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Doxycycline

Dacomitinib

Alclometasone dipropionate

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Arm A: Dacomitinib 45 mg orally daily on a continuous schedule until disease progression, toxicity, death or withdrawal of consent Doxycycline placebo orally BID for 4 weeks Arm B: Dacomitinib 45 mg orally daily on a continuous schedule until disease progression, toxicity, death or withdrawal of consent Doxycycline 100 mg orally BID for 4 weeks

Dacomitinib 45 mg orally daily on a continuous schedule until disease progression, toxicity, death or withdrawal of consent Topical alclometasone diproprionate cream 0.05% applied to face, hands, feet, neck, back and chest at bedtime for 4 weeks VSL#3 probiotic 4 capsules orally daily or 1 sachet orally daily for up to 5 weeks (starting between Day minus 7 to Day minus 4 and continuing through Day 28)

Cohort III is an interrupted dosing schedule of dacomitinib in the first cycle only

Dacomitinib 45 mg orally daily on a continuous schedule until disease progression, toxicity, death or withdrawal of consent

Dacomitinib 45 mg orally daily on a continuous schedule for the first 10 days in Cycle 1, followed by 4 days off treatment, followed by continuous daily dosing until disease progression, toxicity, death or withdrawal of consent

Doxycycline or Doxycycline placebo BID for 4 weeks

VSL#3 probiotic 4 capsules orally daily or 1 sachet orally daily for up to 5 weeks (starting between Day minus 7 to Day minus 4 and continuing through Day 28)

Probiotic

Topical alclometasone diproprionate cream 0.05% applied to face, hands, feet, neck, back and chest at bedtime for 4 weeks

Alclometasone cream

Pfizer CT.gov Call Center

To assess the impact of prophylactic treatment on the incidence of adverse events in advanced NSCLC patients (post chemotherapy) treated with dacomitinib daily as a single agent. To assess the impact of an interrupted dacomitinib dosing schedule in Cycle 1 on the incidence of adverse events in first-line advanced NSCLC patients with an EGFR mutation (HER-1 mutation, HER-2 mutation or HER-2 amplification).

Study Of Dacomitinib (PF-00299804) In Advanced NSCLC Patients (Post Chemo Or Select First Line) To Evaluate Prophylactic Intervention On Derm And GI AEs And PRO

ARCHER 1042: A PHASE 2 STUDY OF DACOMITINIB IN ADVANCED NON-SMALL CELL LUNG CANCER (POST-CHEMOTHERAPY OR SELECT FIRST LINE PATIENTS) TO EVALUATE PROPHYLACTIC INTERVENTION ON DERMATOLOGIC AND GASTROINTESTINAL ADVERSE EVENTS AND PATIENT REPORTED OUTCOMES

Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

SDAEI of all causality and all grades were evaluated in participants in Cohort I. These SDAEIs included dermatitis acneiform, dry skin, exfoliative rash, nail discoloration, nail disorder, paronychia, pruritus, rash, skin exfoliation, skin fissures, skin infection, skin laceration and skin ulcer.

95% confidence interval (CI) calculated using exact method based on binomial distribution.

After protocol amendment 1, Arm C was removed from Cohort I and enrollment to Arm C was terminated. Only 7 participants were enrolled in Cohort I Arm C as a result. Given the smaller sample size, analyse of Outcome Measure 1 was not conducted in Cohort I Arm C.

SDAEI of all causality and Grade ≥2 were evaluated in participants in Cohort I. These SDAEIs included dermatitis acneiform, dry skin, exfoliative rash, nail discoloration, nail disorder, paronychia, pruritus, rash, skin exfoliation, skin fissures, skin infection, skin laceration and skin ulcer. Adverse events (AEs) were graded for severity using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, Version 4.0).

95% CI calculated using exact method based on binomial distribution. After protocol amendment 1, Arm C was removed from Cohort I and enrollment to Arm C was terminated. Only 7 participants were enrolled in Cohort I Arm C as a result. Given the smaller sample size, analyse of Outcome Measure 2 was not conducted in Cohort I Arm C.

