tratamento adjuvante · 2020. 12. 23. · 1. agarwala ss, lee sj, yip w, et al. phase iii...

Sanjiv S. Agarwala, MD

Professor, Temple University

St Luke’s Cancer Center

Bethlehem, PA, USA

Tratamento Adjuvante

Overview of Melanoma Patient Treatment Journey1

DistantMedical Oncologist

LocalDermatologist

RegionalSurgeon / Medical Oncologist

Adjuvant Therapyfor HR (High Risk) patients

Primary Tumor surgery

+/- Lymph Node Dissection (LND) Unresectable Disease

Clinically Detectable

Clinically Undetectable

RelapseRFSSurgery

Advanced/Metastatic Disease

1. Adapted from: Dummer R. Discussant on Adjuvant Melanoma. Presented at: European Society for Medical Oncology 2017 Congress; September 11, 2017; Madrid, Spain.

NEO-Adjuvant Adjuvant Advanced

Outline

• Background and Rationale for Adjuvant Therapy

• Interferon

• Checkpoint inhibitors

– Ipilimumab

– Anti-PD1 (nivolumab, pembrolizumab)

• Targeted therapy (MAPK pathway)

– Monotherapy

– Combination

• Putting it together

• Metastatic melanoma is still a deadly disease

– 5-year survival rate: 15% to 20%1

– 10-year survival: 10% to 15%1

• Early intervention may lead to improve long-term

cure rates2

• Prognostic factors for assessing risk for recurrence

are evolving and becoming more clearly defined2

Melanoma: Why Use Adjuvant Therapy?

1. American Cancer Society. Survival Rates for Melanoma Skin Cancer, by Stage. American Cancer Society Web site. https://www.cancer.org/cancer/melanoma-skin-

cancer/detection-diagnosis-staging/survival-rates-for-melanoma-skin-cancer-by-stage.html. Updated May 20, 2016. Accessed July 9, 2018.2. Thalanayar PM, Agarwala SS, Tarhini AA. Melanoma adjuvant therapy. Chin Clin Oncol. 2014;3(3):26-37. doi: 10.3978/j.issn.2304-3865.2014.03.02.

Prognosis of Melanoma is Dependent upon Its AJCC Stage1,2

• Role of accurate surgical staging is better defined in 20183

1. Buzaid AC and Gershenwald JE. Tumor node metastasis (TNM) staging system and other prognostic factors in cutaneous melanoma. Up To Date Web site. https://www.uptodate.com/contents/tumor-node-

metastasis-tnm-staging-system-and-other-prognostic-factors-in-cutaneous-melanoma. Updated May 29, 2018. Accessed July 15, 2018.

2. Balch CM, Gershenwald JE, Soong SJ, et al. Final Version of 2009 AJCC Melanoma Staging and Classification. J Clin Oncol. 2009;27:6199-6206.

3. Grob JJ, Schadendorf D, Lorigan P, et al. Eighth American Joint Committee on Cancer (AJCC) melanoma classification: Let us reconsider stage III. Eur J Cancer. https://doi.org/10.1016/j.ejca.2017.11.023.

High Risk Patients:

Higher Recurrence Rate and Relatively Poor Survival

https://doi.org/10.1016/j.ejca.2017.11.023

• Numerically, the most deaths from melanoma are estimated to be in

patients initially diagnosed with stage II or III disease

Why Adjuvant Therapy?

aCalculated from the total estimated new cases in 2017 (87,110 patients).

National Cancer Institute. Cancer stat facts: melanoma of the skin. https://seer.cancer.gov/statfacts/html/melan.html. Accessed April 2017.

Stage at diagnosis

Proportion of cases at

diagnosis, %Estimated new cases in 2017a

5-year relative survival rate, %

Estimated deaths after

5 years

I

Local disease84 73,173 98.5 1098

II/III

Regional spread9 7840 62.9 2909

IV

Distant spread4 3484 19.9 2791

Agents of Historical Interest That Were Tested in Adjuvant

Therapy1,2

• BCG

• Corynebacterium

parvum

• Levamisole

• Transfer factor

• Vaccines

• Limb Perfusion

• DTIC

• Autologous BMT

• Biochemotherapy

• Antibodies

• IFN

1. Nogueira JAM, Arbizu MV, and Temprano RP. Adjuvant Treatment of Melanoma. ISRN Dermatol. 2013;2013:1-17. doi: 10.1155/2013/545631.

2. Thalanayar PM, Agarwala SS, Tarhini AA. Melanoma adjuvant therapy. Chin Clin Oncol. 2014;3(3):26-37. doi: 10.3978/j.issn.2304-3865.2014.03.02.

Outline


• Interferon


– Ipilimumab



– Monotherapy

– Combination


Schedule Dose Frequency Duration

Low Dose Dose Frequency Duration

3 MIU 3 x weekly 18 – 24 months

Intermediate Dose

Induction 10 MIU 5 x weekly 4 weeks

Maintenance 10 MIU 3 x weekly 12 -24 months

5 MIU 3 x weekly 24 months

High Dose

Induction 20 MIU/m2 5 x weekly 4 weeks

Maintenance 10 MIU/m2 3 x weekly 11 months

Short Course

Induction X 1 20 MIU/m2 5 x weekly 4 weeks

Intermittent

Induction X 3 20 MIU/m2 20 MIU/m2 5 x weekly for 4

weeks Q 4 months

Adjuvant IFN-α-2b Regimens1

1. National Comprehensive Cancer Network. Melanoma (Version 2.2018). National Comprehensive Cancer Network Web site. https://www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf. Updated January 19,

2018. Accessed July 15, 2018.

Study/PI Stage NTreatment agent/

dosage/duration

Median Follow

up (yr)

Impact onComment

RFS OS

E16841

(HDI vs.

OBS)T4, N+ 287

IFNα2b 20 MU/m2/D IV for 1

month. Then, 10 MU/m2 SC

TIW for 11 months vs.

Observation

6.90.61;

P=0.001

0.67;

P=0.01

Recurrent nodes 64%.

Greatest benefit microscopic

nodal disease.

Competing causes of death at

12.6yrs FU.

12.60.72;

P=0.02

0.82;

P=0.18

E16902

(HDI vs.

LDI)T4, N+ 642


month. Then, 10 MU/m2 SC


3 MU/D given SC TIW for 2

years vs. Observation

4.30.78;

P=0.051.0

51% nodal recurrent. Cross

over of obs pts to HDI at

relapse (n=38 pts). 17 pts in

obs arm received HDI for

nodal relapse.

6.60.81;

P=0.091.0

E16943

(HDI vs.

GMK

vaccine)

T4, N+ 880


month. Then 10 MU/m2 SC


GMK vaccine for 96 wks

1.30.67;

P=0.0004

0.72;

P=.023Early closure for vaccine

futility at 2 yrs.

Benefit greatest in node –ve.2.10.75;

P=0.006

0.76;

P=0.04

EORTC

189914

(PegIFN vs.

OBS)

N1-2 1256

PegIFNα2b given SC at 6

µg/kg/week (8 weeks) then 3

µg/kg/week (5 years) vs.

