Trial Of PF-00299804 In Patients With Advanced Refractory Lung Cancer

PFS4m was defined as percent chance of being event free (event defined as progressive disease \[PD\] or death due to any cause, whichever occurred first) at 4 months. Progression was defined using Response Evaluation Criteria in Solid Tumors (RECIST), as at least 20 percent (%) increase in the sum of longest dimensions (LD) of target lesions, taking as reference the smallest sum of LD recorded since the treatment started and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.

Time frame: Month 4

Population: Full analysis set (FAS) included all enrolled participants.

The highest dose at which less than (\<) 33 percent (%) of participants experienced dose-limiting toxicities (DLT) was to be designated as the maximum tolerated dose (MTD) as well as the RP2D. DLT was defined as any of the following events: Grade 3/4 (severe or life-threatening/ disabling adverse event \[AE\]) nausea, vomiting, or diarrhea (despite the use of adequate/maximal medical intervention and/or prophylaxis); Grade greater than or equal to (\>=) 3 (severe or life-threatening/disabling AE or death related to AE) non-hematological toxicity; delayed (which delayed scheduled treatment for \>14 days) recovery from toxicity related to treatment with PF-00299804; Grade 4 neutropenia (absolute neutrophil count \[ANC\] \<500 cells per cubic millimeter \[cells/mm\^3\] for 5 or more consecutive days or febrile neutropenia \[fever \>=38.5 degrees Celsius with ANC \<1000 cells/mm\^3\]); and Grade 4 thrombocytopenia (\<25,000 cells/mm\^3) or bleeding which required platelet transfusion.

Time frame: Baseline up to Day 21

Population: As-treated population included all enrolled participants who received at least 1 dose of study medication.

Rac was calculated by dividing AUC0-24 (C1D14) by AUC0-24 (C0D-9).

Time frame: 0 (pre-dose), 2, 4, 6, 8, 24 hours post-dose on C0D-9, 0 (pre-dose), 2, 4, 6, 8, 24 hours post-dose on C1D14

Population: PK analysis set for Phase 1 included all participants who received at least 1 dose of study medication and had at least 1 measured plasma concentration.

AUC0-24: Area under the plasma concentration versus time curve from time zero (pre-dose) to 24 hours post dose. Data in PF- 00299804 45 mg treatment arm at C0D-9 represents participants from Phase 1 only and at C1D14 represents participants from both Phase 1 and Phase 2.

Time frame: 0 (pre-dose), 2, 4, 6, 8, 24 hours post-dose on Cycle 0 Day -9 (C0D-9) for Phase 1, 0 (pre-dose), 2, 4, 6, 8, 24 hours post-dose on C1D14 for Phase 1 and 2

Population: PK analysis set included all participants who received at least 1 dose of study drug and had at least 1 measured plasma concentration. number analyzed=participants evaluable for specified time-point. PK analysis was done by dose level instead of by phase. Participants started from the same dose level were combined together for PK analysis.

AUCinf: Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞).

Time frame: 0 (pre-dose), 2, 4, 6, 8, 24, 72, 144, 216 hours post-dose on C0D-9

Population: PK analysis set for Phase 1 included all participants who received at least 1 dose of study medication and had at least 1 measured plasma concentration.

AUClast: Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration.

Time frame: 0 (pre-dose), 2, 4, 6, 8, 24, 72, 144, 216 hours post-dose on C0D-9

Population: PK analysis set for Phase 1 included all participants who received at least 1 dose of study medication and had at least 1 measured plasma concentration.

Data in PF-00299804 45 mg treatment arm represents participants from both Phase 1 and Phase 2.

Time frame: 0 (pre-dose), 2, 4, 6, 8, 24 hours post-dose on C1D14 for Phase 1 and 2

Population: PK analysis set included all participants who received at least 1 dose of study drug and had at least 1 measured plasma concentration. PK analysis was done by dose level instead of by phase. Participants started from the same dose level were combined together for PK analysis.

Number of participants with BOR according to RECIST: CR= disappearance of all target and non-target lesions. PR= at least 30% decrease in sum of LDs of target lesion, taking as reference baseline sum LD, associated to non-progressive disease response for non-target lesions. Stable/no response= neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Objective progression= at least a 20% increase in sum of LDs of target lesions, taking as reference the smallest sum of LD recorded since treatment started and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.

