Immunotherapy is the Preferred Initial Treatment for Most Patients with Metastatic BRAF V600 Mutant Melanoma Michael B. Atkins, M.D. Deputy Director Georgetown-Lombardi.

Immunotherapy is the Preferred Initial Treatment for Most Patients with

Metastatic BRAFV600 Mutant Melanoma

Michael B. Atkins, M.D.Deputy Director

Georgetown-Lombardi Comprehensive Cancer Center

The case for immunotherapy---

Immunotherapy produces durable unmaintained tumor responses

Immunotherapy works as well against BRAFV600 mutant melanoma as WT tumors

Immunotherapy is getting better Better drugs Better patient selection

BRAF inhibitors work as well in patients with prior immune therapy; the converse is not so

High Dose IL-2 Therapy*

RR: 16% (43 / 270) Some large volume and

visceral Most soft tissue and lung

Durable responses Median 8.9 mos CR: not reached

Survival Median 12 mos 11% >@ 5yrs

*Atkins et al JCO, 1999 (N=270)

Pooled data from phase II studies CA184-008 and CA184-022:ipilimumab monotherapy 10 mg/kg (N=227)

mWHO CR/PR/SD = 27.8%

irRC CR/PR/SD with WHO PD = 9.7%

Other PD or unknown = 62.6%

1.0

0.8

0.6

0.4

0.2

0

Pro

po

rtio

n a

live

0 2 4 6 8 10 12 14 16 18 20 22 24 26

Wolchok, Hodi et al

Overall survival for 51-patient cohort Rx’d w/ 10 mg/kg x 4 + maintenance

~26% 2 yr OS estimate also seen in 165-pt cohort from expanded access trial

Kevin Heller, BMS—data presented in part at ESMO 2009, ASCO 2010, 2011 posters

Relationship of MAPKinase pathway mutations and response to HD IL-2

Mutation All CR/PR SD/PD P-value

BRAF 60 14(23%) 46 (77%)

0.05NRAS 15 7 (47%) 8 (53%)

WT 26 3 (12%) 23 (88%)

Joseph, Sullivan et al- JIT 2011

A significantly larger proportion of patients with BRAF or NRAS mutant tumors achieved CR/PR compared to those with WT tumors.

Produces durable unmaintained responses; not restricted by BRAF status

Activity powerful enough to work in the CNS and overcome concurrent immunosuppression

Activity seen in patients with prior IL-2 Activity seen in patients with elevated LDH, liver metastases,

etc Treatment more widely applicable

Ipilimumab Therapy

BRAF inhibitor Therapy - Limitations

Median PFS of only 6-7 months Median OS 13-16 months Forrest plot suggests most of the benefit

confined to patients with M1c disease

Sosman et al NEJM 2012, Chapman et al ASCO 2012Sosman et al NEJM 2012, Chapman et al ASCO 2012

100

90

80

70

60

50

40

30

20

10

0

Ove

rall

surv

ival

(%

)

0 6 12 18 24

Vemurafenib (n=337)

Median f/u 12.5 months

Dacarbazine (n=338)

Median f/u 9.5 months

338

337

173

280

79

178

24

44

0

1

244

326

111

231

50

109

4

7

9.7 13.6

Overall survival (February 01, 2012 cut-off) censored at crossover

Hazard ratio 0.70 (95% CI: 0.57–0.87)p<0.001 (post-hoc)

Time (months)No. at riskDacarbazine

Vemurafenib

15.9

BRIM2

All patients 675

Age: <65 years≥65 years

514161

Sex: FemaleMale

294381

ECOG status: 0 1

459216

Disease stage: IIIc M1a M1b M1c

3374

127441

LDH: Normal Elevated

391284

FactorNumber

of patients

0.2 0.4 0.6 1.0 2 4 106

Favors vemurafenib

Favors dacarbazine

20

Hazard ratio and 95% confidence interval

Overall survival by baseline characteristic (February 01, 2012 cut-off) censored at crossover


Median PFS of only 6-7 months Median OS 13-16 months Forest plot suggests most of the benefit

confined to patients with M1c disease Combination BRAF-MEK inhibition may offer

some advantages…

Sosman et al ASCO 2012, Chapman et al ASCO 2012Sosman et al ASCO 2012, Chapman et al ASCO 2012


Median PFS of only 6-7 months Median OS 13-16 months Forest plot suggests most of the benefit

confined to patients with M1c disease Combination BRAF-MEK inhibition may offer

some advantages, but median PFS still only 7-10 months

Sosman et al ASCO 2012, Chapman et al ASCO 2012, Weber et al, ASCO 2012



Thus, BRAF (+/- MEK) inhibitor treatment postpones but does not prevent the tragedy of metastatic melanoma



Treatment for BRAF Mutant Melanoma

Years after stage IV diagnosis

Pro

por

tion

Sur

vivi

ng

Ipilimumab

0 1 2 3 4 5

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

BRAFi

PRESENTED BY: Michael B. Atkins

Which is preferred?