Observation

3.80.82;

P=0.0110.98 Impact on RFS, DMFS and OS

in ulcerated tumour & 1

microscopic node. No benefit if

not ulcerated.7.6

0.87;

P=0.0550.96

Interferon Trials Leading to Regulatory

Approval

1. Kirkwood JM, Strawderman MH, Ernstoff, MS, et al. Interferon -2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol. 1996;14(1):7–17.

2. Kirkwood JM, Ibrahim JG, Sondak VK, et al. High- and low-dose interferon -2b in high-risk melanoma: first analysis of Intergroup Trial E1690/S9111/C9190. J Clin Oncol. 2000;18(12):2444–2458.

3. Kirkwood JM, Ibrahim JG, Sosman JA, et al. High-dose interferon -2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected

stage IIB-III melanoma: results of Intergroup Trial E1694/S9512/C509801. J Clin Oncol. 2001;19(9):2370–2380.

4. Eggermont AMM, Suciu S, Santinami M, et al. Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991,

a randomised phase III trial. Lancet. 2008;372(9633):117-126.

1. Kirkwood JM, Manola J, Ibrahim J, et al. A Pooled Analysis of Eastern Cooperative Oncology Group and Intergroup Trials of Adjuvant High-Dose Interferon for

Melanoma. Clin Cancer Res. 2004;10(5):1670-1677.

E1684 Updated Efficacy1

(ITT at 12.6 yr Median Follow-up)

Dose: 20 MU/m2/D IV for 1 month, then, 10 MU/m2 SC TIW for 11 months1

Conclusions: Improvements in RFS and OS led to FDA approval1

Interferon: Shorter Duration & New Formulation

• ECOG 1697 tested a shorter duration of HDI treatment1

– 4-week induction dose of 20 MU/m2/day for 5 days weekly1

• EORTC 18991 tested use of pegylated IFN: once weekly

dosing and lower dose with comparable AUC2

– Covalent bonding to a polyethylene glycol moiety

increases absorption and half-life3

– Approved by the FDA for use in adjuvant therapy in

melanoma in 2011 (brand name: SYLATRON™)4

1. Agarwala SS, Lee SJ, Yip W, et al. Phase III Randomized Study of 4 Weeks of High-Dose Interferon-α-2b in Stage T2bNO, T3a-bNO, T4a-bNO, and T1-4N1a-2a (microscopic) Melanoma: A Trial of the Eastern

Cooperative Oncology Group–American College of Radiology Imaging Network Cancer Research Group (E1697). J Clin Oncol. 2017;35(8):885-892.

2. Eggermont AMM, Suciu S, Santinami M, et al. Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial.

Lancet. 2008;372(9633):117-126.

3. Thalanayar PM, Agarwala SS, Tarhini AA. Melanoma adjuvant therapy. Chin Clin Oncol. 2014;3(3):26-37. doi: 10.3978/j.issn.2304-3865.2014.03.02.

4. Interferon (Intron® A or Sylatron™). Melanoma Research Alliance Web site. https://www.curemelanoma.org/patient-eng/melanoma-treatment/adjuvant-therapy/interferon-intron-a-or-sylatron/.

Updated May 2016. Accessed July 18, 2018.

Defined as T3:

Breslow thickness >1.5 mm (AJCC 6th ed) >2.0 mm (AJCC 7th ed)

or

Any thickness with microscopically positive nodal disease (N1a–N2a)

ECOG 1697 Study Design1

Patients with intermediate-

and high-risk melanoma

R

A

N

D

O

M

I

Z

A

T

I

O

N

Postoperative

adjuvant

IFN alfa-2b

20 MU/m2/day

for 5 days/week

4 weeks

Observation

1:1

1. Agarwala SS, Lee SJ, Yip W, et al. Phase III Randomized Study of 4 Weeks of High-Dose Interferon-α-2b in Stage T2bNO, T3a-bNO, T4a-bNO, and T1-4N1a-2a (microscopic) Melanoma:

A Trial of the Eastern Cooperative Oncology Group–American College of Radiology Imaging Network Cancer Research Group (E1697). J Clin Oncol. 2017;35(8):885-892.

E1697 Induction Only HD IFN vs. Observation1

1. Agarwala SS, Lee SJ, Yip W, et al. Phase III Randomized Study of 4 Weeks of High-Dose Interferon-α-2b in Stage T2bNO, T3a-bNO, T4a-bNO, and T1-4N1a-2a (microscopic) Melanoma:

A Trial of the Eastern Cooperative Oncology Group–American College of Radiology Imaging Network Cancer Research Group (E1697). J Clin Oncol. 2017;35(8):885-892.

Conclusion: No impact on RFS or OS with four-week long regimen, which supports the

use of the 1-year regimen used in E16841

Stratified by:

• Microscopic (N1) vs. palpable (N2)

• 1 vs. 2-4 vs. 5+ nodes

• Breslow

• Ulceration

• Gender

• Site

Observation

Peg-IFN alfa-2b

• Induction (8 weeks) 6 µg/kg/week

• Maintenance (5 years or distant

metastasis) 3 µg/kg/week

• Dose reduction to 3, 2, 1 to maintain

performance status

Primary Endpoints:

• Relapse-free survival (RFS)

• Distant metastasis-free survival (DMFS)

Patients (n=1,256):

Resected TxN1-2M0 melanoma, within

7 weeks of lymphadenectomy

Randomization

EORTC 18991 (PEG-IFN) Study Design1

1. Eggermont AMM, Suciu S, Santinami M, et al. Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991,

a randomised phase III trial. Lancet. 2008;372(9633):117-126.

EORTC 18991 RFS1

1. Eggermont AMM, Suciu S, Santinami M, et al. Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma:

final results of EORTC 18991, a randomised phase III trial. Lancet. 2008;372(9633):117-126.

Conclusion: No OS or DMFS benefit was observed with peg-IFN, only in RFS.

Thirty-seven percent of patients discontinued treatment due to toxicity.1

The Interferon Controversy

• Conflicting efficacy data among trials1

– Only E1684 showed an OS advantage

– All other trials showed only RFS advantage

• Which dosage and schedule to use was controversial1

• Toxicity was significant2

– AEs include: acute constitutional symptoms, chronic fatigue, myelosuppression, hepatotoxicity, and neurologic and psychologic effects

• IFN has been superseded by newer agents

1. Ives NJ, Suciu S, Eggermont AMM, et al. Adjuvant interferon-α for the treatment of high-risk melanoma: An individual patient data meta-analysis. Eur J Cancer. 2017;82:171-183.

2. Sosman JA. Adjuvant therapy for cutaneous melanoma. Up To Date Web site. https://www.uptodate.com/contents/adjuvant-therapy-for-cutaneous-melanoma. Updated June 12, 2018.

Accessed July 13, 2018.

