered orally, 600 mg, twice per day (1200 mg per day) until progression, 
refusal or unacceptable toxicity. Trial treatment may also continue beyond progression, with 
physician and patient agreement, for as long as the patient may still derive clinical benefit as per 
investigator decision. Treatment has to start as soon as possible after enrolment, ideally within 7 
days. Treatment visits are planned at treatment start (week 0) and then every 2 weeks (±3 days) 
for the first 12 weeks and every 4 weeks (±3 days) thereafter. 
 
1.5 Statistical design, sample size & power 
According to the protocol, the trial targets a best OR rate of 35% and considers an OR rate of 15% 
as too low.  
 


ALERT-lung SAP – Final analysis  
Page 7 of 20 
Based on a one-sided exact test for proportions, the trial is designed to test the following 
hypotheses: H0: p0 ≤0.15 vs HA: pA>0.35, where p is the rate of best OR (ORR) at a one-sided 
significance level of 0.025 and a power of at least 0.80.  
 
A significance level of 0.015 and power of 0.82 are achieved with a sample size of 41 
evaluable patients. The null hypothesis will be rejected and the alternative hypothesis 
accepted if at least 12 patients achieve OR.  
 
The total sample size of 44 patients allows for up to 3 patients to be replaced if a patient is 
ineligible (retrospective review), has not started the experimental treatment or is lost to follow-
up before evaluation of response. 
1.6 Total trial duration 
Clinical visits are expected to span approximately 44 months after enrolment of the first patient. 
Assuming an accrual rate of approximately 1 patient per month and a start-up period of 6 months 
as the trial is activated by participating centres, the final trial report is expected to be available 
approximately 5 years after the enrolment of the first patient. 


ALERT-lung SAP – Final analysis  
Page 8 of 20 
2 Statistical considerations for final analysis 
2.1 Premature trial closure 
Since the activation of the ALERT-lung trial in April 2018, promising new agents for the 
treatment of RET-rearranged NSCLC have been introduced. At the same time, in a Japanese 
study, alectinib has shown only moderate activity in this indication. 
For both the aforementioned reasons, ETOP decided to prematurely close the ALERT-lung 
trial, by March 31, 2021. Follow-up and safety information will be updated until 31 March 
2021.  
 A final analysis will be performed based on all enrolled patients and respective available 
information collected up to trial’s premature closure. 
 
2.2 Study’s endpoints 
2.2.1 Primary endpoint 
Overall response (OR) is defined as best overall response (complete response (CR) or partial 
response (PR) according to RECIST criteria v1.1 from the start of trial treatment across all 
time points until the end of trial treatment.  
Objective response rate (ORR) will be calculated as the rate of patients achieving CR or PR 
over the total number of patients in the analysis cohort. 
2.2.2 Secondary endpoints 
Secondary endpoints, according to the protocol, include disease control at 24-weeks, PFS, OS, 
safety and tolerability. More specifically: 
- 
Disease control (DC) is defined as complete or partial response, or disease stabilisation at 
24 weeks. Accordingly, disease control rate (DCR) will be calculated as the rate of 
patients achieving DC over the total number of patients in the analysis cohort. 
- 
PFS is defined as the time from the date of enrolment until documented progression 
(based on RECIST 1.1 criteria) or death, if progression is not documented. Censoring (for 
patients without a PFS/death event) will occur at the date of last tumour assessment if 
patient is lost to follow-up or refuses further documentation of follow-up. 
- 
OS is defined as time from the date of enrolment until death from any cause. Censoring will 
occur at the last follow-up date. 


ALERT-lung SAP – Final analysis  
Page 9 of 20 
All safety parameters will be summarised in tables to evaluate the safety profile of patients treated 
with alectinib in terms of: 
- 
Adverse events including adverse events leading to dose modifications or interruptions, 
study drug withdrawal, and death 
- 
Any cause adverse events; Treatment-related adverse events 
- 
Severe, serious, and selected adverse events  
- 
Deaths  
- 
Laboratory parameters and abnormalities, vital signs and ECGs  
 
2.2.3 Exploratory endpoints 
Other endpoints that will be presented, in an exploratory frame, include: 
- 
Time to treatment failure (TTF) is defined as time from the date of enrolment until 
discontinuation of protocol treatment for any reason (including progression of disease, 
death, treatment discontinuation due to any reason, such as treatment toxicity or 
investigator’s decision, withdrawal/lost to follow-up (LFU)). Censoring for TTF (patients 
on treatment) will occur at the last follow-up date. 
 
