Lung Non-Squamous Non-Small Cell Carcinoma, Stage IVA Lung Cancer AJCC v8, Stage IVB Lung Cancer AJCC v8, Stage IV Lung Cancer AJCC v8
Conditions
Brief summary
This National Cancer Institute (NCI)-NRG ALK Protocol phase II trial studies how well a combination of different biomarker/ALK inhibitors work in treating patients with stage IV ALK positive non-squamous non-small cell lung cancer. Lorlatinib, ceritinib, alectinib, brigatinib, ensartinib, and crizotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as pemetrexed, cisplatin, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether a combination of biomarker/ALK inhibitors or chemotherapy may work better in treating patients with ALK positive non-squamous non-small cell lung cancer.
Detailed description
PRIMARY OBJECTIVES: I. To assess whether ALK kinase domain mutations (G1202/C1156Y/I1171/L1196/ V1180/ F1174/compound mutation) associated with drug resistance are prognostic for objective response to subsequent ALK inhibitor therapy. II. To assess whether subsequent pemetrexed based chemotherapy improves objective response comparing to ALK inhibitor therapy for no ALK mutation patients. III. To evaluate objective responses of patients with specific genetic alterations (ALKL1198F/MET double mutation or high-level MET gene amplification) treated with crizotinib. SECONDARY OBJECTIVES: I. Progression-free survival (PFS). II. Duration of response (DOR). III. Overall survival (OS). IV. Intracranial objective response rate (ORR). V. Safety and tolerability. CORRELATIVE SCIENCE OBJECTIVE: I. Establish concordance between tumor and liquid biopsies. OUTLINE: Patients with a G1202R or G1202del mutation receive either lorlatinib orally (PO) once daily (QD) or brigatinib PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients with a C1156Y mutation receive either lorlatinib PO QD, brigatinib PO QD, or alectinib PO twice daily (BID). Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients with a I1171 mutation receive either lorlatinib PO QD, ceritinib PO QD, or brigatinib PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients with a L1196 mutation receive either lorlatinib PO QD, brigatinib PO QD, ensartinib PO QD, alectinib PO BID, or ceritinib PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients with a V1180 mutation receive either lorlatinib PO QD, brigatinib PO QD, or ceritinib PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients with a F1174 mutation receive either alectinib PO BID, lorlatinib PO QD, or brigatinib PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients with a compound mutation receive lorlatinib PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients with an ALK L1198F mutation alone or with another mutation, and patients with high level MET amplification receive crizotinib PO BID. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients with no ALK-resistant mutations receive either lorlatinib PO QD, ceritinib PO QD, alectinib PO BID, brigatinib PO QD, or ensartinib PO QD, or pemetrexed intravenously (IV) over 10 minutes on day 1 and either cisplatin IV or carboplatin IV on day 1. ALK inhibitor cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Pemetrexed-based treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Maintenance treatment of pemetrexed may continue until disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 30 days, every 3 months for 2 years, every 6 months for 3 years, and annually thereafter.