Interferon

Outline


• Interferon


– Ipilimumab



– Monotherapy

– Combination


Ipilimumab in Melanoma

• Standard Dose

– 3mg/kg administered intravenously over 90 minutes every 3 weeks for a total of 4 doses1

– Approved by the FDA for metastatic melanoma in 20112

• High Dose

– 10mg/kg administered intravenously over 90 minutes every 3 weeks for 4 doses, followed by 10

mg/kg every 12 weeks for up to 3 years or until documented disease recurrence or unacceptable

toxicity1

– Approved by the FDA for adjuvant therapy of melanoma in 20153

1. YERVOY (ipilumumab) injection. FDA Web site. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125377s087lbl.pdf. Updated July 2017. Accessed July 16, 2018.

2. Mulcahy N. FDA Approves Ipilimumab for Advanced Melanoma. Medscape Web site. https://www.medscape.com/viewarticle/739604. Published March 25, 2011. Accessed July 13, 2018.

3. Nelson R. FDA Approves Ipilimumab (Yervoy ) for Use in Stage III Melanoma. Medscape Web site. https://www.medscape.com/viewarticle/853413. Published October 28, 2015. Accessed July 13, 2018.

EORTC 18071 Phase 3 Study Design1,2

Key eligibility criteria

• Stage IIIA, IIIB, or IIIC

melanoma metastatic to

lymph node

• Complete and adequate

resection of stage III

melanoma

• No prior systemic therapy

Stratified by:

• Stage (IIIA vs IIB vs IIIC 1-3

positive lymph nodes vs

IIIC ≥ 4 positive lymph nodes)

• Region of the world

R

A

N

D

O

M

I

Z

A

T

I

O

N

Treat up to a

maximum of 3 years

or until disease

progression,

intolerable toxicity,

or withdrawal

Primary endpoint

RFS

Secondary

endpoints

OS, DMFS, safety,

HRQOL

Randomized, double-blind, phase 3 study

1:1

N = 951

Induction

Ipilimumab 10 mg/kg

Q3W × 4

(n = 475)

Placebo

Q3W × 4

(n = 476)

Ipilimumab 10 mg/kg

Q12W up to

3 years

Placebo

Q12W up to

3 years

Maintenance

Wk 1 Wk 12 Wk 24

DMFS, distant metastasis-free survival; HRQOL, health-related quality of life; OS, overall survival; PFS, progression-free survival; Q3W,

every 3 weeks; Q12W, every 12 weeks; RFS, relapse-free survival.

1. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet

Oncol. 2015;16(5):522-530.

2. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Ipilimumab (IPI) vs placebo (PBO) after complete resection of stage III melanoma: final overall survival results from the EORTC 18071

randomized, double-blind, phase 3 trial. Presented at: European Society for Medical Oncology 2016 Congress ; October 8, 2016; Copenhagen, Denmark.

IPI PBO

Events/patients 264/475 323/476

HR (95% CI) 0.76 (0.64, 0.89)

Log-rank P value P < 0.001

Median RFS, months (95% CI)

27.6 (19.3, 37.2)

17.1 (13.6, 21.6)

EORTC 18071/CA184-029: Survival

IPI PBO

Death/patients 162/475 214/476

HR (95% CI) 0.72 (0.58, 0.88)

Log-rank P value 0.001

IRC = institutional review committee.

Adapted from Eggermont AM et al. N Engl J Med. 2016;375:1845-1855.

Recurrence-free Survival (per IRC)

41%

30%

Years0 1 2 3 4 5 6 7 8

0

10

20

30

40

50

60

70

80

90

100

Number of patients at risk

475 283 217 184 161 77 13 1

476 261 199 154 133 65 17 0

IPI

PBO

Pat

ien

ts A

live

an

dW

ith

ou

t Re

curr

en

ce (%

)

Overall Survival

Years0 1 2 3 4 5 6 7 8

0

10

20

30

40

50

60

70

80

90

100


475 431 369 325 290 199 62 4

476 413 348 297 273 178 58 8

IPI

PBO

Pat

ien

ts A

live

(%)

65%

54%

Ipilimumab(n = 471)

Placebo

(n = 474)

Any Grade Grade 3/4 Any grade Grade 3/4

Any AE, % 98.7 54.1 91.1 26.2

Treatment-related AE, % 94.1 45.4 59.9 4.0

Treatment-related AE discontinuation, %

48.0 32.9 1.5 0.6

Any immune-related AE, % 90.4 41.6 39.7 2.7

5 patients (1.1%) died in the ipilimumab group

• 3 patients with colitis (2 with gastrointestinal perforations)

• 1 patient with myocarditis

• 1 patient had multiorgan failure with Guillain-Barré syndrome

EORTC 18071 Safety Summary1,2

1. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind,

phase 3 trial. Lancet Oncol. 2015;16(5):522-530.

2. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Ipilimumab (IPI) vs placebo (PBO) after complete resection of stage III melanoma: final overall survival results from the EORTC 18071

randomized, double-blind, phase 3 trial. Presented at: European Society for Medical Oncology 2016 Congress ; October 8, 2016; Copenhagen, Denmark.

R

A

N

D

O

M

I

Z

E

Patients with

resectable stage

IIIB or IIIC or IV

(M1a or M1b)

N=1500 +

High dose interferon

Ipilimumab 10mg/kg

E1609 Phase III Trial to Assess Adjuvant Dose vs. Metastatic Dose

vs. HD-IFN1

Primary Endpoint: RFS, OS

Secondary Endpoints: Safety, Quality of life, immunologic correlates of RFS, OS

Completed accrual: 8/2014- Results anticipated: 2018

Ipilimumab 3mg/kg

1. National Cancer Institute (NCI). Ipilimumab or High-Dose Interferon Alfa-2b in Treating Patients With High-Risk Stage III-IV Melanoma That Has Been Removed by Surgery.

ClinicalTrials.gov Web site. https://clinicaltrials.gov/ct2/show/NCT01274338. Published January 11, 2011. Updated July 2, 2018. Accessed July 10, 2018.

E1609 RFS Ipi10 vs. Ipi31

(Concurrently randomized patients)

HR = 1.0, 95%CI (0.81, 1.24)

1. Tarhini AA, Lee SJ, Hodi S, et al. A phase III randomized study of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon alfa-2b for resected high-risk melanoma (U.S.

Intergroup E1609): Preliminary safety and efficacy of the ipilimumab arms. Presented at: American Society of Clinical Oncology 2017 Annual Meeting; June 4, 2017; Chicago, IL.

E1609 Safety Summary

Based on all toxicity data as of 3/2/20171

Ipi3 (n = 516) Ipi10 (n = 503)

Any Grade Grade 3/4 Any Grade Grade 3/4

Any AE, % 98.4 53.3 100 65.4

Treatment-related AE, % 96.0 36.6 98.8 56.5

Treatment-related AE leading

to discontinuation, %34.9 25.0 53.7 42.9

Any immune-related AE, % 73.6 18.8 86.9 34.0

1. Tarhini AA, Lee SJ, Hodi S, et al. A phase III randomized study of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon alfa-2b for resected high-risk melanoma (U.S. Intergroup E1609):

Preliminary safety and efficacy of the ipilimumab arms. Presented at: American Society of Clinical Oncology 2017 Annual Meeting; June 4, 2017; Chicago, IL.

