A Study Of PF-06463922 An ALK/ROS1 Inhibitor In Patients With Advanced Non Small Cell Lung Cancer With Specific Molecular Alterations

Phase 2CompletedNCT01970865

Pfizer364 enrolled

Overview

Phase 1 and 2 trial to study the safety, pharmacokinetics, pharmacodynamics, patient reported outcomes and efficacy of PF-06463922 in ALK + advanced non-small cell lung cancer patients and ROS1+ advanced non small cell lung cancer patients .

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

364

Conditions

ALK-positive Non Small Cell Lung Cancer (NSCLC) and ROS1-positive NSCLC

Interventions

PF-06463922DRUG

Oral, starting dose 10mg once a day, dose escalation in Phase 1 until recommended Phase 2 dose determined, continuous daily dosing, cycles lasting 21 days

CrizotinibDRUG

Oral, starting dose of 250 mg BID continuous daily dosing every 21 days

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria * Evidence of histologically or cytologically confirmed diagnosis of metastatic NSCLC (Stage IV, AJCC v7.0) that carries an ALK rearrangement, as determined by the Food and Drug Administration (FDA) approved FISH assay (Abbott Molecular Inc) or by Immunohistochemistry (IHC) (Ventana Inc), or a ROS1 rearrangement as determined by FISH or RT PCR or Next Generation Sequencing (NGS) via a local diagnostic test (LDT). All patients (ALK positive and ROS1 positive) must have archival tissue sample available and collected prior to enrollment. * Disease Status Requirements: Phase 1: ALK-positive NSCLC and ROS1-positive patients must either be treatment naïve in the advanced setting or have had disease progression after at least 1 previous ALK/ROS1 inhibitor therapy(ies). Phase 2: ALK-positive NSCLC patients must either be or have had: * Treatment naïve (ie, no prior chemotherapy in the metastatic disease setting and no prior ALK inhibitor therapy allowed). * Disease progression after crizotinib only. No prior chemotherapy is allowed in the metastatic disease setting. * Disease progression after crizotinib and 1 or 2 prior regimens of chemotherapy in the metastatic disease setting. * Disease progression after 1 prior ALK inhibitor therapy other than crizotinib. Patients may have had any number of prior chemotherapy regimens in any disease setting. * Disease progression after 2 prior ALK inhibitor therapies. Patients may have had any number of prior chemotherapy regimens in any disease setting. * Disease progression after 3 prior ALK inhibitor therapies. Patients may have had any number of prior chemotherapy regimens in any disease setting. ROS1-positive NSCLC patients may be: * Treatment naïve (ie, no prior chemotherapy in the metastatic disease setting and no prior ROS inhibitor therapy). * Any number of prior therapies (ie, chemotherapy and/or ROS inhibitor therapies). * Tumor Requirements: All Patients must have at least one measurable target extracranial lesion according to RECIST v1.1. In addition patients with asymptomatic CNS metastases (including patients asymptomatic by means of stable or decreasing doses of steroids within the last 2 weeks prior to study entry) will be eligible. Patients who have leptomeningeal disease (LM) or carcinomatous meningitis (CM) are eligible. * Adequate Bone Marrow, Pancreatic Function, Renal Function and Liver Function. * Negative Serum pregnancy test for females of childbearing potential Exclusion Criteria * Radiation therapy (except palliative to relieve bone pain) within 2 weeks of study entry. Whole brain radiation must have completed at least 4 weeks prior to study entry. * Systemic anti cancer therapy completed within a minimum of 5 half lives of study entry. * Prior therapy with an antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways, including, but not limited to, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T lymphocyte associated antigen 4 (anti-CTLA-4) antibody. * Active and clinically significant bacterial, fungal, or viral infection including hepatitis B (HBV), hepatitis C (HCV), known human immunodeficiency virus (HIV), or acquired immunodeficiency syndrome (AIDS) related illness. * Clinically significant cardiovascular disease (that is, active or \<3 months prior to enrollment): cerebral vascular accident/stroke, myocardial infarction, unstable angina, congestive heart failure (New York Heart Association Classification Class ≥ II), second-degree or third-degree AV block (unless paced) or any AV block with PR \>220 msec. Ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥2, uncontrolled atrial fibrillation of any grade, bradycardia defined as \<50 bpm (unless patient is otherwise healthy such as long-distance runners, etc.), machine-read ECG with QTc \>470 msec, or congenital long QT syndrome. * History of extensive, disseminated, bilateral or presence of Grade 3 or 4 interstitial fibrosis or interstitial lung disease including a history of pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis and pulmonary fibrosis. * Current use or anticipated need for food or drugs that are known strong or moderate CYP3A4 inhibitors, inducers and substrates; drugs that are CYP2C9 substrates; drugs that are sensitive CYP2B6 substrates; drugs that are strong CYP2C19 inhibitors; drugs that are strong CYP2C8 inhibitors; and drugs that are P-gp substrates.