Interventions
DRUGAlectinib
Given PO
DRUGBrigatinib
Given PO
DRUGCarboplatin
Given IV
DRUGCeritinib
Given PO
DRUGCisplatin
Given IV
DRUGCrizotinib
Given PO
DRUGEnsartinib
Given PO
DRUGLorlatinib
Given PO
DRUGPemetrexed
Given IV
Sponsors
National Cancer Institute (NCI)
NRG Oncology
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 Food and Drug Administration (FDA) approved assay (Vysis fluorescence in situ hybridization \[FISH\] 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 tyrosine-kinase inhibitor (TKI) within 3 months of study enrollment (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 Tumors (RECIST) 1.1 after one second generation ALK inhibitor, including LDK378 (ceritinib), alectinib, ensartinib, and brigatinib (may not have received more than one 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 enrollment * Prior lorlatinib (third-generation ALK inhibitor) is not allowed * Prior chemotherapy is not allowed except for one 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 enrollment * The patient or a legally authorized 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 one measurable target extracranial lesion according to RECIST 1.1 * Eastern Cooperative Oncology Group (ECOG) performance status 0-2 * 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 breast-feeding due to potential harm to the fetus 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
* 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 * Palliative RT (\< 10 fractions) must have been completed at least 48 hours prior to study entry. Stereotactic or small field brain irradiation must have 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 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 * 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 * Active inflammatory gastrointestinal disease (such as Crohns, ulcerative colitis), chronic diarrhea, symptomatic diverticular disease, or any gastrointestinal disease that would affect the absorption of oral medications or increase the risk of toxicity * Clinically significant cardiovascular abnormalities, as determined by the treating/registering physician, such as uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA) classification of 3, unstable angina or poorly controlled arrhythmia, or myocardial infarction within 6 months * Active and clinically significant bacterial, fungal, or viral infection * Patients with active or chronic pancreatitis based on lipase elevation, symptoms, and radiographic findings * 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 * Patients must not plan to receive any other investigational agents during the course of therapy * 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) * No chemotherapy and/or immunotherapy allowed after step 1 registration
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR), Per Investigator Assessment Using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 Criteria | Baseline to 24 weeks | ORR= number of subjects with best overall response (BOR) of complete or partial response (CR, PR) divided by number of evaluable subjects. BOR= best response recorded from start of treatment to first progression (PD)/new anticancer therapy, otherwise last follow-up. * CR: disappearance of target and non-target lesions; no new lesions; pathological lymph nodes \< 10mm. * PR: 30% decrease in target lesions; non-target lesions not progressed or not evaluated; no new lesions. * PD: 20% increase of target lesions and/or new lesion(s). ORR was to be compared using Fisher's exact test within each ALK inhibitor treatment arm (each mutation vs. no mutation) and also within the subset of subjects with no mutation comparing each experimental arm vs. pemetrexed. Due to early accrual closure (few subjects), only the number of subjects with BOR of CR or PR are provided, by mutation, no statistical testing. Analysis was to occur after each patient was potentially followed ≥ 24 weeks. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS), Per Investigator Assessment Using RECIST v1.1 Criteria | Baseline to the date of the first disease progression / progressive disease, death, or last known follow-up. Maximum follow-up time was 33.6 months, median 8.9 months. | Progression-free survival time is defined as the time from second step registration to the date of the first disease progression / progressive disease (PD), death, or last known follow-up (censored). Progressive disease is defined as a 20% increase of target lesions and/or new lesion(s). Percentage of participants progression-free at a given time (PFS) was to be estimated by the Kaplan-Meier method. Median PFS and PFS at specific time points was to be reported, with 95% confidence intervals, for each mutation (or no mutation)/regimen combination. Due to early accrual closure resulting in few participants, only the number of participants who progressed or died, by mutation, with no statistical testing. |
