Skip to main content
. 2022 Jan 7;2022(1):CD013453. doi: 10.1002/14651858.CD013453.pub2

NCT03737994.

Study name Targeted treatment for ALK positive patients who have previously been treated for non‐squamous non‐small cell lung cancer
Methods Study design: randomised controlled trial
Study grouping: parallel group
Participants Baseline characteristics
ALK L1198F mutation (alone or in combination with another ALK mutation) receive crizotinib orally, daily, continously. Cycles repeat every 21 days.

  • Median age (range):

  • Female %:

  • Ethnicity Asian %:

  • ECOG 0 to 1 %:

  • Never smoked %:

  • Stage of disease IV at entry %:

  • Adenocarcinoma %:

  • Brain metastases at entry %:

  • Previous chemotherapy %:

  • Previous targeted therapy %:


Cy1156Y mutation receive either lorlatinib orally, daily, alectinib orally, twice daily, or brigatinib orally, daily, continuously. Cycles repeat every 21 days.

  • Median age (range):

  • Female %:

  • Ethnicity Asian %:

  • ECOG 0 to 1 %:

  • Never smoked %:

  • Stage of disease IV at entry %:

  • Adenocarcinoma %:

  • Brain metastases at entry %:

  • Previous chemotherapy %:

  • Previous targeted therapy %:


Compound mutation receive lorlatinib orally, daily, continuously. Cycles repeat every 21 days.

  • Median age (range):

  • Female %:

  • Ethnicity Asian %:

  • ECOG 0 to 1 %:

  • Never smoked %:

  • Stage of disease IV at entry %:

  • Adenocarcinoma %:

  • Brain metastases at entry %:

  • Previous chemotherapy %:

  • Previous targeted therapy %:


F1174 receive either lorlatinib orally, daily, alectinib orally, twice daily, or brigatinib orally, daily, continuously. Cycles repeat every 21 days.

  • Median age (range):

  • Female %:

  • Ethnicity Asian %:

  • ECOG 0 to 1 %:

  • Never smoked %:

  • Stage of disease IV at entry %:

  • Adenocarcinoma %:

  • Brain metastases at entry %:

  • Previous chemotherapy %:

  • Previous targeted therapy %:


G1202 (including G1202del and G1202R) receive either lorlatinib orally, daily or brigatinib orally, daily, continuously. Cycles repeat every 21 days.

  • Median age (range):

  • Female %:

  • Ethnicity Asian %:

  • ECOG 0 to 1 %:

  • Never smoked %:

  • Stage of disease IV at entry %:

  • Adenocarcinoma %:

  • Brain metastases at entry %:

  • Previous chemotherapy %:

  • Previous targeted therapy %:


I1171 mutation receive either lorlatinib orally, daily, ceritinib orally, daily, or brigatinib orally, daily. Cycles repeat every 21 days.

  • Median age (range):

  • Female %:

  • Ethnicity Asian %:

  • ECOG 0 to 1 %:

  • Never smoked %:

  • Stage of disease IV at entry %:

  • Adenocarcinoma %:

  • Brain metastases at entry %:

  • Previous chemotherapy %:

  • Previous targeted therapy %:


L1196 (including L1196M) mutation receive either lorlatinib orally, daily, ceritinib orally, daily, alectinib orally, twice daily, brigatinib orally, daily, or ensartinib orally, daily, continuously. Cycles repeat every 21 days.

  • Median age (range):

  • Female %:

  • Ethnicity Asian %:

  • ECOG 0 to 1 %:

  • Never smoked %:

  • Stage of disease IV at entry %:

  • Adenocarcinoma %:

  • Brain metastases at entry %:

  • Previous chemotherapy %:

  • Previous targeted therapy %:


MET amplification receive crizotinib orally, daily, continuously. Cycles repeat every 21 days.

  • Median age (range):

  • Female %:

  • Ethnicity Asian %:

  • ECOG 0 to 1 %:

  • Never smoked %:

  • Stage of disease IV at entry %:

  • Adenocarcinoma %:

  • Brain metastases at entry %:

  • Previous chemotherapy %:

  • Previous targeted therapy %:


No ALK‐resistant mutations receive lorlatinib orally, daily, ceritinib orally, daily, alectinib orally, twice daily, brigatinib orally, daily, ensartinib orally, daily, or pemetrexed +/− carboplatin. ALK inhibitor cycles repeat every 21 days. Chemotherapy cycles repeat every 21 days, up to 6 cycles.