E1609 Treatment Related Deaths1

Ipi3 (2 patients/516; 0.4%)

Colitis / Bowel perforation

Colitis / Death NOS

(Colitis requiring steroids & infliximab. C-diff

infection. D/C in stable condition. Withdrew

consent. Death)

Ipi10 (8 patients/503; 1.6%)

Colitis

Colitis / Colonic perforation

Colitis

Colitis / Ventricular tachycardia

(Gr4 Colitis, later rehab, DVT, pneumonia, VT)

Colitis / Nervous system disorder

(GI toxicity with subsequent neurologic

decline; 81 y.o.)

Pneumonitis

Thromboembolic event / Hypopituitarism

Cardiac arrest

(Syncope, sepsis, sudden death)

1. Tarhini AA, Lee SJ, Hodi S, et al. A phase III randomized study of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon alfa-2b for resected high-risk melanoma (U.S.

Intergroup E1609): Preliminary safety and efficacy of the ipilimumab arms. Presented at: American Society of Clinical Oncology 2017 Annual Meeting; June 4, 2017; Chicago, IL.

aSelect trials in cutaneous melanoma are shown. bNote staging based on AJCC Staging 8th Edition.

ECOG = Eastern Cooperative Oncology Group; MAGE = melanoma-associated antigen; NED = no evidence of disease; PD-L1 = programmed death ligand 1;

PEMBRO = pembrolizumab.

1. www.clinicaltrials.gov. Accessed April 2017. 2. Data on file NIVO 297.

Current Relevant Phase 3 Trialsa,1

Study Design Patient populationAccrual

goalPrimary endpoint

Status(primary

completion)

KEYNOTE 054(EORTC 1325)

PEMBRO vs PBO Completely resected, high-risk stage III 900RFS/RFS in PD-L1+

Ongoing(August 2017)

CheckMate 238 NIVO vs IPICompletely resected, high-risk stage IIIB/C or IV

800 RFSOngoing(November 2018)

EORTC 18081PEG-IFN 2 years vs observation

Completely resected, ulcerated primary melanoma T(2-4)bN0M0

1200 RFSOngoing(April 2019)

SWOG S1404PEMBRO or IPI vs

high-dose IFN-α

Completely resected, high-risk stage IIIA (N2a), IIIB, IIIC, or IV

1378OS/RFS/

PD-L1Recruiting(June 2020)

CheckMate 9152 NIVO+IPI vs NIVOCompletely resected, stage IIIB/C/D or IV NEDb

900 RFSRecruiting(December 2020)

BRIM8 Vemurafenib vs PBOSurgically resected, BRAF mutant melanoma at high risk for recurrence

503 DFSOngoing(June 2017)

COMBI-ADDabrafenib + trametinib vs PBO

Completely resected, BRAF mutant, high-risk stage IIIA (LN metastasis > 1 mm), IIIB, or IIIC. Stage I/II with initial resectable LN recurrence

852 RFSOngoing(December 2017)

Immunotherapy Targeted therapy

Outline


• Interferon


– Ipilimumab



– Monotherapy

– Combination


Patients with:

• High-risk, completely

resected stage IIIB/IIIC

or stage IV (AJCC 7th

edition) melanoma

• No prior systemic

therapy

• ECOG 0-1

Enrollment period: March 30, 2015 to November 30, 2015

Follow-up

Maximum

treatment

duration of

1 year

NIVO 3 mg/kg IV Q2W

and

IPI placebo IV

Q3W for 4 doses

then Q12W from week 24

IPI 10 mg/kg IV

Q3W for 4 doses

then Q12W from week 24

and

NIVO placebo IV Q2W

1:1

n = 453

n = 453

Stratified by:

1) Disease stage: IIIB/C vs IV M1a-M1b vs IV M1c

2) PD-L1 status at a 5% cutoff in tumor cells

CheckMate 238 Study Design1

1. Weber J, Mandala M, Del Vecchio M, et al. Adjuvant therapy with nivolumab (NIVO) versus ipilimumab (IPI) after complete resection of stage III/IV melanoma: Updated results from a phase III trial (CheckMate 238). Presented

at: American Society of Clinical Oncology 2018 Annual Meeting; June 4, 2018; Chicago, IL.

NIVO(n = 453)

IPI(n = 453)

Median age, years 56 54

Male, % 57 59

Stage IIIB+IIIC, % 81 81

Macroscopic lymph node involvement (% of stage IIIB+IIIC) 60 58

Ulceration (% of stage IIIB+IIIC) 42 37

Stage IV, % 18 19

M1c without brain metastases (% stage IV) 17 17

PD-L1 expression ≥5%, % 34 34

BRAF mutation, % 41 43

LDH ≤ ULN, % 91 91

Melanoma subtype, %

Cutaneous 86 83

Mucosal 4 3

Acral 4 4

CheckMate 238 Baseline Patient Characteristics and Treatment

Summary1



• Median doses were 24 (1-26) in the NIVO group and 4 (1-7) in the IPI group

• 61% of patients in the NIVO group and 27% in the IPI group completed 1 year of treatment

CheckMate 238

Primary Endpoint RFS in All Patients1

NIVO IPI


Median (95% CI) 30.8 (30.8, NR)a 24.1 (16.6, NR)

HR (95% CI) 0.66 (0.54, 0.81)

Log-rank P value

CheckMate 238 Subgroup Analysis of RFS: Disease Stage III and IV1

NIVO

IPI

RF

S (

%)

Months

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 27 333 9 15 21 3024

368 291 258 230 22 0320 272 240 217NIVO 4166

366 259 207 179 18 0298 223 190 169IPI 3121


72%

61%

64%

52%

67%

55%

NIVO

IPI

RF

S (

%)

Months

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 27 333 9 15 21 3024

82 59 51 48 6 071 56 49 45NIVO 337

87 55 44 37 5 065 47 40 35IPI 228


63%

56%

58%

44%

61%

47%

aMedian estimate not reliable or stable due to few patients at risk.

Stage III

NIVO IPI


Median (95% CI) NR 25.5 (16.6, NR)

HR (95% CI) 0.68 (0.54, 0.85)

Stage IV

NIVO IPI


Median (95% CI) 30.8 (15.9, NR)a 15.4 (8.5, NR)

HR (95% CI) 0.68 (0.44, 1.06)



• There were no treatment-related deaths in the NIVO group

• There were 2 (0.4%) treatment-related deaths in the IPI group

(marrow aplasia and colitis), both >100 days after the last dose

AE, n (%)

NIVO (n = 452) IPI (n = 453)

Any grade Grade 3/4 Any grade Grade 3/4

Any AE 438 (97) 115 (25) 446 (98) 250 (55)

Treatment-related AE 385 (85) 65 (14) 434 (96) 208 (46)

Any AE leading to

discontinuation44 (10) 21 (5) 193 (43) 140 (31)

Treatment-related AE leading

to discontinuation35 (8) 16 (4) 189 (42) 136 (30)

CheckMate 238 Safety Summary1



EORTC 1325/KEYNOTE-54 Study Design1

Pembrolizumab 200

mg IV Q3W until

progression or

recurrence,

up to 2 years

Recurrence >6

months

Recurrence

Cross-over

Pembrolizumab

200 mg IV Q3W

1 year

Placebo

IV Q3W

1 year

Randomized

1:1

High-risk,

resected, Stage III

cutaneous

melanoma

N=1019

Total of 18 doses UNBLINDING

UNBLINDING/ Cross-over:

Anti-PD-1 for all or just as good if only for those at time of recurrence?