| Duration of Overall Response, Per Investigator Assessment Using RECIST v1.1 | Baseline to the date of the first disease progression / progressive disease, death, or last known follow-up. Maximum follow-up time was 33.6 months, median 8.9 months. | Duration of overall response (DOR) is defined as the time from the first occurrence of a documented BOR of CR or PR to the first date of recorded disease progression (PD) or death from any cause (whichever occurs first). BOR is the best response recorded from the start of treatment to first progression (PD)/new anticancer therapy, otherwise last follow-up. * CR: disappearance of target and non-target lesions; no new lesions; pathological lymph nodes \< 10mm. * PR: 30% decrease in target lesions; non-target lesions not progressed or not evaluated; no new lesions. * PD: 20% increase of target lesions and/or new lesion(s). Median DOR was to be estimated, with 95% confidence intervals, for each mutation/regimen combination using the Kaplan-Meier method. Due to early accrual closure resulting in few subjects, only the mean and range DOR are provided, by mutation, and no statistical testing was done. |
| Overall Survival (OS) | Baseline to the date of death or last known follow-up. Maximum follow-up time was 33.6 months, median 8.9 months. | Survival time is defined as the time from second step registration to the date of death, or last known follow-up (censored). Percentage of participants alive at a given time (OS) was to be estimated by the Kaplan-Meier method. Median OS and OS at specific time points was to be reported, with 95% confidence intervals, for each mutation/regimen combination. Due to early accrual closure resulting in few patients, only the number of participants who died are provided, by mutation, and no statistical testing was done. |
| Intracranial Objective Response Rate, Per Investigator Assessment Using RECIST v1.1 | Baseline to 24 weeks | Intracranial objective response rate (IORR) is defined as the number of participants with central nervous system (CNS) metastasis complete or partial response (CR, PR) divided by the number of evaluable participants with baseline CNS metastasis and no prior CNS radiation therapy. Participants who required additional treatment (for their non-cranial systemic disease) would be considered as non-responders (if they have not previously had an intracranial response). * CR: disappearance of target and non-target lesions; no new lesions; pathological lymph nodes \< 10mm. * PR: 30% decrease in target lesions; non-target lesions not progressed or not evaluated; no new lesions. IORR was to be estimated for each mutation/regimen combination, with the associated 95% confidence intervals (using Clapper-Pearson method). Due to early accrual closure resulting in few subjects, only the number of subjects with CR or PR are provided, by mutation, with no statistical testing. |
| Number of Participants by Highest Grade Adverse Event Reported | Baseline to the date of last known follow-up. Maximum follow-up time was 33.6 months, median 8.9 months. | Common Terminology Criteria for Adverse Events (version 4.0) grades adverse event severity from 1=mild to 5=death. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORJessica J Lin
NRG Oncology
Participant flow
Pre-assignment details
Tissue and blood submissions were required after first step registration, before second step registration (treatment assignment). Of 16 participants screened, 10 were assigned to treatment.
Participants by arm
| Arm | Count |
|---|---|
| Lorlatinib Participants with G1202 (including G1202del and G1202R), C1156Y, I1171, L1196 (including L1196M), V1180, or F1174 mutations, compound mutation\*, or no mutations, can be assigned to receive lorlatinib. \*Compound mutation = two or more resistance mutation excluding those with L1198F or L1189F/MET amplification = L1198F mutation alone or in combination, or no ALK mutation but any MET amplification.
Lorlatinib: 100 mg orally once a day with or without food. Treatment continues until disease progression or unacceptable toxicity. | 3 |
| LDK378 (Ceritinib) Participants with I1171, L1196 (including L1196M), or V1180 mutations, or no having no ALK-resistance mutations or MET amplifications, can be assigned to receive ceritinib
Ceritinib: 450 mg orally once a day with food. Treatment continues until disease progression or unacceptable toxicity. | 1 |
| Brigatinib Participants with G1202 (including G1202del and G1202R), C1156Y, I1171, L1196 (including L1196M), V1180, or F1174 mutations, or having no ALK-resistance mutations or MET amplifications, can be assigned to receive brigatinib.
Brigatinib: 90 mg orally once a day (with or without food) for the first 7 days; if tolerated, with no respiratory symptoms, increase the dose to 180 mg once daily. Treatment continues until disease progression or unacceptable toxicity. | 2 |
| Ensartinib Participants with L1196 (including L1196M) mutations or having no ALK-resistance mutations or MET amplifications can be assigned to receive ensartinib.
Ensartinib: 225 mg orally once a day with or without food. Treatment continues until disease progression or unacceptable toxicity. | 3 |
| Pemetrexed +/- Cisplatin or Carboplatin Participants with no ALK-resistance mutations or MET amplifications can be assigned to receive pemetrexed, which optionally can be combined with cisplatin or carboplatin.
