Adjuvant Therapy for MelanomaWhat is the role of PegIFN in relation

to HDIFN?

Adjuvant Therapy for MelanomaWhat is the role of PegIFN in relation

to HDIFN?

John M. Kirkwood, MDProfessor of Medicine, Dermatology and Translational Science

University of Pittsburgh School of Medicine &Cancer Institute

Melanoma Committee, Eastern Cooperative Oncology Group

International Melanoma Working Group kirkwood@pitt.edu

John M. Kirkwood, MDProfessor of Medicine, Dermatology and Translational Science

University of Pittsburgh School of Medicine &Cancer Institute

Melanoma Committee, Eastern Cooperative Oncology Group

International Melanoma Working Group kirkwood@pitt.edu

Relapse and Mortality Risk of Operable Melanoma Guides Adjuvant Therapy

Relapse and Mortality Risk of Operable Melanoma Guides Adjuvant Therapy

Local stage I disease: IA-B/IIA Lower risk•Primary risk guided by Breslow thickness & ulceration•Primary >2mm thick, ulcerated (T3b) or >4 mm (T4)

IIB Intermediate risk

Regional Stage III Lymph Node Disease: IIIA High risk•Sentinel lymph node status: key prognostic assessment for >1 mm thick primaries

– Risk varies by numbers of nodes involved 1, 2-3, >3 (N1, 2, 3)

– Microscopic: Stage IIIA 35% relapse risk

– Macroscopic: Stage IIIB >60% relapse risk IIIB Higher risk

Distant Resectable Stage IV Disease: IV Highest risk

Local stage I disease: IA-B/IIA Lower risk•Primary risk guided by Breslow thickness & ulceration•Primary >2mm thick, ulcerated (T3b) or >4 mm (T4)

IIB Intermediate risk

Regional Stage III Lymph Node Disease: IIIA High risk•Sentinel lymph node status: key prognostic assessment for >1 mm thick primaries

– Risk varies by numbers of nodes involved 1, 2-3, >3 (N1, 2, 3)

– Microscopic: Stage IIIA 35% relapse risk

– Macroscopic: Stage IIIB >60% relapse risk IIIB Higher risk

Distant Resectable Stage IV Disease: IV Highest risk

Cooperative group/PI

Eligibility  

n  

Treatment agent/dosage/duration

Impact on

DFS OS

NCCTG 837052Creagan T3-4, N1 262

IFNα2a 20 MU/m2/D IM TIWx3 mos + -

ECOG 1684Kirkwood

T4, N1 

287 

IFNα2b 20 MU/m2/D IVx1 mo 10 MU/m2 SC TIW for 11 mos

+ +

at 6.9 –12.6 yrs

E1690 Intergroup Kirkwood  

T4, N1  

642  

IFNα2b 20 MU/m2/D IVx1 mo 10 MU/m2 SC TIWx11 mos vs 3 MU/D SC TIWx2 yrs

+ -

at 4.3 – 6.6 yrs

WHO #16Cascinelli

N1-2 

444 

IFNα2a 3 MU/D SC TIWx3 yrs  +/- -

EORTC 18871Kleeberg

T3-4, N1 

830 

IFNα2b 1 MU/D SC QODx1 yr vsIFNg 0.2 mg/D SC QODx1yr - -

E1694 IntergroupKirkwood 

T4, N1  

880  

IFNα2b 20 MU/m2/D IVx1 mo 10 MU/m2 SC TIWx11 mos vs GMK vaccine x 96 wks 

+ +

at 1.3 –2.1 yrs 

ECOG 2696 Kirkwood

T4, N1, M1  

107 

GMK + IFN or -->IFN vs GMK 

+ -

at 1.4 – 2.6 yrs

UKCCR Aim-HighHancock

T4, N1 

674 

IFNα2a 3 MU/D SC QODx2 yrs   - -

EORTC 18952 Eggermont

T4, N1-2 

1488 

IFNα2b 10MU/d then10 MU TIW x1 or 5 MU TIW x 2 years

++

--

EORTC 18991 Eggermont

 TxN1-2 

 1256 

 Peg-IFN alfa-2b SC 6 µg/kg/week (8 weeks) then 3 µg/kg/week (5 years) vs Observation 

+, +/- at 3.8-7.6 yrs -

FrenchGrob

T2-T4 (≥1.5mm), N0 489

IFNα2a 3 MU SC TIW x 18 mo vsObs + -

AustrianPehamberger

T2-T4 (≥1.5mm), N0 311

IFNα2a 3 MU SC QD x 3 wks then TIW x 1 yr vsObs + -

Questions Regarding IFN Adjuvant TherapyQuestions Regarding IFN Adjuvant Therapy

• Relapse free survival benefit (RFS) correlation with overall survival (OS) benefit?

• Difference by disease/stage burden?

