Full Clinical Study Report
Protocol A5481044

CLINICAL STUDY REPORT SYNOPSIS
Sponsor: Pfizer Inc
Investigational Product: Palbociclib (PD-0332991)
Clinical Study Report Synopsis: Protocol A5481044
Protocol Title: A Randomized, Multicenter, Double-Blind Phase 2 Study of Palbociclib
Plus Cetuximab Versus Cetuximab for the Treatment of Human Papillomavirus-Negative,
Cetuximab-Naïve Patients With Recurrent/Metastatic Squamous Cell Carcinoma of the Headand Neck After Failure of One Prior Platinum-Containing Chemotherapy Regimen
Investigators:

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Study Centers: The study was conducted at 48 centers in Czech Republic, Hungary, Italy,
Japan, Republic of Korea, Mexico, Poland, Romania, Russian Federation, Serbia, Slovakia,
Spain, Taiwan, Ukraine, and United States.
Publications Based on the Study: None
Study Initiation and Completion Dates: First Patient First Visit (FPFV):
10 September 2015; Primary Completion Date: 19 July 2018; Last Patient Last Visit (LPLV):
Ongoing.
Report Date: 05 February 2019
Previous Report Date(s): Not applicable
Phase of Development: Phase 2
Study Objectives: The primary objective of the study was to demonstrate that the
combination of palbociclib with cetuximab was superior to cetuximab in prolonging overall
survival (OS) in human papillomavirus (HPV)-negative, cetuximab-naïve patients withrecurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) in
whom 1 prior platinum-containing chemotherapy had failed.
The secondary objectives of the study were to compare secondary measure of efficacy
between the treatment arms; to compare safety and tolerability between the treatment arms;
to compare Patient-Reported Outcome (PRO) measures between the treatment arms; tocharacterize the correlations between baseline biomarker (eg, p16, Rb) expression in tumor
tissue and clinical efficacy in both treatment arms; and to characterize steady state troughconcentrations for palbociclib, and trough and maximum concentrations for cetuximab inpatients with R/M SCCHN.

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CLINICAL STUDY REPORT SYNOPSIS

090177e19093015d\Approved\Approved On: 20-Mar-2019 01:44 (GMT)METHODS
Study Design: This was an international, multicenter, randomized, double-blind,placebo-controlled, parallel-group Phase 2 study comparing the efficacy and safety ofpalbociclib in combination with cetuximab versus cetuximab in HPV-negative,
cetuximab-naïve patients with R/M SCCHN after failure of 1 platinum-containing regimen.
Approximately 120 patients were to be randomized 1:1 between the investigational arm(Arm A: palbociclib + cetuximab) and the comparator arm (Arm B: placebo + cetuximab).
Crossover between treatment arms was prohibited. Patients randomized to Arm A(investigational arm) received oral palbociclib 125 mg once daily (QD) with food on Day 1
to Day 21 followed by 7 days off treatment in a 28-day cycle in combination with cetuximab,
400 mg/m2 initial dose as a 120-minute intravenous (IV) infusion followed by 250 mg/m2
weekly infused over 60 minutes. Patients randomized to Arm B (comparator arm) received
oral placebo QD with food on Day 1 to Day 21 followed by 7 days off treatment in a 28-day
cycle in combination with cetuximab 400 mg/m2 initial dose as a 120-minute IV infusion
followed by 250 mg/m2 weekly infused over 60 minutes.
Diagnosis and Main Criteria for Inclusion: Confirmed HPV-negative SCCHN tumor of
the oral cavity, oropharynx, hypopharynx or larynx, not amenable for salvage surgery orradiotherapy with measurable disease and documented progressive disease (PD) according to
Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 following receipt of atleast 2 cycles of 1 platinum-containing chemotherapy regimen administered for R/M disease(minimum 50 mg/m2 for cisplatin, minimum area under the curve [AUC] >4 for carboplatin).
No prior nasopharyngeal cancer, salivary gland or sinus tumors. No prior use of cetuximab
in the R/M disease treatment setting and any CDK4/6 or epidermal growth factor receptor(EGFR) inhibitor (except cetuximab during curative radiotherapy).
Study Treatment:
Palbociclib
was supplied as capsules containing 75 mg, 100 mg, or 125 mg equivalents of palbociclib
free base. The sponsor supplied the oral drug formulation to sites in high-density
polyethylene (HDPE) bottles containing 75 mg, 100 mg, or 125 mg capsules. The capsules
could be differentiated by their size and color.
Placebos for palbociclib were indistinguishable from the palbociclib capsules and were
supplied as capsules matching in size and color the various palbociclib formulations. The
sponsor supplied placebo to sites in HDPE bottles.

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Protocol A5481044

CLINICAL STUDY REPORT SYNOPSIS

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Cetuximab was commercially available in multiple presentations. Presentations containing
100 mg of cetuximab per vial were used in this study. Commercial supplies of cetuximab
were centrally sourced and provided to sites.

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Protocol A5481044

CLINICAL STUDY REPORT SYNOPSIS
Efficacy Evaluations: The primary efficacy endpoint was OS. Following the End of
Treatment visit, survival status was collected in all patients every 2 months (7 days) fromthe last dose of study treatment. Secondary efficacy endpoints included progression-freesurvival (PFS), objective response (OR), clinical benefit response (CBR) and duration of
response (DR), according to RECIST version 1.1, as assessed by investigator.
Pharmacokinetic, Biomarker, and Patient Reported Outcomes Evaluations:Pharmacokinetics

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Plasma PK samples (3 mL venous dipotassium ethylenediamine tetraacetic acid [K2EDTA]
blood) for palbociclib determination were to be collected prior to dosing (pre-dose) on
Cycle 1 Day 15 (C1D15) and C2D15. Palbociclib samples were assayed using a validated,sensitive and specific high-performance liquid chromatography tandem mass spectrometric(LC-MS/MS) method.
Serum PK samples (3 mL venous blood samples were collected into appropriately labeledtubes containing no additives) for cetuximab determination were to be collected prior to IV
infusion (pre-dose) and immediately prior to completion of the IV infusion (post-dose) on
C1D15 and C2D15. Cetuximab samples were assayed using a validated, sensitive andspecific enzyme-linked immunosorbent (ELISA) method.
Biomarkers
All patients had to provide a formalin-fixed paraffin embedded (FFPE) archival tumor
specimen at Screening, specifically a FFPE tissue block that contained sufficient tissue togenerate at least 15 unstained slides, each with tissue sections that were 5 microns thick, or atleast 15 unbaked glass slides, each containing an unstained 5 micron FFPE tissue section if
FFPE tissue block could not be submitted. Archival or de novo FFPE tumor tissue samples
were used for biomarker analyses (Rb, p16) by immunohistochemistry (IHC).

The detailed
methods corresponding to biomarker analysis are going to be included in the supplemental
clinical study report (CSR).

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CLINICAL STUDY REPORT SYNOPSIS
Optional de novo tumor biopsy collected at Screening, C1D15 or C2D15 (pre-dose, 1 time
point only) and at the time of progression/End of Treatment was strongly encouraged; nomore than 3 time points were collected in total. In all cases, these specimens were provided
in addition to the archival tumor tissue specimen that was required for enrollment.
Patient Reported Outcomes

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Patient reported global quality of life (QOL), functioning and disease/treatment related
symptoms were assessed using the European Organization for Research and Treatment ofCancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30), and European Organization
for Research and Treatment of Cancer Head and Neck Module 35 (EORTC QLQ-H&N35)
instruments. Patients completed each instrument at pre-dose on Day 1 of Cycles 1-3, then on
Day 1 of every other subsequent Cycle starting with Cycle 5 (eg, Cycles 5, 7, 9, etc), andthen at the End of Treatment visit. Four (4) weeks after discontinuation of study treatment
due to PD, patients, including patients starting post-study anti-cancer therapy, werecompleting the questionnaires at the Follow-up Visit.
Safety Evaluations: Safety evaluations included clinical monitoring, adverse events (AEs),
safety laboratory tests, 12-lead electrocardiograms (ECGs), vital signs (heart rate, bloodpressure [BP]), physical examination, and Eastern Cooperative Oncology Group (ECOG)
performances.
Statistical Methods:
Efficacy Analysis
The intent-to-treat (ITT) population included all patients who were randomized, with study
drug assignment designated according to initial randomization, regardless of whether patients
received study drug or received a different drug from that to which they were randomized.
The ITT population was the primary population for evaluating all efficacy endpoints andpatient characteristics.
The as-treated (AT) population or safety analysis set included all patients who received atleast 1 dose of study medication, with treatment assignments designated according to actual
study treatment received. The AT population was the primary population for evaluating
treatment administration/compliance and safety. Efficacy and clinical benefit endpoints
could be assessed in this population as well.
Primary Efficacy Analysis
OS was defined as the time from the date of randomization to the date of death due to any
cause. OS (in months) was calculated as (date of death − randomization date +1)/30.4. For
patients lacking survival data beyond the date of their last follow-up, the OS time wascensored on the last date they were known to be alive. Patients lacking survival data beyond
randomization had their OS times be censored at randomization. Following the End ofPage 5

Full Clinical Study Report
Protocol A5481044

CLINICAL STUDY REPORT SYNOPSIS
Treatment visit, survival status was collected in all patients every 2 months (7 days) fromthe last dose of study treatment. Information on subsequent anti-cancer therapy was alsocollected.
OS was summarized in the ITT population using the Kaplan-Meier methods. The median
event time and 2-sided 95% and 80% confidence intervals (CIs) for the median were
provided. A stratified (by ECOG) log-rank test was used to compare OS between the
2 treatment arms and the hazard ratio (HR) and its 80% and 95% CIs were estimated. The
survival probabilities at 6 and 12 months were provided with their 95% CIs.
The log-rank (unstratified) test (1-sided,  = 0.1) was used to evaluate the primary efficacy
endpoint, OS, in the ITT population as well. The same analysis could be used in AT
populations.