Carboplatin: Carboplatin is optional. Dosing of area under the curve (AUC) = 5 once every 3 weeks (on Day 1 of a 21 day cycle with pemetrexed) intravenously, prepared and administered per institution policy. Continues for 4-6 cycles.
Cisplatin: Cisplatin is optional. 75 mg/m\^2 intravenously once every 3 weeks (on Day 1 of a 21 day cycle with pemetrexed), prepared and administered per institution policy.
Pemetrexed: Pemetrexed may be given alone or with either cisplatin or carboplatin. Pemetrexed 500 mg/m2 administered intravenously on Day 1 of a 21 day cycle, optionally with cisplatin or carboplatin for 4-6 cycles. Then pemetrexed (as a single agent) continues until progression or significant toxicity. | 1 |
| Total | 10 |
Baseline characteristics
| Characteristic | Lorlatinib | LDK378 (Ceritinib) | Brigatinib | Ensartinib | Pemetrexed +/- Cisplatin or Carboplatin | Total |
|---|---|---|---|---|---|---|
| Age, Customized <= 49 years | 1 Participants | 1 Participants | 2 Participants | 1 Participants | 0 Participants | 5 Participants |
| Age, Customized 50-59 years | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants |
| Age, Customized 60-69 years | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants |
| Age, Customized >= 70 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 1 Participants | 1 Participants | 3 Participants | 1 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Has CNS metastases | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Mutation I1171 | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 3 Participants |
| Mutation No ALK-resistance mutation / MET amplification | 2 Participants | 0 Participants | 1 Participants | 3 Participants | 1 Participants | 7 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 0 Participants | 2 Participants | 3 Participants | 1 Participants | 9 Participants |
| Sex: Female, Male Female | 2 Participants | 0 Participants | 2 Participants | 2 Participants | 1 Participants | 7 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 0 / 2 | 0 / 1 | 0 / 1 | 1 / 1 | 2 / 3 |
| other Total, other adverse events | 1 / 1 | 2 / 2 | 1 / 1 | 1 / 1 | 1 / 1 | 2 / 3 |
| serious Total, serious adverse events | 0 / 1 | 2 / 2 | 0 / 1 | 0 / 1 | 1 / 1 | 1 / 3 |
Outcome results
Primary
Objective Response Rate (ORR), Per Investigator Assessment Using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 Criteria
ORR= number of subjects with best overall response (BOR) of complete or partial response (CR, PR) divided by number of evaluable subjects. BOR= best response recorded from start of treatment to first progression (PD)/new anticancer therapy, otherwise last follow-up. * CR: disappearance of target and non-target lesions; no new lesions; pathological lymph nodes \< 10mm. * PR: 30% decrease in target lesions; non-target lesions not progressed or not evaluated; no new lesions. * PD: 20% increase of target lesions and/or new lesion(s). ORR was to be compared using Fisher's exact test within each ALK inhibitor treatment arm (each mutation vs. no mutation) and also within the subset of subjects with no mutation comparing each experimental arm vs. pemetrexed. Due to early accrual closure (few subjects), only the number of subjects with BOR of CR or PR are provided, by mutation, no statistical testing. Analysis was to occur after each patient was potentially followed ≥ 24 weeks.