Patient Reported Outcomes (PROs) of Health Related Quality of Life (HRQoL) \& disease/treatment-related symptoms were assessed using Dermatologic Survey (Skindex-16) that assesses "bother". It includes 3 multi-item scales: symptoms, emotions \& functioning. Individual scaled scores \& total scores were determined. Skindex questions were transformed to a linear scale of 0 (never bothered) to 100 (always bothered). Subscale scores are an average of non-missing questions in a given scale if greater than (\>) 75% of total subscale questions are non-missing. The Total Score is an average of all non-missing questions in the Skindex if \>75% of total questions are non-missing. A negative change score represents a better quality of life. A change score of 10 points is considered clinically significant.

Skindex completion criteria were defined as completion of 3 out of 4 items for questions 1 to 4, 6 out of 7 items for questions 5 to 11, 4 out of 5 items for questions 12 to 16 for the visit.

Diarrhea AEs of all causality, all grade and Grade ≥2 were evaluated in participants in Cohort II. AEs were graded for severity using the NCI-CTCAE, Version 4.0.

95% CI calculated using exact method based on binomial distribution.

Diarrhea severity was assessed using the modified-OMDQ. This questionnaire is comprised of 6 questions in total; however, only two items relate to diarrhea symptoms (item 5 and item 6). Symptoms scores were developed for both the full questionnaire and for the diarrhea-only questions for each completed survey. Mucositis questions were transformed to a score range of 0 to 10. Increasing OMDQ values are associated with greater symptom burden.

Modified OMDQ completion criteria were defined as completion of all 4 questions (questions 2, 4, 5 and 6).

M/T = mouth and throat.

SDAEI of all causality and all grades were evaluated in participants in Cohort II. These SDAEIs included dermatitis acneiform, dry skin, exfoliative rash, nail discoloration, nail disorder, paronychia, pruritus, rash, skin exfoliation, skin fissures, skin infection, skin laceration and skin ulcer.

95% CI calculated using exact method based on binomial distribution.

SDAEI of all causality and Grade ≥2 were evaluated in participants in Cohort II. These SDAEIs included dermatitis acneiform, dry skin, exfoliative rash, nail discoloration, nail disorder, paronychia, pruritus, rash, skin exfoliation, skin fissures, skin infection, skin laceration and skin ulcer. AEs were graded for severity using the NCI-CTCAE, Version 4.0.

95% CI calculated using exact method based on binomial distribution.

PROs of HRQoL and disease/treatment-related symptoms were assessed using Dermatologic Survey (Skindex-16) that assesses "bother". It includes 3 multi-item scales: symptoms, emotions \& functioning. Individual scaled scores \& total scores were determined. Skindex questions were transformed to a linear scale of 0 (never bothered) to 100 (always bothered). Subscale scores are an average of non-missing questions in a given scale if \> 75% of total subscale questions are non-missing. The Total Score is an average of all non-missing questions in the Skindex if \>75% of total questions are non-missing. A negative change score represents a better quality of life. A change score of 10 points is considered clinically significant.

Skindex completion criteria were defined as completion of 3 out of 4 items for questions 1 to 4, 6 out of 7 items for questions 5 to 11, 4 out of 5 items for questions 12 to 16 for the visit.

AUC0-24 is the area under the plasma concentration-time curve (AUC) from time 0 to 24 hours post-dose. AUC0-120 is the AUC from time 0 to 120 hours post-dose. AUC was calculated by the linear trapezoidal method using a non-compartmental pharmacokinetic (PK) analysis.

ng\*hr/mL = nanogram hours per milliliter

Cmax was obtained from direct inspection of the data. ng/mL = nanograms per milliliter

Tmax was obtained from direct inspection of the data as the time of first occurence of Cmax.

Medications used concomitantly for SDAEIs, diarrhea and mucositis were evaluated for all participants who received dacomitinib on a continuous basis with a preemptive prophylactic (Cohorts I and II) or as an interrupted dosing regimen (Cohort III).

AUCtau was the AUC from time 0 to the end of the dosing interval, where the dosing interval was 24 hours. AUCtau was calculated by the linear/log trapezoidal method using a non-compartmental PK analysis.