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Secondary Efficacy Analyses
PFS was defined as the time from the date of randomization to the date of the first
documentation of objective tumor progression as per RECIST version 1.1 or death due to any
cause in the absence of documented PD, whichever occurred first. If tumor progression data
included more than 1 date, the first date was used. PFS (in months) was calculated as (firstevent date − randomization date +1)/30.4.
PFS based on the assessment of investigators was summarized in the ITT population using
the Kaplan-Meier method. The median event time and corresponding 2-sided 95% CI for the
median were provided for PFS. The HR and its 80% and 95% CIs were estimated. A
stratified (by ECOG) log-rank test and an unstratified log-rank test (1-sided,  = 0.1) wasused to compare PFS between the 2 treatment arms.
OR was defined as the overall complete response (CR) or partial response (PR) according to
the RECIST version 1.1. Objective response rate (ORR) was defined as the proportion ofpatients with best overall response (BOR) of CR or PR relative to all randomized.
The number and proportion of patients achieving objective response (CR or PR) weresummarized in the ITT population along with the corresponding exact 2-sided 95% CI
calculated using a method based on Clopper-Pearson method. The
Cochran-Mantel-Haenszel (CMH) test stratified by ECOG and exact test was used tocompare OR between the 2 treatment arms.
CBR was defined as the overall CR, PR, or stable disease 24 weeks according to the
RECIST version 1.1. Clinical benefit response rate (CBRR) was defined as the proportion ofpatients with CR, PR, or stable disease 24 weeks relative to all randomized patients andrandomized patients with measurable disease at baseline.
The number and proportion of patients achieving disease control response (CR or PR or
stable disease) were summarized in the ITT population along with the corresponding exact

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CLINICAL STUDY REPORT SYNOPSIS
2-sided 95% CI calculated using a method based on Clopper-Pearson method. The CMH test
stratified by ECOG and exact test were used to compare CBR between the 2 treatment arms.
The number and proportion of patients achieving CBR (CR or PR or stabledisease24 weeks) were summarized in the ITT population along with the corresponding
exact 2-sided 95% CI calculated using a method based on Clopper-Pearson method. The
CMH test stratified by ECOG and exact test were used to compare CBR between the
2 treatment arms.
Unconfirmed BOR and CBR were in using. The unconfirmed CR/PR was presented as
CR/PR.

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DR was defined as the time from the first documentation of objective tumor response (CR orPR) to the first documentation of disease progression or to death due to any cause, whicheveroccurred first. If tumor progression data included more than 1 date, the first date was used.
DR was calculated as [the date response ended (ie, date of PD or death) – first CR or PR date+ 1)]/30.4. DR was only calculated for the subgroup of patients with an objective tumor
response.
DR was summarized using the Kaplan-Meier methods. DR was calculated for the subgroupof patients achieving objective disease response (CR or PR). The median event time and2-sided 95% CI for the median were provided.
Pharmacokinetic Analysis
PK analysis set was defined as a subset of AT patients who were treated with the study
treatments and had at least measured plasma concentration for at least 1 analyte (palbociclib
and/or cetuximab).
Palbociclib PK concentrations were summarized descriptively by nominal time within thetreatment arm. To be included within the descriptive summaries for PK parameters, each PK
sample was required to fulfill the requirements of a palbociclib steady-state trough sample(steady-state pre-dose concentration [Ctrough]). Palbociclib Ctrough was defined as a pre-dose
plasma concentration following at least 7 consecutive days of 125 mg daily dose without
dosing interruption and the time window for the PK collection was to be between 24 hour2 hour and 24 minutes post-dose the day prior to PK collection and no more than 1 hourpost-dose on the day of PK collection. Additionally, within-patient mean of the palbociclib
Ctrough (WPM-Ctrough) was listed by patient and summarized descriptively within the treatment
arm.
Cetuximab PK concentrations were summarized descriptively by nominal time within eachtreatment arm. To be included within the descriptive summaries for PK parameters, each PK
sample had to meet the requirements of a cetuximab steady-state pre-dose or post-dose
sample. A cetuximab Ctrough was defined as serum sample collected prior to the start of acetuximab IV infusion and after at least 2 consecutive weeks of cetuximab IV infusions

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Protocol A5481044

CLINICAL STUDY REPORT SYNOPSIS
without interruption or prior dose reduction for the Cycle 1 Day 15 collection or after at least
3 consecutive weeks of cetuximab IV infusions without interruption or prior dose reduction
for other visits. A cetuximab steady-state end-of-infusion serum concentration (Cendinf) was
defined as a as serum sample collected after at least 3 consecutive weeks of cetuximab IV
infusions without interruption or prior dose reduction and was collected at the end ofcetuximab infusion time 10% of the actual duration of the cetuximab infusion (ie within6 minutes of the end of infusion time for a 60-minute infusion). Additionally,
within-patient mean cetuximab Ctrough (WPM-Ctrough) and within-patient mean cetuximab
Cendinf (WPM-Cendinf) were listed by patient and summarized descriptively by treatment arm.
Biomarker Analysis090177e19093015d\Approved\Approved On: 20-Mar-2019 01:44 (GMT)The biomarker analysis set was defined as all patients treated with cetuximab in combination
with placebo or palbociclib (AT population) who had at least 1 screening biomarker
assessment. Analysis sets were defined separately for serum, plasma, archival tumor tissue,
and de novo tumor biopsies. If a biomarker had both Screening and on treatment/End of
Treatment assessments, the analysis set was defined as all patients treated with cetuximab in
combination with placebo or palbociclib with paired biomarker assessments.

Biomarkers were assessed separately from serum, plasma, archival tumor tissue and de novo
tumor biopsies. In each case, summaries of baseline levels, ratio to baseline (whereappropriate), expression and mutation were reported, by treatment group and combined. For
continuous variables, summary statistics could include the mean, ratio to baseline, standard
deviation, 25th median, and 75th quartile, percent coefficient of variation (%CV), andminimum/maximum levels of biomarker measures; for categorical variables, summary could
include number and percentage, odds ratio as appropriate. Statistical analyses comparing
treatment groups were performed using the appropriate method (exact Wilcoxon Rank Sum
test for continuous variables, Fisher’s exact test or Wilcoxon Signed Rank for discretevariables). Cox proportional hazard methods for biomarkers included as covariates to predict
PFS/OS, or Kaplan-Meier analysis stratified by  or < median biomarker value (forcontinuous biomarkers) or presence/absence (for discrete biomarkers) could be performed.
For p16 and Rb expression in the palbociclib and cetuximab treatment group, the relationshipof the biomarkers (individually) with PFS and OS were explored at baseline. A sensitivity
analysis of p16 (absent versus any staining intensity level) versus PFS was performed, suchas p16 as a covariate in a Cox model. Receiver Operating Characteristic (ROC) curve
analysis were performed using the baseline biomarkers as predictors of PFS and OS; theAUC was calculated. Curves were produced for median PFS and OS times, along with4 months before median, 2 months before median, 2 months after median and 4 months after
median. If increasing values of the biomarker led to better PFS/OS response, the actual valueof the biomarker was used in the ROC analysis. If increasing values of the biomarker led toworse PFS/OS response, the ROC analysis was to be used the inverse of the biomarker value

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CLINICAL STUDY REPORT SYNOPSIS

090177e19093015d\Approved\Approved On: 20-Mar-2019 01:44 (GMT)with 1/0 being set to 0. The biomarker value which produced the maximal
sensitivity/1-specificity point was identified for each curve.

Patient Reported Outcome Analysis
PRO analysis set was defined as a subset of ITT patients, who had both baseline and at least
1 follow-up PRO assessment before treatment discontinuation. Change from baseline
analyses were performed on the PRO evaluable population as appropriate. For eachtreatment group and at each time point, the number and percentage of patients whocompleted these instruments were summarized, as the reasons for non-completion of thesemeasures. An instrument was considered completed if at least 1 item was answered by thepatient. For each domain or scale a completion status table was provided showing thenumbers and percentages of patients at each visit and the numbers and percentages ofpatients at that visit who completed none, at least 1, or all of the items for that domain orscale. Post treatment discontinuation observation was excluded from primary analyses set
and only included in pre-specified sensitivities or post-hoc analyses.
Safety Analysis
All patients treated with at least 1 dose of study treatment (ie, palbociclib/placebo or
cetuximab) were included in all the safety analyses. Listings of AE, serious AE (SAE), death,laboratory data, vital signs, and physical examinations were provided according to reporting
standard.

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CLINICAL STUDY REPORT SYNOPSISRESULTS
Patient Disposition and Demography:
Patient disposition is summarized in Table S2. By the time of data cutoff (19 July 2018), a
total of 125 patients were randomized to palbociclib + cetuximab and placebo + cetuximab
arms with 65 and 60 patients, respectively; among them, 124 patients received study
treatments. One (1) patient in the palbociclib + cetuximab treatment arm was randomized
but not treated. Twenty-six (26) patients were ongoing on the study as of data cutoff.

090177e19093015d\Approved\Approved On: 20-Mar-2019 01:44 (GMT)The demographic characteristics (ITT population) were well balanced in both treatment arms.
The majority of patients were male (113 [90.4%]). The mean age forpalbociclib + cetuximab arm was 58.3 years (range: 38 to 83 years) and mean body massindex (BMI) was 22.9 kg/m2 (range: 14.35 to 34.52 kg/m2). The mean age forplacebo + cetuximab arm was 60.9 years (range: 32 to 80 years) and mean BMI was
21.9 kg/m2 (range: 15.40 to 38.97 kg/m2). The majority of patients (93 [74.4%]) were ofWhite race.
The primary diagnosis for all patients (125) was SCCHN. The median (range) duration of
the disease under study since histopathological diagnosis was 1.7 years (0.2 to 16.7 years) for
patients in the palbociclib + cetuximab arm and 2.3 years (0.6 to 32.2 years) for patients inthe placebo + cetuximab arm.
All patients (125) had a measurable disease presented at baseline and an adequate baseline
assessment. Baseline characteristics were generally well balanced between both treatment
arms, except some unbalance between treatment arms observed in primary diagnosis sites athypopharynx and oropharynx, and in initial diagnosis at Stage II and III.
For the location of primary diagnosis (SCCHN), oral cavity was the most common site of
disease (palbociclib + cetuximab arm: 25 [38.5%] vs placebo + cetuximab arm: 25 [41.7%]),
followed by larynx (palbociclib + cetuximab arm: 18 [27.7%] vs placebo + cetuximab arm:
16 [26.7%]), oropharynx (palbociclib + cetuximab arm: 9 [13.8%] vs placebo + cetuximab
arm: 14 [23.3%]), and hypopharynx (palbociclib + cetuximab arm: 13 [20.0%] vsplacebo + cetuximab arm: 5 [8.3%]). About 31 (24.8%) patients had >4 disease sites
involved (palbociclib + cetuximab arm: 16 [24.6%] vs placebo + cetuximab arm: 15 [25.0%]).
Most patients already had advanced SCCHN at the time of initial diagnosis with 23 (18.4%)
patients in Stage III (palbociclib + cetuximab arm: 15 [23.1%] vs placebo + cetuximab arm:
8 [13.3%]), 45 (36.0%) patients in Stage IVA (25 [38.5%] vs 20 [33.3%]), 4 (3.2%) patientsin Stage IVB (3 [4.6%] vs 1 [1.7%]) and 14 (11.2%) patients in Stage IVC (7 [10.8%] vs
7 [11.7%]). For the disease stage at baseline, majority of patients (92 [73.6%]) had SCCHN
in Stage IVC (45 [69.2%] vs 47 [78.3%]). At the time of recurrence, most patients(58 [46.4%]) exhibited both distant and locoregional recurrence of disease (28 [43.1%] vs
30 [50.0%]).