Time frame: Baseline to 24 weeks
Population: Eligible participants who started protocol treatment and had post-baseline disease assessment. Treatment arms with no evaluable participants are not shown.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Lorlatinib | Objective Response Rate (ORR), Per Investigator Assessment Using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 Criteria | Mutation = I1171: BOR of CR or PR | 1 Participants |
| Lorlatinib | Objective Response Rate (ORR), Per Investigator Assessment Using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 Criteria | Mutation = None: BOR of CR or PR | 2 Participants |
| LDK378 (Ceritinib) | Objective Response Rate (ORR), Per Investigator Assessment Using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 Criteria | Mutation = I1171: BOR of CR or PR | 0 Participants |
| Brigatinib | Objective Response Rate (ORR), Per Investigator Assessment Using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 Criteria | Mutation = I1171: BOR of CR or PR | 0 Participants |
| Brigatinib | Objective Response Rate (ORR), Per Investigator Assessment Using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 Criteria | Mutation = None: BOR of CR or PR | 1 Participants |
| Ensartinib | Objective Response Rate (ORR), Per Investigator Assessment Using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 Criteria | Mutation = None: BOR of CR or PR | 0 Participants |
Secondary
Duration of Overall Response, Per Investigator Assessment Using RECIST v1.1
Duration of overall response (DOR) is defined as the time from the first occurrence of a documented BOR of CR or PR to the first date of recorded disease progression (PD) or death from any cause (whichever occurs first). BOR is the best response recorded from the start of treatment to first progression (PD)/new anticancer therapy, otherwise last follow-up. * CR: disappearance of target and non-target lesions; no new lesions; pathological lymph nodes \< 10mm. * PR: 30% decrease in target lesions; non-target lesions not progressed or not evaluated; no new lesions. * PD: 20% increase of target lesions and/or new lesion(s). Median DOR was to be estimated, with 95% confidence intervals, for each mutation/regimen combination using the Kaplan-Meier method. Due to early accrual closure resulting in few subjects, only the mean and range DOR are provided, by mutation, and no statistical testing was done.
Time frame: Baseline to the date of the first disease progression / progressive disease, death, or last known follow-up. Maximum follow-up time was 33.6 months, median 8.9 months.
Population: Eligible participants who started protocol treatment and had complete or partial response. Treatment arms with no evaluable participants are not shown.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Lorlatinib | Duration of Overall Response, Per Investigator Assessment Using RECIST v1.1 | Mutation = I1171 | 27.9 months |
| Lorlatinib | Duration of Overall Response, Per Investigator Assessment Using RECIST v1.1 | Mutation = None | 19.2 months |
| LDK378 (Ceritinib) | Duration of Overall Response, Per Investigator Assessment Using RECIST v1.1 | Mutation = None | 3.5 months |
Secondary
Intracranial Objective Response Rate, Per Investigator Assessment Using RECIST v1.1
Intracranial objective response rate (IORR) is defined as the number of participants with central nervous system (CNS) metastasis complete or partial response (CR, PR) divided by the number of evaluable participants with baseline CNS metastasis and no prior CNS radiation therapy. Participants who required additional treatment (for their non-cranial systemic disease) would be considered as non-responders (if they have not previously had an intracranial response). * CR: disappearance of target and non-target lesions; no new lesions; pathological lymph nodes \< 10mm. * PR: 30% decrease in target lesions; non-target lesions not progressed or not evaluated; no new lesions. IORR was to be estimated for each mutation/regimen combination, with the associated 95% confidence intervals (using Clapper-Pearson method). Due to early accrual closure resulting in few subjects, only the number of subjects with CR or PR are provided, by mutation, with no statistical testing.
Time frame: Baseline to 24 weeks
Population: No participants with baseline CNS metastasis had evaluable post-baseline CNS metastasis assessment.
Secondary
Number of Participants by Highest Grade Adverse Event Reported
Common Terminology Criteria for Adverse Events (version 4.0) grades adverse event severity from 1=mild to 5=death. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data.
Time frame: Baseline to the date of last known follow-up. Maximum follow-up time was 33.6 months, median 8.9 months.