Immunotherapy is getting better

Clinical Activity of BMS-936558 in Melanoma Patients

4 melanoma patients had a persistent reduction in baseline target lesions in the presence of new lesions but were not classified as responders for the ORR calculation

Pop NORR

n (%)

Median Duration of Response (95% CI)

[individual pt response]

SD 24 wk

n (%)

PFSR at 24 wk

(%)

All

MEL106 33 (31)

Not ReachedRange: 1.8+ to 25.7 6 (6) 42

MEL

17 6 (35) Not Reached[3.7+, 4.2+, 5.6, 5.6, 5.6+, 11.2+]

0 41

18 5 (28) Not Reached [1.8+, 4.2, 7.4+, 7.6+, 9.2+]

1 (6) 33

34 11 (32)24 months (22.9- NR)

[1.9+, 5.5+, 7.5, 7.5, 11.1+, 13.4+, 18.4+, 22.9, 23.2+, 24, 24.9+]

4 (12) 48

17 7 (41)Not Reached

[9.2+, 9.3, 11.1, 12.9, 18.8+, 22+, 22.4+]

1 (6) 55

20 4 (20) 25.7 months (17.0-25.7)[17, 18+, 24.6+, 25.7]

0 30

3mg/kg

Changes in Target Lesions Over Time inMelanoma Patients (3mg/kg)

Dose Group: 3mg/kg

+: 1st Occurence of New Lesion

On Study Status(On/Off) Off On

% C

hang

e Fr

om B

asel

ine

In T

arge

t Les

ions

Tum

or B

urde

n

-100

-90

-80

-70

-60

-50

-40

-30

-20

-10

0

10

20

30

40

50

60

Weeks Since Initiation Of Treatment

0 10 20 30 40 50 60 70 80 90 100 110 120 130

Of 33 patients with OR (all dose levels) 29 were treated 1 year (before July 3, 2012) and 14 had responses of 1 year 4 were treated <1 year and 4 had responses ranging from 1.8-5.3 months

MK-3475 (Unconfirmed + Confirmed Responses) in Advanced MEL Patients

Complete Response(N, 95% CI)

Objective Response(N, 95% CI)

Disease Control Rate

(N, 95% CI)

All MELN=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/kgIncludes all patients who received first dose as of April 25, 2012. Centrally available response information as of Oct 19, 2012Objective response= confirmed and unconfirmed complete and partial responseDisease control rate= objective response + stable disease

Hamid SMR 11/11/12

Clinical Activity in a Melanoma Patient-1

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

Courtesy of A. Ribas M.D.

Baseline: 13/Apr/2012 27/July/2012

Clinical Activity in a Melanoma Patient-1

MK-3475 Characteristics of Responses (irRC): Time to Respond & Duration for 43 Patients with Objective

Response

On Treatment Duration in Weeks

• Median duration of treatment, • 7.6 months + (3.3-11+)

• one patients discontinued due to PD and four patients discontinued due to AEs

Immunotherapy for Melanoma

PRESENTED BY: Michael B. Atkins

Years after stage IV diagnosis

Pro

por

tion

Sur

vivi

ng

Ipilimumab

Anti-PD1

Anti PD1 + x

0 1 2 3 4 5

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0 ???

IL-2

Checkpoint blockade vs oncogene-mutation targeted therapy for melanoma

# Annual Cases

Proportion c\ mutation

% RR Median Durability of remission

Pt years

BRAF + cKIT

9000 0.5 0.5 0.6 yrs 1350 pt yrs

Anti-CTLA4/Anti-PD1

9000 N/A 0.33 2 years 6000 pt yrs

Annual pt-years of remission

Adapted from Drew Pardoll

Treatment Selection Opportunities

NSCLC

Melanoma

RCC

**2 pts still under evaluation

42 pts include 18 MEL, 10 NSCLC, 7 CRC, 5 RCC, and 2 CRPC.

