Evolving Treatment Options in Melanoma: Utilizing Genetic Features to Optimize Therapy

Antoni Ribas, MDProfessorDepartment of Medicine and Hematology-OncologyUniversity of California, Los AngelesLos Angeles, California

Evolving Treatment Options in Melanoma: Utilizing Genetic Features to Optimize Therapy

This program is supported by educational grants from

In association with Translational Research in Oncology

clinicaloptions.com/oncologyTranslational Research 2012

About These Slides

DisclaimerThe materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

Our thanks to the presenters who gave permission to include their original data

Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent

These slides may not be published or posted online without permission from Clinical Care Options


Program Faculty

Program DirectorDennis J. Slamon, MD, PhDTRIO ChairmanChief, Division of Hematology/OncologyDavid Geffen School of Medicine at UCLALos Angeles, California

FacultyAntoni Ribas, MDProfessorDepartment of Medicine and Hematology-OncologyUniversity of California, Los AngelesLos Angeles, California


Faculty Disclosures

Antoni Ribas, MD, has disclosed that he has received consulting fees from Amgen, Celgene, Genentech/Roche, GlaxoSmithKline, Millennium, Novartis, and Prometheus.

Dennis J. Slamon, MD, PhD, has disclosed that he has received consulting fees from Genentech, GlaxoSmithKline, and Roche.


*Data collected using PubMed; search criteria: “melanoma clinical trial.”US National Library of Medicine and National Institutes of Health.

Total number of clinical trial publications*: 3337

> 3000 Trials Between 1970 and 2010 Had No Real Clinical Impact

0

50

100

150

200

250

1970 1995 2005 2010

Clin

ical

Tria

l Pub

licat

ions

(n)*

Publication Yr20001975 1980 1985 1990


Yrs

Immunotherapy Targeted Therapy

Perc

ent A

live

Perc

ent A

live

1 2 30 1 2 30Yrs

1. Hodi FS, et al. N Engl J Med. 2010;363:711-723. 2. Chapman PB, et al. N Engl J Med. 2011;364:2507-2516.

OS

(%)

Mos0

0

100

48

80

60

40

20

403224168 56

OS

(%)

Mos0

0

100

10

80

60

40

20

86531 122 4 1197

HR: 0.37 (95% CI: 0.26-0.55; P < .001)

Dacarbazine(n = 336)

Vemurafenib (n = 336)

Improved OS in Melanoma With Ipilimumab and Vemurafenib


Oncogenic cell proliferation and survival

< 5% melanomas (mucosal, acral)

~ 50% melanomas (< age)[2,3]

~ 20% melanomas (> age)[2,3]

KIT inhibitors: imatinib, nilotinib, dasatinib[4]

BRAF inhibitors: vemurafenib, dabrafenib[4]

MEK inhibitors: trematenib, TAK733[4]

BRAF

MEK

ERK

NRAS

cKIT

cKIT, NRAS, BRAF mutated in ~ 70% of melanomas,usually mutually exclusive[1]

1. Sosman JA, et al. ASCO 2011 Educational Book. 2. Arkenau HT, et al. Br J Cancer. 2011;104:392-398. 3. Thomas N, et al. Cancer Epidemiol Biomarkers Prev. 2007;16:991-997. 4. Nikolaou VA, et al. J Invest Dermatol. 2012;132:854-863.

MAP Kinase Pathway Targeting in Melanoma


Vemurafenib Inhibition of MAPK Signaling in BRAF V600 Melanoma Biopsies[1]

Baseline[2] Day 15

Ras GTP

pERK

Cyclin D

Ki67

Cyclin D

BRAFV600

MEK

ERK

P

P

Cell cycle(Ki67)

Vemurafenib

RTK

Y-PY-P

GF

1. Ribas A. HemOnc Today: Melanoma. 2012. 2. Flaherty KT, et al. N Engl J Med. 2010;363:809-819.


Baseline, 3/15/2011 Cycle 4 Day 1, 6/8/2011

PLX4032 = RG7204 = vemurafenib

Tumor Response to Vemurafenib


Sosman 2012 [2]

Chapman 2011[3]

Flaherty 2010[1]

1. Flaherty KT, et al. N Engl J Med. 2010;363:809-819. 2. Sosman JA, et al. N Engl J Med. 2012;366:707-714. 3. Chapman PB, et al. N Engl J Med. 2011;364:2507-2516.