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CLINICAL STUDY REPORT SYNOPSIS
Table S2. Patient Disposition Summary

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Number (%) of Patients

Palbociclib +Cetuximabn (%)

Screened
Screen failed
Not met inclusion criteria only
Met exclusion criteria only
Not met inclusion and exclusion criteria
Died – inclusion/exclusion criteria not applicable
Randomized (ITT)
65 (100)
Treated64 (98.5)
Randomized but not treated
1 (1.5)
Received at least 1 dose of both palbociclib/placebo and62 (95.4)
cetuximab
Received at least 1 dose of cetuximab but never received
1 (1.5)palbociclib/placebo
Received at least 1 dose of palbociclib/placebo but never1 (1.5)received cetuximab
Ongoing on study
15 (23.1)
Discontinued from study
50 (76.9)
Patient died45 (69.2)
Patient refused further follow-up
1 (1.5)
Lost to follow-up
1 (1.5)Other
1 (1.5)
Withdrew consent
2 (3.1)
Ongoing on any study drug
4 (6.2)
Ongoing on study treatment palbociclib/placebo
4 (6.2)
Ongoing on study treatment cetuximab
4 (6.2)
Ongoing on both treatments
4 (6.2)60 (92.3)
Discontinued from any study druga
Discontinued from both study drugs
60 (92.3)
Discontinued from palbociclib/placebo only0
Reason to discontinue from any study drug:
Discontinued from palbociclib/placebob
60 (92.3)
Objective progression or relapse
33 (50.8)
Global deterioration of health status0
Adverse event
9 (13.8)
Patient died10 (15.4)
Lost to follow-up
0
No longer willing to participate in study
2 (3.1)Other
6 (9.2)
Discontinued from cetuximabb
60 (92.3)
Objective progression or relapse
33 (50.8)
Global deterioration of health status0
Adverse event
9 (13.8)
Patient died10 (15.4)
Lost to follow-up
0
No longer willing to participate in study
1 (1.5)Other
7 (10.8)
ITT population included all patients who were randomized.
Abbreviations: ITT = intent-to-treat population; n = number of patients.
a. Palbociclib had to be discontinued if cetuximab was discontinued.
b. These categories were not mutually exclusive.

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Placebo +Cetuximab
n (%)

Total

60 (100)
60 (100)060 (100)

n (%)
226
101
84
15
1
1
125 (100)
124 (99.2)
1 (0.8)122 (97.6)

01 (0.8)0

1 (0.8)11 (18.3)
49 (81.7)
42 (70.0)02 (3.3)0
5 (8.3)7 (11.7)
7 (11.7)
7 (11.7)
7 (11.7)
53 (88.3)
53 (88.3)
026 (20.8)
99 (79.2)
87 (69.6)
1 (0.8)3 (2.4)1 (0.8)7 (5.6)
11 (8.8)
11 (8.8)
11 (8.8)
11 (8.8)
113 (90.4)
113 (90.4)
053 (88.3)
35 (58.3)
1 (1.7)7 (11.7)5 (8.3)
1 (1.7)3 (5.0)1 (1.7)53 (88.3)
36 (60.0)
1 (1.7)5 (8.3)6 (10.0)
1 (1.7)3 (5.0)1 (1.7)113 (90.4)
68 (54.4)
1 (0.8)16 (12.8)
15 (12.0)
1 (0.8)5 (4.0)7 (5.6)113 (90.4)
69 (55.2)
1 (0.8)14 (11.2)
16 (12.8)
1 (0.8)4 (3.2)8 (6.4)

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CLINICAL STUDY REPORT SYNOPSIS
Efficacy Results:
Overall Survival
The OS is summarized in Table S3 and plotted in Figure S1. At the data cutoff date
(19 July 2018), there were 45 (69.2%) deaths in the palbociclib + cetuximab treatment arm
and 42 (70.0%) deaths in the placebo + cetuximab treatment arm. The estimated median OS
was 9.7 months (95% CI [7.3, 13.9]) in the palbociclib + cetuximab treatment arm and7.8 months (95% CI [6.7, 10.6]) in the placebo + cetuximab treatment arm. The estimatedHR using stratified (by ECOG per randomization) analysis was 0.820 (95% CI [0.536, 1.253];p-value = 0.180), which showed a numerical trend in favor of palbociclib + cetuximab but
was not statistically significant. The study did not meet its primary endpoint of OS withpalbociclib + cetuximab treatment arm when compared with placebo + cetuximab treatmentarm.

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Figure S1. Kaplan-Meier Plot of Overall Survival - Intent-to-Treat Set

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Table S3. Summary of Overall Survival – Intent-to-Treat Set

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Palbociclib + Cetuximab(N = 65)
45 (69.2)

Placebo + Cetuximab(N = 60)
42 (70.0)

Number of deaths, n (%)
Cause of death, n (%)
Disease under study
41 (63.1)
37 (61.7)
Study treatment toxicity
1 (1.5)0Unknown
3 (4.6)2 (3.3)Other
1 (1.5)3 (5.0)
Number censored, n (%)
20 (30.8)
18 (30.0)
Reason for censorship, n (%)
Patient remained in follow-up
18 (27.7)
16 (26.7)
Patient no longer being followed for survival
2 (3.1)2 (3.3)
Survival probability at Month 6a (95% CIb)
74.4 (61.6, 83.5)
65.9 (51.8, 76.7)
Survival probability at Month12a (95% CIb)
38.4 (25.8, 50.9)
33.6 (21.0, 46.7)
Survival probability at Month 24a (95% CIb)
9.9 (2.2, 24.7)
7.6 (0.8, 25.3)
Survival probability at Month 36a (95% CIb)
NE
NE
Kaplan-Meier estimated of time to event(month) quartiles (95% CI)c25%
5.9 (3.2, 7.2)
4.3 (3.2, 6.9)50%
9.7 (7.3, 13.9)
7.8 (6.7, 10.6)
75%
17.3 (13.9, 21.6)
14.9 (10.6, NE)
Stratified analysisd:
Hazard ratioe
0.820
80% CI of hazard ratio
0.621-1.082
95% CI of hazard ratio
0.536-1.253
p-valuef
0.180040
Unstratified analysis:
Hazard ratioe
0.812
80% CI of hazard ratio
0.616-1.070
95% CI of hazard ratio
0.532-1.239
p-valuef
0.166827
Abbreviations: CI = confidence interval; ECOG = Eastern Cooperative Oncology Group; N/n = number ofpatients; NE = not estimable.
a. Estimated from the Kaplan-Meier curve.
b. Calculated from the product-limit method.
c. Based on the Brookmeyer and Crowley method.
d. Stratified by ECOG per randomization.
e. Assuming proportional hazards, hazard ratio less than 1 indicated reduction in hazard rate in favor of
palbociclib + cetuximab.
f. One (1)-sided p-value from the log-rank test.

Progression Free Survival
Summary of PFS based on investigator assessment is presented in Table S4. At the data
cutoff date (19 July 2018), 50 (76.9%) out of 65 patients in the palbociclib + cetuximab
treatment arm and 47 (78.3%) out of 60 patients in the placebo + cetuximab treatment arm
had experienced disease progression or death. The estimated HR using stratified (by ECOG
per randomization) analysis was 1.000 (95% CI [0.669, 1.495]; p-value = 0.495), whichshowed no difference between the 2 treatment arms. The median PFS was 3.9 months

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090177e19093015d\Approved\Approved On: 20-Mar-2019 01:44 (GMT)(95% CI [3.6, 5.6]) in the palbociclib + cetuximab treatment arm and 4.6 months (95% CI[2.3, 5.5]) in the placebo + cetuximab treatment arm. The study did not meet its key
secondary endpoint of PFS based on the investigator’s assessment.

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Table S4. Summary of Progression Free Survival Based on Investigator Assessment Intent-to-Treat Set

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Palbociclib + Cetuximab(N = 65)
50 (76.9)

Placebo + Cetuximab(N = 60)
47 (78.3)

Number with event, n (%)
Type of event, n (%)
Objective progression
35 (53.8)
37 (61.7)
Death without objective progression
15 (23.1)
10 (16.7)
Number censored, n (%)
15 (23.1)
13 (21.7)
Reason for censorship, n (%)
No on-study disease assessments
6 (9.2)2 (3.3)Given new anti-cancer treatment prior to
1 (1.5)0tumor progression
Unacceptable gap (>18 weeks) between PD or0
2 (3.3)death to the most recent prior adequate
assessment
Discontinued treatment without disease
4 (6.2)3 (5.0)progression or deathAE
1 (1.5)0
Lost to follow-up / patient refused
1 (1.5)3 (5.0)continued treatment for reason other thanAE
Other
2 (3.1)0
In follow-up for progression
4 (6.2)6 (10.0)
46.8( 33.4, 59.1)
50.2 (36.5, 62.4)
Probability at Month 4a (95% CIb)
Probability at Month 6a (95% CIb)
36.0 (23.7, 48.4)
32.8 (20.8, 45.3)
Probability at Month 12a (95% CIb)
9.9 (3.3, 20.8)
16.6 (7.9, 28.0)
Kaplan-Meier estimated of time to event (month)quartiles(95% CI)c25%
2.9 (1.9, 3.6)
1.9 (1.7, 2.3)50%
3.9 (3.6, 5.6)
4.6 (2.3, 5.5)75%
9.4 (5.6, 11.3)
8.3 (5.5, 18.5)
Stratified analysisd:
Hazard ratioe
1.000
80% CI of hazard ratio
0.769-1.301
95% CI of hazard ratio
0.669-1.495
p-valuef
0.495258
Unstratified analysis:
0.994
Hazard ratioe
80% CI of hazard ratio
0.766-1.291
95% CI of hazard ratio
0.667-1.483
p-valuef
0.488102
Abbreviations: AE = adverse event; CI = confidence interval; ECOG = Eastern Cooperative Oncology Group;
N/n = number of patients; PD = progressive disease.
a. Estimated from the Kaplan-Meier curve.
b. Calculated from the product-limit method.
c. Based on the Brookmeyer and Crowley method.
d. Stratified by ECOG per randomization.
e. Based on the Cox Proportional hazards model.
f. One (1)-sided p-value from the log-rank test reflected the sign of the test statistic (z-Score).