Locations (77)

Outcomes

Primary Outcomes

Number of Participants With Cycle 1 Dose-Limiting Toxicities (DLTs) in Phase 1

DLT: any of following adverse events (AEs) attributable to PF-06463922: (1) hematologic: grade 4 neutropenia for \>7 days; febrile neutropenia; grade\>=3 neutropenic infection; grade\>=3 thrombocytopenia with bleeding; grade 4 thrombocytopenia; (2) non-hematologic: grade\>=3 pancreatitis; grade\>=3 toxicities (excluding grade \>=3 laboratory abnormalities not requiring dose modifications) persisting after optimal treatment with standard medical therapy; symptomatic grade \>=3 QT interval corrected for heart rate (QTc) prolongation, or asymptomatic grade \>=3 prolongation that had been confirmed by repeat testing, re-evaluation by qualified person, persisted after correction of reversible causes; \>=20% decrease from baseline in left ventricular ejection fraction (LVEF); (3) other: failure to deliver at least 16 out of 21 prescribed daily total dose due to toxicities attributable to study drug; failure to restart dosing after 21 days (1 cycle) delay due to toxicity attributable to study drug.

Time frame: Cycle 1 (21 days)

Percentage of Participants With Overall and Intracranial Objective Response (Phase 2)

Objective response (OR) refers to confirmed complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1. Intracranial OR refers to confirmed CR or PR considering only lesions within brain. CR was defined as the disappearance of all non-lymph node target lesions (where all target lesions are recorded with a length of 0 milliliter (mm) on Target Lesions electronic case report form (eCRF). Any pathological lymph nodes (recorded as target lesion) must have reduction in short axis to \<10 mm. PR was defined as a 30 percent (%) or more decrease in sum of lesion dimensions (SLD) of target lesions, taking as reference the baseline SLD. Results presented here were based on independent central review.

Time frame: 3 years

Secondary Outcomes

Percentage of Participants With Overall and Intracranial Objective Response (Phase 1)

Objective response (OR) refers to confirmed CR or PR according to RECIST version 1.1. Intracranial OR refers to confirmed CR or PR considering only lesions within brain. CR was defined as the disappearance of all non-lymph node target lesions (where all target lesions are recorded with a length of 0 mm on Target Lesions eCRF). Any pathological lymph nodes (recorded as target lesion) must have reduction in short axis to \<10 mm. PR was defined as a 30 % or more decrease in SLD of target lesions, taking as reference the baseline SLD. Results presented here were based on independent central review.

Data from ClinicalTrials.gov

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Highlands Oncology Group/Research

Fayetteville, Arkansas, United States

Highlands Oncology Group

Rogers, Arkansas, United States

Chao Family Comprehensive Cancer Center

Orange, California, United States

UC Irvine Medical Center

Orange, California, United States

University of Colorado Cancer Center

Aurora, Colorado, United States

University of Colorado Hospital - Anschutz Inpatient Pavilion (AIP)

Aurora, Colorado, United States

University of Colorado Hospital - Anschutz Outpatient Pavilion (AOP)

Aurora, Colorado, United States

University of Colorado Hospital - Anschutz Outpatient Pavillion (AOP)

Aurora, Colorado, United States

University of Colorado Hospital

Aurora, Colorado, United States

MDZ: Yale-New Haven Hospital

New Haven, Connecticut, United States

...and 67 more locations

Time frame: From start of study treatment until CR or PR (maximum of 8 years approximately)