Vemurafenib: Tumor Response by Metastatic Stage


All Grades, n (%) Grade 3, n (%) Grade 4, n (%)Overall 130 (99) 79 (60) 5 (4)* Arthralgia 78 (59) 8 (6) – Rash 69 (52) 9 (7) – Photosensitivity reaction 69 (52) 4 (3) – Fatigue 56 (42) 2 (2) – Alopecia 48 (36 ) – – Pruritus 38 (29) 3 (2) – Skin papilloma 38 (29) – – cuSCC/KA† 34 (26) 34 (26) – Nausea 30 (23) 2 (2) – Elevated liver enzymes 23 (17) 8 (6)‡ 4 (3)§

Includes AEs reported in ≥ 20 patients

*1 patient with 2 grade 4 AEs.†Cases of cuSCC/KA were generally managed with simple excision and did not generally require dose modification.‡Managed with dose reduction; 1 removed from study.§Led to discontinuation of therapy.

Ribas A, et al. ASCO 2011. Abstract 8509.

BRIM2: Toxicities With Vemurafenib


cuSCC/KAs

– Incidence: 26%

– Median time: 8 wks (range: 2-36)

– Median number of cuSCC/KAs per patient: 1 (range: 1-7)

– Each dot represents wks to development of first cuSCC/KA lesion

0 5 10 15 20 25 3530 40Wks on Vemurafenib

Median


BRIM2: cuSCC/KA Development With Vemurafenib


CRAF

MEK1/2

ERK

P

P

BRAFV600

1. Hatzivassiliou G, et al. Nature. 2010;464:431-435. 2. Heidorn SJ, et al. Cell. 2010;140:209-221. 3. Poulikakos PI, et al. Nature. 2010;464:427-430.

MAPK signaling

CRAF

MEK1/2

ERK

P

P

BRAF

MAPK signaling

RAS

CRAF

MEK1/2

ERK

P

P

BRAF

BRAFi

MAPK signaling[1-3]

RAS

MEK1/2

ERK

P

P

BRAFV600

BRAFi

MAPK signaling[1-3]

CRAF

BRAF Inhibition: Differential Effects in BRAF V600 and BRAF Wild-Type Cells

BRAF V600 Mutant Melanoma BRAF Wild-Type Cells


MEK1/2

ERK

P

P

BRAFV600

MAPK signaling

MEK1/2

ERK

P

P

BRAFV600

BRAFi

MAPK signaling

CRAF

MEK1/2

ERK

P

P

BRAF

MAPK signaling

RAS

CRAF

MEK1/2

ERK

P

P

BRAF

BRAFi

MAPK signaling

HRASQ61

Paradoxical MAPK activation with RAF inhibitors

CRAF CRAF

Su F, et al. N Engl J Med. 2012;366:207-215.

Paradoxical MAPK Activation by BRAF Inhibitors in HRAS-Mutated cuSCC/KAs

BRAF V600 Mutant Melanoma BRAF Wild-Type Cells


16140Approx timing CT assessments

Continued responseProgressive diseaseTime to response

Mos4 6 8 10 122

Time on study

Median duration of response: 6.7 mos(range: 1.3-12.7; 95% CI: 5.6-9.8)


Acquired Resistance to Vemurafenib: Time to Response, Progression in BRIM2


Melanoma

Stroma

Response and Relapse With Vemurafenib

Nazarian R, et al. Nature. 2010;468:973-977.

