Biomarkers for PD-1 checkpoint inhibition Suzanne L. Topalian Johns Hopkins University School of Medicine Sidney Kimmel Comprehensive Cancer Center Thirteenth Annual Kidney Cancer Symposium October 24, 2014
Disclosures Consultant for: Bristol-Myers Squibb (uncompensated), Five Prime Therapeutics, GSK, Jounce Therapeutics, and Amplimmune (spouse) Grant/Research support from: Bristol-Myers Squibb Stock options: Jounce Therapeutics (spouse)
Royalties through institution: Amplimmune (spouse)
Objective response rate (%)
Clinical activity of PD-1 and PD-L1 blocking antibodies validates this pathway as a target for cancer therapy 50 40
MK-3475
30
Nivolumab
20
BMS-936559
10
Anti-PD-1
Anti-PD-L1
MPDL3280A nr
0 Melanoma
NSCLC
nr, not reported
RCC
ASCO 2014: New evidence for activity in advanced bladder cancer (ORR 25%, MPDL), SCCHN (20%, MK-3475; 14%, MEDI4736); ovarian cancer (17%, nivo)
Objective response rate (%)
Clinical activity of PD-1 and PD-L1 blocking antibodies validates this pathway as a target for cancer therapy 50
????
40 30
MK-3475 Nivolumab
20
BMS-936559
10
MPDL3280A nr
0 Melanoma
NSCLC
nr, not reported
RCC
Anti-PD-1
Anti-PD-L1
Role of PD-1 pathway in suppressing antitumor immunityActivation (cytokines, lysis, prolif., migration)
APC
T cell B7.1
MHC-Ag
CD28 TCR Signal 1
PD-1 PD-L1 Tumor
(-)
Inhibition (anergy, exhaustion, death)
(-)
(-)
Tumor
AntiPD-1
Factors potentially influencing response to PD-1 pathway blockade 2) T cell migration/proliferation
APC
T cell B7.1
MHC-Ag
CD28 TCR
1) T cell specificity
Tumor
PD-1 PD-L1
(-)
3) Tumor cell PD-L1 expression
(-)
(-)
Tumor
AntiPD-1
Mutational heterogeneity in cancer creates opportunities for immune recognition Lawrence et al., Nature 2013
Does tumor mutational density predict response to immunotherapy (pre-Rx marker)? Is successful immunotherapy associated with reactivity against specific mutant tumor antigens (on-Rx marker)?
Cancer exome-guided on-treatment analysis of effects of ipilimumab: Evolution of dominant CD8+ T cell response against melanoma-associated mutation in a responding patient 5X
1075 non-synonomous somatic mutations
Adapted from van Rooij et al., JCO 2013
On-treatment biomarkers: selective infiltration of CD8+ T cells precedes melanoma response to anti-PD-1 Pre-Rx
Pre-Rx
2.6 cm 1 12 wk post Dose
4 wk post Dose 1
2.4 cm 8 wk post Dose 3
4 wk post Dose 3
Intermittent dosing regimen of nivolumab (Brahmer et al., JCO 2010)
Melanoma
Preliminary correlation of PD-L1 expression in pre-treatment tumor biopsies, with clinical response to anti-PD-1 therapy 18/18
Proportion of patients
1
Kidney
0.8 18/31
0.6
0.4
CR/PR PD-L1(+) NR
13/31
0.2
Lung
p=0.002 0/18
0 PD-L1(+)
PD-L1(-) 49 patients include 20 with melanoma,13 NSCLC, 7 colon, 6 kidney, and 3 prostate cancer (adapted from Topalian et al., NEJM 2012)
PD-L1 IHC methods currently in testing JHU
BMS
Merck
Roche
mAb clone
5H1
28-8
22C3
SP142
Automated
No
Yes
Yes
Yes
Staining location scored
Membrane
Membrane
Membrane
Membrane
Cell type(s) scored
Tumor cells
Tumor cells
Tumor and/or infiltrating imm. cells
Infiltrating immune cells
Positive cutoff
≥ 5%
≥ 5%
≥ 1%
≥ 1% to ≥ 10% (“IHC 1-2-3”)
Note: these assays are still under development pending additional clinical correlative data
n=
iv
ba iz d & s e um N t a ab ec lA M k SC el O an 20 om 14 a )
(T o l op u al m ia a N n et a b S iv l. N o EJ lid (W o l eb u m M 2 T er 0 u AS ab 12) m N CO M or iv 2 e s 01 o (G l 3 l ro um ) an ss om o et ab a M al. M P D AS e C (H L O la er 3 20 n bs 2 13 o te 8 ) m 0 t a M al a A PD SC So O (H L 20 lid am 3 id 28 13) T um e M t al A 0a or P SC M s O e (S DL 20 la or 3 13 n ia l e 28 ) om ta 0 Pe l E a a m C C 2 NS (D b 01 C au r 3) L C d ol et iz a u Pe l A m m A C R ab (G b 20 an r 14 M dh ol ) el i e iz an u t M al m om PD AAC a b (P R a ow L3 20 N 14 S el 2 C se 8 0 ) LC Pe t al A a B m SCO la (S b 20 dd el r 14 e w o er li ) r te z u t Pe al A m m SCO ab (R bro 201 He i l 4) a
N
Intra-tumoral PD-L1 expression and response to PD-1/PD-L1 blockade
Response Rates 42 44 34 94 30 53 113 129 65 55 411
Unselected 21% 32% 29% 22% 23% 23% 40% 19% 26% 18% 40%
PD-L1 + 36% 67% 44% 39% 27% 46% 49% 37% 43% 46% 49%
PD-L1 − 0% 19% 17% 13% 20% 15%* 13% 11% 11% 11% 13%
Presented by: Margaret Callahan
Pitfalls for PD-L1 “biomarker”: Immunologic heterogeneity of anatomically and chronologically distinct tumors Patient no.
Clinical Resp.
Biopsy site
1
NR
SQ met #1
5-10
SQ met #2
0
Skin primary
20
LN met
0
Skin primary
5
SQ met
0
LN met
0
Skin primary
5
LN met #1
0
LN met #2
5
Lung met #1
5
Lung met #2
50
2
3
4
5
NR
CR
NR
PR
PD-L1 IHC (%pos. tumor cells)
Variable expression of PD-L1 among melanoma lesions from individual patients receiving anti-PD-1 therapy. “PD-L1+ tumor”: ≥ 5% tumor cells with cell surface PD-L1 expression “PD-L1+ patient”: patient in whom any tumor is/was PD-L1+ (Topalian et al., NEJM 2012)
Pitfalls for PD-L1 biomarker: focal expression in some tumors “Marker negative” specimen or sampling error???
Invasive primary melanoma, nodular subtype. 10% of tumor cells express PD-L1.
Tumor
Lymphs
Association of TILs with tumor PD-L1: TILs are necessary but not sufficient for PD-L1 expression in melanoma % of cases
100 80
TILs No TILs
60
p