Time to Tumor Response (TTR) and Intracranial TTR (Phase 1)

Time to tumor response (TTR) was defined as the time from the first dose of study treatment to the first documentation of objective tumor response (CR or PR). For participants whose objective response proceeded from PR to CR, the onset of PR was taken as the onset of response. CR was defined as the disappearance of all non-lymph node target lesions (where all target lesions are recorded with a length of 0 mm on Target Lesions eCRF). Any pathological lymph nodes (recorded as target lesion) must have reduction in short axis to \<10 mm. PR was defined as a 30 % or more decrease in SLD of target lesions, taking as reference the baseline SLD. TTR was only calculated for the subgroup of participants with a confirmed objective tumor response. Intracranial TTR was only calculated for participants with confirmed intracranial objective response. Results presented here were based on independent central review.

Time frame: From start of study treatment to the first documentation of objective tumor response (CR or PR) (maximum of 8 years approximately)

Number of Participants With Duration of Response (DOR) and Intracranial DOR (Phase 1)

Duration of response(DOR): time from first documentation of objective tumor response (CR/PR) to first documentation of disease progression (PD) or to death due to any cause, whichever occurred first. DOR: calculated for subgroup of participants with confirmed objective tumor response. Intracranial DOR: calculated for participants with confirmed intracranial objective response. CR:disappearance of all non-lymph node target lesions (where all target lesions are recorded with length of 0mm on Target Lesion eCRF). Any pathological lymph node (recorded as target lesion) must have reduction in short axis to \<10mm. PR:30% or more decrease in SLD of target lesion, taking as reference baseline SLD. PD:20% or more increase in the SLD of target lesions relative to baseline or smallest SLD (nadir) recorded since first dose. In addition, also demonstrate absolute increase of at least 5mm (\>=5mm) relative to baseline or smallest SLD (nadir) recorded since first dose.

Time frame: From start of study treatment to first documentation of PD or to death due to any cause, whichever occurred first (maximum of 8 years approximately)

Percentage of Participants Achieving Disease Control and Intracranial Disease Control at 12 and 24 Weeks (Phase 1)

Tumor response was evaluated according to RECIST version 1.1, and disease control: confirmed CR, confirmed PR, or stable disease (SD). Intracranial assessment was only performed for participants CNS metastases. CR was defined as disappearance of all non-lymph node target lesions (where all target lesions are recorded with length of 0mm on Target Lesions eCRF). Any pathological lymph nodes (recorded as target lesion) must have reduction in short axis to \<10 mm. PR was defined as 30% or more decrease in SLD of target lesions, taking as reference baseline SLD. Progressive disease: 20% or more increase in SLD of target lesions relative to baseline or smallest SLD (nadir) recorded since first dose. In addition to relative increase of 20%, SLD must also demonstrate absolute increase of at least 5mm (\>=5mm) relative to baseline or smallest SLD (nadir) recorded since first dose. Results presented here were based on independent central review.

Time frame: 12 and 24 weeks

Probability of First Event Being a Central Nervous System (CNS) Progression, Non CNS Progression, or Death (Phase 1)

The probability of the first event being a CNS progression, a non-CNS progression, or death was evaluated with a competing risk approach by estimating cumulative incidence functions (range: 0-1) relative to the analysis set. The time to first event being a Competing Event (either "CNS progression" or "non CNS progression" or "Death") was defined as time from first dose until the date of that specific event. Participants not known to have any of the Competing Events were censored on the date they were last assessed for disease status for PFS. Participants who presented one type of event were counted as a competing cause of failure for the analysis of other type of events. For each type of event, the cumulative incidence function corresponding to the nearest time point preceding 1 year is presented. The results are based on independent central review.

Time frame: 3 years

Progression-Free Survival (PFS) (Phase 1)

PFS was defined as the time from the first dose of study treatment to the first documentation of objective PD or to death on study due to any cause, whichever came first. Progressive disease was defined by a 20% or more increase in the SLD of target lesions relative to baseline or the smallest SLD (nadir) recorded since first dose. In addition to the relative increase of 20%, SLD must also demonstrate an absolute increase of at least 5 mm (\>= 5 mm) relative to baseline or the smallest SLD (nadir) recorded since the first dose. Results presented here were based on independent central review.