10/02/08 (Pre) 11/26/08 (2+ mos) 02/20/09 (4+ mos)

Pt #43, UCLA


Mechanisms of Acquired Resistance to BRAF Inhibitors

Survival

BRAFV600E

MEK

ERK

P

P

BRAF inhibitor

[1] NRASQ61

COT[2]

CRAF

[5]MEK-dependentprogression

[3,4]

MEKi

PDGFRβ or IGF1R or EGFR

[1,6-8]

PI3K

AKT

MEK-independentprogression

PI3Ki or AKTi

[4,6,9-11]

1. Nazarian R, et al. Nature 2010. 2. Johannessen CM, et al. Nature. 2010. 3. Poulikakos, et al. Nature 2011. 4. Shi H, et al. Cancer Discov. 2012. 5. Wagle N, et al. J Clin Oncol. 2011.

6. Villanueva J, et al. Cancer Cell. 2010. 7. Prahallad A, et al. Nature. 2012. 8. Corcoran RB, et al. Cancer Discov. 2012. 9. Jiang CC, et al. Clin Cancer Res. 2011. 10. Atefi M, et al. PLoS One. 2011. 11. Su F, et al. Cancer Res. 2012.


BRAFi MEKi No activity[2]

BRAFi Local Tx + BRAFiOccasional prolonged responses[1]

BRAFi BRAFi ORR 19%[3]

MEKi

BRAFi ORR 50% to 74%,[4] increased PFS?MEKi

Progression of melanomaBRAFi: vemurafenib, dabrafenibMEKi: trametinib

1. Kim KB, et al. ASCO 2011. Abstract 8519. 2. Kim KB. SMR 2011. Abstract.3. Flaherty K, et al. SMR 2011. Abstract 12. 4. Infante JR, ASCO 2011. Abstract CRA8503.

Treating Resistance to BRAFi


Target host

Target tumor

Immunotherapy TargetedTherapy

Metastatic Melanoma: Treatment Advances


Immunotherapy for Melanoma: Response

Oncogenic cell proliferation and survival

BRAF

MEK

ERK

cKitNRAS

Antitumor immune response

IL-2IFN-αAnti-CD40Anti-CD137Anti-OX40

Anti-CTLA4

Anti–PD-1RR ~ 10%, but many are durable

< 5% melanomas, RR 15%

50% melanomas, RR 55%

< 5% melanomas, RR 30%

KIT inhibitors

BRAF inhibitors

MEK inhibitors


1. Hodi FS, et al. N Engl J Med. 2010;363:711-723. 2. Robert C, et al. N Engl J Med. 2011;364:2517-2526.

Ipi + gp100 Ipigp100

MedianOS, Mos

10.010.16.4

95%CI

8.5-11.58.0-13.85.5-8.7

HR0.680.66

P Value< .001.003

Ipi + D Placebo + D

MedianOS, Mos

11.29.1

95% CI

9.4-13.67.8-10.5

HR0.72

P Value< .001

Est 1, 2, 3-Yr Survival, %

47.3, 28.5, 20.836.3, 17.9, 12.2

Ipilimumab + gp100 vs gp100[1] Ipilimumab vs Placebo[2]

OS

(%)

Mos0

0

100

48

80

60

40

20

403224168 565244362820124

Patients at Risk, nIpi + gp 100Ipigp100

403137136

620

1783

33135

542416

1153823

2237958

000

410

751

24135

42187

813017

1635632

29710693

Patie

nts

Surv

ival

(%)

Mos0

0

100

38

80

60

40

20

322620146 484634282216104

Patients at Risk, nIpi + DPlacebo + D

2 4442408 12 18 24 30 36

250252

3119

5634

6142

7956

10478

181160

00

23

5231

5942

7447

9172

131116

199190

230229

45

107

1711

157136

11489

8564

6844

5637

4126

CensoredCensored

Ipilimumab-dacarbazine

Placebo-dacarbazine

Ipilimumab Induces Durable Tumor Responses in a Subset of Patients: OS


Ribas A. SMR 2011. Abstract 72.

