ALEctinib for the Treatment of Pretreated RET-rearranged Advanced Non-small Cell Lung Cancer (ALERT-lung)

A Single Arm Phase II Trial Evaluating the Activity of Alectinib for the Treatment of Pretreated RET-rearranged Advanced NSCLC

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

Study Overview

• Status: Terminated
• Conditions: Non-small Cell Lung Cancer; Non-small Cell Lung Cancer Metastatic; Non-small Cell Lung Cancer Recurrent
• Intervention / Treatment: Drug: Alectinib

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.

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium
    • Institut Jules Bordet
• Ireland
  • Dublin, Ireland
    • St. James Hospital
• Italy
  • Bari, Italy
    • IRCCS Instituto Tumori Giovanni Paolo II
  • Milano, Italy
    • Instituto Europeo di Oncologia (IEO)
  • Turin, Italy
    • University Hospital of Turin
  • Verona, Italy
    • Universita di Verona
• Netherlands
  • Amsterdam, Netherlands
    • The Netherlands Cancer Institute Amsterdam
  • Maastricht, Netherlands
    • University Medical Center Maastricht
• Spain
  • Alicante, Spain
    • Hospital General de Alicante
  • Barcelona, Spain
    • Hospital Sant Pau
  • Barcelona, Spain, 08035
    • Vall d'Hebron University Hospital
  • Barcelona, Spain
    • Hospital Quiron Dexeus
  • La Coruna, Spain
    • Hospital Teresa Herrara
  • Madrid, Spain
    • Hospital Universitario 12 de Octubre
  • Madrid, Spain
    • Hospital Puerta de Hierro
  • Málaga, Spain
    • Hospital Regional Universitario Carlos Haya
• Switzerland
  • Fribourg, Switzerland
    • Hfr Fribourg
  • Genève, Switzerland
    • Hôpital Universitaire de Genève
  • Zurich, Switzerland
    • UniversitätSpital Zürich

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Histologically or cytologically documented non-small cell lung carcinoma
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)
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.
4. RET rearrangement detected by FISH, Nanostring or by parallel-sequencing on FFPE tumour tissue assessed locally.
5. Availability of FFPE tumour material for central confirmation of RETrearrangement
6. Measurable or non-measurable, but radiologically evaluable (except for skin lesions) disease according to RECIST v1.1 criteria
7. Age ≥18 years
8. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2
9. Life expectancy >3 months

10. Adequate haematological function:

    • Haemoglobin ≥9 g/dL
    • Neutrophil count ≥1.5 ×109/L
    • Platelet count ≥100 × 109/L
    • WBC ≥2 ×109/L
11. Adequate renal function: Calculated creatinine clearance ≥45 mL/min (according to Cockcroft-Gault formula)

12. Adequate liver function:

    • Total bilirubin ≤2x ULN (except patients with Gilbert Syndrome, who can have total bilirubin ≤3.0 mg/dL)
    • ALT and AST ≤3x ULN (≤5x ULN for patients with concurrent liver ¨ metastasis)
13. Patient capable of proper therapeutic compliance, and accessible to correct followup.
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.
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.
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)
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.

Exclusion Criteria:

1. Untreated, active CNS metastases
2. Carcinomatous meningitis
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
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

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
6. Patients with baseline symptomatic bradycardia
7. Previous treatment with any RET TKI or RET targeted therapy.
8. Known EGFR, ALK, ROS, and BRAF mutation (in addition to RET rearrangement)
9. Any concurrent systemic anticancer therapy.
10. Any GI disorder that may affect absorption of oral medications, such as malabsorption syndrome or status post major bowel resection.
11. History of hypersensitivity to any of the additives in the alectinib drug formulation.
12. Known HIV positivity or AIDS-related illness.
13. Women who are pregnant or in the period of lactation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 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.

Drug: Alectinib; 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.; Other Names: Alecensa