Cmax was obtained from direct inspection of the data.

Ctrough was the pre-dose plasma concentration of dacomitinib at steady state obtained from direct inspection of the data.

Number of participants analyzed is the total number of participants in the treatment group in the indicated population, n is the number of participants contributing to the summary statistics.

Ctrough was the pre-dose plasma concentration of the dacomitinib metabolite PF-05199265 at steady state obtained from direct inspection of the data.

Number of participants analyzed is the total number of participants in the treatment group in the indicated population, n is the number of participants contributing to the summary statistics.

Pfizer

The same event may appear as both an AE \& SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant \& non-serious in another, or 1 participant may have experienced both a serious \& non-serious event during the study. Summaries inclusive of events occurring after start of treatment.

Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS single-blind (participant blinded) doxycycline placebo capsules PO taken twice daily for 4 weeks (prophylactic treatment).

Cohort I: Arm A (Dacomitinib 45 mg + Doxycycline Placebo)

Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS single-blind (participant blinded) doxycycline 100 mg capsules PO taken twice daily for 4 weeks (prophylactic treatment).

Cohort I: Arm B (Dacomitinib 45 mg + Doxycycline 100 mg)

Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS open-label topical alclometasone diproprionate cream 0.05% applied to face, hands, feet, neck, back and chest at bedtime for 4 weeks (prophylactic treatment).

Cohort I: Arm C (Dacomitinib 45mg+Alclometasone Diproprionate)

Open-label dacomitinib 45 mg tablets PO taken once daily until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal PLUS open-label VSL#3 probiotic 4 capsules PO taken once daily or 1 sachet PO taken once daily starting on either Days -7, -6, -5 or -4 per site/participant preference, and continuing through Cycle 1 Day 28 (for a total of up to 5 weeks \[range of 32 to 35 days\]) PLUS open-label topical alclometasone diproprionate cream 0.05% applied to face, hands, feet, neck, back and chest at bedtime for 4 weeks (prophylactic treatment).

Cohort II (Dacomitinib 45mg + VSL#3 Probiotic + Alclometasone)

Open-label dacomitinib 45 mg tablets PO, taken once daily Cycle 1 Day 1 through and including Cycle 1 Day 10; no dacomitinib was taken on Cycle 1 Days 11, 12, 13 and 14; resumption of dacomitinib 45 mg PO once daily taken continuously from Cycle 1 Day 15 onwards until progression of disease, intolerance to dacomitinib treatment, or participant withdrawal.

Cohort III (Dacomitinib 45 mg)

Total

Age, Continuous

Sex: Female, Male

As Treated Population - included all participants who received at least 1 dose of study treatment assigned at enrollment.

Pfizer ClinicalTrials.gov Call Center

Evaluable Population - included all participants who received the study treatment assigned at enrollment, but did not discontinue dacomitinib treatment less than 6 weeks from first dosing due to either disease progression or death.

Percentage of Participants With Select Dermatologic Adverse Events of Interest (SDAEI) (All Causality, All Grade) in the First 8 Weeks of Treatment by Treatment Arm for Cohort I

Percentage of Participants With SDAEI (All Causality, Grade Greater Than or Equal to [≥] 2) in the First 8 Weeks of Treatment by Treatment Arm for Cohort I

Symptoms: Cycle 1 Day 8 (n=41, 42, 4)

Symptoms: Cycle 1 Day 15 (n=41, 42, 3)

Symptoms: Cycle 1 Day 22 (n=42, 40, 4)

Symptoms: Cycle 2 Day 1 (n=41, 42, 4)

Symptoms: Cycle 2 Day 8 (n=42, 39, 4)

Symptoms: Cycle 2 Day 15 (n=37, 40, 4)

Symptoms: Cycle 2 Day 22 (n=35, 39, 4)

Symptoms: EoT (n=7, 3, 0)

Emotion: Cycle 1 Day 8 (n=41, 42, 4)

Emotion: Cycle 1 Day 15 (n=41, 42, 3)

Emotion: Cycle 1 Day 22 (n=42, 40, 4)

Emotion: Cycle 2 Day 1 (n=41, 42, 4)

