INTRoduCTIoN Methods MeTHodS oBjeCTIveS ...

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TPS6107. Phase IB study of pembrolizumab in combination with chemoradiotherapy (CRT) for locally-advanced squamous cell carcinoma of the head and neck ...
LGF TPS6107 !, ,-26()&+(%"72&"'(&"'.('4"-!!&(+"(-!+)6@A(+%(%%6> Phase IB study of pembrolizumab in combination with chemoradiotherapy (CRT) LGFM for 3',*2&(2,%%+"'(&(-!!''$@ > A locally-advanced squamous cell carcinoma of the head and neck (LA-SCCHN) !, ,-26()&+(%"72&"'(&"'.('4"-!!&(+"(-!+)6@A(+%(%%6>LGFM

2 1 2 1 1 3 G9+$2-2(-"-2 H9"%%"&!+%,)'(, G9,!%66' ',' H96' ''-!(4$ G9"!% (!+G92,'22&%I9!+",. Steven-3'+'",(4%% F. Powell1, Mark M. Gitau , William C. Spanos , Ashley W. Jensen , Ryan K. Nowak , Michele M. Lohr , Susan E. Puumala , LGFM 3',*2&(2,%%+"'(&(-!!''$@ > A !, ,-26()&+(%"72&"'(&"'.('4"-!!&(+"(-!+)6@A(+%(%%6> 3 3 4 5 5 5 1 Christie A. Ellison , Lora J. Black , Jonathan D. Cheng , Assuntina G. Sacco , Kathryn A. Gold , Ezra E.W. Cohen , John H. Lee I I J K K G

%%",(' 9 (+ '%$ 9 ('-!'+2+3"3%@ •  -6'(%+"%"-6  ))+(5"&-%6LKF9FFF" '(,,)+6+ Treatment

'-+(2.(' G Pembrolizumab 200 mg CRT? •  (&)%-,)(',@A •  3+%%2+3"3%@A         Stage PRIMARY OBJECTIVES SECONDARY OBJECTIVES 1  ))+(5"&-%6LKF9FFF" '(,,)+6+ Treatment days III-IVB Pembrolizumab 200 with approximately ",-!L-!&(,-(&&('&%" 650,000 diagnoses per year CRT? •  3+%%2+3"3%@A • #.3, (&)%-,)(',@A Treatment Naïve Concurrent Treatment ''64(+%>4"4"-! +--+-&'-' • 

((+ "('%('-+(%- Adjuvant days •  +&"',,-'+(+92+.3().('(+ -7 (load), 15, 36 III-IVB Completed •  +( +,,"('>+2+3"3%@A •  -6'(%+"%"-6 SCCHN? " 2+H;-26!&>FHKNLHFM Pembrolizumab 200 mg days 57, 78, 99, G Pembrolizumab 200 mg Stage • Safety and Tolerability • Progression-Free Survival (PFS)

'-+(2.(' ))+(5"&-%6LKF9FFF" '(,,)+6+  @ A • 

((+ "('%('-+(%- +--+-&'-' Treatment

>  Weekly Cisplatin 40 mg/m2 •  +&"',,-'+(+92+.3().('(+ -7 (load), 15, 36         •  3+%%2+3"3%@A CRT? • 57, (&)%-,)(',@A • CRT remains a standard of care, curative option for 120, 141 SCCHN? days mg days 78, 99, III-IVB •  ((+ ",-'--,-,",@A+- Pembrolizumab 200 days 1, 8, 15,Treatment 22, 29, 36 •  K>6+,2+3"3%+-,+&"'%,,-!'KFR • Complete Response (CR) • Overall Survival (OS) Yes Treatment Naïve Concurrent @ A  ",-!L-!&(,-(&&('&%" ''64(+%>4"4"-! Yes Adjuvant •  "('%('-+(%- +--+-&'-'

