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?
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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, -
9 9(+ - @",-'-&-,-,,A",, &,## " 2+G " 2+G "#* *2&(2,%%+"'(&(-!(+%3"-6 +"(+!&(-!+)69+"(-!+)69(+ @5%2"' %")A9(+()!+6'59!6)()!+6'59(+ "&&2'(-!+)6(+ ! !&% # F>G .3"'.(', • Clinical analysis of this strategy is warranted $"% UGN ('2++'-.3&%" ''6@5%2"' ,$"' MDSC populations & !$$ %+6'5 @5%2"' %")A9(+()!+6'59!6)()!+6'59(+ "&&2'(-!+)6(+
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9 9(+ - @",-'-&-,-,,A",, GG UGN ('2++'-.3&%" ''6@5%2"' ,$"' RNA $"% IHC .3"'.(', & ,"$' T",)%.'JF& =&H -.,.%'%6,",
& "' ? ,%%%',*2&(2,%%+"'(&,A Sequencing Tumor
)! )$# G"( +)!"(&)%-+,)(',@+A:(+ >(&)%--!-+-&'-'"& "' ,-26 • %())+>+,('OKR(''"'-+3%(+-!)+()(+. • 2%%'%6,",-@A)()2%.(' • "' %>+&9&2%.>,"-9()'>%%-+"%()&+(%"72& *$# $()5*$# ,"$'%"#( the analysis of safety data ####$# +'"' #!,'6"7 -!(, >(&)%-&-(%"+,)(',@A:(+ >"3-%,-('(,(,-26-+-&'-9 @ >IJMKA2,"'(&"'.('4"-!,-'+9",)%.'> ((%"'"%"'-+,-4"%%,.&-2,"' 5-&,,,,&'-,'(%%(4>2) • Clopper-Pearson 95% confidence interval for the proportion • +-&'-9-26","-,9'(++%.3,-26)+(2+,4!"%('.3-+-&'- "$,("$!4A+,)(', +', (((("#) >-!(%( "(&)%-+,)(',@)A",%3 ,2+ +6 >(&)%--!-+-&'-'"& "' ,-26 ,9'".3"').'-,4"-!,-
> • "' %>+&9&2%.>,"-9()'>%%-+"%()&+(%"72& ####$# +(2-%"'"'" 2+J ,('"'(&"%",-+"2.(' 6 52) 3%2-(-!-!,-6'6(-!",'(3% G(GH6BF7 +(2-%"'"'" 2+J $''!*-!$$ 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