increasing role of radiation therapy in melanoma alone and ... · • tumor ag presentation by dcs...

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