>  Weekly Cisplatin 40 mg/m2 •  +&"',,-'+(+92+.3().('(+ -7 (load), 15, 36 Completed mg days 57, 78,120, •  • +( +,,"('>+2+3"3%@A •  -6'(%+"%"-6 SCCHN? LA-SCCHN ))+(5"&-%6LKF9FFF" '(,,)+6+G 99, ,-(3+%%+,)(',+- 141 Radiation 70 Gy in 35 Pembrolizumab 200 mg Stage rate at Treatment End @ A H Treatment • Locoregional Control Rate (LCR)

>  •  ",-'--,-,",@A+ &&2'%+'",+".%"'-!!(,-+,)(',-( Weekly Cisplatin 40 mg/m2 days 1, 8, 15, 22, 29, 36 •  K>6+,2+3"3%+-,+&"'%,,-!'KFR •  3+%%2+3"3%@A CRT? •  (&)%-,)(',@A Yes fractions 120, 141 @A Yes days III-IVB Pembrolizumab 200 •  ",-'--,-,",@A+- 1, 8, 15, 22, 29, 36 •  K>6+,2+3"3%+-,+&"'%,,-!'KFR Yes -7days • Distant Metastasis (DM) rate • 5-year survival • rates remain less than 50% Yes 35 •  •  ((+ "('%('-+(%- +--+-&'-' •  ,-(3+%%+,)(',+- +&"',,-'+(+92+.3().('(+ (load), 15, 36 Radiation 70 Gy in 2,"' -! B •  '--+',%.('%+,+!&(',-+--!--! H SCCHN?

&&2'%+'",+".%"'-!!(,-+,)(',-( H

> 

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mg days 57,Treatment 78, 99, Radiation 70 Gy in 35 PR, SD,120, or 141 Weekly Cisplatin 40 mg/m2 fractions fractions End days 1, 8, 15, 22, 29, 36 Salvage SurgeryYes PD Imaging Radiation 70 Gy in 35 Treatment PR, SD, or (if feasible) (PET/CT) fractions End

•  ,-(3+%%+,)(',+- @ A • Best overall@A response rate (ORR) ,2+36 )+( +&&-!+)-(+G@>GA'"-,%" ' 2 @A Immune clearance is in the host response to CRT •  ",-'--,-,",@A+- •  critical K>6+,2+3"3%+-,+&"'%,,-!'KFR Yes @> G9> HA"'-+.('&6)%6+(%"' • PRO using the FACT H&N survey •  2,"' -! B •  2,"' -! B •  '--+',%.('%+,+!&(',-+--!--! •  '--+',%.('%+,+!&(',-+--!--! •  ,-(3+%%+,)(',+- I9J H "&&2',)( 2+"'  Treatment ,2+36

&&2'%+'",+".%"'-!!(,-+,)(',-( )+( +&&-!+)-(+G@>GA'"-,%" ' • Recent translational research demonstrated that the Safety and Survival PR, SD, or ,2+36 $"' '$''!*$#?%%6(2-(&,4"%% )+( +&&-!+)-(+G@>GA'"-,%" ' @A End PD @> G9> HA"'-+.('&6)%6+(%"' Follow-up &+(%"72&",!2&'"7

J&('(%('%'.(6 (++%-4"-!,%"'> G5)+,,"(',('-!$( •  2,"' -! B Salvage Surgery programmed death receptor 1 (PD-1) and its ligand •  '--+',%.('%+,+!&(',-+--!--! Imaging PD @> G9> HA"'-+.('&6)%6+(%"' I9J Biomarker Correlation – All efficacy outcomes will be Treatment Salvage Surgery "&&2',)( 2+"'  -!-%($,-!","'-+.(''&6+,-(+>%%.3"-6"' > G HHI)!+&5-,- Imaging CR PR, SD, or (if feasible) ,2+36 Safety and Survival )+( +&&-!+)-(+G@>GA'"-,%" ' (PET/CT) $"' '$''!*$#?%%6(2-(&,4"%% I9J "&&2',)( 2+"'  (PD-L1, PD-L2)&+(%"72&",!2&'"7

