increasing role of radiation therapy in melanoma alone and ... · • tumor ag presentation by dcs...
TRANSCRIPT
Increasing Role of Radiation Therapy in
Melanoma Alone and in Combination
with Other Modalities
2/27/16
Emory School of Medicine
Amit Maity, MD, PhD
Professor and Vice-Chair, Clinical Division
Dept. of Radiation Oncology
Perelman School of Medicine of the University of
Pennsylvania
2
Radiation therapy for melanoma
Historically used for
• Primary disease: very limited use
• Regional disease:
– s/p resection: to improve local control in
selected situations
– palliation in unresectable cases
• Metastatic disease
3
Radiation therapy for regional disease
Phase 3 studies +/- nodal adjuvant RT for
melanoma
Group # pts. RT dose
(Gy)
Local
relapse (LR)
rate
Hazard ratio
for LR
5 yr OS 5 yr DFS
Mayo
(1978)
56 50 11 (RT) vs.
3% (no RT)
- - -
ANZMTG/
TROG
(2015)
123 48 21 vs. 36%
(p = 0.023)
0.52 (95%
CI: 0.31 –
0.88)
NS NS
4
NCCN recommendations for adjuvant RT
Risk of nodal recurrence is related to:
• # nodes involved
• extranodal extension
• size of tumor
5
Can radiation be used in a completely
different way in the treatment of melanoma,
to augment immune response?
6
15 Gy25 Gy
Evidence that immune response plays major role in response to RT:
Lee Y, et al. “Therapeutic effects of ablative radiation on local tumor
require CD8+ T cells: changing strategies for cancer treatment.”
Immunodeficiency abrogates antitumor effect of RT
For optimal local control after RT, CD8+ cells are required.
Lee Y, et al. Blood 2009
7
RT can augment immune response
T cell migration and effector T cell function
• Endothelial cell adhesion molecules
(VCAM-1, E-selectin,..)
• T cell chemokines
• MHC molecules on tumor cells
• FAS death receptor on tumor cells
• CXCL16 (recruits activated effector T cells)
TLR4 on dendritic cells (DCs)
vascular permeability: influx of leukocytes
priming of T cells in draining lymph nodes
• tumor Ag presentation by DCs
Shiao SL and Coussens LM
J Mammary Gland Biol Neoplasia 2012
Burnette, et al.
Frontiers Oncol 2012
8
By its nature, RT is a local form of therapy
However, can it be used to potentiate a systemic response?
Preclinical studies: Formenti and Demaria, Fu and Weichselbaum and other groups
Irradiated tumors can potentially serve as a source of tumor antigens in vivo, where dying tumor cells would release various tumor antigens slowly over time.
Using irradiated tumor as in situ tumor vaccine
9
Strategies for Anticancer ImmunotherapyS
RS
/ H
yR
T
Weinberg R The Biology of Cancer
10
Ipilimumab improves OS in metastatic
melanoma
Clinical design676 pts with met melanoma
Progression despite one prior Rx
Ipi vs. gp100 vaccine vs. both q3wk x 4
ResultsIpi arms extended
median survival by 4mo
Improved 1 yr survival from 25% to 43%
Hodi, et al. NEJM 2010
11
Ipilimumab improves OS in metastatic
melanoma
Clinical design676 pts with met melanoma
Progression despite one prior Rx
Ipi vs. gp100 vaccine vs. both q3wk x 4
ResultsIpi arms extended
median survival by 4mo
Improved 1 yr survival from 25% to 43%
Hodi, et al. NEJM 2010
Overall response rate is only 10-15%!