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Objective Response
Best Overall Response: Best overall response is summarized in Table S5. The odds ratiousing stratified (by ECOG per randomization) analysis showed no difference between the
2 treatment arms.
Table S5. Summary of Best Overall Response – Intent-to-Treat Set

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Palbociclib + Cetuximab(N = 65)65 (100)

Placebo + Cetuximab(N = 60)
60 (100)

Number of patients with measurable
disease at baseline, n (%)
CR
2 (3.1)0PR
16 (24.6)
15 (25.0)
Stable/No response
11 (16.9)
14 (23.3)
Objective progression
9 (13.8)
20 (33.3)
Indeterminate
27 (41.5)
11 (18.3)
Objective response rate (CR+PR)
18 (27.7)
15 (25.0)
95% exact CIa
17.3, 40.2
14.7, 37.9
Stratified analysisb:
Odds ratioc (95% exact CI)
1.137 (0.475, 2.734)
p-valued
0.4570
Unstratified analysis:
Odds ratioc (95% exact CI)
1.149 (0.480, 2.772)
p-valued
0.4457
Unconfirmed best overall response was in using. The unconfirmed CR/PR was presented as CR/PR.
Abbreviations: CI = confidence interval; CR = complete response; ECOG = Eastern Cooperative Oncology
Group; N/n = number of patients; PR = partial response.
a. CI was calculated using the exact (Clopper-Pearson) method based on binomial distribution.
b. Stratified by ECOG per randomization.
c. An odds ratio >1 means better response in favor of palbociclib + cetuximab.
d. One (1)-sided p-value was from exact test.

Clinical Benefit Response: CBR based on investigator assessment is summarized in Table S6,
which showed no difference between the 2 treatment arms.

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Table S6. Summary of Clinical Benefit Response - Intent-to-Treat Set

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Palbociclib + Cetuximab(N = 65)65 (100)

Placebo + Cetuximab(N = 60)
60 (100)

Number of patients with measureable disease atbaseline, n (%)
CR
2 (3.1)0PR
16 (24.6)
15 (25.0)
6 (9.2)7 (11.7)
SD 24 weeks
SD <24 weeks
5 (7.7)7 (11.7)
Objective progression
9 (13.8)
20 (33.3)
Indeterminate
27 (41.5)
11 (18.3)
24 (36.9)
22 (36.7)
Benefit response (CR+PR+SD 24 weeks)
95% exact CIa
25.3, 49.8
24.6, 50.1
Stratified analysisb:
1.013 (0.461, 2.230)
Odds ratioc (95% exact CI)
p-valued
0.5605
Unstratified analysis:
Odds ratioc (95% exact CI)
1.011 (0.459,2.233)
p-valued
0.5621
Unconfirmed clinical benefit response was in using. The unconfirmed CR/PR was presented as CR/PR.
Abbreviations: CI = confidence interval; CR = complete response; ECOG = Eastern Cooperative Oncology
Group; N/n = number of patients; PR = partial response; SD = stable disease.
a. CI was calculated using the exact (Clopper-Pearson) method based on binomial distribution.
b. Stratified by ECOG per randomization.
c. An odds ratio >1 means better response in favor of palbociclib + cetuximab.
d. One (1)-sided p-value was from exact test.

Duration of Objective Response
Duration of objective response is summarized only on the 18 patients in thepalbociclib + cetuximab arm and 15 patients in the placebo + cetuximab arm who had
objective tumor response (unconfirmed CR or PR), which showed in Table S7. The
estimated median DR showed no differences between the 2 treatment arms.

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Table S7. Summary of Duration of Objective Response - Intent-to-Treat Set

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Palbociclib + Cetuximab(N = 65)18
15 (83.3)

Placebo + Cetuximab(N = 60)
15
8 (53.3)

Patients with a response (CR/PR)
Number (%) of patients with objective
progression or death
Number (%) of patients censored3 (16.7)
7 (46.7)
Kaplan-Meier estimated of duration of response(CR/PR) in months quartiles(95% CI)a25%
3.7 (1.4, 7.5)
4.8 (1.4, 7.4)50%
7.6 (3.7, 7.7)
7.4 (3.6, NE)
75%
7.7 (7.6, 15.8)
NE (7.4, NE)
Stratified analysisb:
Hazard ratioc
1.451
80% CI of hazard ratio
0.815-2.583
95% CI of hazard ratio
0.601-3.504
Unstratified analysis:
Hazard ratioc
1.571
80% CI of hazard ratio
0.889-2.776
95% CI of hazard ratio
0.657-3.752
Abbreviations: CI = confidence interval; CR = complete response; ECOG = Eastern Cooperative Oncology
Group; N = number of patients; NE = not estimable; PR = partial response.
a. Based on the Brookmeyer and Crowley method.
b. Stratified by ECOG per randomization.
c. Assuming proportional hazards, hazard ratio <1 indicated reduction in hazard rate in favor of
palbociclib + cetuximab.

Pharmacokinetic, Biomarker, and Patient Reported Outcomes Results:
Pharmacokinetic Results
Plasma Palbociclib PK: Following daily 125 mg oral doses of palbociclib with concomitantadministration of cetuximab, palbociclib steady-state exposures were comparable on Day 15of Cycles 1 and 2 (Table S8). A single palbociclib PK sample that was below the lower limitof quantitation (BLQ) reported supporting information within the case report form (CRF) that
met the acceptance criteria for a Ctrough parameter, and the reported geometric mean summary
statistics for palbociclib Cycle 2 Day 15 Ctrough and the WPM-Ctrough were heavily influenced
by this single sample. As a result, the interpretation of the palbociclib PK data from thisstudy was focused on the arithmetic mean and %CV. The mean palbociclib WPM-Ctroughwas 71.64 ng/mL, which is consistent with data reported from prior studies dosing
palbociclib at 125 mg QD in patients with advanced cancer.

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Table S8. Summary of Plasma Palbociclib Steady-State PK Parameters Following
Daily 125 mg Oral Doses of Palbociclib with Concomitant Cetuximab
Treatment
Parameter (Units)N

PK Parameter Summary Statistics
Geometric Mean
(Geometric Mean %CV)

Mean
(%CV)

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Ctrough (ng/mL)
Cycle 1 Day 15
27
64.11 (45)69.75 (40)Cycle 2 Day 15
2840.96 (2622)
67.79 (43)
WPM-Ctrough (ng/mL)a37
47.66 (1231)
71.64 (42)Abbreviations: %CV = percent coefficient of variation; Ctrough = steady-state pre-dose concentration;
N = number of patients contributing to the summary statistics; PK = pharmacokinetic(s);WPM-Ctrough = within-patient mean steady-state pre-dose concentration.
a. Within-patient mean of steady-state Ctrough.

Serum Cetuximab PK: Cetuximab PK parameters were comparable in the presence andabsence of concomitant palbociclib treatment, based on similar median, geometric mean, andrange of cetuximab Ctrough and Cendinf across treatment arms (Table S9). From visualinspection of the data, it could be concluded that concomitant administration of palbociclib
had no clinically significant effect on cetuximab PK.
Table S9. Summary of Serum Cetuximab Steady-State PK Parameters by
Treatment
Parameter (Units)

Parameter Summary Statisticsa by Treatment
Palbociclib + Cetuximab
Placebo + Cetuximab

Ctrough (ng/mL)
Cycle 1 Day 15
39706.407 (92)42914.095 (62)Cycle 2 Day 15
51005.307 (74)52995.663 (71)
WPM-Ctrough (ng/mL)b
45605.949 (83)46796.538 (63)Cendinf (ng/mL)
Cycle 1 Day 15145748.275 (43)137185.479 (61)Cycle 2 Day 15149155.706 (38)153310.061 (39)
WPM-Cendinf (ng/mL)b
149119.179 (36)148063.341 (39)Abbreviations: %CV = percent coefficient of variation; Cendinf = steady-state end-of-infusion concentration;
Ctrough = steady-state pre-dose concentration; PK = pharmacokinetic(s); WPM-Cendinf = within-patient mean
steady-state end-of-infusion concentration; WPM-Ctrough = within-patient mean steady-state pre doseconcentration.
a. Geometric mean (%CV).
b. Within-patient mean of steady-state Ctrough or Cendinf values, respectively.

Biomarker Results
In the following subgroup analysis, the 95% CIs and p-values were provided to help gauge
the precision of the estimates but they were not adjusted for multiplicity.

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CLINICAL STUDY REPORT SYNOPSISIHC Biomarker Assessment (p16, Rb,)

In general, the analyses showed that staining for these cell cycle related markers was broadly
distributed for all parameters considered. All samples submitted for analysis weresuccessfully stained and analyzed. In general, there was not significant difference between
the 2 treatment arms for Rb
staining parameter . For p16, however, there wasa trend toward greater positive tumor cells in the placebo + cetuximab arm versus thepalbociclib + cetuximab arm (p-value = 0.0926), and this was further illustrated by asignificant difference in the percent positive cell at the cytoplasmic staining level(p-value = 0.0463), and a trend for the H-score for the cytoplasmic staining(p-value = 0.0502).

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p16 Analysis
A total of 113 patients were included in the IHC analyses: 58 in palbociclib + cetuximab arm
and 55 in placebo + cetuximab arm. Two (2) analysis methods based on the p16 IHC
analysis were utilized, one based on a conventional cutoff to consider a sample
HPV-negative (<70% p16-positive tumor cells) and the other based on an optimized cutoff
for the activity of the test arm (palbociclib + cetuximab) derived from an ROC curve analysis.
Conventional 70% p16-Positive Tumor Cell Cutoff: Initial analysis of the p16 status was
based on the conventional cutoff of 70% p16-positive tumor cells to call out cases that might
be considered HPV-positive. Specifically, p16 expression was scored as positive if strong
and diffuse nuclear and cytoplasmic staining was present in at least 70% of the tumor cells.
Testing and interpretation were centralized. Based on this cutoff, 54 of the 58 samples tested
in the palbociclib + cetuximab arm and 48 of 55 samples tested in the placebo + cetuximab
arm were considered qualified as HPV-negative and included in the PFS and OS analyses.
The median PFS were similar between the palbociclib + cetuximab and theplacebo + cetuximab treatments, 3.7 months (95% CI: 3.2, 5.6) and 5.0 months(95% CI: 3.3, 7.2), respectively (HR = 1.228; 95% CI: 0.789, 1.911; p-value = 0.364). The
PFS analyses for p16-negative groups derived from the specified cutoff point are summarizedin Table S10.
The median OS were similar between the palbociclib + cetuximab and theplacebo + cetuximab treatments, 9.9 months (95% CI: 7.1, 13.9) and 8.0 months (95% CI:
7.0, 14.7), respectively (HR = 0.947; 95% CI: 0.589, 1.521; p-value = 0.824). The OS
analyses for p16-negative groups derived from the specified cutoff point are summarized inTable S11.