Correlative endpoints include:  
- 
Type of RET fusion and other transcripts 
Co-mutations detected with either Next Generation Sequencing (NGS), or Copy Number 
Variations. Correlative endpoints will be used in the subgroup analysis. 
 
 


ALERT-lung SAP – Final analysis  
Page 10 of 20 
(Serious) Adverse Events  
Adverse events (AE) 
The main criterion for treatment tolerability is the occurrence of toxicities and adverse events. 
The severity and causality will be classified according to the NCI CTCAE v4.0. The CTCAE v4.0 is 
available for downloading (http://evs.nci.nih.gov/ftp1/CTCAE/About.html). 
An AE is defined as any untoward medical occurrence that occurs from the date of signature of 
inform consent until 30 days after all trial treatment discontinuation, regardless of whether it is 
considered related to a medication.  
Serious Adverse Events (SAE) 
A SAE is defined in general as any undesirable medical occurrence/adverse drug experience that, 
at any dose: 
▪ 
results in death (any cause, except progression of cancer under study) 
▪ 
is life-threatening 
▪ 
requires or prolongs inpatient hospitalization (>24 hours) 
▪ 
results in persistent or significant disability/incapacity 
▪ 
constitutes an important medical event 
▪ 
is a congenital anomaly or birth defect (including neonatal deaths and abortions) 
▪ 
is a secondary malignancy/second primary malignancy 
Adverse events of special interest (AESI) 
AEs of special interest for this trial are the following:  
- 
Drug-induced liver injury. Cases of potential drug-induced liver injury that include an 
elevated ALT or AST in combination with either an elevated bilirubin or clinical jaundice, 
as defined by Hy’s law. 
- 
Suspected transmission of an infectious agent by the IMP. Any organism, virus, or 
infectious particle (e.g., prion protein transmitting spongiform encephalopathy), 
pathogenic or non-pathogenic, is considered an infectious agent. A transmission of an 
infectious agent may be suspected from clinical symptoms or laboratory findings 
indicating an infection in a patient exposed to a medicinal product. This term applies 
only when a contamination of the study drug is suspected.   


ALERT-lung SAP – Final analysis  
Page 11 of 20 
- 
Adverse events associated with an overdose. An overdose is the accidental or 
intentional use of a drug in an amount higher than the dose being studied. An overdose 
or incorrect administration of IMP is not itself an AE, but it may result in an AE.  
 
Severity Grade of (serious) adverse event 
The (serious) AE severity grade provides a qualitative assessment of the extent or intensity of a 
specific event, as determined by the investigator or as reported by the patient. The severity grade 
does not reflect the clinical seriousness of the event, only the degree or extent of the affliction or 
occurrence (e.g. severe nausea, mild seizure), and does not reflect the relationship to trial drug. 
Severity grade for other adverse events not covered in the toxicity grading scale: 
Grade 1 
Mild- transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required 
Grade 2 
Moderate- mild to tolerate limitation in activity; some assistance may be 
needed; no or minimal medical intervention/therapy required 
Grade 3 
Severe- marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalization is possible 
Grade 4 
Life-threatening- extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, hospitalization or hospice 
care probable 
Grade 5 
Fatal- the event results in death 
Causality of (serious) adverse event 
The investigator must determine the relationship between the administration of trial drug(s) and 
the occurrence of an AE/SAE following the definitions indicated below: 
• 
Not suspected (unrelated/unlikely): The temporal relationship of the adverse event to 
trial drug(s) administration makes a causal relationship unlikely or remote, or other 
medications, therapeutic interventions, or underlying conditions provide a sufficient 
explanation for the observed event. 
• 
Suspected (possible/probable/definite): The temporal relationship of the adverse event 
to trial drug(s) administration makes a causal relationship possible, and other 
medications, therapeutic interventions, or underlying conditions do not provide a 
sufficient explanation for the observed event. 
 