Emotion: Cycle 2 Day 8 (n=42, 39, 4)

Emotion: Cycle 2 Day 15 (n=37, 40, 4)

Emotion: Cycle 2 Day 22 (n=35, 39, 4)

Emotion: EoT (n=7, 3, 0)

Functioning: Cycle 1 Day 8 (n=41, 42, 4)

Functioning: Cycle 1 Day 15 (n=41, 42, 3)

Functioning: Cycle 1 Day 22 (n=42, 40, 4)

Functioning: Cycle 2 Day 1 (n=41, 42, 4)

Functioning: Cycle 2 Day 8 (n=42, 39, 4)

Functioning: Cycle 2 Day 15 (n=37, 40, 4)

Functioning: Cycle 2 Day 22 (n=35, 39, 4)

Functioning: EoT (n=7, 3, 0)

Total: Cycle 1 Day 8 (n=41, 42, 4)

Total: Cycle 1 Day 15 (n=41, 42, 3)

Total: Cycle 1 Day 22 (n=42, 40, 4)

Total: Cycle 2 Day 1 (n=41, 42, 4)

Total: Cycle 2 Day 8 (n=42, 39, 4)

Total: Cycle 2 Day 15 (n=37, 40, 4)

Total: Cycle 2 Day 22 (n=35, 39, 4)

Total: EoT (n=7, 3, 0)

PRO Skindex Analysis Population: participants that met primary endpoint analysis \& Skindex specific criteria: a) Skindex completion criteria (as above) for initial visit \& end of Cycle 2 or EoT visit; b) Skindex completion criteria for at least 5 of 6 visits between initial visit \& end of Cycle 2 visit. n = number of participants completing scale.

Mean Change From Baseline (Cycle 1 Day 1) Skindex-16 Scale Scores (Total Score, Symptoms Score, Emotion Score, and Functioning Score) by Treatment Arm for Cohort I

All Causality, All Grade

All Causality, Grade ≥2

Percentage of Participants With Diarrhea AEs (All Causality, All Grade and Grade ≥2) in the First 8 Weeks of Treatment for Cohort II

M/T Soreness Categories: Cycle 1 Day 8 (n=37)

M/T Soreness Categories: Cycle 1 Day 15 (n=37)

M/T Soreness Categories: Cycle 1 Day 22 (n=37)

M/T Soreness Categories: Cycle 2 Day 1 (n=37)

M/T Soreness Categories: Cycle 2 Day 8 (n=35)

M/T Soreness Categories: Cycle 2 Day 15 (n=36)

M/T Soreness Categories: Cycle 2 Day 22 (n=27)

M/T Soreness Categories: Cycle 3 Day 1 (n=19)

M/T Soreness Categories: Cycle 4 Day 1 (n=13)

M/T Soreness Categories: Cycle 5 Day 1 (n=10)

M/T Soreness Categories: Cycle 6 Day 1 (n=8)

M/T Soreness Categories: EoT (n=30)

M/T Soreness Categories: Follow-up (n=22)

M/T Soreness Scale: Cycle 1 Day 8 (n=37)

M/T Soreness Scale: Cycle 1 Day 15 (n=37)

M/T Soreness Scale: Cycle 1 Day 22 (n=37)

M/T Soreness Scale: Cycle 2 Day 1 (n=37)

M/T Soreness Scale: Cycle 2 Day 8 (n=35)

M/T Soreness Scale: Cycle 2 Day 15 (n=36)

M/T Soreness Scale: Cycle 2 Day 22 (n=27)

M/T Soreness Scale: Cycle 3 Day 1 (n=19)

M/T Soreness Scale: Cycle 4 Day 1 (n=13)

M/T Soreness Scale: Cycle 5 Day 1 (n=10)

M/T Soreness Scale: Cycle 6 Day 1 (n=8)

M/T Soreness Scale: EoT (n=30)

M/T Soreness Scale: Follow-up (n=22)

Diarrhea Categories: Cycle 1 Day 8 (n=37)

Diarrhea Categories: Cycle 1 Day 15 (n=37)

Diarrhea Categories: Cycle 1 Day 22 (n=36)