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Table S10. Summary of Progression Free Survival Based on Investigator Assessment
for p16 Negative – Biomarker Analysis Set
p16 Status: Negativea
Number of patients
Number with event
Type of event
Objective progression
Death without objective progression
Number censoredReason for censorship
No adequate baseline assessments
No on-study disease assessments
Given new anti-cancer treatment prior to tumor
progression
Unacceptable gap (>18 weeks) between
progressive disease or death to the most recent
prior adequate assessment
Discontinued treatment without diseaseprogression or deathAE
Global deterioration of health status
Lost to follow-up/patient refused continued
treatment for reason other than AE
Other
In follow-up for progression
Probability of being event free at Month 4b (95% CIc)
Probability of being event free at Month 6b (95% CIc)
Probability of being event free at Month 12b (95% CIc)
Kaplan-Meier estimated of time to event (month)quartiles(95% CI)d
25%
50%
75%
Versus placebo + cetuximab
Hazard ratioe
80% CI of hazard ratio
95% CI of hazard ratio
p-valuef
p16 Status: Negative (with Specified Cutoff Point)g
Number of patients
Number with event
Type of event
Objective progression
Death without objective progression
Number censoredReason for censorship
No adequate baseline assessments
No on-study disease assessments
Given new anti-cancer treatment prior to tumor
progression
Unacceptable gap (>18 weeks) between
progressive disease or death to the most recent
prior adequate assessment
Discontinued treatment without diseaseprogression or death
AE

Palbociclib + Cetuximab

Placebo + Cetuximab

45
34 (75.6)

39
30 (76.9)25 (55.6)
9 (20.0)
11 (24.4)

21 (53.8)
9 (23.1)
9 (23.1)

04 (8.9)1 (2.2)0
2 (5.1)00

2 (5.1)3 (6.7)

1 (2.6)00
1 (2.2)00
1 (2.6)2 (4.4)3 (6.7)34.7 (20.2, 49.6)
29.4 (16.0, 44.1)
11.4 (3.2, 25.5)

0
4 (10.3)
55.4 (37.8, 69.9)
40.8 (24.7, 56.3)
20.0 (8.6, 34.7)

1.9 (1.8, 3.2)
3.7 (3.0, 4.0)
7.2 (3.8, 14.1)

2.6 (1.6, 3.7)
4.7 (3.3, 7.3)
9.3 (5.6, NE)

1.331
0.963-1.840
0.811-2.184
0.258

Page 2154
43 (79.6)

48
37 (77.1)

29 (53.7)
14 (25.9)
11 (20.4)

28 (58.3)
9 (18.8)
11 (22.9)

04 (7.4)
1 (1.9)02 (4.2)00

2 (4.2)3 (5.6)

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Table S10. Summary of Progression Free Survival Based on Investigator Assessment
for p16 Negative – Biomarker Analysis Set
Palbociclib + Cetuximab
Placebo + Cetuximab
Global deterioration of health status
00
Lost to follow-up/patient refused continued
1 (1.9)1 (2.1)
treatment for reason other than AE
Other
2 (3.7)0
In follow-up for progression
3 (5.6)6 (12.5)
40.9 (26.9, 54.4)
55.5 (39.9, 68.6)
Probability of being event free at Month 4b (95% CIc)
34.4 (21.3, 47.9)
39.3 (25.1, 53.3)
Probability of being event free at Month 6b (95% CIc)
Probability of being event free at Month 12b (95% CIc)
8.1 (2.2, 19.3)
19.9 (9.4, 33.1)
Kaplan-Meier estimated of time to event (month)quartiles(95% CI)d25%
2.0 (1.8, 3.5)
1.9 (1.6, 3.4)50%
3.7 (3.2, 5.6)
5.0 (3.3, 7.2)75%
9.4 (5.5, 11.3)
9.3 (7.1, NE)
Versus placebo + cetuximab
1.228
Hazard ratioe
80% CI of hazard ratio
0.919-1.639
95% CI of hazard ratio
0.789-1.911
p-valuef
0.364
If event count 8 in either of the comparison group, the hazard ratio and p-value were not provided.
Abbreviations: AE = adverse event; CI = confidence interval; IHC = immunohistochemistry; NE = not estimable;
PFS = progression-free survival; ROC = Receiver Operating Characteristic.
a. p16 status was utilizing the cutoff points identified by the ROC analysis for the PFS and the p16-positive tumor
cells. For the palbociclib + cetuximab treatment arm, p16 IHC negative was defined as % positive tumor cells 1.
For the placebo + cetuximab treatment arm, p16 IHC negative was defined as %positive tumor cells 4.
b. Estimated from the Kaplan-Meier curve.
c. Calculated from the product-limit method.
d. Based on the Brookmeyer and Crowley Method.
e. Based on the Cox Proportional hazards model.
f. Two (2)-sided p-value from the log-rank test.
g. p16 status was utilizing the specified cutoff points, p16 IHC negative was defined as %positive tumor cells <70%.

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Table S11. Summary of Overall Survival for p16 Negative – Biomarker Analysis Set
p16 Status: Negativea
Number of patients
Number of deaths
Cause of death
Disease under study
Study treatment toxicity
Unknown
Other
Number censoredReason for censorship
Patient remained in follow-up
Patient no longer being followed for survival
Survival probability at Month 6b (95% CIc)
Survival probability at Month12b (95% CIc)
Survival probability at Month 24b (95% CIc)
Survival probability at Month 36b (95% CIc)
Kaplan-Meier estimated of time to event (month)quartiles(95% CI)d
25%
50%
75%
Versus placebo + cetuximab
Hazard ratioe
80% CI of hazard ratio
95% CI of hazard ratio
p-valuef
p16 Status: Negative (with Specified Cutoff Point)g
Number of patients
Number of deaths
Cause of death
Disease under study
Study treatment toxicity
Unknown
Other
Number censoredReason for censorship
Patient remained in follow-up
Patient no longer being followed for survival
Survival probability at Month 6b (95% CIc)
Survival probability at Month12b (95% CIc)
Survival probability at Month 24b (95% CIc)
Survival probability at Month 36b (95% CIc)
Kaplan-Meier estimated of time to event (month)quartiles(95% CI)d
25%
50%
75%
Versus placebo + cetuximab
Hazard ratioe
80% CI of hazard ratio
95% CI of hazard ratio
p-valuef

Palbociclib + Cetuximab

Placebo + Cetuximab45
29 (64.4)31
22 (71.0)

26 (57.8)
1 (2.2)3 (6.7)0
16 (35.6)

18 (58.1)
01 (3.2)3 (9.7)9 (29.0)

14 (31.1)
2 (4.4)72.3 (56.3, 83.2)
44.0 (28.3, 58.6)
15.2 (3.6, 34.4)
NE

9 (29.0)069.6 (49.6, 82.9)
33.5 (17.0, 50.9)
12.0 (1.2, 36.0 )NE

5.0 ( 3.0, 7.2)
9.7 (7.1, 15.6)
18.0 (13.9, NE)

5.1 (2.6, 7.0)
7.5 (5.9, 14.1)
14.8 (10.2, NE)

0.870
0.605-1.251
0.499-1.517
0.627
54
37 (68.5)

48
32 (66.7)

33 (61.1)
1 (1.9)3 (5.6)
1 (1.9)17 (31.5)

27 (56.3)
02 (4.2)3 (6.3)16 (33.3)

15 (27.8)
2 (3.7)73.2 (59.0, 83.2)
38.8 (25.0, 52.4)
12.2 (2.9, 28.6)
NE

15 (31.3)
1 (2.1)73.3 (57.7, 83.9)
38.6 (23.9, 53.2)
9.7 (1.0, 30.7)NE

5.9 (3.1, 7.1)
9.9 (7.1, 13.9)
17.3 (11.7, NE)

5.9 (3.3, 7.1)
8.0 (7.0, 14.7)
17.3 (11.8, NE)

0.947
0.694-1.291
0.589-1.521
0.824

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Table S11. Summary of Overall Survival for p16 Negative – Biomarker Analysis Set
Palbociclib + Cetuximab
Placebo + Cetuximab
If event count 8 in either of the comparison group, the hazard ratio and p-value were not provided.
Abbreviations: CI = confidence interval; IHC = immunohistochemistry; NE = not estimable; OS = overall survival;
ROC = Receiver Operating Characteristic.
a. p16 status was utilizing the cutoff points identified by the ROC analysis for the OS and the p16-positive tumor
cells. For the palbociclib + cetuximab treatment arm, p16 IHC negative was defined as % positive tumor cells 1.
For the placebo + cetuximab treatment arm, p16 IHC negative was defined as %positive tumor cells 0.
b. Estimated from the Kaplan-Meier curve.
c. Calculated from the product-limit method.
d. Based on the Brookmeyer and Crowley Method.
e. Assuming proportional hazards, hazard ratio less than 1 indicated reduction in hazard rate in favor of
palbociclib + cetuximab.
f. Two (2)-sided p-value from the log-rank test.
g. p16 status was utilizing the specified cutoff points, p16 IHC negative was defined as %positive tumor cells <70%.