  • Median age (range):

  • Female %:

  • Ethnicity Asian %:

  • ECOG 0 to 1 %:

  • Never smoked %:

  • Stage of disease IV at entry %:

  • Adenocarcinoma %:

  • Brain metastases at entry %:

  • Previous chemotherapy %:

  • Previous targeted therapy %:


Overall

  • Median age (range):

  • Female %:

  • Ethnicity Asian %:

  • ECOG 0 to 1 %:

  • Never smoked %:

  • Stage of disease IV at entry %:

  • Adenocarcinoma %:

  • Brain metastases at entry %:

  • Previous chemotherapy %:

  • Previous targeted therapy %:


Inclusion criteria
PRIOR TO STEP 1 REGISTRATION. Patients must have histologically or cytologically confirmed stage IV ALK‐positive non‐squamous non‐small cell lung carcinoma (NSCLC) (includes M1a, M1b, M1c stage disease, American Joint Committee on Cancer (AJCC) 8th edition). ALK rearrangement must have been demonstrated by a US Food and Drug Administration (FDA)‐approved assay (Vysis fluorescence in situ hybridisation (FISH) or Ventana immunohistochemistry (IHC)) or by next‐generation sequencing (NGS). Patient must be willing and able to undergo a fresh biopsy, or if patient has a biopsy after progression on current TKI within 3 months of study enrolment (and has continued TKI for clinical benefit per treating physician), this tissue may be used. Must have sufficient tissue. Patient must have progressive disease as defined by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 after 1 second‐generation ALK inhibitor, including LDK378 (ceritinib), alectinib, ensartinib, and brigatinib (may not have received more than 1 second‐generation ALK inhibitor). Patient may have received prior crizotinib; however, the second‐generation ALK inhibitor received must be the last treatment given prior to study enrolment. Prior lorlatinib (third‐generation ALK inhibitor) is not allowed. Prior chemotherapy is not allowed except for 1 prior cycle received at the time of original diagnosis of metastatic NSCLC with no evidence of disease progression following the cycle. NOTE: prior adjuvant or neoadjuvant chemotherapy is allowed if last dose was received more than 12 months prior to enrolment. The patient or a legally authorised representative must provide study‐specific informed consent prior to step 1 registration.
PRIOR TO STEP 2 REGISTRATION. Absolute neutrophil count (ANC) >= 1500 cells/mm^3 (within 28 days prior to step 2 registration). Platelets >= 100,000 cells/mm^3 (within 28 days prior to step 2 registration). Estimated creatinine clearance >= 60 mL/min by the Cockcroft Gault formula (within 28 days prior to step 2 registration). Total bilirubin =< 1.5 x upper limit of normal (ULN) (except for patients with documented Gilbert's syndrome) (within 28 days prior to step 2 registration). Aspartate aminotransferase (AST) =< 2.5 x ULN, =< 5 x ULN if liver metastases are present (within 28 days prior to step 2 registration). Alanine aminotransferase (ALT) =< 2.5 x ULN, =< 5 x ULN if liver metastases are present (within 28 days prior to step 2 registration). Patients with asymptomatic treated or untreated brain metastases are eligible. Treated brain metastases are eligible as long as patients have measurable disease outside the brain according to RECIST 1.1. Patients must be on a stable or decreasing dose of steroids for at least 7 days prior to step 2 registration. Anticonvulsants are allowed as long as the patient is neurologically stable and not deteriorating. Patients enrolled with asymptomatic brain metastases (mets) must have at least 1 measurable target extracranial lesion according to RECIST 1.1. ECOG PS 0 to 2/acute effects of any prior therapy resolved to baseline severity or to Common Terminology Criteria for Adverse Events (CTCAE) grade =< 1 (except for alopecia, hearing loss). Not taking any medications that may interact with selected study medication based on stratification. Patients must be able to take oral medications (i.e. swallow whole tablets/capsules). All females of childbearing potential must have a blood test or urine study within 14 days prior to step 2 registration to rule out pregnancy. A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: has not undergone a hysterectomy or bilateral oophorectomy; or has not been naturally postmenopausal for at least 24 consecutive months (i.e. has had menses at any time in the preceding 24 consecutive months). Women must not be pregnant or breastfeeding due to potential harm to the foetus or infant from ALK inhibitors and the unknown risk. Women of childbearing potential and sexually active males must agree to use an accepted and effective method of contraception or to abstain from sexual intercourse for the duration of their participation in the study.
Exclusion criteria
PRIOR TO STEP 2 REGISTRATION: Major surgery within 2 weeks of study entry. Minor surgical procedures (e.g. port insertion, pleurex catheter placement) are allowed, and all wounds must not show signs of infection or draining. PRIOR TO STEP 2 REGISTRATION: Palliative radiation therapy (RT) (< 10 fractions) must have been completed at least 48 hours prior to study entry. Stereotactic or small field brain irradiation must have been completed at least 1 week prior to study entry. Whole brain RT or other palliative RT must have been completed at least 2 weeks prior to study entry. PRIOR TO STEP 2 REGISTRATION: Prior dose of next‐generation ALK inhibitor (LDK378 (ceritinib), alectinib, ensartinib, lorlatinib) within 5 days prior to step 2 registration. Prior dose of brigatinib within 7 days prior to step 2 registration. PRIOR TO STEP 2 REGISTRATION: History of interstitial lung disease or interstitial fibrosis, including a history of pneumonitis, obliterative bronchiolitis, pulmonary fibrosis. Patients with a history of prior radiation pneumonitis are not excluded. PRIOR TO STEP 2 REGISTRATION: Active inflammatory gastrointestinal disease (such as Crohn's, ulcerative colitis), chronic diarrhoea, symptomatic diverticular disease, or any gastrointestinal disease that would affect the absorption of oral medications or increase the risk of toxicity. PRIOR TO STEP 2 REGISTRATION: Clinically significant cardiovascular abnormalities, as determined by the treating/registering physician, such as uncontrolled hypertension, congestive heart failure New York Heart Association classification of 3, unstable angina, or poorly controlled arrhythmia, or myocardial infarction within 6 months. PRIOR TO STEP 2 REGISTRATION: Active and clinically significant bacterial, fungal, or viral infection. PRIOR TO STEP 2 REGISTRATION: Patients with active or chronic pancreatitis based on lipase elevation, symptoms, and radiographic findings. PRIOR TO STEP 2 REGISTRATION: Other concomitant serious illness or organ system dysfunction that in the opinion of the investigator would either compromise patient safety or interfere with the evaluation of the safety of the study drug. PRIOR TO STEP 2 REGISTRATION: Patients must not plan to receive any other investigational agents during the course of therapy. PRIOR TO STEP 2 REGISTRATION: Patients with active malignancy other than ALK‐positive non‐squamous NSCLC within the last 2 years are excluded (note: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, papillary thyroid cancer treated with curative intent, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease‐free for 2 years are eligible). PRIOR TO STEP 2 REGISTRATION: No chemotherapy and/or immunotherapy allowed after step 1 registration.
Interventions Intervention characteristics
ALK L1198F mutation (alone or in combination with another ALK mutation) receive crizotinib orally, daily, continously. Cycles repeat every 21 days.