Correlation of PD-L1 expression in pretreatment tumor biopsies with clinical outcomes in Anti-PD-1 Therapy

Association Between Pretreatment Tumor PD-L1 Expression and Clinical Response

Response Status PD-L1 Positive no. (%)

PD-L1 Negative no. (%)

Totalno. (%)

CR/PR 9 (36) 0 9 (21)

Nonresponder 16* (64) 17 (100) 33 (79)

All Patients 25 17 42

Topalian S, et al. NEJM 2012;366:2443-2454.

Prop

ortio

n of

pati

ents

p=0.006

0

0.2

0.4

0.6

0.8

1

PD-L1(+) PD-L1(-)

PD-L1(+)PD-L1(-)9/25

16*/25

17/17

0/17† analysis not pre-planned and based on subset of subjects'.

†

Sequencing of Treatment

Baseline characteristics

Ove

rall

resp

on

se r

ate

(%)

30

40

50

70

60

80

BRIM2- ORR by pre-defined subgroups

20

0

Age

<65 65Alltreatedpatients

Alltreatedpatients

Sex

F M

LDH at enrollment

1.0–1.5xULN

>1.5xULN

Normal

ECOG PS

0 1

Stage

M1a/M1b

M1c

# priortherapies

1 >1

Previous IL-2

Yes No

10

Overall ORR of 53% (IRC)

RR (size proportional to the number of patients in the subgroup)

95% Confidence intervals

Ribas et al ASCO 2011Ribas et al ASCO 2011

BRAF inhibition +/- prior immunotherapy

MAPKi PFS

IT initially PFS 6.7 mo (CI 4.3-9.1 mo)MAPKi initially PFS 5.6 mo (CI 4.7-6.8 mo)

p-value 0.43, log rank

MAPKi OS

IT initially OS 19.6 mo (CI 10.0- mo)MAPKi initially OS 13.4 mo (CI 10.1-17 mo)

p-value 0.40, log rank

OS

(pr

obab

ility

)

Time (mo)

Ackerman/Sullivan-BIDMC/MGH-SITC 2012

Immunotherapy following MAPKI: DFHCC/MIA Retrospective Data

– 193 patients discontinued MAPKi therapy (176 with disease progression)

• Median OS 2.9 mos (CI 1.8-4.4 mos) from last dose of MAPKi

• Single agent ipilimumab treatment (n=34 pts) No tumor responses (2 SD)Median PFS 2.7 mos, median OS 5 mos50% of patients received < 4 doses All Pts alive > 1 year- are back on MAPK inhibitors inhibitors

– Summary: • Patients progressing on BRAFi appear unlikely to respond to

ipilimumab• Those alive either had slow growing disease and short period

of RAFi treatment due to toxicity or are back on a RAFi


OS 5.0 mo (CI 3.0-8.8 mo)

long term survivors all treated with additional MAPKi

OS

(pr

obab

ility

)

Time (mo)

PFS 2.7 mo (CI 1.8-3.1 mo)

Ipilimumab following BRAF inhibitor Therapy


Treatment Selection in Patients with BRAF Mutant Melanoma: Conclusions

Current data suggests that for many patients with BRAFV600E melanoma (asymptomatic, immune infiltrate), starting with immunotherapy offers them a chance for longterm benefit without compromising their benefit from subsequent BRAFi therapy

Two shots on goal are better than one

E1612: Ipi vs Vemurafenib

ECOG PS1. 02. 1

Stage 1. St III or

M1a/b2. M1c

Prior therapy1. No prior Rx2. Prior Rx

RANDOMIZE

Arm 1:

Ipi 3 or 10mg/kg q 3wks x 4 +/- maint q12 wks

Arm 2:

Vemurafenib 960mg BID

ECOG and SWOG protocol – Atkins, ChmielowskiTumor measurements q12 wks

ECOG and SWOG protocol – Atkins, ChmielowskiTumor measurements q12 wks

Ipi 3 or 10mg/kg q 3wks x 4 +/- maint q12 wks

Vemurafenib 960mg BID

PD

PD

Treatment Selection in Patients with BRAF Mutant Melanoma: Conclusions

Current data suggests that for many patients with BRAFV600E melanoma (asymptomatic, immune infiltrate), starting with immunotherapy offers them a chance for longterm benefit without compromising their benefit from subsequent BRAFi therapy

Newer immunotherapies are approaching the efficacy (RR and PFS) of BRAFi with more durability

Immunotherapy may be the better of the two shots

Immunotherapy is the Preferred Initial Treatment for Most Patients with Metastatic BRAF V600 Mutant Melanoma Michael B. Atkins, M.D. Deputy Director Georgetown-Lombardi.

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