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Best Overall Response (BOR)	Best overall response (OR = CR or PR), per investigator assessment. OR was determined using the Response Evaluation Criteria in Solid Tumors (RECIST v1.1). OR is defined as the best overall response [Complete Response (disappearance of all target and non-target lesions, no new lesions) or Partial Response (at least a 30% decrease in the sum of the longest diameter of target lesions taking as reference the baseline sum of diameters, no measurable increase in a non-target lesion, no new lesions)] across all assessment points. Radiological tumour assessments were performed using CT scans.	Evaluated from enrollment through study completion, up to a maximum of 28 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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) by RECIST v1.1 criteria. Complete Response (CR): disappearance of all target and non-target lesions and no new lesions detected; Partial Response (PR): at least 30% decrease in the sum of the longest diameter of target lesions taking as reference the baseline sum of diameters (no measurable increase in a non-target lesion and no new lesion detected); Stable disease (SD): at most 20% increase or at most 30% decrease in the sum of the longest diameter of target lesions taking as reference the baseline sum of diameters (no measurable increase in a non-target lesion and no new lesion detected). Radiological tumour assessments were performed using CT scans.	From first documented response (CR, PR, SD, non-CR/non-PD) to 24 weeks or first documented progression or death from any cause, whichever came first, assessed every 8 weeks (±4 days).
Progression-free Survival (PFS)	Progression-free survival time was measured from the date of enrolment until documented progression or death from any cause, whichever came first. PFS is assessed according to RECIST 1.1 criteria. Progressive disease: at least a 20% increase in the sum of the longest diameter of target lesions taking as reference the baseline sum of diameters, or a measurable increase in a non-target lesion, or the appearance of new lesions.	Evaluated from enrollment through study completion, up to a maximum of 28 months.
Overall Survival (OS)	Overall survival time is measured from the date of enrolment until death from any cause.	Evaluated from enrollment through study completion, up to a maximum of 28 months.
Number of Patients Experienced Adverse Events	The safety and tolerability of alectinib treatment is assessed through analysis of the worst grade of toxicity/adverse events according to CTCAE v4.0 criteria observed over the whole treatment period.	Evaluated from enrollment through study completion, up to a maximum of 28 months.

Collaborators and Investigators

• Sponsor: ETOP IBCSG Partners Foundation
• Collaborators: Hoffmann-La Roche
• Investigators: Study Chair: Enriqueta Felip, MD-PhD, Vall d'Hebron University Hospital; Study Chair: Jürgen Wolf, MD-PhD, University Hospital Cologne; Study Chair: Egbert F. Smith, MD-PhD, The Netherlands Cancer Institute Amsterdam

Publications and helpful links

General Publications

• Gainor JF, Shaw AT. Novel targets in non-small cell lung cancer: ROS1 and RET fusions. Oncologist. 2013;18(7):865-75. doi: 10.1634/theoncologist.2013-0095. Epub 2013 Jun 28.
• Takeuchi K, Soda M, Togashi Y, Suzuki R, Sakata S, Hatano S, Asaka R, Hamanaka W, Ninomiya H, Uehara H, Lim Choi Y, Satoh Y, Okumura S, Nakagawa K, Mano H, Ishikawa Y. RET, ROS1 and ALK fusions in lung cancer. Nat Med. 2012 Feb 12;18(3):378-81. doi: 10.1038/nm.2658.
• Lin JJ, Kennedy E, Sequist LV, Brastianos PK, Goodwin KE, Stevens S, Wanat AC, Stober LL, Digumarthy SR, Engelman JA, Shaw AT, Gainor JF. Clinical Activity of Alectinib in Advanced RET-Rearranged Non-Small Cell Lung Cancer. J Thorac Oncol. 2016 Nov;11(11):2027-2032. doi: 10.1016/j.jtho.2016.08.126. Epub 2016 Aug 17.
• Gautschi O, Milia J, Filleron T, Wolf J, Carbone DP, Owen D, Camidge R, Narayanan V, Doebele RC, Besse B, Remon-Masip J, Janne PA, Awad MM, Peled N, Byoung CC, Karp DD, Van Den Heuvel M, Wakelee HA, Neal JW, Mok TSK, Yang JCH, Ou SI, Pall G, Froesch P, Zalcman G, Gandara DR, Riess JW, Velcheti V, Zeidler K, Diebold J, Fruh M, Michels S, Monnet I, Popat S, Rosell R, Karachaliou N, Rothschild SI, Shih JY, Warth A, Muley T, Cabillic F, Mazieres J, Drilon A. Targeting RET in Patients With RET-Rearranged Lung Cancers: Results From the Global, Multicenter RET Registry. J Clin Oncol. 2017 May 1;35(13):1403-1410. doi: 10.1200/JCO.2016.70.9352. Epub 2017 Mar 13.
• Kodama T, Tsukaguchi T, Satoh Y, Yoshida M, Watanabe Y, Kondoh O, Sakamoto H. Alectinib shows potent antitumor activity against RET-rearranged non-small cell lung cancer. Mol Cancer Ther. 2014 Dec;13(12):2910-8. doi: 10.1158/1535-7163.MCT-14-0274. Epub 2014 Oct 27.

Study record dates

Study Major Dates

• Study Start (Actual): November 6, 2018
• Primary Completion (Actual): March 31, 2021
• Study Completion (Actual): March 31, 2021

Study Registration Dates

• First Submitted: January 5, 2018
• First Submitted That Met QC Criteria: February 23, 2018
• First Posted (Actual): February 26, 2018

Study Record Updates

• Last Update Posted (Actual): April 8, 2025
• Last Update Submitted That Met QC Criteria: March 31, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: advanced NSCLC; RET-rearrangement
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Tyrosine Kinase Inhibitors; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Alectinib
• Other Study ID Numbers: ETOP 12-17; 2017-002063-17 (EudraCT Number); MO30176 (Other Identifier: Roche)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No