interaction may play a role in immune End -!",,0'  (if feasible) PD correlated with baseline PD-L1 expression based on the Safety and Survival Follow-up J&('(%('%'.(6 @> G9> HA"'-+.('&6)%6+(%"' (PET/CT) (++%-4"-!,%"'> G5)+,,"(',('-!$( $"' '$''!*$#?%%6(2-(&,4"%% Salvage Surgery 3,4 Imaging $''!*-(' I9J escape of SCCHN during CRT -!-%($,-!","'-+.(''&6+,-(+>%%.3"-6"' •  >G"'!"".('"'(&"'.('4"-!",)%.'>, > G HHI)!+&5-,- "&&2',)( 2+"'  CR Follow-up &+(%"72&",!2&'"7 J&('(%('%'.(6 (++%-4"-!,%"'> G5)+,,"(',('-!$( Dako PD-L1 IHC 22C3 pharmDx test (if feasible) Safety and Survival (PET/CT) $"' '$''!*$#?%%6(2-(&,4"%% -!",,0'  ,2 ,-,,6'+ 6"')+>%"'"% &(2, Follow-up " 2+I; 6 '%2,"(''5%2,"('+"-+" J&('(%('%'.(6 -!-%($,-!","'-+.(''&6+,-(+>%%.3"-6"' (++%-4"-!,%"'> G5)+,,"(',('-!$( CR K Pembrolizumab is&+(%"72&",!2&'"7

a humanized IgG4 monoclonal antibody !$.0)$")'0> G HHI)!+&5-,- &(%@" 2+GA  $''!*-(' •  >G"'!"".('"'(&"'.('4"-!",)%.'>, -!-%($,-!","'-+.(''&6+,-(+>%%.3"-6"' > G HHI)!+&5-,- CR -!",,0'           •  %"'"%'%6,",(-!",,-+- 6",4++'- 3*5* that blocks this interaction ,-,,6'+ 6"')+>%"'"% &(2, -!",,0',2  " 2+I; 6 '%2,"(''5%2,"('+"-+" "#*  *2&(2,%%+"'(&(-!(+%3"-6 +"(+!&(-!+)69+"(-!+)69(+ K !$.0)$")'0 &(%@" 2+GA  •  >G"'!"".('"'(&"'.('4"-!",)%.'>, $''!*-(' @5%2"' %")A9(+()!+6'59!6)()!+6'59(+ "&&2'(-!+)6(+  ! !&% # •  >G"'!"".('"'(&"'.('4"-!",)%.'>, • PD-1 inhibition in• combination with cisplatin-based         %"'"%'%6,",(-!",,-+- 6",4++'- 3*5* !$$ %+6'5 ,2 ,-,,6'+ 6"')+>%"'"% &(2, ,2 ,-,,6'+ 6"')+>%"'"% &(2, " 2+I; 6 '%2,"(''5%2,"('+"-+" " 2+I; 6 '%2,"(''5%2,"('+"-+" "#*  *2&(2,%%+"'(&(-!(+%3"-6 +"(+!&(-!+)69+"(-!+)69(+ CRT suggests synergy in a pre-clinical SCCHN mouse K Flow !$.0)$")'0 !$.0)$")'0 K - 

9 9(+  -  @",-'-&-,-,,A",, " 2+G &(%@"  "2+GA 2+G &(%@" 2+GA  @5%2"' %")A9(+()!+6'59!6)()!+6'59(+ "&&2'(-!+)6(+  ! !&% #          Cytometry  UGN ('2++'-.3&%" ''6@5%2"' ,$"' •  5 %"'"%'%6,",(-!",,-+- 6",4++'- 3*5* model (Figure 1) !$$ %+6'5           •  %"'"%'%6,",(-!",,-+- 6",4++'- 3*5* ,%%%',*2&(2,%%+"'(&,A "#*  *2&(2,%%+"'(&(-!(+%3"-6 +"(+!&(-!+)69+"(-!+)69(+ CD4,& CD8," Tregs, - 