12
Baselin
e
1-1
1-1
1
Abscopal effect in melanoma patient after treatment
with CP-870,893 and tremelimumab
51-year-old man with refractory metastatic melanoma (BRAF WT)Enrolled on clinical trial UPCC 05609 (PI, Vonderheide)1-13-11: Received anti-CTLA-4 mAb tremelimumab (10 mg/kg) (T1/2 3 weeks)1-14-11: Received agonistic CD40 mAb CP-870,893 (0.2 mg/kg)
13
Baselin
e
1-1
1-1
1
4 w
eeks
2-8
-11
5 m
on
ths
6-2
4-1
111 m
on
ths
12
-13
-11
Abscopal effect in melanoma patient after treatment
with CP-870,893 and tremelimumab
14
Baselin
e
1-1
1-1
1
4 w
eeks
2-8
-11
5 m
on
ths
6-2
4-1
111 m
on
ths
12
-13
-11
Abscopal effect in melanoma patient after treatment
with CP-870,893 and tremelimumab
1-31-11 to 2-14-11: Hypofractionated short-course RT to left chest wall
15
Baselin
e
1-1
1-1
1
4 w
eeks
2-8
-11
5 m
on
ths
6-2
4-1
111 m
on
ths
12
-13
-11
Abscopal effect in melanoma patient after treatment
with CP-870,893 and tremelimumab
16
Postow, et al.
NEJM 2012
“Immunologic
Correlates of the
Abscopal Effect in
a Patient with
Melanoma”
9.5 Gy x 3
17
Previously treated or untreated stage IV
melanoma
Index lesion >1 cm
ECOG PS 0 or 1
Adequate renal, hepatic, and hematological
function
No presence or history of CNS lesion
No prior radiation therapy that precludes SBRT
RADVAXTM: A Stratified phase I/II dose escalation trial of
hypofrac RT followed by ipilimumab in metastatic melanoma
18
UPCC 06611 “RADVAX”
Clinicaltrials.gov NCT01497808
Hypofractionated
RT to single
‘index’ lesion(over 3- 7 days)
ipilimumab
i.v. q3weeks x 41st ipi 5 days after RT
RT #3
Stratum 1: lung or bone
DL1 8 Gy x 2; DL2 8 Gy x 3
Stratum 2: liver or s.c.
DL1 6Gy x 2; DL2 6 Gy x 3
Enrollment
Baseline studies
and stagingFollow up
Restaging
Biosamples and analysis
RT #2RT #1
RADVAX™ Trial Schema
19
Dose 8 Gy x 2
(n=6)
6 Gy x 2
(n=6)
8 Gy x 3
(n=4)
6 Gy x 3
(n= 6)
Site of index
(irradiated) lesion:
lung Liver/
subcutaneous
lung Liver/
subcutaneous
Gender
Male 5 (83%) 5 (83%) 2 (50%) 5 (83%)
Female 1 (17%) 1 (17%) 2 (50%) 1 (17%)
Patient age (years)
18-44 0 0 0 0
45-64 3 (50%) 2 (33%) 3 (75%) 0
>=65 3 (50%) 4 (67%) 1 (25%) 6 (100%)
ECOG PS
0 4 (67%) 3 (50%) 3 (75%) 2 (33%)
1 2 (33%) 3 (50%) 1 (25%) 4 (67%)
Patient characteristics
20
Results
22 patients enrolled • Lung (n=10); liver (n=3); subcutaneous (n=9)
No dose limiting acute toxicities related to RT, Dose-limiting colitis related to ipilimumab: 2
patients; one case of cytokine release syndrome after ipilimumab
Sixteen grade 3 toxicities (11 patients)• anemia most common (4 patients)
no grade 4 or 5 toxicities
21
Baseline 4d s/p SBRT 2mo s/p ipi #4
SBRT
to index
lesion
Tumor response to SBRT/ipilimumab
RECIST: -68% (exclude index)
22
23
RT + anti CTLA4: improved response in mice
Long-term
control
24
Survival in mice and patients
25
Insights into resistance to RT + anti CTLA4 in mice
26
Insights into resistance to RT + anti CTLA4 in mice
27
Insights into resistance to RT + anti CTLA4 in mice
28
Insights into resistance to RT + anti CTLA4 in mice
Resistant tumors show increased PD-L1 on melanoma cells
29
Mouse melanoma model: PD-L1 knockout (or blockade) improves
response to RT + anti CTLA-4
PD-L1 CRISPR koA.
30
Mouse melanoma model: PD-L1 knockout (or blockade) improves
response to RT + anti CTLA-4
PD-L1 CRISPR koA.
Days Days
Results with combination RxB.