Time frame: From start of study treatment to first documentation of PD or to death due to any cause, whichever occurred first (maximum of 8 years approximately)

Overall Survival (OS) (Phase 1)

OS was defined as the time from first dose to the date of death due to any cause. For participants still alive at the time of analysis, the OS time was censored on the last date the participants were known to be alive. Estimates of OS and its 95% confidence interval were determined using Kaplan-Meier method.

Time frame: 3 years

Maximum Observed Plasma Concentration (Cmax) of PF-06463922 Following Single Oral Doses (Phase 1)

Maximum observed plasma concentration (Cmax) of PF-06463922 was observed directly from data.

Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 1 for 25 mg QD and 150 mg QD groups; pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7 for all other groups.

Maximum Observed Plasma Concentration (Cmax) of PF-06463922 Following Multiple Oral Doses (Phase 1)

Maximum Observed Plasma Concentration (Cmax) of PF-06463922 was observed directly from data.

Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24 hours post-dose on Cycle 1 Day 15 (24-hour samples not collected for BID groups).

Time for Cmax (Tmax) of PF-06463922 Following Single Oral Doses (Phase 1)

Tmax of PF-06463922 was observed directly from data as time of first occurrence.

Time for Cmax (Tmax) of PF-06463922 Following Multiple Oral Doses (Phase 1)

Tmax of PF-06463922 was observed directly from data as time of first occurrence.

Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24 hours post-dose on Cycle 1 Day 15 (24-hour samples not collected for BID groups).

Area Under the Plasma Concentration-Time Profile From Time Zero to Time Tau (AUCtau) of PF-06463922 Following Single Oral Doses (Phase 1)

Tau refers to the dosing interval, and it equals to 12 or 24 hours for BID or QD dosing, respectively. AUCtau was determined using linear/log trapezoidal method.

Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 1 for 25 mg QD and 150 mg QD groups; pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, and 24 hours post-dose on Day -7 for all other groups.

Area Under the Plasma Concentration-Time Profile From Time Zero to Time Tau (AUCtau) of PF-06463922 Following Multiple Oral Doses (Phase 1)

Tau refers to the dosing interval, and it equals to 12 or 24 hours for BID or QD dosing, respectively. AUCtau was determined using linear/log trapezoidal method.

Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24 hours post-dose on Cycle 1 Day 15 (24-hour samples not collected for BID groups)

Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of PF-06463922 Following Single Oral Doses (Phase 1)

Apparent Oral Clearance (CL/F) of PF-06463922 Following Single Oral Doses (Phase 1)

Apparent Oral Clearance (CL/F) of PF-06463922 Following Multiple Oral Doses (Phase 1)

Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24 hours post-dose on Cycle 1 Day 15 (24-hour samples not collected for BID groups)

Apparent Volume of Distribution (Vz/F) of PF-06463922 Following Single Oral Doses (Phase 1)

Observed Accumulation Ratio (Rac) of PF-06463922 Following Multiple Oral Doses (Phase 1)

Rac was calculated as Day 15 AUCtau/Day -7 AUCtau or Day 1 AUCtau, where AUCtau was the area under the plasma concentration-time profile from time 0 to time tau (12 and 24 hours for BID and QD dosing regimen, respectively).

Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24 hours post-dose on Cycle 1 Day 15 (24-hour samples not collected for BID groups)

Terminal Half-Life of PF-06463922 Following Single Oral Doses (Phase 1)

Terminal plasma half-life was defined as the time measured for the plasma concentration to decrease by one half, and calculated as loge(2)/kel, where kel was the rate constant for terminal phase.

Steady State Accumulation Ratio (Rss) of PF-06463922 Following Multiple Oral Doses (Phase 1)

Rss was calculated as Day 15 AUCtau/Day -7 AUCinf, where AUCtau was the area under the plasma concentration-time profile from time 0 to time tau (12 and 24 hours for BID and QD dosing regimen, respectively), and AUCinf was the area under the plasma concentration-time profile from time 0 extrapolated to infinite time.

Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24 hours post-dose on Cycle 1 Day 15 (24-hour samples not collected for BID groups)

Renal Clearance (CLr) of PF-06463922 (Phase 1)

Renal clearance was calculated as Aetau/AUCtau, where Aetau was the cumulative amount of drug recovered unchanged in urine up to dosing interval tau (24 hours for QD dosing regimen), and AUCtau was the area under the plasma concentration-time profile from time 0 to time tau (24 hours for QD dosing regimen).

Time frame: 0-4 hours, 4-12 hours and 12-24 hours post-dose on Cycle 1 Day 15

Percent of PF-06463922 Recovered Unchanged in Urine up to Dosing Interval (AEtau%) (Phase 1)

Dosing interval was 24 hours for QD dosing regimen. Aetau% was calculated as 100\*Ae24/dose, where Ae24 was the cumulative amount of drug recovered unchanged in urine up to 24 hours post-dose.

Time frame: 0-4 hours, 4-12 hours and 12-24 hours post-dose on Cycle 1 Day 15

Maximum Observed Plasma Concentration (Cmax) of Midazolam (Phase 1)

Cmax of midazolam was observed directly from data. Only participants in 25 mg and 150 mg QD groups were given midazolam. Day -7 data reflected the PK assessment before administration of PF-06463922, and Cycle 1 Day 15 data reflected the PK assessment after multiple doses of PF-06463922 were administered.

Time frame: Pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15

Time for Cmax (Tmax) of Midazolam (Phase 1)

Tmax of midazolam was observed directly from data as time of first occurrence. Only participants in 25 mg and 150 mg QD groups were given midazolam. Day -7 data reflect the PK assessment before administration of PF-06463922, and Cycle 1 Day 15 data reflect the PK assessment after multiple doses of PF-06463922 were administered.

Time frame: Pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15

Area Under the Plasma Concentration-Time Profile From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Midazolam (Phase 1)

Area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration (AUClast) of midazolam was determined using linear/log trapezoidal method. Only participants in 25 mg and 150 mg QD groups were given midazolam. Day -7 data reflect the PK assessment before administration of PF-06463922, and Cycle 1 Day 15 data reflect the PK assessment after multiple doses of PF-06463922 were administered.

Time frame: Pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15

Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of Midazolam (Phase 1)

AUCinf was calculated as AUClast + (Clast\*/kel), where AUClast was the area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration, Clast\* was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis, and kel was the rate constant for terminal phase. Only participants in 25 mg and 150 mg QD groups were given midazolam. Day -7 data reflect the PK assessment before administration of PF-06463922, and Cycle 1 Day 15 data reflect the PK assessment after multiple doses of PF-06463922 were administered.

Time frame: Pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15

Apparent Oral Clearance (CL/F) of Midazolam (Phase 1)

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL/F was calculated as dose/AUCinf, where AUCinf was the area under the plasma concentration-time profile from time 0 extrapolated to infinite time. Only participants in 25 mg and 150 mg QD groups were given midazolam. Day -7 data reflect the PK assessment before administration of PF-06463922, and Cycle 1 Day 15 data reflect the PK assessment after multiple doses of PF-06463922 were administered.

Time frame: Pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15

Apparent Volume of Distribution (Vz/F) of Midazolam (Phase 1)

Vz/F was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug, and calculated as dose/(AUCinf\*kel), where AUCinf was the area under the plasma concentration-time profile from time 0 extrapolated to infinite time, kel was the rate constant for terminal phase. Only participants in 25 mg and 150 mg QD groups were given midazolam. Day -7 data reflect the PK assessment before administration of PF-06463922, and Cycle 1 Day 15 data reflect the PK assessment after multiple doses of PF-06463922 were administered.

Time frame: Pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15

Terminal Half-Life of Midazolam (Phase 1)

Terminal plasma half-life was defined as the time measured for the plasma concentration to decrease by one half, and calculated as loge(2)/kel, where kel was the rate constant for terminal phase. Only participants in 25 mg and 150 mg QD groups were given midazolam. Day -7 data reflect the PK assessment before administration of PF-06463922, and Cycle 1 Day 15 data reflect the PK assessment after multiple doses of PF-06463922 were administered.