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)! )$#  G"( +)!"(&)%-+,)(',@+A:(+ >(&)%--!-+-&'-'"& "' ,-26 •  %())+>+,('OKR(''"'-+3%(+-!)+()(+. •  2%%'%6,",-@A)()2%.(' •  "' %>+&9&2%.>,"-9()'>%%-+"%()&+(%"72& *$#  $()5*$# ,"$'%"#( the analysis of safety data ####$# +'"'  #!,'6" 7 -!(, >(&)%-&-(%"+,)(',@A:(+ >"3-%,-('(,(,-26-+-&'-9 @ >IJMKA2,"'(&"'.('4"-!,-'+9",)%.'>   ((%"'"%"'-+,-4"%%,.&-2,"' 5-&,,,,&'-,'(%%(4>2) • Clopper-Pearson 95% confidence interval for the proportion •  +-&'-9-26","-,9'(++%.3,-26)+(2+,4!"%('.3-+-&'- "$,("$!4A+,)(', +', (((("#) >-!(%( "(&)%-+,)(',@)A",%3 ,2+ +6 >(&)%--!-+-&'-'"& "' ,-26 ,9'".3"').'-,4"-!,- 

>   •  "' %>+&9&2%.>,"-9()'>%%-+"%()&+(%"72& ####$# +(2-%"'"'" 2+J ,('"'(&"%",-+"2.(' 6 52) 3%2-(-!-!,-6'6(-!",'(3% G(GH6BF7 +(2-%"'"'" 2+J $''!*-!$$ H>G +(2)A >(&)%--!-+-&'-'"& "' ,-26 '(' 9-%%%-+"%()&+(%"72& Efficacy (&"'.('  4"%%'+(%%-( HFFO:GIK@GGA;GGIM>JLJL"3-%,-('(,(,-26-+-&'-9 IGL-+-&'--2&(+,)"&',''6,%3 ,2+ "%,)"&',4"%%(%%- HKIHFFGH •  (++%.3%((,&)%,(%%-2+"' -!+)6'-GH&('-!,)(,->-+-&'- •  6 '%2,"(''5%2,"('+"-+"+%",-"'" 2+I Safety and Survival Follow-up >(&)%--!-+-&'-'"& "' ,-26 $'(4% &'-, +$!+)B(!&(+)''(+,+! -Receive at least one dose of study treatment, •  "' %>+&9&2%.>,"-9()'>%%-+"%()&+(%"72& &('-!,)(,->-+-&'- ####$# (+-+',%.('%+,+! J"$9-%   $'(4% &'-, +(2-%"'"'" 2+J progression at 3, 6, 12, 24, 36, 48, and 60 months (+-+',%.('%+,+! G  4"%%'+(%%-( •  -262'-!+(2 !-!+$ '3,. -(+-2",+( +&@ A9 following treatment and neck imaging (CT) $)&"''  (,&! with head •  (++%.3%((,&)%,(%%-2+"' -!+)6'-GH&('-!,)(,->-+-&'-   )   )GJ-+-&'--2&(+,)"&',''6,%3 ,2+ "%,)"&',4"%%(%%- specimens will be collected for translational research $'(4% &'-, (+-+',%.('%+,+! Acknowledgements • Correlative blood samples collected during therapy and •  -262'-!+(2 !-!+$ '3,. -(+-2",+( +&@ •  (++%.3%((,&)%,(%%-2+"' -!+)6'-GH&('-!,)(,->-+-&'-

at 12 months post-treatment

+$!+)B(!&(+)''(+,+! • Study funded through the Merck Investigator Studies Program (MISP), Merck Sharp & Dohme Corp and Sanford Research

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