• Durability of benefit in advanced disease that assures RFS, OS adjuvant impact?

• Optimal duration of therapy?

• Dose-response relationship?

• Role of intravenous IFN induction?

• Relapse free survival benefit (RFS) correlation with overall survival (OS) benefit?

• Difference by disease/stage burden?

• Durability of benefit in advanced disease that assures RFS, OS adjuvant impact?

• Optimal duration of therapy?

• Dose-response relationship?

• Role of intravenous IFN induction?

0.0

0.2

0.4

0.6

0.8

1.0

0 2 4 6 8 10 12 14 16

Time (Years)

Pro

po

rtio

n A

live

an

dR

ela

pse

Fre

eE1684: IFN vs Observation**

0.0

0.2

0.4

0.6

0.8

1.0

0 1 2 3 4 5 6 7 8 9 10Time (Years)

Pro

po

rtio

n A

live

an

dR

ela

pse

Fre

e

0-2 2-4 4-6 6-8 8-10

Observ. 105/212 16/94 5/72 2/44 0/13IFN 98/215 15/108 5/85 2/53 0/20

E1690: IFN vs Observation*

0.0

0.2

0.4

0.6

0.8

1.0

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5Time (Years)

Pro

po

rtio

n A

live

an

dR

ela

pse

Fre

e

0-1 1-2 2-3 3-4 4-5

IFN 118/436 28/257 8/123 3/47 0/3GMK 153/439 40/240 6/113 3/40 0/0

E1694: IFN vs GMK**

E1684, E1690, and E1694: Durable and Significant Impact upon Relapse-free * and Overall Survival**

E1684, E1690, and E1694: Durable and Significant Impact upon Relapse-free * and Overall Survival**

Time Interval (Years)0-2 2-4 4-6 6-8 8-10 10-12 12-14 14-16

Observ. 89/140 12/51 3/39 0/35 1/32 1/29 0/15 0/3IFN 73/146 14/68 3/53 1/50 2/48 2/44 0/31 0/10

(No. events/No. at risk)

Kirkwood et al., J Clin Onc. 1996, 2000, 2001; Clin Cancer Res. 2004;10:1670; Tarhini and Kirkwood J Clin Onc. 2012

Time Interval (Years)

(No. events/No. at risk)

Time Interval (Years)

(No. events/No. at risk)

HR=1.38

P2=0.02

HR=1.24P2=0.09

HR=1.33P2=0.006

Rationale for Adjuvant Therapy: Improved Responsiveness of Micro-metastatic Disease

Rationale for Adjuvant Therapy: Improved Responsiveness of Micro-metastatic Disease

• IFNα therapy of advanced melanoma: 16% response rate, survival benefit unknown– Response inversely correlated with

disease burden, durable in one-third– Mechanisms unclear; agent pleiotropic

• IFNα adjuvant therapy: greater impact, relapse/mortality reduced up to 33%

• IFNα therapy of advanced melanoma: 16% response rate, survival benefit unknown– Response inversely correlated with

disease burden, durable in one-third– Mechanisms unclear; agent pleiotropic

• IFNα adjuvant therapy: greater impact, relapse/mortality reduced up to 33%

Do Benefits of IFNα Differ by Stage?Do Benefits of IFNα Differ by Stage?Trial Benefit Greatest

•E1684 high tumor burden (N1-2b)

•E1690 intermediate tumor (N1-2a)

•E1694 lower tumor burden (T4, N-)benefit across stages with high-dose IFNα

•18952 lower burden N1

•18991 lower burden N1

•18071 lower burden N1benefit confined to microscopic disease with PegIFN

Trial Benefit Greatest

•E1684 high tumor burden (N1-2b)

•E1690 intermediate tumor (N1-2a)

•E1694 lower tumor burden (T4, N-)benefit across stages with high-dose IFNα

•18952 lower burden N1

•18991 lower burden N1

•18071 lower burden N1benefit confined to microscopic disease with PegIFN

Meta-analysis #RCT RFS OS Comment

Ives, JCO. 2007

12 + -/+ ↑ benefit with ↑IFN dose

Wheatley,ASCO. 2007

13 +OR=0.87, 95% CI=0.81-0.93,

p=0.00006

+OR=0.9, 95% CI=0.84-0.97,

p=0.008

OS benefit of 3% (CI 1%-5%) at 5 yrs

Mocellin,JNCI. 2010

14 +HR = 0.82, 95% CI = 0.77-0.87;

P < .001

+HR = 0.89,

95% CI=0.83-0.96; P = .002

18% DFS benefit

11% OS benefit

Meta-analyses of IFN trials demonstrate an impact of IFN on RFS and OS

Meta-analyses of IFN trials demonstrate an impact of IFN on RFS and OS

IFNα as Paradigm for Adjuvant TherapyIFNα as Paradigm for Adjuvant Therapy

• Relapse-free benefit in all regimens• intermediate dose impact is transient• HDI impact is durable to >10+ years

• Survival improved in 2 of 14 trials • HDI only demonstrates OS benefit

• Mechanisms evaluated for HDI, IDI: • anti-angiogenic(-/?), • pro-apototic(-/?), • immunological (+/?)