090177e19093015d\Approved\Approved On: 20-Mar-2019 01:44 (GMT)ROC Curve Analysis for the Determination of Cutpoint: To further ascertain the sensitivity
and specificity of the p16 IHC staining assay beyond the conventional cutoff and to optimize
the cutoff for the activity of each test arm, ROC curve analyses were performed forcorrelation with PFS and with OS.
Disease-Free Survival Association Analysis: p16 status was established utilizing the cutoff
points identified by the ROC analysis for the PFS and the p16-positive tumor cells. For thepalbociclib + cetuximab treatment arm, p16-negative was defined as 1% positive tumor
cells. For the placebo + cetuximab treatment arm, p16-negative was defined as 4% positive
tumor cells. Based on these cutpoints, 45 of the 58 samples tested in thepalbociclib + cetuximab arm and 39 of 55 samples tested in the placebo + cetuximab arm
were considered qualified as p16-negative and included in the PFS analysis. The median
PFS were similar between the palbociclib + cetuximab and the placebo + cetuximab
treatments, 3.7 months (95% CI: 3.0, 4.0) and 4.7 months (95% CI: 3.3, 7.3), respectively(HR = 1.331; 95% CI: 0.811, 2.184; p-value = 0.258).
Overall Survival Association Analysis: p16 status was established utilizing the cutoff points
identified by the ROC analysis for the OS and the p16-positive tumor cells. For thepalbociclib + cetuximab treatment arm, p16-negative was defined as 1% positive tumor
cells. For the placebo + cetuximab treatment arm, p16-negative was defined as 0% positive
tumor cells. Based on these cutpoints, 45 of the 58 samples tested in thepalbociclib + cetuximab arm and 31 of 55 samples tested in the placebo + cetuximab arm
were considered qualified as p16-negative and included in the OS analysis.
The median OS were similar between the palbociclib + cetuximab and theplacebo + cetuximab treatments, 9.7 months (95% CI: 7.1, 15.6) and 7.5 months (95% CI:
5.9, 14.1), respectively (HR = 0.870; 95% CI: 0.499, 1.517; p-value = 0.627).

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Rb Analysis
Rb protein-loss was rare, with a total of 3 (2.7%) cases detected in the 113 tumors tested, 1 in
the palbociclib + cetuximab arm and 2 in the placebo + cetuximab arm, respectively.
Disease-Free Survival Association Analysis: In the group of patients whose tumors were
Rb-positive (as defined by Rb IHC with 1% positive tumor cells), the median PFS weresimilar between the palbociclib + cetuximab and the placebo + cetuximab arms, 3.9 months(95% CI: 3.5, 6.2) and 4.6 months (95% CI: 2.6, 5.6), respectively (HR = 1.038; 95% CI:
0.679, 1.588; p-value = 0.860). Since there were so few Rb-negative tumor cases no analysis
could be conclusive.

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Overall Survival Association Analysis: In the group of patients whose tumors were
Rb-positive, the median OS for the palbociclib + cetuximab arm was numerically superior
when compared to the placebo + cetuximab arm, 10.5 months (95% CI: 7.1, 15.6) versus
7.8 months (95% CI: 6.9, 11.8), HR = 0.815 (95% CI: 0.519, 1.281; p-value = 0.376). Since
there were so few Rb-negative tumor cases no analysis could be conclusive.

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Patient Reported Outcomes Results
EORTC QLQ-C30
Completion Rate: The percentage of patients completing at least 1 question at baseline on
EORTC QLQ-C30 are 96.9% (n = 63 patients) in the palbociclib + cetuximab treatment arm

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and 96.7% (n = 58 patients) in the placebo + cetuximab treatment arm. The percentage ofpatients completing at least 1 question on EORTC QLQ-C30 dropped to less than 10% after
Cycle 11 in the palbociclib + cetuximab treatment arm and after Cycle 15 in theplacebo + cetuximab treatment arm.
Global Quality of Life: Baseline mean scores for global QOL were similar between
palbociclib + cetuximab and placebo + cetuximab treatment arms (50.9 [95% CI: 45.4, 56.5]
vs 50.4 [95% CI: 44.6, 56.3]). The between-treatment comparison in mean change frombaseline scores showed no statistically significant difference (0.132 [95% CI: -6.02, 6.28],
p-value = 0.9662).

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EORTC QLQ-C30 Functional Scales: The EORTC QLQ-C30 functional scales consist of the
5 scales: physical functioning, role functioning, emotional functioning, cognitive functioning,and social functioning. Baseline scores for all 5 functional scales were similar between the
2 treatment arms. Baseline scores for the functional scales depicted high functional levels inboth treatment arms.
The overall change from baseline scores for all 5 functional scales was not found to bestatistically significantly different between the 2 treatment arms.
Symptom Scales: The EORTC QLQ-C30 symptom scales consist of the 9 symptoms: fatigue,nausea and vomiting, pain, dyspnoea, insomnia, appetite loss, constipation, diarrhea, andfinancial difficulties. Mean baseline scores for the symptoms of the EORTC QLQ-C30 weresimilar in both treatment arms for all symptoms. Baseline scores for the symptoms indicate
low symptom severity in both treatment arms.
The overall change from baseline scores for all 9 symptom scales was not found to bestatistically significantly different between the 2 treatment arms. The overall change frombaseline within each treatment arm indicated numerical improvement in fatigue(palbociclib + cetuximab arm: -2.788 [95% CI: -7.04, 1.46] vs placebo + cetuximab
arm: -5.124 [95% CI: -9.50, -0.75]), nausea and vomiting (-0.869 [95% CI: -2.63, 0.90]
vs -1.040 [95% CI: -2.82, 0.74]), pain (-5.977 [95% CI: -11.06, -0.90] vs -6.096[95% CI: -11.32, -0.87]), insomnia (-4.623 [95% CI: -10.33, 1.08] vs -5.018[95% CI: -10.88, 0.84]), constipation (-4.120 [95% CI: -10.30, 2.06] vs -1.326[95% CI: -7.72, 5.07]), and financial difficulties (-5.258 [95% CI: -11.61, 1.10] vs -0.273[95% CI: -6.83, 6.29]) while worsening in dyspnoea (3.074 [95% CI: -2.15, 8.30] vs 5.086[95% CI: -0.27, 10.45]) and diarrhoea (4.255 [95% CI: 1.34, 7.17] vs 1.744[95% CI: -1.24, 4.73]) for both treatment arms. Appetite loss score showed improvement inplacebo + cetuximab arm (-0.687 [95% CI: -7.04, 5.67]) while worsening inpalbociclib + cetuximab arm (2.247 [95% CI: -3.89, 8.38]). The within treatment arm
change from baseline scores were not statistically significant (based on 95% CI) for either
treatment arm for most symptoms except pain (both treatment arms), fatigue(placebo + cetuximab arm) and diarrhea (palbcociclib + cetuximab arm).

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Mean baseline scores for the symptoms of the EORTC QLQ-H&N35 were similar in both
treatment arms for all symptoms except nutritional supplements (palbociclib + cetuximab:
20.6 vs placebo + cetuximab: 34.5), opening mouth (23.8 vs 32.8), weight gain (19.0 vs 10.3)
and feeding tube (8.1 vs 13.8). Baseline scores for the symptoms indicate low symptom
severity in both treatment arms except pain killers (63.5 vs 63.8).
The overall change from baseline in dry mouth was found to be statistically significant
favoring palbociclib + cetuximab arm compared with placebo + cetuximab arm (-6.300[95% CI: -10.50, -2.10]) vs 3.444 [95% CI: -0.82, 7.71]; p-value = 0.0016). The overallchange from baseline in sticky saliva was found to be statistically significant favoring
palbociclib + cetuximab arm compared with placebo + cetuximab arm (-3.912[95% CI: -9.70, 1.88]) vs 4.680 [95% CI: -1.22, 10.58]; p-value = 0.0423). The overallchange from baseline in feeding tube was found to be statistically significant favoring
palbociclib + cetuximab arm compared with placebo + cetuximab arm (-6.364[95% CI: -9.58, -3.15]) vs -0.107 [95% CI: -3.30, 3.08]; p-value = 0.0070). The estimateddifference in overall change from baseline score for dry mouth, sticky saliva, and feedingtube were -9.744 (95% CI: -15.75, -3.74), -8.592 (95% CI: -16.88, -0.30), and -6.258(95% CI: -10.79, -1.73), respectively.
Time to Deterioration of Patient Reported Pain Symptom as Assessed by EORTCQLQ-H&N35: Time to deterioration in patient reported pain symptom as an increase of10 points from baseline as assessed by the EORTC QLQ H&N35 is provided in Table S13.
Patients who had an event of pain deterioration of 10 points while on study were 25 (38.5%)
in the palbociclib + cetuximab arm and 19 (31.7%) in the placebo + cetuximab arm. The
median time to deterioration for pain was 8.6 months (95% CI: 1.9, not estimable [NE]) in
the palbociclib + cetuximab arm and 16.7 months (95% CI: 3.7, NE) in theplacebo + cetuximab arm. The HR for time to deterioration of pain was 1.304 (95% CI:
0.717-2.368; p-value = 0.382) with no statistically significant differences between treatment
arms observed.

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Table S13. Time to Deterioration in Patient Reported Pain Symptom – Increase of
10 Points from Baseline as Assessed by the EORTC QLQ-H&N35 Intent-to-Treat Set

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Palbociclib + Cetuximab(N = 65)
25 (38.5)

Placebo + Cetuximab(N = 60)
19 (31.7)

Patient had symptom of pain deterioration of10 points while on study (n [%])
Patient did not have symptom of pain
40 (61.5)
41 (68.3)
deterioration of 10 points while on study (n [%])
Reason for censorship
No symptom of pain assessment or no2 (3.1)2 (3.3)baseline
Off treatment prior to symptom of pain
27 (41.5)
32 (53.3)
deterioration
Patient died in study prior to symptom of pain
9 (13.8)
3 (5.0)deterioration
Patient alive and in study without symptom of
2 (3.1)4 (6.7)
pain deterioration at time of analysis
Kaplan-Meier estimates of time to event (month)
Quartiles (95% CI)a25%
1.2 (1.0, 1.9)
1.9 (1.0, 6.0)50%
8.6 (1.9, NE)
16.7 (3.7, NE)
75%
NE (13.0, NE)
NE (16.7, NE)
Unstratified analysis:
Hazard ratiob (95% exact CI)
1.304 (0.717-2.368)
p-valuec
0.382
Abbreviations: CI = confidence interval, EORTC QLQ-H&N35 = European Organization for Research andTreatment of Cancer Head and Neck Module 35; N/n = number of patients; NE = not estimable.
a. Based on the Brookmeyer and Crowley method.
b. Assuming proportional hazards, a hazard ratio <1 indicated a reduction in hazard rate in favor of
palbociclib + cetuximab.
c. Used a 2-sided unstratified log-rank test and an unstratified Cox proportional hazards model.

Time to Deterioration in Swallowing from Baseline as Assessed by the EORTC QLQ-H&N35:
EORTC QLQ-H&N35 symptom of swallowing time to deterioration as an increase of10 points is provided in Table S14. Patients who had event of swallowing deterioration of10 points while on study were 14 (21.5%) in the palbociclib + cetuximab arm and 19(31.7%) in the placebo + cetuximab arm. The median time to deterioration for swallowing
was 13.0 months (95% CI: 8.6, NE) in the palbociclib + cetuximab arm and 9.3 months(95% CI: 9.3, NE) in the placebo + cetuximab arm. The HR for time to deterioration ofswallowing was 0.655 (95% CI: 0.327-1.312; p-value = 0.241), which indicated a trend infavor of the palbociclib + cetuximab arm compared with the placebo + cetuximab arm,
though not statistically significant.