Part 1: Adjuvant Therapy Part 2: Post Recurrence

Stratification factors:✓ Stage: IIIA (>1 mm metastasis) vs. IIIB vs. IIIC 1-3 positive lymph nodes vs. IIIC ≥4 positive lymph nodes✓ Region: North America, European countries, Australia/New Zealand, other countriesPrimary Endpoints:• RFS (per investigator) in overall population, and RFS in patients with PD-L1-positive tumorsSecondary Endpoints:• DMFS and OS in all patients, and in patients with PD-L1-positive tumors; Safety, Health-related quality of life

1. Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma [published online ahead of print April 15, 2018].

N Engl J Med. doi: 10.1056/NEJMoa1802357.

EORTC 1325/KEYNOTE-54 Baseline Patient Characteristics1

Pembrolizumab (N=514) Placebo (N=505)

Median age (years) 54 54

Male (%) 63 60

Stage (%)

IIIA 15 15

IIIB 47 46

IIIC with 1-3 positive LN 17 19

IIIC with ≥4 positive LN 21 20

Ulceration of primary (%) 41 39

1 vs. 2-3 vs. ≥4 positive LN (%) 44 vs. 34 vs. 21 47 vs. 33 vs. 20

Lymph node involvement (%)

Microscopic 36 32

Macroscopic 64 68



HR = 0.57

EORTC 1325/KEYNOTE-54

Recurrence-Free Survival in the ITT Population1

Primary Endpoint



EORTC 1325/KEYNOTE-54 Recurrence-Free Survival1

HR = 0.32Stage IIIA HR = 0.56Stage IIIB HR = 0.58Stage IIIC



EORTC 1325/KEYNOTE-54 Immune-Related Adverse Events

(irAE)1

Pembrolizumab (N=509) Placebo (N=502)

Any Grade, % Grade 3-5, % Any Grade, % Grade 3-5, %

Any irAE 37.3 7.1 9.0 0.6

Endocrine 23.4 1.8 5.0 0

Gastrointestinal 3.9 2.0 0.8 0.4

Colitis 3.7 2.0 0.6 0.2

Pancreatitis 0.4 0.2 0.2 0.2

Hepatitis 1.8 1.4 0.2 0.2

Other irAE 2.9 1.0 1.0 0

Nephritis 0.4 0.4 0.2 0

Uveitis 0.4 0 0 0

Myositis* 0.2 0.2 0.2 0

Myocarditis 0.2 0.2 0 0

* One treatment-related death due to myositis



Patient Populations Evaluated in Adjuvant Trials With Immuno-Oncology Agents

Study Design

Patient population (completely resected disease)

IIIA IIIB IIICIIID

(only in AJCC Staging 8th Edition)

IV

CA184-029 IPI 10 mg/kg vs PBO ✔ ✔ ✔

US Intergroup E1609IPI 10 mg/kg and IPI 3 mg/kg vs HD IFN

✔ ✔✔

(M1a/M1b)

CheckMate 238 NIVO vs IPI 10 mg/kg ✔ ✔ ✔

CheckMate 915 NIVO+IPI vs NIVO2 ✔ ✔ ✔ ✔

KEYNOTE 054(EORTC 1325)

PEMBRO vs PBO ✔ ✔ ✔

SWOG S1404PEMBRO or IPI vs

HD IFN-α✔ (N2A) ✔ ✔ ✔

1. www.clinicaltrials.gov. Accessed April 2017. 2. Data on file NIVO 297.

Outline


• Interferon


– Ipilimumab



– Monotherapy

– Combination


BID, twice daily; DFS, disease-free survival; DMFS, distant metastasis-free survival; HRQoL. Health-related quality of life; OS, overall survival.a Patients with stage IIIA melanoma were eligible if they had one or more nodal metastasis >1 mm in diameter.

Cohort 1 = 314(Stage IIC, IIIAa, IIIB)

Stratified by disease

stage and geographic

region

Placebo

x 52 weeks | (n=157)

Vemurafenib 960 mg BID

x 52 weeks | (n=157)

Cohort 2 = 184(Stage IIIC)

Stratified by geographic

region

Placebo

x 52 weeks | (n=91)

Vemurafenib 960 mg BID

x 52 weeks | (n=93)

1:1

1:1

• Primary endpoint

– Disease-free Survival (DFS)

• Secondary endpoints

– DMFS

– OS

– Safety

– HRQoL

BRIM8 Study Design: Phase III, international, multicenter, double-blind, randomized, placebo-controlled study1

1. Lewis K, Maio M, Demidov L, et al. BRIM8: a randomized, double-blind, placebo-controlled study of adjuvant vemurafenib in patients (pts) with completely resected, BRAFV600+ melanoma at high risk for recurrence.

Presented at: European Society for Medical Oncology 2017 Congress; September 11, 2017; Madrid, Spain.

BRIM8 Pre-specified Exploratory DFS Analysis in Pooled ITT Population1

aNot significant because primary endpoint was not met in Cohort 2. CI, confidence interval; DFS, disease-free survival; DMFS,

distant metastasis-free survival; HR, hazard ratio; NE, not estimable.

Vemurafenib

(n = 250)

Placebo

(n = 248)

Events, n (%) 97 (39) 125 (50)

Median DFS, months (95%

CI)

NE

(29.8 – NE)

25.8

(20.5 – NE)

Hazard ratio (95% CI)

log-rank P-value

0.65 (0.50 to 0.85)

P= 0.0013a

▪ The pre-specified exploratory pooled analysis of the 2 cohorts demonstrates an overall clinical benefit

Patients at risk, n

100

80

60

40

20

0

0 9 18 27 36 48

Pati

en

ts A

liv

e a

nd

Dis

ease

-Fre

e (

%)

Time (months)

Vemurafenib

Placebo

Censored

82.2%

63.1%

62.2%

53.1%+

3 12 21 30 396 15 24 33 42 5145

Vemurafenib 250 233 222 205 190 176 164 138 101 65 53 44 37 25 20 5 2 −

Placebo 248 200 117 160 151 139 133 118 96 64 51 44 39 30 19 8 2 −

+++++ + +++++++

+++ ++++++++++++++++++++++++++++++++++++++++++++++++++ +++++ +++++++++++++++ ++++++++++++ + ++++

++

++

++

++ ++ ++++ +++++++++++++++ +++++++ +++ ++++ ++ ++++++++ +++++++

+

+

+++++++++++ + +

+

19% 9% ~5%



BRIM8 Primary DFS Endpoint (Cohort 1, Stage IIC–IIIB)1

aCannot be considered significant because primary endpoint was not met in Cohort 2. CI, confidence interval; DFS, disease-free survival; HR, hazard ratio, NE, not estimable.