Time frame: Pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15

Number of Participants With ALK Mutation Based on Plasma CNA Analysis (Phase 1)

Plasma circulating nucleic acid (CNA) samples were analyzed for ALK kinase domain mutations by digital polymerase chain reaction (PCR) BEAMing technology. Number of participants with one or more ALK mutations is presented.

Time frame: Screening (up to 28 days)

Number of Participants With ALK Mutation Based on Tumor Tissue Analysis (Phase 1)

Tumor tissues from archived tissue specimens and/or a de novo biopsy were analyzed for ALK kinase domain mutations. Number of participants with one or more ALK mutations is presented.

Time frame: Screening (up to 28 days)

Number of Participants Who Improved, Worsened or Remained Stable in EORTC QLQ-C30 (Phase 1)

European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ)-C30 (version 3.0) consists of 30 questions assessing 5 functional domains (physical, role, emotional, cognitive and social), global quality of life (QoL), disease/treatment related symptoms (fatigue, nausea/vomiting, pain, dyspnea, insomnia, appetite loss, constipation and diarrhea), and the perceived financial impact of disease. Each scale was transformed to a range of 0 to 100 using standard EORTC algorithm. For global QoL and functional scales, higher score indicate better performance, and improvement was defined as an increase of at least 10 points, worsening was defined as a decrease of at least 10 points. For symptom scales, higher score indicates worse symptoms, and improvement was defined as a decrease of at least 10 points, worsening was defined as an increase of at least 10 points. All scales which had not improved nor worsened were considered stable.

Time frame: From start of study treatment until end of treatment (maximum of 8 years approximately)

Number of Participants Who Improved, Worsened or Remained Stable in EORTC QLQ-LC13 (Phase 1)

EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms, and improvement was defined as a decrease of at least 10 points, worsening was defined as an increase of at least 10 points. All scales which had not improved nor worsened were considered stable.

Time frame: From start of study treatment until end of treatment (maximum of 8 years approximately)

Change From Baseline in Mini Mental State Examination (MMSE) Score (Phase 1)

In Phase 1, the MMSE was collected to assess mental status. The MMSE is a 30 item questionnaire that tests 5 areas of cognitive function: orientation, registration, attention and calculation, recall and language. The maximum score is 30 and minimum score is 0. Highest score indicates no cognitive impairment, lowest score indicates severe cognitive impairment. The MMSE was removed under Amendment 6 of the study protocol, and not required for Phase 2, as the tool was not considered meaningful for assessment of cognitive function.

Time frame: Baseline, Day 1 of Cycle 1-52, and end of treatment (up to 3 years)

Time to Tumor Response (TTR) and Intracranial TTR (Phase 2 and DDI Sub-study)

Time to tumor response (TTR) was defined as the time from the first dose of study treatment to the first documentation of objective tumor response (CR or PR). For participants whose objective response proceeded from PR to CR, the onset of PR was taken as the onset of response. TTR was only calculated for the subgroup of participants with a confirmed objective tumor response. Intracranial TTR was only calculated for participants with confirmed intracranial objective response. CR was defined as the disappearance of all non-lymph node target lesions (where all target lesions are recorded with a length of 0 mm on Target Lesions eCRF). Any pathological lymph nodes (recorded as target lesion) must have reduction in short axis to \<10 mm. PR was defined as a 30 % or more decrease in SLD of target lesions, taking as reference the baseline SLD. Results presented here were based on independent central review.

Time frame: From first dose of study treatment to the first documentation of objective tumor response (CR or PR) (maximum of 7.5 years for Phase 2 and up to a maximum of 6 years approx. for DDI sub study)

Duration of Response (DOR) and Intracranial DOR (Phase 2 and DDI Substudy)

Duration of response(DOR): time from first documentation of objective tumor response (CR/PR) to first documentation of PD or to death due to any cause, whichever occurred first. DOR: calculated for subgroup of participants with confirmed objective tumor response. Intracranial DOR: calculated for participants with confirmed intracranial objective response. CR:disappearance of all non-lymph node target lesions (where all target lesions are recorded with length of 0mm on Target Lesion eCRF). Any pathological lymph node (recorded as target lesion) must have reduction in short axis to \<10mm. PR:30% or more decrease in SLD of target lesion, taking as reference baseline SLD. PD:20% or more increase in the SLD of target lesions relative to baseline or smallest SLD (nadir) recorded since first dose. In addition, also demonstrate absolute increase of at least 5mm (\>=5mm) relative to baseline or smallest SLD (nadir) recorded since first dose.