Time frame: Baseline until disease progression or initiation of new anti-cancer therapy or death, assessed every 2 (odd-numbered) cycles up to 12 months after EOT (EOT: up to Day 1723)

Population: Response-evaluable population included all enrolled participants who received at least 1 dose of study medication, had an adequate baseline tumor assessment, and had at least 1 on-study tumor assessment after first dosing.

DLQI: 10-item questionnaire to measure how much the participant's skin problem has impacted their life over the previous week. All questions were answered on a 4-point Likert scale ranging from 0 (not at all/not relevant) to 3 (very much/prevented work or studying). The DLQI was calculated by summing the score of each question and ranged from 0 to 30, where higher scores indicate more quality of life impairment.

Time frame: C1D1 (baseline), D1 of each subsequent cycle up to C44

Population: FAS included all enrolled participants. Here number analyzed signifies participants who were evaluable for specified time-point for each treatment arm, respectively.

Time in weeks from first documentation of objective tumor response to objective tumor progression or death due to any cause, whichever occurred first. Duration of tumor response was calculated as (the date of the first documentation of objective tumor progression or death due to any cause minus the date of the first CR or PR \[which ever occurred first\] that was subsequently confirmed plus 1) divided by 7. DR was calculated for the subgroup of participants with a confirmed objective tumor response.

Time frame: Baseline until disease progression or initiation of new anti-cancer therapy or death, assessed every 2 (odd-numbered) cycles up to 12 months after EOT (EOT: up to Day 506 for Phase 1 and up to Day 1723 for Phase 2)

Population: Analysis population included sub-set of participants from response-evaluable population, who had a confirmed objective tumor response (CR or PR).

Rss was calculated by dividing AUC0-24 (C1D14) by AUCinf (C0D-9).

Time frame: 0 (pre-dose), 2, 4, 6, 8, 24, 72, 144, 216 hours post-dose on C0D-9, 0 (pre-dose), 2, 4, 6, 8, 24 hours post-dose on C1D14

Population: PK analysis set for Phase 1 included all participants who received at least 1 dose of study medication and had at least 1 measured plasma concentration.

Data in PF-00299804 45 mg treatment arm at Cycle 0 Day -9 (C0D-9) represents participants from Phase 1 only and at C1D14 represents participants from both Phase 1 and Phase 2.

Time frame: 0 (pre-dose), 2, 4, 6, 8, 24, 72, 144, 216 hours post-dose on C0D-9 for Phase 1, 0 (pre-dose), 2, 4, 6, 8, 24 hours post-dose on C1D14 for Phase 1 and 2

Population: Pharmacokinetic (PK): all participants who received at least 1 dose of study drug and had at least 1 measured plasma concentration. number analyzed=participants evaluable for specified time-point. PK analysis was done by dose level instead of by phase. Participants started from the same dose level were combined together for PK analysis.

Data in PF-00299804 45 mg treatment arm represents participants from both Phase 1 and Phase 2.

Time frame: 0 hours (pre-dose) on C2D1, C3D1, C4D1

Population: PK analysis set included all participants who received at least 1 dose of study drug and had at least 1 measured plasma concentration. PK analysis was done by dose level instead of by phase. Participants started from the same dose level were combined together for PK analysis.number analyzed = participants evaluable for specified time-point.

EORTC QLQ-C30: included global health status/quality of life (QoL), functional (Fn) scales (physical, role, cognitive, emotional, and social), symptom scales (fatigue, pain, nausea/vomiting), and single items (dyspnea, appetite loss, insomnia, constipation, diarrhea, and financial difficulties). Scores were averaged, transformed to 0-100 scale; higher score for Global Qol/Fn scales=better level of QoL/functioning or higher score for symptom scales/items=greater degree of symptoms. Overall scale change is categorized as Improved (if average scales change from baseline: for Global QoL/Fn scales \>=10; for symptom scale/item \<=-10), Worsened (if average scales change from baseline: for Global QoL/Fn scales \<=-10; for symptom scale/item \>=10), and Stable (if average scales change from baseline \>-10 but \<10 for Global QoL/Fn scales and symptom scale/item) and participants in each category are reported.

Time frame: Baseline up to end of treatment (up to Day 889)

Population: FAS included all enrolled participants. Here N (number of participants analyzed) signifies participants who were evaluable for this measure.