Population: Eligible participants who started protocol treatment, with adverse event data. Treatment arms with no evaluable participants are not shown.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Lorlatinib | Number of Participants by Highest Grade Adverse Event Reported | Mutation = I1107 | Grade 1 | 0 Participants |
| Lorlatinib | Number of Participants by Highest Grade Adverse Event Reported | Mutation = I1107 | Grade 5 | 0 Participants |
| Lorlatinib | Number of Participants by Highest Grade Adverse Event Reported | Mutation = none | Grade 3 | 2 Participants |
| Lorlatinib | Number of Participants by Highest Grade Adverse Event Reported | Mutation = I1107 | Grade 2 | 0 Participants |
| Lorlatinib | Number of Participants by Highest Grade Adverse Event Reported | Mutation = none | Grade 5 | 0 Participants |
| Lorlatinib | Number of Participants by Highest Grade Adverse Event Reported | Mutation = I1107 | Grade 3 | 1 Participants |
| Lorlatinib | Number of Participants by Highest Grade Adverse Event Reported | Mutation = none | Grade 4 | 0 Participants |
| Lorlatinib | Number of Participants by Highest Grade Adverse Event Reported | Mutation = none | Grade 1 | 0 Participants |
| Lorlatinib | Number of Participants by Highest Grade Adverse Event Reported | Mutation = none | Grade 2 | 0 Participants |
| Lorlatinib | Number of Participants by Highest Grade Adverse Event Reported | Mutation = I1107 | Grade 4 | 0 Participants |
| LDK378 (Ceritinib) | Number of Participants by Highest Grade Adverse Event Reported | Mutation = I1107 | Grade 5 | 0 Participants |
| LDK378 (Ceritinib) | Number of Participants by Highest Grade Adverse Event Reported | Mutation = I1107 | Grade 2 | 0 Participants |
| LDK378 (Ceritinib) | Number of Participants by Highest Grade Adverse Event Reported | Mutation = I1107 | Grade 3 | 1 Participants |
| LDK378 (Ceritinib) | Number of Participants by Highest Grade Adverse Event Reported | Mutation = I1107 | Grade 4 | 0 Participants |
| LDK378 (Ceritinib) | Number of Participants by Highest Grade Adverse Event Reported | Mutation = I1107 | Grade 1 | 0 Participants |
| Brigatinib | Number of Participants by Highest Grade Adverse Event Reported | Mutation = I1107 | Grade 4 | 0 Participants |
| Brigatinib | Number of Participants by Highest Grade Adverse Event Reported | Mutation = I1107 | Grade 1 | 0 Participants |
| Brigatinib | Number of Participants by Highest Grade Adverse Event Reported | Mutation = I1107 | Grade 2 | 0 Participants |
| Brigatinib | Number of Participants by Highest Grade Adverse Event Reported | Mutation = I1107 | Grade 3 | 1 Participants |
| Brigatinib | Number of Participants by Highest Grade Adverse Event Reported | Mutation = none | Grade 1 | 0 Participants |
| Brigatinib | Number of Participants by Highest Grade Adverse Event Reported | Mutation = none | Grade 3 | 0 Participants |
| Brigatinib | Number of Participants by Highest Grade Adverse Event Reported | Mutation = I1107 | Grade 5 | 0 Participants |
| Brigatinib | Number of Participants by Highest Grade Adverse Event Reported | Mutation = none | Grade 2 | 0 Participants |
| Brigatinib | Number of Participants by Highest Grade Adverse Event Reported | Mutation = none | Grade 4 | 0 Participants |
| Brigatinib | Number of Participants by Highest Grade Adverse Event Reported | Mutation = none | Grade 5 | 1 Participants |
| Ensartinib | Number of Participants by Highest Grade Adverse Event Reported | Mutation = none | Grade 5 | 0 Participants |
| Ensartinib | Number of Participants by Highest Grade Adverse Event Reported | Mutation = none | Grade 4 | 0 Participants |
| Ensartinib | Number of Participants by Highest Grade Adverse Event Reported | Mutation = none | Grade 1 | 0 Participants |
| Ensartinib | Number of Participants by Highest Grade Adverse Event Reported | Mutation = none | Grade 2 | 0 Participants |
| Ensartinib | Number of Participants by Highest Grade Adverse Event Reported | Mutation = none | Grade 3 | 3 Participants |
Secondary
Overall Survival (OS)
Survival time is defined as the time from second step registration to the date of death, or last known follow-up (censored). Percentage of participants alive at a given time (OS) was to be estimated by the Kaplan-Meier method. Median OS and OS at specific time points was to be reported, with 95% confidence intervals, for each mutation/regimen combination. Due to early accrual closure resulting in few patients, only the number of participants who died are provided, by mutation, and no statistical testing was done.