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2.3 Analysis populations 
Intention-To-Treat Cohort: The Intention-To-Treat (ITT) cohort will include all patients 
enrolled in the trial. 
Efficacy Cohort: The efficacy cohort will encompass all evaluable patients, i.e., all enrolled 
patients excluding patients that were found to be ineligible (in retrospective review), patients that 
have never started the trial treatment and patients that are lost to follow-up before their first 
response evaluation (by RECIST 1.1). 
Safety Cohort: The safety cohort will include all enrolled patients that have received at least one 
dose of trial treatment. 
 
 
 


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3 Primary efficacy analysis of OR 
The primary analysis of OR will be performed on all the patients included in the efficacy cohort. 
OR rate (ORR) will be estimated as the rate of patients achieving CR or PR over the total number 
of patients in the efficacy cohort, along with the corresponding 95% exact binomial confidence 
interval (CI). 
Formal hypothesis testing 
According to the protocol, the trial has been designed to test the null hypothesis H0: ORR0 ≤0.15 
versus the alternative HA: ORRA >0.15 evaluated at 0.35, using a one-sided exact test for 
proportions,  at a one-sided significance level of 0.025 and a power of at least 0.80. The attained 
alpha of 0.015 and power of 82% will be achieved with a sample size of 41 evaluable patients. 
The null hypothesis H0 would be rejected and the alternative hypothesis HA accepted if at least 
12 patients achieve OR. 
Due to trial’s premature closure, the target sample size has not been reached and, thus the above 
formal testing cannot be performed. However, an adhoc hypothesis testing (based again on 
binomial distribution) will be performed using the available data. 
 
OR analysis will also include: 
- 
A waterfall plot to graphically depict the best percent change in tumor size (sum of target 
lesions diameter) from the baseline tumor assessment before enrolment.  
- 
A spider plot to graphically depict the percent changes in tumor size (sum of target lesions 
diameter) from the baseline tumor assessment before enrolment, over time.  
- 
Depending on the number of available responses (i.e., if at least 5), the use of univariate 
and multivariate logistic regression models will be explored to investigate the effect of the 
clinicopathological variables of interest (gender, age category, smoking history, ECOG 
performance status at enrolment, and stage at enrolment) on ORR. 
 
 


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4 Additional secondary analyses 
In this section, detailed information about the additional analyses that will be performed in the 
frame of the final efficacy analysis for ALERT-lung trial is presented. 
4.1 Patient accrual and baseline characteristics 
- 
Patient accrual by centre and by country will be presented in tabular format. 
- 
In addition, expected vs. observed accrual will be graphically displayed. 
- 
For patients deemed ineligible (patients registered in the online database but eventually 
not enrolled), a table summarizing the reasons for non-enrolment will be provided. 
- 
Patient & tumor baseline characteristics (categorical variables: ethnicity, gender, smoking 
history, ECOG performance status at enrolment, tumor stage at enrolment, and continuous 
variables: age at enrolment) will be presented. Frequencies and corresponding 
percentages will be presented for categorical variables (if missing cases exist, a separate 
category named “Missing” will be created), while the following descriptive measures will 
be considered for the continuous variables: n (non-missing sample size), mean, 95% CI for 
the mean, median, maximum and minimum value.  
- 
Also available information on medical history and prior treatment will be summarised. 
- 
Molecular characteristics at baseline (enrolment): Type of RET fusion and other 
transcripts; Co-mutations detected with either Next Generation Sequencing (NGS), or 
Copy Number Variations. Comparisons will also be performed with assessments at 
subsequent time points (PD) whenever available. 
Note: For the efficacy analysis (e.g. subgroup analysis, logistic regression models) age will be 
categorised according to the observed median.  
 
4.2 Follow-up information and treatment administration 
Firstly, a consort flow diagram will be created.  
Median follow-up (FU) of the patients along with the respective interquartile range (IQR) and the 
number (%) of patients that are still alive, will be summarized in a table. Median follow-up time 
will be estimated based on the method of reverse censoring of OS. A Kaplan-Meier plot will be 
provided for illustrative reason. 
Treatment information will be summarized and presented in a tabular format. More specifically: 


ALERT-lung SAP – Final analysis  
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- 
The number of patients that started treatment will be reported. For those patients 
enrolled, progressed but with physician’s and their own agreement continued receiving 
treatment, information on treatment failure after first progression will be additionally 
provided. 
- 
The number of patients that did not receive any dose of trial treatment, along with reasons 
for not doing so will also be presented. 
- 
Number of treatment failures, the 6-month TTF estimate and median TTF time along with 
the corresponding 95% CIs and the reasons for treatment failure/discontinuation will be 
presented.   
- 
TTF will be graphically depicted via a Kaplan Meier plot.  
- 
For patients with treatment failure, information for further lines of treatment will also be 
provided. 
 