Time frame: From first dose of study treatment to first documentation of PD or to death due to any cause, whichever occurred first (maximum of 7.5 years for Phase 2 and up to a maximum of 6 years approx. for DDI sub study)

Percentage of Participants Achieving Disease Control and Intracranial Disease Control at Week 12 and 24 (Phase 2 and DDI Substudy)

Tumor response was evaluated according to RECIST version 1.1, and disease control was defined as confirmed CR, confirmed PR, or stable disease (SD). CR was defined as the disappearance of all non-lymph node target lesions (where all target lesions are recorded with a length of 0 mm on Target Lesions eCRF). Any pathological lymph nodes (recorded as target lesion) must have reduction in short axis to \<10 mm. PR was defined as a 30 % or more decrease in SLD of target lesions, taking as reference the baseline SLD. SD= when neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD is observed, taking as reference the smallest sum diameters while on study. Intracranial assessment was only performed for participants CNS metastases. Results presented here were based on independent central review.

Time frame: Weeks 12 and 24

Time to Progression on the Last Prior Therapy (Phase 2)

TTP on the last prior therapy was defined as time from the first dose date of the last prior treatment regimen to the date of progression. Progressive disease was defined by a 20% or more increase in the SLD of target lesions relative to baseline or the smallest SLD (nadir) recorded since first dose. In addition to the relative increase of 20%, SLD must also demonstrate an absolute increase of at least 5 mm (\>= 5 mm) relative to baseline or the smallest SLD (nadir) recorded since the first dose.

Time frame: From first dose of study treatment to the date of progression (maximum of 7.5 years for Phase 2)

Time to Tumor Progression (TTP) and Intracranial TTP (Phase 2 and DDI Substudy)

Time to progression (TTP) was defined as the time from the first dose of study treatment to the first documentation of objective PD. Intracranial TTP was defined as the time from the first dose of study treatment to the date of the first documentation of objective progression of intracranial disease, based on either new brain metastases or progression of existing brain metastases. Progressive disease was defined by a 20% or more increase in the SLD of target lesions relative to baseline or the smallest SLD (nadir) recorded since first dose. In addition to the relative increase of 20%, SLD must also demonstrate an absolute increase of at least 5 mm (\>= 5 mm) relative to baseline or the smallest SLD (nadir) recorded since the first dose. Results presented here were based on independent central review.

Time frame: From first dose of study treatment to the first documentation of objective PD (maximum of 7.5 years for Phase 2 and up to a maximum of 6 years approx. for DDI sub study)

Probability of First Event Being a Central Nervous System (CNS) Progression, Non CNS Progression, or Death (Phase 2)

Probability of first event being CNS progression, non-CNS progression, or death was evaluated with competing risk approach by estimating cumulative incidence functions (range: 0-1) relative to analysis set. Time to first event being Competing Event (either "CNS progression" or "non CNS progression" or "Death") = time from first dose until date of that specific event. Participants not known to have any of Competing Events were censored on date they were last assessed for disease status for PFS. Participants who presented one type of event were counted as competing cause of failure for analysis of other type of events. For each type of event, cumulative incidence function corresponding to nearest time point preceding 1 year is presented. PD:20% or more increase in SLD of target lesion relative to baseline or smallest SLD (nadir) recorded since first dose. SLD must demonstrate absolute increase of atleast 5mm(\>=5 mm) relative to baseline or smallest SLD (nadir) recorded since first dose.