Before Ipilimumab04/22/11

After Ipilimumab08/05/11


CTLA4 Response Since 2004[2]

CTLA4 Response Since 2003[1]

1. Forbes. March 2, 2009. 2. Forbes. October 15, 2007.

“Miracle Survivors”: Reproducible but Low Frequency With CTLA4 Blocking MAbs


Anti-PD1 antibodies may be more relevant to unleash an anti-melanoma immune response than anti-CTLA4 antibodies

Ribas, NEJM June 2, epub ahead of print

Anti-PD1


1. Restifo NP, et al. Nat Rev Immunol. 2012;12:269-281. 2. Rosenberg SA, et al. Clin Cancer Res. 2011;17:4550-4557.

Durable complete responses with autologous TILs[2]

Similar efficacy regardless of prior therapy

Adoptive Cell Transfer[1]

Prop

ortio

ns S

urvi

ving

0

1.0

0.6

0.4

12Survival Time (Mos)

72 84 966048240 36

0.8

0.2No TBI (n = 43)

All patients (n = 93)

TBI 1200 (n = 25)TBI 200 (n = 25)

Median follow-up: 62 mos

Survival of Patients With Metastatic Melanoma Treated With Autologous

TILs and IL-2

ACT With Tumor-Infiltrating Lymphocytes for Patients With Metastatic Melanoma


TCR Engineering: Adoptive Cell Transfer

KVP

RN

QD

WL

HLAHuman

melanoma

Melanoma-specific

lymphocyte

Take TCR genes from one patient who beat melanoma and use them to engineer a melanoma-fighting immune system in other patients

TCR-redirected

lymphocyte

2005 2010 CD8 IHC


Low frequency of tumor responses

Highly durable

IL-2: limited by short-term toxicities

Anti-CTLA4: limited by midterm autoimmune toxicities

High frequency of tumor responses

Variable durability

Limited by requirements of preparative conditioning and IL-2

Active immunotherapy Cytokines

– IL-2 Antibodies

– Anti-CTLA4

Adoptive cell transfer T-cell cloning

– From blood– From tumors: TIL

T-cell genetic engineering– T-cell receptors– Chimeric antigen receptors

General clinical effects

Immunotherapy for Melanoma


1. Hodi FS, et al. N Engl J Med. 2010;363:711-723. 2. Chapman PB, et al. N Engl J Med. 2011;364:2507-2516.

OS

(%)

Mos0

0

100

48

80

60

40

20

403224168 56

OS

(%)

Mos0

0

100

10

80

60

40

20

86531 122 4 1197

HR: 0.37 (95% CI: 0.26-0.55; P < 0.001)

Dacarbazine(n = 336)

Vemurafenib (n = 336)

Yrs

Immunotherapy Targeted Therapy

Perc

ent A

live

Perc

ent A

live

1 2 30 1 2 30Yrs

Combination

Perc

ent A

live

1 2 30Yrs

?

Combining Immunotherapy and Targeted Therapy for Melanoma?


BRAF V600 PositiveSOC Experimental

Vemurafenib

Ipilimumab

BRAF V600 NegativeSOC Experimental

HD IL-2

Ipilimumab

HD IL-2

Novel BRAFi + MEKi

Anti-PD1

TIL ACT

Open questions:Immunotherapy vs BRAFi for first line?Immunotherapy + BRAFi?Treatment of BRAFi resistance?Prevention of BRAFi resistance?Role of MTKi?Role of chemotherapy?

Anti-PD1

TIL ACT

Special considerations:Uncommon BRAF mutationsNRAS mutants with MAPK dependency

Treatment of Advanced Melanoma in 2012


Conclusions

“2011: The year of melanoma”

– George Sledge, MD, President of ASCO

Scientific advances translate into improved patient care

The mechanism of resistance to BRAF inhibitors predicts sensitivity to the addition of secondary treatments

– MEK inhibitors

– PI3K/AKT/mTOR inhibitors

Combining immunotherapy and BRAF-targeted therapy in the clinic is warranted

Go Online for More CCO Coverage of Chicago 2012!

Capsule Summaries of all the key data, plus CME-certified Slidesets exploring the clinical implications of these findings

Downloadable slides: for use as a study resource or in your noncommericial presentations

clinicaloptions.com/oncology

http://www.clinicaloptions.com/oncology

Documents

Evolving Treatment Options in Melanoma: Utilizing Genetic Features to Optimize Therapy