4.3 Secondary and exploratory efficacy endpoints 
 
4.3.1 Disease control rate  
Clinical efficacy will be further explored by the estimation of disease control rate (DCR) in the 
efficacy cohort.  
- 
Disease control rate (DCR) at 24 weeks will be presented along with its 95% exact 
binomial CI.   
- 
The use of univariate and multivariate logistic regression models will be considered (if 
possible, taking into account the limited number of enrolled patients) to investigate the 
effect of the clinicopathological variables of interest (gender, age category, smoking 
history, ECOG performance status at enrolment, and stage at enrolment) on DCR. 
 
4.3.2 Progression-free survival  
PFS will be evaluated in the efficacy cohort by the Kaplan-Meier method. Specifically, the PFS 
analysis will include: 
- 
The total number (%) of PFS events observed, the 6-month estimate, median and 
respective 95% CIs.  


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- 
Graphical representation of PFS via Kaplan-Meir plots, overall and separately by each 
clinicopathological variable of interest (if possible due to the limited number of enrolled 
patients). 
- 
A table with information about the sites of progression. 
 
4.3.3 Overall survival   
Similar to PFS, OS will be evaluated in the efficacy cohort. OS analysis will include: 
- 
The total number (%) of OS events observed, the 12-month estimate, median and 
respective 95% CIs.  
- 
Graphical representation of OS via Kaplan-Meir plots, overall and separately by each 
clinicopathological variable of interest (if possible due to the limited number of enrolled 
patients). 
- 
Summary table of the death causes. 
 
4.3.4 Sensitivity efficacy analysis  
A secondary analysis of all efficacy endpoints evaluated in the ITT cohort (if different than the 
efficacy cohort) will also be performed. Efficacy endpoints to be re-assessed include overall 
response rate (ORR), disease control rate (DCR) at 24 weeks, progression-free survival (PFS), 
overall survival (OS). 
 
4.3.5 Safety and tolerability  
The safety and the tolerability of the trial treatment will be evaluated by the occurrence of AEs 
on all patients that have received at least one dose of trial treatment (safety cohort). 
Classification of severity and causality will be performed according to CTCAE v4.0 and will be 
presented using tables and bar charts. For each subject, each AE will be analysed according to the 
worst grade of toxicity observed over the whole treatment period.  
 Safety and tolerability assessment will include the following: 
- 
Overview of the number of patients who experienced an AE/SAE, as well as the number of 
patients in the safety cohort who did not experience an event, along with respective 
percentages.   
- 
Number of AEs/SAEs/AESIs (any cause or treatment-related) and rate of occurrence per 
month of follow-up. 
- 
Number of patients experiencing a specific number of AEs/SAEs. 


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- 
Distribution of AEs/SAEs by grade and CTCAE category. Six columns, one for each grade 
and one for all (any) grades, will be shown. An additional column indicating which events 
were SAEs -or started as AEs and became SAEs later on- will be also available. In this 
column, the frequency of the SAEs and the severity grade will be given. The percentages 
that will accompany the frequencies will be based on the respective frequency of an event 
over the total number of patients in the safety cohort. This table will include all AEs/SAEs 
irrespective of their relation to the trial treatment. 
- 
Analogous table focusing only on the treatment related AEs/SAEs. 
- 
A bar plot illustrating frequencies of AEs/SAEs (only AEs/SAEs with frequency >2% (or 
any other relevant %) will be presented). A similar plot by CTCAE category will be 
produced.  
- 
A bar plot illustrating frequencies of treatment related AEs/SAEs. 
- 
Number and corresponding percentages of treatment related AEs/SAEs, leading either to 
treatment discontinuation or death. 
- 
Maximum severity of AEs/SAEs per patient. 
- 
Number of SAEs by centre. 
- 
For all fatal SAEs, cause of death will be provided. 
 