Time frame: Baseline to the date of death or last known follow-up. Maximum follow-up time was 33.6 months, median 8.9 months.
Population: Eligible participants who started protocol treatment, with post-baseline survival status. Treatment arms with no evaluable participants are not shown.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Lorlatinib | Overall Survival (OS) | Mutation = None: deaths | 0 Participants |
| Lorlatinib | Overall Survival (OS) | Mutation = I1171: deaths | 0 Participants |
| LDK378 (Ceritinib) | Overall Survival (OS) | Mutation = I1171: deaths | 0 Participants |
| Brigatinib | Overall Survival (OS) | Mutation = I1171: deaths | 0 Participants |
| Brigatinib | Overall Survival (OS) | Mutation = None: deaths | 1 Participants |
| Ensartinib | Overall Survival (OS) | Mutation = None: deaths | 2 Participants |
Secondary
Progression-free Survival (PFS), Per Investigator Assessment Using RECIST v1.1 Criteria
Progression-free survival time is defined as the time from second step registration to the date of the first disease progression / progressive disease (PD), death, or last known follow-up (censored). Progressive disease is defined as a 20% increase of target lesions and/or new lesion(s). Percentage of participants progression-free at a given time (PFS) was to be estimated by the Kaplan-Meier method. Median PFS and PFS at specific time points was to be reported, with 95% confidence intervals, for each mutation (or no mutation)/regimen combination. Due to early accrual closure resulting in few participants, only the number of participants who progressed or died, by mutation, with no statistical testing.
Time frame: Baseline to the date of the first disease progression / progressive disease, death, or last known follow-up. Maximum follow-up time was 33.6 months, median 8.9 months.
Population: Eligible participants who started protocol treatment and had post-baseline disease assessment. Treatment arms with no evaluable participants are not shown.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Lorlatinib | Progression-free Survival (PFS), Per Investigator Assessment Using RECIST v1.1 Criteria | Mutation = I1107: progression or death | 0 Participants |
| Lorlatinib | Progression-free Survival (PFS), Per Investigator Assessment Using RECIST v1.1 Criteria | Mutation = none: progression or death | 1 Participants |
| LDK378 (Ceritinib) | Progression-free Survival (PFS), Per Investigator Assessment Using RECIST v1.1 Criteria | Mutation = I1107: progression or death | 0 Participants |
| Brigatinib | Progression-free Survival (PFS), Per Investigator Assessment Using RECIST v1.1 Criteria | Mutation = I1107: progression or death | 1 Participants |
| Brigatinib | Progression-free Survival (PFS), Per Investigator Assessment Using RECIST v1.1 Criteria | Mutation = none: progression or death | 1 Participants |
| Ensartinib | Progression-free Survival (PFS), Per Investigator Assessment Using RECIST v1.1 Criteria | Mutation = none: progression or death | 2 Participants |
Other Pre-specified
Agreement of Biopsy Mutation and Circulating Free Deoxyribonucleic Acid (cfDNA) Mutation Results
For each mutation, the agreement of the biopsy result (present, absent, unavailable) and the cfDNA result (present, absent, unavailable) would be assessed. Agreement of cfDNA and biopsy results will be considered separately for MET amplification and for the gene mutations. This outcome measure was to be contingent upon FDA approval of the outcome measure analysis plan, which was not pursued due to the early accrual closure.
Time frame: Baseline
Population: No assay data for analysis was received.