Immunotherapy for Melanoma: The End of The Beginning. Jedd D. Wolchok, MD, PhD

Jedd D. Wolchok, MD, PhD

Immunotherapy for Melanoma:

The End of The Beginning

ME RI MA SL - O K ER NGE

CR (n = 17) PR (n = 26)

CR + PR (n = 43)

High-Dose IL-2 Therapy*

• RR: 16% (43/270)

• Durable responses

–

Median 8.9 mos

–

CR: not reached

*Atkins et al. JCO, 1999 (n=270)

0 10 20 30 40 50 60 70 80 90 130 0.8 0.6 0.4 0.2 0.0 1.0 100 110 120 P roba bi li ty of c ont inui ng re s pons e

Duration of response, months

Ipilimumab Augments T-Cell Activation

and Proliferation

Adapted from O’Day et al. Plenary session presentation, abstract #4, ASCO 2010.

T-cell

APC

TCR HLA CD80/ CD86

T-cell

inhibition

CTLA-4 CD28

T-cell

APC

TCR HLA

T-cell

activation

CD28 TCR HLA

T-cell

APC

CD80/ CD86

T-cell

remains active

Ipilimumab

blocks

CTLA-4

T-cell

APC

CTLA-4 CD80/ CD86 TCR HLA

Kaplan-Meier Analysis of Survival

Years

Ipilimumab + gp100 (A) Ipilimumab alone (B) gp100 alone (C)

1

2

3

4

Comparison HR P-value Arm A vs C 0.68 0.0004 Arm B vs C 0.66 0.0026 Arm A vs B 1.04 0.7575

Survival Rate Ipilimumab + gp100 Ipilimumab alone gp100 alone

1-year 44% 46% 25%

Proportion Aliv e 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Years 0 1 2 3 4 6

Study 024: Overall Survival

Estimated

Survival Rate 1 Year 2 Year 3 Year* Ipilimumab + DTIC

n=250 47.3 28.5 20.8

Placebo + DTIC n=252

36.3 17.9 12.2

*3-year survival was a post-hoc analysis

Ipilimumab + DTIC

Immune-Related Adverse Events

• Rash (approx 20%)

• Colitis/enteritis (approx 15%)

• Elevated AST/ALT (approx 10%)

• Thyroiditis (2 cases)

• Adrenal insufficiency (1 case)

• Hypophysitis (4 seen in 170 patients at MSKCC)

Severity is inversely related to vigilance of surveillance.

If detected early, most are easily treated and reversible.

Ipilimumab Pattern of Response:

Responses After the Appearance and Subsequent

Disappearance of New Lesions

3 mg/kg ipilimumab

Q3W X 4

Pre-treatment

Week 36: Still Regressing

Week 12: Progression Week 20: Regression New lesions Source: 2008 ASCO Abstract #3020 Wolchok.

July 2006

Four Patterns of Response to

Ipilimumab Therapy were Observed

• 2 conventional:

– Response in baseline lesions

– ‘Stable disease’ with slow, steady decline in total tumor

volume

• 2 novel:

– Response after initial increase in total tumor volume

– Response in index plus new lesions at or after the

Peptide/MHC

CTLA-4

CD28

TCR

B7-1,2

APC

Tumor

APC

IL-2

Attenuated or

Terminated

Proliferation

CTLA-4 Blockade

Enhances Tumor-Specific Immune Responses

Unrestrained

Proliferation

Necrotic Death Vaccines Chemotherapy Irradiation Hormone therapy Anti-angiogenesis Antibodies

• April 2004: 33 woman w/ pT2aN0 (Stage IB)

melanoma arising in upper back (non-ulcerated,

2mf)

• October 2008: Left pulmonary nodule detected

incidentally by CXR with CT scan/PET confirmation

(also with additional RLL 3mm nodule)

• December 2008: 2 cycles of Cisplatin, Vinblastine,

Temodar

• February 2009:

Left lower lobectomy

• August 2009: Unresectable recurrence

8/09 A-A’’ 11/10 B-B’’ 9/09 12/09 Ipilimumab Radiation 10/11 E-E’’ 4/11 D-D’’ Unresectable Recurrence 12/10 F Response Stable 1/11 C-C’’ Slow Progression Stable Induction

August 2009

November 2010

January 2011

April 2011

October 2011

A A’ B’ C’ D’ E’ B C D’’ D E’’ E C’’ B’’ A’’