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Table S14. Time to Deterioration in Swallowing as Assessed with EORTCQLQ-H&N35 – Increase of 10 Points from Baseline- Intent-to-Treat Set

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Palbociclib + Cetuximab(N = 65)
14 (21.5)

Placebo + Cetuximab(N = 60)
19 (31.7)

Patient had symptom of swallowing deterioration of10 points while on study (n [%])
Patient did not have symptom of swallowing
51 (78.5)
41 (68.3)
deterioration of 10 points while on study (n [%])
Reason for censorship
No symptom of swallowing assessment or no2 (3.1)2 (3.3)baseline
Off treatment prior to symptom of swallowing
35 (53.8)
32 (53.3)
deterioration
Patient died in study prior to symptom of
10 (15.4)
3 (5.0)swallowing deterioration
Patient alive and in study without symptom of
4 (6.2)4 (6.7)swallowing deterioration at time of analysis
Kaplan-Meier estimates of time to event (month)
Quartiles (95% CI)a25%
7.4 (1.9, 13.0)
3.5 (1.4, 9.3)
50%
13.0 (8.6, NE)
9.3 (9.3, NE)
75%
NE (11.4, NE)
NE (10.1, NE)
Unstratified analysis:
Hazard ratiob (95% exact CI)
0.655 (0.327-1.312)
p-valuec
0.241
Abbreviations: CI = confidence interval; EORTC QLQ-H&N35 = European Organization for Research andTreatment of Cancer Head and Neck Module 35; N/n = number of patients, NE = not estimable.
a. Based on the Brookmeyer and Crowley method.
b. Assuming proportional hazards, a hazard ratio <1 indicated a reduction in hazard rate in favor of
palbociclib + cetuximab.
c. Used a 2-sided unstratified log-rank test and an unstratified Cox proportional hazards model.

Safety Results:
Overall, 116 (93.5%) of all patients (as-treated population) experienced a total of
884 treatment-emergent AEs (TEAEs): 60 (93.8%) patients in the palbociclib + cetuximab
arm experienced 512 TEAEs and 56 (93.3%) patients in the placebo + cetuximab arm
experienced 372 TEAEs. A higher percentage of patients reported Grade 3 or 4 TEAEs in
the palbociclib + cetuximab arm than in the placebo + cetuximab arm(palbociclib + cetuximab arm: 33 [51.6%] vs placebo + cetuximab arm: 18 [30.0%]). The
proportion of patients with Grade 5 TEAEs (palbociclib + cetuximab arm: 15 [23.4%] vsplacebo + cetuximab arm: 11 [18.3%]) and SAEs (palbociclib + cetuximab arm: 25 [39.1%]
vs placebo + cetuximab arm: 19 [31.7%]) were slightly higher in the palbociclib + cetuximab
arm.
Similar percentages of patients in each treatment arm had TEAEs that were associated withpermanent discontinuation of study (palbociclib + cetuximab arm: 14 [21.9%] vsplacebo + cetuximab arm: 10 [16.7%]) and permanent discontinuation of treatment

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CLINICAL STUDY REPORT SYNOPSIS(palbociclib + cetuximab arm: 17 [26.6%] vs placebo + cetuximab arm: 12 [20.0%]);15 (23.4%) of the patients discontinued palbociclib in the palbociclib + cetuximab arm, and
12 (20.0%) of patients discontinued placebo in the placebo + cetuximab arm. A comparable
percentage of patients permanently discontinued the treatment with cetuximab due to TEAEs
in both treatment arms (palbociclib + cetuximab arm: 16 [25.0%] vs placebo + cetuximab
arm: 11 [18.3%]).

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A larger proportion of patients in the palbociclib + cetuximab arm (57 [89.1%]) had
treatment-related TEAEs when compared with the patients in the placebo + cetuximab arm(47 [78.3%]). The percentages of patients with treatment-related Grade 3 or Grade 4 TEAEs
and SAEs were higher in the palbociclib + cetuximab arm (34 [53.1%] and 7 [10.9%]) thanin the placebo + cetuximab arm (9 [15.0%] and 2 [3.3%]). There was 1 (1.6%) Grade 5
treatment-related TEAE was reported in palbociclib + cetuximab arm and no patient in theplacebo + cetuximab arm reported Grade 5 treatment-related TEAEs. The patient with
Grade 5 treatment-related TEAE died due to cardio-respiratory arrest, which was considered
to be related to cetuximab as well as disease under study.
In the palbociclib + cetuximab treatment arm, 5 (7.8%) of patients discontinued palbociclib
treatment and 6 (9.4%) of patients discontinued cetuximab treatment due to treatment-related
TEAEs. In the placebo + cetuximab arm, only 1 (1.7%) patient discontinued placebo andcetuximab treatments due to treatment-related TEAEs. There was 1 (1.6%) patient in thepalbociclib + cetuximab treatment arm discontinued the study due to treatment-related
TEAEs while no patient in the placebo + cetuximab arm discontinued the study due totreatment-related TEAEs.
The proportion of patients had at least 1 TEAE was comparable between thepalbociclib + cetuximab treatment arm and the placebo + cetuximab treatment arm(60 [93.8%] vs 56 [93.3%]). The most frequently reported TEAEs (25%) in thepalbociclib + cetuximab arm were RASH (39 [60.9%]), rash (27 [42.2%]), NEUTROPENIA(27 [42.2%]), LEUKOPENIA (24 [37.5%]), ANEMIA (23 [35.9%]), anaemia (23 [35.9%]),and neutropenia (18 [28.1%]). The most frequently reported TEAEs (25%) in theplacebo + cetuximab arm were RASH (34 [56.7%]) and rash (21 [35.0%]) (Table S15).
The following TEAEs were reported at a 20% higher frequency in thepalbociclib + cetuximab arm compared with the placebo + cetuximab arm: NEUTROPENIA(27 [42.2%] vs 0), LEUKOPENIA (24 [37.5%] vs 0), neutropenia (18 [28.1%] vs 0),
THROMBOCYTOPENIA (15 [23.4%] vs 0), ANEMIA (23 [35.9%] vs 9 [15.0%]), anemia(23 [35.9%] vs 9 [15.0%]), and leukopenia (13 [20.3%] vs 0) (Table S15).
The most frequently reported treatment-related TEAEs (25%) in thepalbociclib + cetuximab arm were RASH (39 [60.9%]), rash (27 [42.2%]), NEUTROPENIA(26 [40.6%]), LEUKOPENIA (22 [34.4%]), and neutropenia (18 [28.1%]). The mostfrequently reported treatment-related TEAEs (25%) in the placebo + cetuximab arm were
RASH (32 [53.3%]) and rash (19 [31.7%]). The following treatment-related TEAEs were

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reported at a 20% higher frequency in the palbociclib + cetuximab arm compared with theplacebo + cetuximab arm: NEUTROPENIA (26 [40.6%] vs 0), LEUKOPENIA (22 [34.4%]
vs 0), neutropenia (18 [28.1%] vs 0), and THROMBOCYTOPENIA (14 [21.9%] vs 0).
Between the start of treatment and 28 days after last dose, 15 (23.1%) patients in thepalbociclib + cetuximab arm died, of which majority deaths were due to the disease understudy (13 [20.0%]). While in the placebo + cetuximab arm, 11 (18.3%) patients died andmost deaths were due to the disease under study (8 [13.3%]).

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Following the 28-day observation period after last dose until the date of data cutoff(19 July 2018), 30 (46.2%) patients in the palbociclib + cetuximab arm died, of which
majority deaths were due to the disease under study (28 [43.1%]). While in theplacebo + cetuximab arm, 31 (51.7%) patients died and most deaths were due to the disease
under study (29 [48.3%]).
Overall, a higher percentage of patients in the palbociclib + cetuximab arm than in theplacebo + cetuximab arm experienced at least 1 SAE (25 [39.1%] vs 19 [31.7%]). The mostfrequently reported SAEs in the palbociclib + cetuximab arm were disease progression(7 [10.9%]), pneumonia (4 [6.3%]), and febrile neutropenia (2 [3.1%]); all the other SAEs
were reported in 1 (1.6%) patient each. The most frequently reported SAEs in theplacebo + cetuximab arm were disease progression (6 [10.0%]), pulmonary embolism(2 [3.3%]), and sepsis (2 [3.3%]); all the other SAEs were reported in 1 (1.7%) patient each.
The most frequently reported laboratory test abnormalities in both treatment arms were
hemoglobin decreased (40 [64.5%] vs 22 [37.3%]), lymphocytes decreased (absolute)(45 [88.2%] vs 30 [55.6%]), lymphocytes decreased (%) (43 [74.1%] vs 48 [84.2%]), andmagnesium decreased (27 [43.5%] vs 24 [40.7%]). A higher proportion of patients had whiteblood cells (WBC) count decreased in palbociclib + cetuximab arm (32 [51.6%]) comparing
to placebo + cetuximab arm (1 [1.7%]) and total neutrophils decreased (33 [63.5%] vs1 [1.8%]).
TEAEs of weight decreased were reported by 5 (7.8%) patients in palbociclib + cetuximab
arm and 3 (5.0%) patients in the placebo + cetuximab arm. There were no clinically relevantchanges from baseline in any vital signs neither in the palbociclib + cetuximab arm nor in theplacebo + cetuximab arm.
One (1) patient in palbociclib + cetuximab arm had Grade 4 TEAE of ECG QT prolonged
after discontinued from study treatments due to disease progression. The Grade 4 TEAE of
ECG QT prolonged was considered related to disease under study. One (1) patient inplacebo + cetuximab arm had Grade 1 TEAE of ECG QT prolonged, which was consideredrelated to placebo.