Time frame: From first dose of study treatment until first event of CNS progression (maximum of 7.5 years for Phase 2)

Progression-Free Survival (PFS) (Phase 2 and DDI Substudy)

Time frame: From first dose of study treatment to first documentation of objective PD or death due to any cause, whichever came first (maximum of 7.5 years for Phase 2 and up to a maximum of 6 years approx. for DDI sub study)

Overall Survival (Phase 2 and DDI Substudy)

Time frame: From first dose of study treatment until date of death (maximum of 7.5 years for Phase 2 and up to a maximum of 6 years approx. for DDI sub study)

Maximum Observed Plasma Concentration (Cmax) of PF-06463922 (Phase 2)

Maximum observed plasma concentration (Cmax) of PF-06463922 was observed directly from data.

Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15

Time for Cmax (Tmax) of PF-06463922 (Phase 2)

Tmax of PF-06463922 was observed directly from data as time of first occurrence.

Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15

Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of PF-06463922 (Phase 2)

Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7

Area Under the Plasma Concentration-Time Profile From Time Zero to Time Tau (AUCtau) of PF-06463922 (Phase 2)

Tau refers to the dosing interval, and it equals to 24 hours for QD dosing which was adopted in Phase 2. AUCtau was determined using linear/log trapezoidal method.

Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15

Apparent Oral Clearance (CL/F) of PF-06463922 (Phase 2)

Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15

Apparent Volume of Distribution (Vz/F) of PF-06463922 (Phase 2)

Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7

Terminal Half-Life of PF-06463922 (Phase 2)

Terminal plasma half-life was defined as the time measured for the plasma concentration to decrease by one half, and calculated as loge(2)/kel, where kel was the rate constant for terminal phase.

Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7

Observed Accumulation Ratio (Rac) of PF-06463922 Following Multiple Oral Doses (Phase 2)

Rac was calculated as Day 15 AUCtau/Day -7 AUCtau, where AUCtau was the area under the plasma concentration-time profile from time 0 to time tau (24 hours for QD dosing regimen which was adopted in Phase 2).

Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15

Steady State Accumulation Ratio (Rss) of PF-06463922 Following Multiple Oral Doses (Phase 2)

Rss was calculated as Day 15 AUCtau/Day -7 AUCinf, where AUCtau was the area under the plasma concentration-time profile from time 0 to time tau (24 hours for QD dosing regimen which was adopted in Phase 2), and AUCinf was the area under the plasma concentration-time profile from time 0 extrapolated to infinite time.

Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15

Number of Participants With ALK Mutation Based on Plasma CNA Analysis (Phase 2)

Plasma CNA samples were analyzed for ALK kinase domain mutations by Next Generation Sequencing (NGS). Number of participants with one or more ALK mutations is presented.

Time frame: Screening (up to 28 days)

Number of Participants With ALK Mutation Based on Tumor Tissue Analysis (Phase 2)

Tumor tissues from archived tissue specimens and/or a de novo biopsy were analyzed for ALK kinase domain mutations. Number of participants with one or more ALK mutations is presented.

Time frame: Screening (up to 28 days)

Number of Participants Who Improved, Worsened or Remained Stable in EORTC QLQ-C30 (Phase 2 and DDI Sub-study)

Time frame: From first dose of study treatment to end of treatment (maximum of 7.5 years for Phase 2 and up to a maximum of 6 years approx. for DDI sub study)

Number of Participants Who Improved, Worsened or Remained Stable in EORTC QLQ-LC13 (Phase 2 and DDI Sub-study)

Time frame: From first dose of study treatment to end of treatment (maximum of 7.5 years for Phase 2 and up to a maximum of 6 years approx. for DDI sub study)

Number of Participants With Treatment-Emergent Adverse Events (Phase 1, Phase 2 and DDI Sub-study)

AE: any untoward medical occurrence in clinical investigation participant administered a product or medical device, regardless of causal relationship to study treatment. Treatment-emergent AEs (TEAEs): AEs which occurred for first time during effective duration of treatment or AEs that increased in severity during treatment. Serious AEs (SAEs): any untoward medical occurrence at any dose that resulted in death; was life-threatening (immediate risk of death); required inpatient hospitalization or caused prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity (substantial disruption of ability to conduction normal life function). AEs included SAEs and non-serious AEs. Severity was graded as per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.Grade1: mild, Grade2: moderate, Grade3: severe, Grade4: Life threatening consequences; urgent intervention indicated, Grade 5: death related to AE.