Patients at risk, n

100

80

60

40

20

0

0 9 18 27 36 48

Pati

en

ts A

liv

e a

nd

Dis

ease

-Fre

e (

%)

Time (months)

3 12 21 30 396 15 24 33 42 5145

+ +

++

+ ++ ++

+ ++++++++++++++++++ ++++ ++ ++ +++++ +++ +++++++ ++ + +

+++++++

+

+++

+ + ++ +++++++ ++ +++++ ++++++++++++++++++++ +++ +++ + ++++++++ ++++ +++++++++ ++ ++++

+ +++ + + +++

Vemurafenib 157 146 137 129 120 −115 107 94 72 49 38 31 26 18 15 4 2Placebo 157 129 118 106 100 −94 90 79 65 43 35 31 28 22 12 3 1

▪ One year of adjuvant vemurafenib results in 46% DFS risk reduction in stage IIC-IIIB BRAFV600 melanoma,

demonstrating a substantial clinical benefit vs. placebo

Vemurafenib

Placebo

Censored

84.3%

66.2%

72.3%

56.5%+18% 16% ~7%

Vemurafenib

(n = 157)

Placebo

(n = 157)

Events, n (%) 45 (29) 72 (46)

Median DFS, months (95% CI) NE36.9

(21.4 – NE)


log-rank P-value

0.54 (0.37 to 0.78)

P= 0.0010a

61%

54%



BRIM8 Primary DFS Endpoint (Cohort 2, Stage IIIC)1

▪ One year of adjuvant vemurafenib increased median DFS vs. placebo in stage IIIC BRAFV600 melanoma

demonstrating a biologic effect, however it did not significantly reduce DFS risk

CI, confidence interval; DFS, disease-free survival; HR, hazard ratio, NE, not estimable.

Vemurafenib

(n = 93)

Placebo

(n =91)

Events, n (%) 52 (56) 53 (58)

Median DFS, months (95% CI)23.1

(18.6 – 26.5)

15.4

(11.1 – 35.9)


log-rank P-value

0.80 (0.54 to 1.18)

P= 0.2598

Patients at risk, n

100

80

60

40

20

0

0 9 18 27 36 48

Pati

en

ts A

liv

e a

nd

Dis

ease

-Fre

e (

%)

Time (months)

3 12 21 30 396 15 24 33 42 5145

+++

+

++++++++++

++ ++++ + + +++ ++ +++ + + +

+

+

++ ++ + +++++++ + +++ + ++ ++

+

+ + + +++ +

Vemurafenib 93 87 85 76 70 61 57 44 29 16 15 13 11 7 5 1 − −

Placebo 91 71 59 54 51 45 43 39 31 21 16 13 11 8 7 5 1 −

Vemurafenib

Placebo

Censored

78.9%

58.0%

46.3%

47.5%+



Outline


• Interferon


– Ipilimumab



– Monotherapy

– Combination


Stratification

• BRAF mutation status (V600E, V600K)

• Disease stage (IIIA, IIIB, IIIC)

Key eligibility criteria

• Completely resected, high-risk stage IIIA (lymph node metastasis > 1 mm), IIIB, or IIIC cutaneous melanoma

• BRAF V600E/K mutation

• Surgically free of disease ≤ 12 weeks before randomization

• ECOG performance status 0 or 1

• No prior radiotherapy or systemic therapy

R

A

N

D

O

M

I

Z

A

T

I

O

N

1:1

Dabrafenib 150 mg BID +

trametinib 2 mg QD

(n = 438)

2 matched placebos

(n = 432)

Treatment: 12 monthsa

Follow-upb

until end of

studyc

• Primary endpoint: RFSd

• Secondary endpoints: OS, DMFS, FFR, safety

N = 870

BID, twice daily; DMFS, distant metastasis-free survival; ECOG, Eastern Cooperative Oncology Group; FFR, freedom from relapse; OS, overall survival; QD,

once daily; RFS, relapse-free survival. a Or until disease recurrence, death, unacceptable toxicity, or withdrawal of consent; b Patients were followed for disease recurrence until the first recurrence

and thereafter for survival; c The study will be considered complete and final OS analysis will occur when ≈ 70% of randomized patients have died or are los t

to follow-up; d New primary melanoma. considered as an event.

COMBI-AD Phase 3 Study Design1

1. Hauschild A, Santinami M, Long G, et al. Adjuvant dabrafenib (D) plus trametinib (T) for resected stage III BRAF V600E/K–mutant melanoma. Presented at:

European Society for Medical Oncology 2017 Congress; September 11, 2017; Madrid, Spain.

CategoryaDabrafenib Plus Trametinib

(n = 438)Placebo (n = 432)

Total (N = 870)

Disease stage, n (%)IIIAIIIBIIICIII (unspecified)

83 (19)169 (39)181 (41)

5 (1)

71 (16)187 (43)166 (38)

8 (2)

154 (18)356 (41)347 (40)13 (1)

Number of positive lymph nodes, n (%)12 or 3≥ 4

177 (40)158 (36)73 (17)

183 (42)150 (35)72 (17)

360 (41)308 (35)145 (17)

Type of lymph node involvement, n (%)MicroscopicMacroscopicNot reported

152 (35)158 (36)128 (29)

157 (36)161 (37)114 (26)

309 (36)319 (37)242 (28)

Primary tumour ulceration, n (%)YesNo

179 (41)253 (58)

177 (41)249 (58)

356 (41)502 (58)

COMBI-AD Selected Baseline Characteristics1

1. Hauschild A, Santinami M, Long G, et al. Adjuvant dabrafenib (D) plus trametinib (T) for resected stage III BRAF V600E/K–mutant melanoma. Presented at:

European Society for Medical Oncology 2017 Congress; September 11, 2017; Madrid, Spain.

COMBI-AD Primary Analysis: RFS and OS Median follow-up at 2.8 years1,2

a Prespecified significance boundary (P = .000019); next interim analysis planned when 50% of events have occurred.

NR, not reached.

Relapse-Free Survival (primary endpoint)

Overall Survival

Group Events, n (%) Median (95% CI), mo HR (95% CI)

Dabrafenib plus trametinib

60 (14) NR (NR-NR) 0.57(0.42-0.79); P = .0006aPlacebo 93 (22) NR (NR-NR)

Group Events, n (%) Median (95% CI), mo HR (95% CI)

Dabrafenib plus trametinib

166 (38) NR (44.5-NR) 0.47(0.39-0.58);

P < .001Placebo 248 (57) 16.6 (12.7-22.1)

Data cutoff: 30 June 2017.