EORTC QLQ-LC13 consisted of 13 questions relating to disease symptoms specific to lung cancer and treatment side effects typical of treatment with chemotherapy and radiotherapy. The 13 questions comprised 1 multi-item scale for dyspnea and 10 single-item symptoms and side effects (coughing, hemoptysis, sore mouth, dysphagia, peripheral neuropathy, alopecia, chest pain, arm pain, other pain, and medicine for pain). Scores averaged, transformed to 0-100 scale; higher symptom score = greater degree of symptoms. Overall scale change is categorized as Improved (if average scales change from baseline \<=-10), Worsened (if average scales change from baseline \>=10), and Stable (if average scales change from baseline \>-10 but \<10) and participants in each category are reported.

Time frame: Baseline up to end of treatment (up to Day 889)

Population: FAS included all enrolled participants. Here N (number of participants analyzed) signifies participants who were evaluable for this measure. Medicine for pain was not summarized because a more comprehensive and reliable summary of concomitant medications was reported separately.

Tumor tissue was analyzed at a sponsor-designated laboratory to investigate EGFR, KRAS and HER2 status (wild type or mutated). Participants who did not provide samples for central laboratory analysis confirmation were classified as unknown. The data for all Phase 1 participants was combined for this outcome.

Time frame: Screening

Population: Biomarker analysis set: all enrolled participants who had baseline samples submitted as per Institutional Review Board/Independent Ethics Committee approval and participant consent. Data was pre-specified in statistical analysis plan to be analyzed and summarized per phase.

OS6m was defined as percent chance of being alive at Month 6.

Time frame: Month 6

Population: FAS included all enrolled participants.

Percentage of participants with objective response based on assessment of confirmed complete response (CR) or confirmed partial response (PR) according to RECIST. CR: disappearance of all target and non-target lesions. PR: at least 30 % decrease in sum of the longest dimensions (LDs) of target lesion, taking as reference the baseline sum LD, associated to non-progressive disease response for non-target lesions. Confirmed responses are those that persist on repeat imaging study at least 4 weeks after initial documentation of response.

Time frame: Baseline until disease progression or initiation of new anti-cancer therapy or death, assessed every 2 (odd-numbered) cycles up to 12 months after end of treatment (EOT) (EOT: up to Day 506)

Population: Response-evaluable population included all enrolled participants who received at least 1 dose of study medication, had an adequate baseline tumor assessment, and had at least 1 on-study tumor assessment after first dosing.

Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.

Time frame: 0 (pre-dose), 2, 4, 6, 8, 24, 72, 144, 216 hours post-dose on Cycle 0 Day -9 (C0D-9)

Population: PK analysis set for Phase 1 included all participants who received at least 1 dose of study medication and had at least 1 measured plasma concentration.

PFS6m was defined as percent chance of being event free (event defined as PD or death due to any cause, whichever occurred first) at 6 months. Progression was defined using RECIST, as at least 20% increase in the sum of longest dimensions (LD) of target lesions, taking as reference the smallest sum of LD recorded since the treatment started and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.

Time frame: Month 6

Population: FAS included all enrolled participants.

Blood specimens were analyzed at a sponsor-designated laboratory for analysis of shed proteins/receptors related to Human Epidermal Growth Factor Receptor (HER) signaling (epidermal growth factor receptor \[EGFR\], HER2). These measurements were determined by enzyme-linked immunosorbent assay (ELISA). The data for all Phase 1 participants was combined for this outcome.

Time frame: Cycle 1 Day 1 (C1D1, Baseline), Day 1 of each odd-numbered cycle up to Cycle 17 for both Phase 1 and Phase 2

Population: Biomarker analysis set: all enrolled participants who had baseline samples submitted as per Institutional Review Board/Independent Ethics Committee approval and participant consent. Data was pre-specified in statistical analysis plan to be analyzed and summarized per phase. Number analyzed = participants evaluable at specified time-point.

Data in PF-00299804 45 mg treatment arm at C0D-9 represents participants from Phase 1 only and at C1D14 represents participants from both Phase 1 and Phase 2.

Time frame: 0 (pre-dose), 2, 4, 6, 8, 24, 72, 144, 216 hours post-dose on Cycle 0 Day -9 (C0D-9) for Phase 1, 0 (pre-dose), 2, 4, 6, 8, 24 hours post-dose on C1D14 for Phase 1 and 2

Population: PK analysis set included all participants who received at least 1 dose of study drug and had at least 1 measured plasma concentration. number analyzed=participants evaluable for specified time-point. PK analysis was done by dose level instead of by phase. Participants started from the same dose level were combined together for PK analysis.