Diarrhea Categories: Cycle 2 Day 1 (n=37)

Diarrhea Categories: Cycle 2 Day 8 (n=34)

Diarrhea Categories: Cycle 2 Day 15 (n=36)

Diarrhea Categories: Cycle 2 Day 22 (n=27)

Diarrhea Categories: Cycle 3 Day 1 (n=19)

Diarrhea Categories: Cycle 4 Day 1 (n=13)

Diarrhea Categories: Cycle 5 Day 1 (n=10)

Diarrhea Categories: Cycle 6 Day 1 (n=8)

Diarrhea Categories: EoT (n=30)

Diarrhea Categories: Follow-up (n=22)

Diarrhea Scale: Cycle 1 Day 8 (n=37)

Diarrhea Scale: Cycle 1 Day 15 (n=37)

Diarrhea Scale: Cycle 1 Day 22 (n=36)

Diarrhea Scale: Cycle 2 Day 1 (n=37)

Diarrhea Scale: Cycle 2 Day 8 (n=34)

Diarrhea Scale: Cycle 2 Day 15 (n=35)

Diarrhea Scale: Cycle 2 Day 22 (n=27)

Diarrhea Scale: Cycle 3 Day 1 (n=19)

Diarrhea Scale: Cycle 4 Day 1 (n=13)

Diarrhea Scale: Cycle 5 Day 1 (n=10)

Diarrhea Scale: Cycle 6 Day 1 (n=8)

Diarrhea Scale: EoT (n=30)

Diarrhea Scale: Follow-up (n=22)

PRO Modified OMDQ Analysis Population; participants meeting primary endpoint analysis \& modified OMDQ specific criteria: a) Modified OMDQ completion criteria for initial visit \& end of Cycle 2 or EoT visit; b) Completion criteria for at least 5 of 6 visits between initial \& end of Cycle 2 visit. n = number of participants completing scale.

Mean Change From Baseline (Cycle 1 Day 1) Modified Oral Mucositis Daily Questionnaire (OMDQ) Scores (Mouth and Throat Soreness Categories and Scale, and Diarrhea Categories and Scale) for Cohort II

Percentage of Participants With SDAEI (All Causality, All Grade) in the First 8 Weeks of Treatment for Cohort II

Percentage of Participants With SDAEI (All Causality, Grade ≥2) in the First 8 Weeks of Treatment for Cohort II

Symptoms: Cycle 1 Day 8 (n=40)

Symptoms: Cycle 1 Day 15 (n=40)

Symptoms: Cycle 1 Day 22 (n=40)

Symptoms: Cycle 2 Day 1 (n=40)

Symptoms: Cycle 2 Day 8 (n=38)

Symptoms: Cycle 2 Day 15 (n=38)

Symptoms: Cycle 2 Day 22 (n=30)

Symptoms: Cycle 3 Day 1 (n=21)

Symptoms: Cycle 4 Day 1 (n=15)

Symptoms: Cycle 5 Day 1 (n=11)

Symptoms: Cycle 6 Day 1 (n=8)

Symptoms: EoT (n=33)

Symptoms: Follow-up (n=23)

Emotion: Cycle 1 Day 8 (n=40)

Emotion: Cycle 1 Day 15 (n=40)

Emotion: Cycle 1 Day 22 (n=40)

Emotion: Cycle 2 Day 1 (n=40)

Emotion: Cycle 2 Day 8 (n=38)

Emotion: Cycle 2 Day 15 (n=37)

Emotion: Cycle 2 Day 22 (n= 30)

Emotion: Cycle 3 Day 1 (n=21)

Emotion: Cycle 4 Day 1 (n=14)

Emotion: Cycle 5 Day 1 (n=11)

Emotion: Cycle 6 Day 1 (n=8)

Emotion: EoT (n=33)

Emotion: Follow-up (n=23)

Functioning: Cycle 1 Day 8 (n=40)

Mean Change From Baseline (Cycle 1 Day 1) Skindex-16 Scale Scores (Total Score, Symptoms Score, Emotion Score, and Functioning Score) for Cohort II

Spots Global Cancer Trial Database for alclometasone cream