31
PD-1 Immune Checkpoint Drives T Cell Exhaustion
32
PD-1 Immune Checkpoint Drives T Cell Exhaustion
33
PD-1 Immune Checkpoint Drives T Cell Exhaustion
Exhausted T cells: Eomes+/PD-1+
Reinvigorated T cells: GzmB+/Ki67+
34
Random Forest modeling
• Anti CTLA-4: reduces Treg
• Anti PD-1/PD-L1: increases CD8 cells (by reinvigoration)
35
Random Forest modeling
• Anti CTLA-4: reduces Treg
• Anti PD-1/PD-L1: increases CD8 cells (by reinvigoration)
CD8/Treg ratio
36
Random Forest modeling
• Anti CTLA-4: reduces Treg
• Anti PD-1/PD-L1: increases CD8 cells (by reinvigoration)
CD8/Treg ratio
37
Random Forest modeling
• Anti CTLA-4: reduces Treg
• Anti PD-1/PD-L1: increases CD8 cells (by reinvigoration)
• RT: increases TCR diversity in TILs
CD8/Treg ratio
38
RADVAX trial: tumor PD-L1 predicts survival after RT + ipilimumab
A.
39
RADVAX trial: tumor PD-L1 predicts survival after RT + ipilimumab
A.
Low PD-L1
Hi PD-L1
B.
40
RADVAX pts.: low tumor PD-L1 predicts T cell reinvigoration post RT/ipi
A. High PD-L1 Low PD-L1
PT. 102 PT. 402
41
RADVAX pts.: low tumor PD-L1 predicts T cell reinvigoration post RT/ipi
Change %
Ki6
7+
Gzm
B+
Tumor Expression
B.
2 pts. with low tumor PD-L1:
%Ki67+/GzmB+ cells increased in PD-1+/Eomes+ T cells after RT/ipi
A. High PD-L1 Low PD-L1
PT. 102 PT. 402
42
Preclinical evidence of PD-1/PD-L1/CTLA-4 with radiation
MELANOMA
BREAST CANCER PANCREATIC CANCER
43
Conclusions
Ipilimumab and hypofractionated XRT are tolerated well in the RADVAXTM trial
No DLTs related to radiation • Toxicities are related to the administration of
ipilimumab
One resistance mechanism to RT + anti CTLA-4 may be upregulation of PD-L1 in tumor and T cell exhaustion
Optimal results in mouse model: RT + anti CTLA-4 + anti PD-1/PD-L1
44
PD-1 RADVAX:
A stratified phase I trial of pembrolizumab (PD-1 mAb)
with hypofractionated radiotherapy in patients
with advanced and metastatic cancers
PI: Amit Maity
45
46
UPCC 40914
Clinicaltrials.gov NCT02303990
PI: Amit Maity
RADVAX: A Stratified Phase I Trial of Pembrolizumab with
Hypofractionated RT in Patients with Advanced/Metastatic Cancers
47
ACCRUAL
49
50
Future Directions
MELANOMA
BREAST CANCER PANCREATIC CANCER
51
PD-L1/CTLA-4-RADVAX:
A stratified phase I trial of MEDI4736 (PD-L1 mAb) and
tremelimumab (CTLA-4 mAb) with hypofractionated
radiotherapy in patients with metastatic
melanoma, lung, breast, and pancreatic cancer
PI: Robert Vonderheide
IRB submitted
STUDY DESIGN
• Single institution, investigator-sponsored phase I trial
• Patients with metastatic melanoma, metastatic non-small cell lung
(NSCLC), metastatic breast cancer, or metastatic pancreatic
cancer.
• Patients will receive MEDI4736 15 mg/kg every 4 weeks by IV
infusion for up to one year, in combination with tremelimumab 3
mg/kg every 4 weeks by IV infusion (tapers to every 12 weeks after
the 4th tremelimumab dose for 2 more doses).
• Two radiotherapy schedules will be evaluated in sequence
- Cohort 1 tests 8 Gy x 3 fractions, given over one week.
- Cohort 2 tests 17 Gy x 1 fraction.
• There will be a maximum of 15 evaluable patients in each
treatment cohort.
52
HFRT to single
index lesion
(8 Gy x 3/17 Gy x 1) Durvalumab
q 2 weeks x 18 or disease
progressionEnroll
Tremelimumab/
durvalumab q 4 weeks x 4 doses UPCC 23915
Clinical trials.gov
NCT02639026
PI: R. Vonderheide
Trial schema