December 2010

Radiation

F Maintenance Maintenance

Eligibility

• Unresectable metastatic melanoma

• At least 2 measurable sites by irRC and mWHO

• One lesion in need of radiotherapy

A Phase II Randomized Study to Evaluate the Efficacy of Combining

Ipilimumab (3mg/kg) with Different Doses/Schedules of External Beam

Radiotherapy

Supported by Ludwig Institute for Cancer Research with correlative support from BMS

Participating Sites:

MSKCC, Stanford University, University of Chicago, NCI

Randomize

Conventional

30Gy (3Gy x 10 fractions)

Starting between 1

st

and 2

nd

dose of ipi

Complete standard ipi induction

High Dose Per Fraction

24Gy (8Gy x 3 fractions)

Starting between 1

st

and 2

nd

dose of ipi

Complete standard ipi induction

Primary Endpoint

Small Molecule Combinations:

RAF inhibitors and Immunotherapy

Boni et al. 2010

Wilmott et al.

2011

Percent tumor growth after therapy

20

40

60

100

150

200

%

T

um

o

r v

o

lum

e

anti-CTLA-4

PLX + anti-CTLA4

PLX

vehicle

Days post tumor induction

Combination of targeted therapy and immune modulation

BRAF-wild type

tumor cells

RAS

RAS mutant

SCCs

RAS

Poulikakos et al. Nature 2010, Hatzivassilou et al. Nature 2010, Heidorn et al. Cell 2010,

pERK

Su et al. NEJM 2012,

Oberholzer et al. JCO 2012

pERK

*

*

T cells

RAS

?

TCR

*

?

?

Paradoxical activation of the MAPK pathway:

Also seen in T cells ?

BMS 908662

PLX4720

Callahan

et al

., manuscript in preparation

IC₅₀: BRAF 4.5 nM BRAFV600E_{6.0 nM CRAF 2.6 nM IC}

50: BRAF 160 nM BRAFV600E13 nM CRAF 6.7* nM

T cells from a patients treated with BMS908662

have enhanced MAPK pathway activity

20

pERK

ki67

pERK

ki67

MAPK signaling

Proliferation

MAPK signaling

Proliferation

BMS908662:

Pt. 2-6

Pt. 2-3

- + +

- - +

- + +

- - +

- + +

- - +

Positive and Negative Signals Regulate T cell Activation

CT-011,MDX-1106, MK-3475, RG7446, AMP224

BMS-

663513,PF-05082566

Ipilimumab, tremelimumab

Anti-OX40

Clinical Activity and Safety of Anti-PD-1

(BMS-936558, MDX-1106)

in Patients with Advanced Melanoma

F.S. Hodi,

1

M. Sznol,

2

D.F. McDermott,

3

R.D. Carvajal,

4

D.P. Lawrence,

5

S.L. Topalian,

6

J.M. Wigginton,

7

D. McDonald,

7

G. Kollia,

7

A. Gupta,

7

J. Sosman

8

1

Dana-Farber Cancer Institute, Boston, MA;

2

Yale Cancer Center, New Haven, CT;

3

Beth Israel Deaconess Medical Center, Boston, MA;

4

Memorial Sloan-Kettering

Cancer Center, New York, NY;

5

Massachusetts General Hospital Cancer

Center, Boston, MA;

6

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

University, Baltimore, MD;

7

Bristol-Myers Squibb, Princeton, NJ;

8

Vanderbilt University Medical Center, Nashville, TN

APC

T cell

Activation

(cytokines, lysis, prolif., migration)

B7.1

CD28

TCR Signal 1

MHC-Ag

Tumor

Role of PD-1 in Suppressing Antitumor

Immunity

Tumor

PD-L1

PD-1

Keir ME et al, Annu Rev Immunol 2008; Pardoll DM, Nat Rev Cancer 2012

(-)

(-)

(-)

Inhibition

(anergy, exhaustion, death)

Anti-PD-1

BMS-936558–Related Adverse Events

Drug-Related

Adverse Event

All Grades

Grades 3-4

Tot Pop*

MEL

Tot Pop

MEL

†

No. (%) of Patients, All Doses

Any adverse event

207 (70)

82 (79)

41 (14)

21 (20)

Fatigue

72 (24)

30 (29)

5 (2)

2 (2)

Rash

36 (12)

21 (20)

—

—

Diarrhea

33 (11)

18 (17)

3 (1)

2 (2)

Pruritus

28 (9)

15 (14)

1 (0.3)

—

Nausea

24 (8)

9 (9)

1 (0.3)

1 (1)

Appetite



24 (8)

7 (7)

—

—

Hemoglobin



19 (6)

7 (7)

1 (0.3)

1 (1)

Pyrexia

16 (5)

5 (5)

—

—

*AEs occurring in ≥5% of the total population.