4.3.6 Subgroup analysis 
Further exploratory analyses include description of primary (ORR) and secondary (DCR, PFS, OS) 
outcomes for patient subgroups of interest, as defined by the following patient or tumour 
characteristics: 
• 
Smoking status (Current/Former vs Never) 
• 
Gender  
• 
Age group 
• 
ECOG PS 
• 
Stage 
• 
Type of prior treatments 
 
Additional subgroup analysis will be performed by molecular characteristics (at enrolment):  
- 
Type of RET fusion  
- 
Co-mutations detected 


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Of note, due to the small number of patients, these analyses will be mainly of exploratory nature. 
Depending on data, Fisher’s exact test will be used for comparing ORR, DCR and log-rank test for 
comparing PFS, OS between different subgroups of patients. 
 


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5 Technical details 
Data will be primarily analysed using the SAS software package (version 9.4), while the R 
statistical software will be also used for specific analyses and plots.  
All final analysis and reviews will be performed according to the Standard Operating Procedures 
(SOPs) of the Frontier-Science Foundation Hellas (FSFH) statistical team. A second statistician, 
the reviewing statistician, will independently reproduce all analyses and summary statistics. The 
reviewing statistician will have an overview of the entire analysis and will explicitly check the 
code producing tables and figures, as well as any other pieces of code as desired. 
5.1 Data Retrieval Information 
On February 8, 2021, ETOP announced the premature closure of the ALERT-lung trial (ETOP 12-
17 ALERT-lung Trial Closure Guidance Letter). Trial will be terminated by March 31, 2021. 
Follow-up and safety information will be updated until March 31. All outstanding data and 
query replies will be submitted by 28 February 2021. Final database lock and trial closure 
date will be on 31 March 2021. 
 
5.2 Missing Data 
Baseline characteristics 
For categorical baseline characteristics if missing cases exist, a separate category named ‘Missing’ 
will be created. As far as continuous values, missing cases will not be replaced by any statistics 
calculated over non-missing data. 
Dates 
If the day of the month is missing for any date used in the analysis, the 15th of the month will be 
used to replace the missing date unless the calculation results in a negative time duration (eg, 
onset date cannot be prior to day one). In this case, the date resulting in one day of duration will 
be used. If the day of the month and the month are missing for any date used in a calculation, 
January 1 will be used to replace the missing date. Missing dates for adverse events will be 
imputed based on the similar principle. 
 
Incomplete tumor assessment information 
In patients who have no on-study assessments: 


ALERT-lung SAP – Final analysis  
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• 
If death is recorded prior to the first planned tumor assessment, the death date will be 
considered as the date of the PFS event. 
• 
If clinical progression is recorded prior to the first planned tumor assessment, the date of 
the reported clinical progression will be considered as the date of the PFS event. 
• 
In any other case, the patient will be censored at the date of enrolment plus 1 day. 
 
5.3 Reporting conventions  
Regarding the estimates presented in the report, the following rules will be adopted: 
• 
P-values ≥0.001 will be reported with three decimal places 
• 
P-values >0.010 will be reported with two significant decimal digits 
• 
P-values less than 0.001 will be reported as ‘<0.001’ 
• 
Means, medians, 95% confidence intervals (CIs), quantiles, and any other statistics, will be 
reported with one decimal digit 
• 
Hazard ratios (HRs) and their 95% CIs will be reported with two decimals 
• 
Estimated parameters, not on the same scale as raw observations (e.g., regression 
coefficients) will be reported with three significant figures 
 
5.4 Multiple recordings of an event for the same patient  
There are some cases where a patient may experience the same event (AE/SAE) more than one 
time. In such cases, the event will be count only once (with the highest grade) for the calculation 
of the total number of events. 
 
5.5 Presentation of results 
The results will be presented through tables and figures. A summary of the results will also 
accompany the main report. First, a short synopsis of the results will be presented through bullets, 
where only the most important findings will be shown. Following that, a more detailed description 
of the results will be provided, sectioned in the following order: 
I. Patient accrual and baseline characteristics  
II. Follow-up and treatment administration  
III. Efficacy analysis 
IV. Safety analysis