  • Type: TKI


Cy1156Y mutation receive either lorlatinib orally, daily, alectinib orally, twice daily, or brigatinib orally, daily, continously. Cycles repeat every 21 days.

  • Type: TKI


Compound mutation receive lorlatinib orally, daily, continuously. Cycles repeat every 21 days.

  • Type: TKI


F1174 receive either lorlatinib orally, daily, alectinib orally, twice daily, or brigatinib orally, daily, continuously. Cycles repeat every 21 days.

  • Type: TKI


G1202 (including G1202del and G1202R) receive either lorlatinib orally, daily or brigatinib orally, daily, continuously. Cycles repeat every 21 days.

  • Type: TKI


I1171 mutation receive either lorlatinib orally, daily, ceritinib orally, daily, or brigatinib orally, daily, continuously. Cycles repeat every 21 days.

  • Type: TKI


L1196 (including L1196M) mutation receive either lorlatinib orally, daily, ceritinib orally, daily, alectinib orally, twice daily, brigatinib orally, daily, or ensartinib orally, daily, continuously. Cycles repeat every 21 days.

  • Type: TKI


MET amplification receive crizotinib orally, daily, continously. Cycles repeat every 21 days.

  • Type: TKI


No ALK‐resistant mutations receive lorlatinib orally, daily, ceritinib orally, daily, alectinib orally, twice daily, brigatinib orally, daily, ensartinib orally, daily, continuously, or pemetrexed +/− carboplatin, intravenously, every 3 weeks. ALK inhibitor cycles repeat every 21 days. Chemotherapy cycles repeat every 21 days, up to 6 cycles.

  • Type: TKI
Outcomes Objective response rate (ORR) [ Time Frame: up to 24 weeks ]
Progression‐free survival (PFS) [ Time Frame: from second step registration to the date of the first recorded occurrence of disease progression or death from any cause (whichever occurs first), assessed up to 7 years ]
Duration of response [ Time Frame: from the first occurrence of a documented best overall response (BOR) of complete response (CR) or partial response (PR) to the first date of recorded disease progression or death from any cause (whichever occurs first), assessed up to 7 years ]
Overall survival (OS) [ Time Frame: from second step registration to the date of death from any cause, assessed up to 7 years ]
Intracranial objective response rate [ Time Frame: up to 7 years]
Incidence of adverse events [ Time Frame: up to 30 days post‐treatment ]
Biopsy mutation and circulating free DNA (cfDNA) mutation results [ Time Frame: up to 30 days post‐treatment ]
Starting date April 2019
Contact information  
Notes clinicaltrials.gov/ct2/show/NCT03737994