†_{Common grade 3-4 AEs also included lymphopenia (3 pts) and abdominal pain}

and lipase increased (2 each). An additional 27 grade 3-4-related AEs were observed and one or more occurred in a single patient.

Changes in Target Lesions Over Time in

Melanoma Patients

Complete Regression of Metastatic Melanoma

(BMS-936558, 3 mg/kg) Associated With Vitiligo

Pre

Post

Normal skin

Boundary

Vitiligo

History: 62-year-old male had previously developed PD

following IL-2, temozolomide, and multiple surgeries.

Preliminary Clinical Efficacy and Safety

of MK-3475 (Anti-PD-1 Monoclonal

Antibody) in Patients with Advanced

Melanoma

Omid Hamid

1

, Adil Daud

2

, Caroline Robert

3

, F. Stephen

Hodi

4

, Wen-Jen Hwu

5

, Richard Kefford

6

, Jedd Wolchok

7

,

Peter Hersey

8

, Roxana Dronca

9

, Richard Joseph

10

, Jeffrey

Weber

11

, Tara Gangadhar

12

, Amita Patnaik

13

, Robert

Iannone

14

, Hassane Zarour

15

, Kevin Gergich

14

, Cong

Chen

14

, S. Peter Kang

14

, Antoni Ribas

16

1 The Angeles Clinic and Research Institute, 2 University of California, San Francisco, 3 Service de Dermatologie Institut Gustave Roussy, 4 Dana-Farber, Harvard Cancer Center, 5 MD Anderson Cancer Center, 6 Westmead Hospital and Melanoma Institute Australia, 7 Memorial Sloan-Kettering Center, 8 Newcastle Melanoma Center, University of Sydney, 9 Mayo Clinic, Rochester, 10 Mayo Clinic, Jacksonville, 11 Moffitt Cancer Center, 12 University of Pennsylvania School of Medicine, 13

South Texas Accelerated Research Therapeutics (START), 14 Merck, Sharp & Dolme, Whitehouse Station, NJ, USA, 15 Hillman Cancer Center, University of Pittsburgh, 16 University of California, Los Angeles

MK-3475 is a High-Affinity Humanized IgG4

PD-1 Blocking Antibody



Similar reactivity to human and cynomolgus PD-1, no reactivity to mouse

or rat PD-1



Humanized IgG4 - no cytotoxic (ADCC/CDC) activity



Contains stabilizing S228P sequence alteration

Mouse variable (CDR) sequences grafted onto human framework

Parental Antibody Mouse IgG1 KD: ~28 pM IC50: ~800 pM EC50: ~118 pM MK-3475 Human IgG4 KD: ~29 pM IC50: ~600 pM EC50: ~70 pM

Adverse Events >10% Incidence All Grades and Corresponding

Drug-Related and Grade 3-5

Part B: All Melanoma Patients: N=132

Adverse Events

All Grades

Grades 3-5

All AEs Drug Related All AEs Drug Related

N (%) N (%) N (%) N (%)

Any Adverse Event 125 (94.6) 95 (71.9) 36 (27.2) 12 (9.0)

Fatigue 37 (28.0) 29 (21.9) 2 (1.5) 1 (0.7) Nausea 31 (23.4) 11 (8.3) 1 (0.7) 0 (0.0) Rash 29 (21.9) 24 (18.1) 2 (1.5) 2 (1.5) Diarrhea 26 (19.7) 18 (13.6) 0 (0.0) 0 (0.0) Cough 25 (18.9) 7 (5.3) 0 (0.0) 0 (0.0) Pruritus 22 (16.6) 19 (14.3) 0 (0.0) 0 (0.0) Arthralgia 18 (13.6) 15 (11.3) 0 (0.0) 0 (0.0) Headache 19 (14.3) 10 (7.5) 2 (1.5) 0 (0.0) Abdominal Pain 18 (13.6) 6 (4.5) 3 (2.2) 1 (0.7) Increased AST 16 (12.1) 10 (7.5) 1 (0.7) 1 (0.7) Pyrexia 15 (11.3) 7 (5.3) 0 (0.0) 0 (0.0) Decreased Appetite 14 (10.6) 5 (3.7) 2 (1.5) 1 (0.7)