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Table S15. Treatment-Emergent Adverse Events by MedDRA Preferred Term (Including all Preferred Terms and ClusteredTerms) and Maximum CTCAE Grade in Descending Order of Frequency in 5% of Patients (All Causalities) –As-Treated Set
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Preferred Term
Any AEs
RASH
Rash
ANEMIA
Anaemia
Dermatitis acneiform
NEUTROPENIALEUKOPENIA
Decreased appetite
Hypomagnesaemia
Neutropenia
FatiguePyrexia
Dysphagia
NauseaSTOMATITIS
THROMBOCYTOPENIA
Diarrhoea
Disease progression
Leukopenia
Asthenia
Constipation
Dry skin
Dyspnoea
Pneumonia
LYMPHOPENIA
Pruritus
White blood cell count decreased
HYPERGLYCEMIA
Neutrophil count decreased
Platelet count decreased
Productive coughHeadache

Grade 1-2
12 (18.8)
33 (51.6)
25 (39.1)
14 (21.9)
14 (21.9)
10 (15.6)6 (9.4)10 (15.6)
10 (15.6)
8 (12.5)5 (7.8)7 (10.9)9 (14.1)
6 (9.4)8 (12.5)
8 (12.5)
10 (15.6)
8 (12.5)0
6 (9.4)5 (7.8)7 (10.9)9 (14.1)
4 (6.3)2 (3.1)4 (6.3)7 (10.9)4 (6.3)5 (7.8)1 (1.6)7 (10.9)6 (9.4)4 (6.3)

Palbociclib + Cetuximab(N = 64)
Grade 3-4
Grade 533 (51.6)
15 (23.4)
6 (9.4)0
2 (3.1)0
9 (14.1)
09 (14.1)
0
4 (6.3)0
21 (32.8)
014 (21.9)
0
2 (3.1)0
3 (4.7)0
13 (20.3)
01 (1.6)000
3 (4.7)000
1 (1.6)0
5 (7.8)0
1 (1.6)00
7 (10.9)
7 (10.9)
0
0
0
0
0
0
0
0
0
5 (7.8)0
6 (9.4)000
7 (10.9)000
9 (14.1)
0
3 (4.7)000
1 (1.6)
0

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Total
60 (93.8)
39 (60.9)
27 (42.2)
23 (35.9)23 (35.9)
14 (21.9)
27 (42.2)
24 (37.5)
12 (18.8)
11 (17.2)
18 (28.1)
8 (12.5)
9 (14.1)
9 (14.1)
8 (12.5)
9 (14.1)
15 (23.4)
9 (14.1)
7 (10.9)
13 (20.3)
5 (7.8)7 (10.9)9 (14.1)
4 (6.3)7 (10.9)
10 (15.6)
7 (10.9)
11 (17.2)
5 (7.8)10 (15.6)
10 (15.6)6 (9.4)5 (7.8)Grade 1-2
27 (45.0)
31 (51.7)
20 (33.3)
5 (8.3)5 (8.3)
11 (18.3)
00
8 (13.3)
7 (11.7)0
7 (11.7)
7 (11.7)
3 (5.0)5 (8.3)5 (8.3)0
5 (8.3)00
7 (11.7)
4 (6.7)3 (5.0)4 (6.7)4 (6.7)
1 (1.7)4 (6.7)0
5 (8.3)00
4 (6.7)4 (6.7)

Placebo + Cetuximab(N = 60)
Grade 3-4
Grade 518 (30.0)
11 (18.3)
3 (5.0)0
1 (1.7)04 (6.7)04 (6.7)0
2 (3.3)00
000
1 (1.7)00
0
00
1 (1.7)000
3 (5.0)02 (3.3)0
1 (1.7)00
0
00
1 (1.7)6 (10.0)0000
1 (1.7)000
4 (6.7)0
1 (1.7)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0

Total
56 (93.3)
34 (56.7)
21 (35.0)
9 (15.0)
9 (15.0)
13 (21.7)
00
9 (15.0)
7 (11.7)08 (13.3)
7 (11.7)
6 (10.0)
7 (11.7)
6 (10.0)05 (8.3)7 (11.7)0
7 (11.7)5 (8.3)3 (5.0)8 (13.3)
5 (8.3)
1 (1.7)4 (6.7)0
5 (8.3)00
4 (6.7)4 (6.7)

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Protocol A5481044

CLINICAL STUDY REPORT SYNOPSIS
Table S15. Treatment-Emergent Adverse Events by MedDRA Preferred Term (Including all Preferred Terms and ClusteredTerms) and Maximum CTCAE Grade in Descending Order of Frequency in 5% of Patients (All Causalities) –As-Treated Set
090177e19093015d\Approved\Approved On: 20-Mar-2019 01:44 (GMT)

Preferred Term

Palbociclib + Cetuximab
Placebo + Cetuximab(N = 64)(N = 60)
Grade 1-2
Grade 3-4
Grade 5
Total
Grade 1-2
Grade 3-4
Grade 5
Total
Hyponatraemia
3 (4.7)
1 (1.6)04 (6.3)2 (3.3)3 (5.0)05 (8.3)
Blood creatinine increased
5 (7.8)00
5 (7.8)3 (5.0)003 (5.0)Dizziness
2 (3.1)00
2 (3.1)6 (10.0)00
6 (10.0)
Hyperglycaemia
3 (4.7)00
3 (4.7)5 (8.3)00
5 (8.3)Lymphopenia
3 (4.7)4 (6.3)0
7 (10.9)
1 (1.7)00
1 (1.7)Neck pain
4 (6.3)
1 (1.6)0
5 (7.8)3 (5.0)003 (5.0)Paronychia
2 (3.1)00
2 (3.1)6 (10.0)00
6 (10.0)
Weight decreased
5 (7.8)00
5 (7.8)2 (3.3)
1 (1.7)0
3 (5.0)Cough
2 (3.1)00
2 (3.1)5 (8.3)00
5 (8.3)
Hypocalcaemia
5 (7.8)1 (1.6)0
6 (9.4)
1 (1.7)00
1 (1.7)
Hypokalaemia
3 (4.7)3 (4.7)0
6 (9.4)
1 (1.7)00
1 (1.7)
Hypotension
3 (4.7)00
3 (4.7)4 (6.7)00
4 (6.7)
Alanine aminotransferase increased
1 (1.6)00
1 (1.6)3 (5.0)2 (3.3)0
5 (8.3)
Aspartate aminotransferase increased
2 (3.1)00
2 (3.1)3 (5.0)1 (1.7)04 (6.7)Hypertension
3 (4.7)
1 (1.6)04 (6.3)0
2 (3.3)0
2 (3.3)Hyperkalaemia
2 (3.1)00
2 (3.1)2 (3.3)
1 (1.7)0
3 (5.0)Oropharyngeal pain
1 (1.6)
1 (1.6)02 (3.1)3 (5.0)003 (5.0)Thrombocytopenia
3 (4.7)2 (3.1)0
5 (7.8)00
00Vomiting
4 (6.3)00
4 (6.3)
1 (1.7)00
1 (1.7)Dehydration0
1 (1.6)0
1 (1.6)3 (5.0)003 (5.0)Hypoalbuminaemia
00003 (5.0)1 (1.7)04 (6.7)
Infection
1 (1.6)00
1 (1.6)2 (3.3)
1 (1.7)0
3 (5.0)Infusion related reaction0
1 (1.6)0
1 (1.6)3 (5.0)003 (5.0)Pain in extremity
1 (1.6)00
1 (1.6)3 (5.0)003 (5.0)Stomatitis
4 (6.3)00
4 (6.3)0
0
0
0
Haematuria
0000
3 (5.0)003 (5.0)
Pain
0
0
0
0
2 (3.3)
1 (1.7)0
3 (5.0)Tumour pain0000
1 (1.7)2 (3.3)0
3 (5.0)Abbreviations: AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Event; MedDRA = Medical Dictionary for Regulatory Activities; N = number ofpatients.

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CLINICAL STUDY REPORT SYNOPSIS

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Conclusions:

The study did not meet its primary endpoint of OS with palbociclib + cetuximab
treatment arm when compared with placebo + cetuximab treatment arm. The estimatedHR using stratified analysis was 0.820 (95% CI [0.536, 1.253]; p-value = 0.180), whichshowed a numerical trend in favor of palbociclib + cetuximab but was not statisticallysignificant. The estimated median OS was 9.7 months (95% CI [7.3, 13.9]) in thepalbociclib + cetuximab treatment arm and 7.8 months (95% CI [6.7, 10.6]) in theplacebo + cetuximab treatment arm.



The study did not meet secondary endpoint of PFS based on the investigator’s assessment.
The estimated HR using stratified analysis was 1.000 (95% CI [0.669, 1.495];
p-value = 0.495), which showed no difference between the 2 treatment arms. The median
PFS was 3.9 months (95% CI [3.6, 5.6]) in the palbociclib + cetuximab treatment arm
and 4.6 months (95% CI [2.3, 5.5]) in the placebo + cetuximab treatment arm.



CR was observed in 2 (3.1%) patients in palbociclib + cetuximab arm and none in theplacebo + cetuximab arm. PR was seen in 16 (24.6%) patients inpalbociclib + cetuximab arm and 15 (25.0%) patients in placebo + cetuximab arm. OR
rate was 27.7% (95% CI [17.3, 40.2]) in palbociclib + cetuximab arm and 25.0% (95% CI[14.7, 37.9]) in placebo + cetuximab arm. CBR was 36.9% (95% CI [25.3, 49.8]) in
palbociclib + cetuximab arm and 36.7% (95% CI [24.6, 50.1]) in placebo + cetuximab
arm. The odds ratio using stratified analysis was 1.013 (95% CI [0.461, 2.230];p-value = 0.5605), which showed no difference between the 2 treatment arms.



Palbociclib exposure following administration of daily 125 mg oral doses withconcomitant treatment with cetuximab in patients with R/M SCCHN, as measured by
WPM-Ctrough, was consistent with prior reported palbociclib PK data in patients withadvanced cancer indicating that concomitant cetuximab use did not have a clinicallymeaningful impact on palbociclib PK.

Cetuximab exposure in patients with R/M SCCHN, as measured by WPM-Ctrough and
WPM-Cendinf in patients without prior dose modifications, was consistent across treatment
arms indicating that concomitant treatment with palbociclib did not have a clinicallymeaningful impact on cetuximab PK.

Tumor tissue p16 IHC
suggested that a certain proportion of thepatients enrolled in the study exhibited characteristics associated with HPV-related
SCCHN.

Use of p16 IHC as a retrospective selection marker with an optimized cutpoint did not
significantly change the study overall outcome.

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CLINICAL STUDY REPORT SYNOPSIS
The PRO results showed similar profiles with EORTC QLQ-C30 scales. No statisticallysignificant differences were observed in global QOL, functioning and symptoms. No
statistically significant difference was observed between treatment arms in delay indeterioration in pain and swallowing difficulty.



The overall change from baseline in symptoms of dry mouth, sticky saliva and feedingtube was found to be statistically significant favoring palbociclib + cetuximab arm
compared with placebo + cetuximab arm.

Overall, the combination of palbociclib + cetuximab was well tolerated and the safety
findings were aligned with the safety profile of both palbociclib and cetuximab. No newsafety findings were identified.

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