438 413 405 392 382 373 355 336 325 299 282 276 263 257 233 202 194 147 116 110 66 52 42 19 7 2 0

432 387 322 280 263 243 219 203 198 185 178 175 168 166 158 141 138 106 87 86 50 33 30 9 3 0 0

Months From Randomization

0

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52

Pro

po

rtio

n A

liv

e a

nd

Re

lap

se

Fre

e 1 y, 88%

2 y, 67%3 y, 58%

1 y, 56%2 y, 44% 3 y, 39%

438 426 416 414 408 401 395 387 381 376 370 366 362 352 328 301 291 233 180 164 105 82 67 28 12 5 0

432 425 415 410 401 386 378 362 346 337 328 323 308 303 284 269 252 202 164 152 94 64 51 17 7 1 0

0

0

0

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54

Pro

po

rtio

n A

live

1 y, 97%2 y, 91%

3 y, 86%

1 y, 94%

2 y, 83%3 y, 77%

Dabra + Tram

Placebo

No. at RiskMonths From Randomization

1. Long GV, Hauschild A, Santinami S, et al. Efficacy outcomes in the phase 3 COMBI-AD study of adjuvant dabrafenib (D) plus trametinib (T) versus placebo (PBO) in patients (pts) with stage III BRAF

V600E/K–mutant melanoma. Presented at: 9th World Congress of Melanoma and 14th International Congress of the Society for Melanoma Research; October 21, 2017; Brisbane, Australia.

2. Long GV, Hauschild A, Santinami M, et al. Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. N Engl J Med. 2017;377(19):1813-1823. doi: 10.1056/NEJMoa1708539.

COMBI-AD RFS1,2

HR = 0.44

Stage IIIA

Data cutoff: 30 June 2017

HR = 0.50

Stage IIIB

HR = 0.45

Stage IIIC

1. Long GV, Hauschild A, Santinami S, et al. Efficacy outcomes in the phase 3 COMBI-AD study of adjuvant dabrafenib (D) plus trametinib (T) versus placebo (PBO) in patients (pts) with stage III BRAF

V600E/K–mutant melanoma. Presented at: 9th World Congress of Melanoma and 14th International Congress of the Society for Melanoma Research; October 21, 2017; Brisbane, Australia.

2. Long GV, Hauschild A, Santinami M, et al. Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. N Engl J Med. 2017;377(19):1813-1823. doi: 10.1056/NEJMoa1708539.

a Eleven patients (3%) in the treatment arm and 10 patients (2%) in the placebo arm had new primary melanomas; 8 (2%) and 7 (2%), respectively, had cutaneous squamous

cell carcinoma/keratoacanthoma; 19 (4%) and 14 (3%), respectively, had basal cell carcinoma; and 10 (2%) and 4 (1%), respectively, had noncutaneous malignancies.

Dabrafenib Plus Trametinib (n = 435) Placebo (n = 432)

AEs, n (%) All Grades Grade 3/4 All Grades Grade 3/4

Any AE (> 20% with

dabrafenib plus trametinib)a422 (97) 180 (41) 380 (88) 61 (14)

Pyrexia 273 (63) 23 (5) 47 (11) 2 (< 1)

Fatigue 204 (47) 19 (4) 122 (28) 1 (< 1)

Nausea 172 (40) 4 (1) 88 (20) 0

Headache 170 (39) 6 (1) 102 (24) 0

Chills 161 (37) 6 (1) 19 (4) 0

Diarrhea 144 (33) 4 (1) 65 (15) 1 (< 1)

Vomiting 122 (28) 4 (1) 43 (10) 0

Arthralgia 120 (28) 4 (1) 61 (14) 0

Rash 106 (24) 0 47 (11) 1 (< 1)

COMBI-AD Common Adverse Events1

1. Hauschild A, Santinami M, Long G, et al. Adjuvant dabrafenib (D) plus trametinib (T) for resected stage III BRAF V600E/K–mutant melanoma. Presented at: European

Society for Medical Oncology 2017 Congress; September 11, 2017; Madrid, Spain.

Outline


• Interferon


– Ipilimumab



– Monotherapy

– Combination


Cross-Trial Comparisons

(Dangerous!)

CM2381 COMBI-AD2 KN0543

Patient PopulationCompletely resected stage IIIB / C

or IV melanoma

Completely resected, BRAF V600E/K -

positive stage IIIA / B / C melanoma

Completely resected stage IIIA / B /

C melanoma

Treatment Nivo Ipi Dab/Tram Placebo Pembro Placebo

N 453 453 438 432 514 505

RFS HR0.65 (97.56% CI:0.51-0.83),

P

Preferred Term, %

CheckMate 2381

(n = 452)Keynote 542

(n = 514)COMBI-AD3

(n = 438)

Any Grade Grade 3/4 Any Grade Grade 3/5 Any Grade Grade 3/4

Total 97 25 93,3 31,6 97

Total (treatment related) 85 14 77,8 14,7 91 41

Gastro-intestinal 25 2 ? ? 33 1

Nausea - - 11,4 0 40 1

Vomiting 28 1

Fatigue ? ? 37,1 0,8 47 4

Pulmonary 1 4.7 0.8

Renal 1 0.4 0.4

Endocrine 23,4 1.8

Adrenal disorder 2 1 0.2

Pituitary disorder 2 2.2 0.6

Thyroid disorder 20 27.6 0.2

Arthralgia 12 0.6 28 1

Headache 39 1

Pyrexia 63 5

Hepatic 9 2 1.8 1.4

Skin 45 1 28.3 0,2 28 1

Hypertension 2 0 0 6 3

Treatment Discontinuation 10 5 13.8 26

Most Frequent AEs with Adjuvant Therapy

1. Weber J, Mandala M, Del Vecchio M, et al. Adjuvant therapy with nivolumab (NIVO) versus ipilimumab (IPI) after complete resection of stage III/IV melanoma: Updated results from a phase III trial (CheckMate 238).

Presented at: American Society of Clinical Oncology 2018 Annual Meeting; June 4, 2018; Chicago, IL.

2. Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma [published online ahead of print April 15, 2018]. N Engl J Med. doi: 10.1056/NEJMoa1802357.

3. Hauschild A, Santinami M, Long G, et al. Adjuvant dabrafenib (D) plus trametinib (T) for resected stage III BRAF V600E/K–mutant melanoma. Presented at: European Society for Medical Oncology 2017 Congress;

September 11, 2017; Madrid, Spain.

ADJUVANT TREATMENT

Observation

or

Nivolumab for resected

Stage IIIB/C (category 1)

(preferred adjuvant

immunotherapy regimen)

or

Dabrafenib/trametinib for

patients with BRAFV600

activating mutation and SLN

metastasis >1 mm (category

1)

or

High-dose ipilimumab for

SLN metastasis >1 mm

or

IFN alfa

NCCN Guidelines Version 2.2018

Melanoma1

PRIMARY TREATMENT

Active nodal basin

surveillance

or

Complete lymph node

dissection (CLND)

WORKUP

• Consider imaging for

baseline staging

(category 2B)

• Imaging to evaluate

specific signs or

symptoms

• Imaging for baseline

staging and to evaluate

specific signs and

symptoms

CLINCIAL /

PATHOLOGICAL

STAGE

Stage IIIA

(sentinel node

positive)

Stage IIIB/C

(sentinel node

positive)

1. National Comprehensive Cancer Network. Melanoma (Version 2.2018). National Comprehensive Cancer Network Web site. https://www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf.