Patients who started treatment with MK-3475 before July 31, 2012 and have entered data by Sept 28, 2012

Preliminary Best Overall Response of MK-3475 (Unconfirmed

+ Confirmed Responses) in Advanced MEL Patients (Part B:

Based RECIST 1.1 and Centrally Reviewed Response Data)

Complete

Response

(N, 95% CI)

Objective Response

(N, 95% CI)

Disease Control

Rate

(N, 95% CI)

All MEL

N=83

5%

(4; 2%-13%)

47%

(39; 34% - 56%)

60%

(50; 48%- 70%)

IPI Naïve

N=58

7%

(4; 2%-18%)

50%

(29; 35% -61 %)

67%

(39; 51%-76%)

IPI Treated

N=25

0 %

40%

(10; 17% -59%)

44%

(11; 24%-68%)

All patients were dosed at 10 mg/kg

Includes all patients who received first dose as of April 25, 2012. Centrally available response information as of Oct 19, 2012

Two patients were excluded due to unavailability of central read at the time of analysis. Objective response= confirmed and unconfirmed complete and partial response

Clinical Activity in a Melanoma Patient

Baseline: 13/Apr/2012

27/July/2012

• 72 yrs old male with melanoma after progressing on bio-chemotherapy, HD IL-2, and ipilimumab • Patient was on oxygen support due to progressive lung disease burden and pleural effusion • After 3 months of MK-3475, the patient is off the oxygen support and continues to respond

Blocking multiple T-cell co-inhibitory pathways

leads to increased tumor rejection.

Data shown is from B16-BL6 melanoma tumors. All mice received FVAX treatment.

ipi

pd-1

induction

maintenance

Dual CTLA-4 + PD-1 Blockade:

Trial Design

Cohort MDX1106 Ipilimumab 1 0.3 mg/kg 3 mg/kg 2 1 mg/kg 3 mg/kg 2A 3 mg/kg 3 mg/kg 3 3 mg/kg 1 mg/kg

ipi

pd-1

Cohort MDX1106 6 1 mg/kg 7 3 mg/kg

Patient 002 (MSKCC)

53 yo male with Stage IV (M1c) melanoma previously treated with temozolomide. He achieved a major PR (92% at 12 weeks, 99% at 18 weeks) without significant toxicity. He underwent a biopsy of a regressing subcutaneous nodule after 12 weeks on treatment, demonstrating robust immune infiltrate. He continues to have stable, near complete regression of disease after 2 years.

Summary

•

Checkpoint blockade is an effective treatment with durable

responses.

•

Intense study of both predictive and pharmacodynamic

biomarkers of response and toxicity will allow for more

intelligent patient selection and novel target discovery.

•

New and promising immune modulators are in clinical

development.

•

Combination therapy will be necessary for immunotherapy to

achieve full potential (other immune modulators, vaccines,

radiation, chemotherapy, targeted therapy, anti-angiogenic

therapy).

Acknowledgments

Jim Allison Wolchok Lab Francesca Avogadri Sadna Budhu Daniel Hirschhorn- Cymerman Nicole Malandro Taha Merghoub Judith Murphy David Schaer Stephanie Terzulli Melanoma-Sarcoma Svc Gary Schwartz Paul Chapman Richard Carvajal Ruth-Ann Roman Evelina Pogoriler Sean Houghton Ludwig Institute Gerd Ritter Sacha Gnjatic Erika Ritter Achim Jungbluth Ludwig Center Sasha Rudensky Jianda Yuan Zhen Yu Mu Matthew Adamow Teresa Rasalan

Support: NCI P01 CA33049 and CA59350, R01 CA056821, RC2 CA148468, Ludwig Trust, Swim Across America, Goodwin

Commonwealth Fund, Melanoma Research Alliance, Breast Cancer Research Foundation Lloyd Old Alan Houghton Immunology Pgm. Eric Pamer Gregoire Altan- Bonet Fox Chase Adam Cohen Yale Mario Sznol Ruth Halaban MD Anderson Pam Sharma