Updated January 19, 2018. Accessed July 10, 2018.

Future Perspectives

KEYNOTE-053/SWOG1404 Study Design1

HDI

Ipilimumab

PembrolizumabIV Q3W x 1 yr

R

A

N

D

O

M

I

Z

A

T

I

O

N

N=1378

Patients:

• ≥18 years of age

• Completely resected stage IIIA

(N2a), IIIB, IIIC, or IV

melanoma of cutaneous origin

or of unknown primary

• PD-L1 expression evaluation

• May have received prior

radiation therapy, but not

neoadjuvant treatment or prior

immunotherapy

Phase 3, randomized trial comparing physician/patient choice of either high dose interferon

or ipilimumab to pembrolizumab in patients with high risk resected melanoma

• 1° EP: OS, PD-L1 status, RFS

• 2° EP: BRAF mutation status,

QOL, incidence of toxicity, long-

term survival, post-relapse therapy

• Estimated primary completion date:

September 2023

1. National Cancer Institute (NCI). High-Dose Recombinant Interferon Alfa-2B, Ipilimumab, or Pembrolizumab in Treating Patients With Stage III-IV High Risk Melanoma That Has Been Removed by Surgery.

ClinicalTrials.gov Web site. https://clinicaltrials.gov/ct2/show/NCT02506153. Published July 23, 2015. Updated June 19, 2018. Accessed July 12, 2018.

Q4W = every 4 weeks; Q6W = every 6 weeks.

Randomized, double-blind, phase 3 study to compare NIVO+IPI to NIVO alone

Primary endpoint: RFSSecondary endpoints: OS, association between PD-L1 and RFSExploratory endpoints: Safety, PROs, DMFS, PK & IG, BiomarkersEstimated enrollment: 900 patients

NIVO+IPINIVO 240 mg IV Q2W plus IPI 1 mg/kg

IV Q6Wfor 1 year of study drug treatment)

NIVONIVO 480 mg IV Q4W

(for 1 year of study drug treatment)

Follow-up

n = 450

n = 450

Unblinded patients

on IPI 10 mg

(Open-label cohort)

IPI 10 mg or

NIVO 480 mg

Stratified by:

PD-L1 expression:

Resected stage IV

Metastatic

Melanoma

312 patients

Treat 1 year

or

until recurrence

or

un-acceptable

toxicity

NIVO 3 mg/kg Q2W + IPI-matched placebo

NIVO 1 mg/kg + IPI 3 mg/kg Q3W for 4

doses then NIVO 3 mg/kg Q2W

IPI +NIVO-matched placebo

Randomize

1:1:1

Stratify by:

•Tumor PD-L1 expression

•Trial site

•Site of metastases

N=104

N=104

N=104

Primary Objective: Recurrence-free survival

IMMUNED: Study Design1

1. Prof. Dr. med. Dirk Schadendorf. Immunotherapy With Nivolumab or Nivolumab Plus Ipilimumab vs. Double Placebo for Stage IV Melanoma w. NED. ClinicalTrials.gov Web site.

https://clinicaltrials.gov/ct2/show/NCT02523313. Published August 14, 2015. Updated November 7, 2017. Accessed July 10, 2018.

TrialStage

II C

Stage

III A

Stage

III B

Stage

III C

Stage

III D

Stage

IV NED

PD - L1

status

BRAF

mt

BRAF all

comersO

ld

sta

gin

g

BRIM81

(vem)

Cohort

1

Cohort 2

n/a ✓✓ ✓ ✓ ✓

COMBI-AD2

(dab + tram)✓ ✓ ✓ n/a ✓

ChM 2383

(nivo)✓ ✓ n/a ✓ ✓ ✓

KN-0544

(pembro)✓ ✓ ✓ n/a ✓ ✓

New

sta

gin

g

ChM 9155

(nivo, ipi)✓ ✓ ✓ ✓ ✓ ✓

Adjuvant Treatment in Melanoma Outlook Summary

1. Hoffmann-La Roche. A Study of Vemurafenib Adjuvant Therapy in Participants With Surgically Resected Cutaneous BRAF-Mutant Melanoma (BRIM8). ClinicalTrials.gov Web site.

https://clinicaltrials.gov/ct2/show/NCT01667419. Published August 17, 2012. Updated December 28, 2017. Accessed July 10, 2018

2. Novartis Pharmaceuticals. A Study of the BRAF Inhibitor Dabrafenib in Combination With the MEK Inhibitor Trametinib in the Adjuvant Treatment of High-risk BRAF V600 Mutation-positive Melanoma After Surgical

Resection. (COMBI-AD). ClinicalTrials.gov Web site. https://clinicaltrials.gov/ct2/show/NCT01682083. Published September 10, 2012. Updated May 8, 2018. Accessed July 10, 2018.

3. Bristol-Myers Squibb. Efficacy Study of Nivolumab Compared to Ipilimumab in Prevention of Recurrence of Melanoma After Complete Resection of Stage IIIb/c or Stage IV Melanoma (CheckMate 238).

ClinicalTrials.gov Web site. https://clinicaltrials.gov/ct2/show/NCT02388906. Published March 17, 2015. Updated July 3, 2018. Accessed July 10, 2018.

4. Merck Sharp & Dohme Corp. Study of Pembrolizumab (MK-3475) Versus Placebo After Complete Resection of High-Risk Stage III Melanoma (MK-3475-054/KEYNOTE-054). ClinicalTrials.gov Web site.

https://clinicaltrials.gov/ct2/show/NCT02362594. Published February 13, 2015. Updated June 12, 2018. Accessed July 10, 2018.

5. Bristol-Myers Squibb. An Investigational Immuno-therapy Study of Nivolumab Combined With Ipilimumab Compared to Nivolumab by Itself After Complete Surgical Removal of Stage IIIb/c/d or Stage IV Melanoma

(CheckMate 915). ClinicalTrials.gov Web site. https://clinicaltrials.gov/ct2/show/NCT03068455. Published March 1, 2017. Updated May 22, 2018. Accessed July 10, 2018.

How I treat High Risk Melanoma

Adjuvant TherapySentinel Node Biopsy Positive

BRAF mutation test

Anti- PD1

Or

Dabrafenib + Trametinib

Anti- PD1

BRAFV600

mutation

negative

BRAFV600

mutation

positive

What Keeps Me Up at Night…

• Metastatic Melanoma may now be curable for some

patients

• Are we curing the same patients in the adjuvant

setting?

• Can we afford adjuvant therapy?

Factors for Consideration in Adjuvant Treatment Decisions

Disease stage/risk of recurrence

Patientwishes

DataRisk-benefit

Optionsfor

advanceddisease

Ulceration

Thickness

Type/no.of positive

+LNs

Obrigado!

tratamento adjuvante · 2020. 12. 23. · 1. agarwala ss, lee sj, yip w, et al. phase iii...

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