• Relapse-free benefit in all regimens• intermediate dose impact is transient• HDI impact is durable to >10+ years

• Survival improved in 2 of 14 trials • HDI only demonstrates OS benefit

• Mechanisms evaluated for HDI, IDI: • anti-angiogenic(-/?), • pro-apototic(-/?), • immunological (+/?)

Recent Trials Address Duration of Therapy Required and Role of Induction

Recent Trials Address Duration of Therapy Required and Role of Induction

• E1697 Intergroup Trial of 1 month IFNα2b– No benefit of 1 month IFN compared to

Observation in 1150 patients with Stage II-III melanoma (Agarwala et al., Proc ASCO 2011)

• EORTC 18991 Trial of 5 years PegIFNα2b– Relapse reduction without improved survival at

7.6 years follow-up (Eggermont JCO 2012)

• Benefit among N1 (microscopic~IIIA), not N2 (IIIB)

– Treatment tolerated a median of ~14 months

• E1697 Intergroup Trial of 1 month IFNα2b– No benefit of 1 month IFN compared to

Observation in 1150 patients with Stage II-III melanoma (Agarwala et al., Proc ASCO 2011)

• EORTC 18991 Trial of 5 years PegIFNα2b– Relapse reduction without improved survival at

7.6 years follow-up (Eggermont JCO 2012)

• Benefit among N1 (microscopic~IIIA), not N2 (IIIB)

– Treatment tolerated a median of ~14 months

Is there evidence for benefit of prolonged therapyEORTC 18991: Pegylated IFN-a2b x 5 years vs. Observation in

Resected Stage III (TxN1-2M0) Melanoma

Is there evidence for benefit of prolonged therapyEORTC 18991: Pegylated IFN-a2b x 5 years vs. Observation in

Resected Stage III (TxN1-2M0) Melanoma

Stratified by:Stratified by:• Microscopic (N1) Microscopic (N1) vs.vs. palpable (N2) palpable (N2)• 1 1 vs.vs. 2-4 2-4 vs.vs. 5+ nodes 5+ nodes• BreslowBreslow• UlcerationUlceration• Gender and siteGender and site

ObservationObservation

Peg-IFN alfa-2b for up to 5 yearsPeg-IFN alfa-2b for up to 5 years

• Induction (8 weeks) 6 Induction (8 weeks) 6 µg/kg/weekµg/kg/week

• Maintenance (5 years or distant Maintenance (5 years or distant metastasis) metastasis) 3 µg/kg/week3 µg/kg/week

• Dose reduction to 3, 2, 1 to Dose reduction to 3, 2, 1 to maintain maintain performance statusperformance status

Primary Endpoints:Primary Endpoints:• Relapse-free survival (RFS)Relapse-free survival (RFS)• Distant metastasis-free survival (DMFS)Distant metastasis-free survival (DMFS)

Patients (n=1,256):Patients (n=1,256): Resected TxN1-2M0 melanoma, within Resected TxN1-2M0 melanoma, within 7 weeks of lymphadenectomy7 weeks of lymphadenectomy

RandomizationRandomization

Eggermont AM, et al. Lancet 2008; 372: 117–26J Clinical Oncology 2012

EORTC 18991: Outcome at 7.6 yrs. Is diminished compared with 3.8 yrs. maturity

EORTC 18991: Outcome at 7.6 yrs. Is diminished compared with 3.8 yrs. maturity

Outcome (ITT)

2007 2012

HR (95% CI) P Value HR (95% CI)* P Value

RFS 0.82 (0.71-0.96) .01 0.87 (0.76-1.00) .05

DMFS 0.88 (0.75-1.03) .11 0.93 (0.81-1.07) .33

OS 0.98 (0.82-1.16) .78 0.96 (0.82-1.11) .57

•RFS benefit of adjuvant peginterferon maintenance sustained at 7.6 years follow-up •No change in DMFS or OS observed from 2007 to 2011

•RFS benefit of adjuvant peginterferon maintenance sustained at 7.6 years follow-up •No change in DMFS or OS observed from 2007 to 2011

• RFS benefit diminished at 7.6 years• No significant impact upon DMFS or OS early or at maturity

• RFS benefit diminished at 7.6 years• No significant impact upon DMFS or OS early or at maturity

EORTC 18991: Outcome in N1 population in 2007, 2012

EORTC 18991: Outcome in N1 population in 2007, 2012

• Stage III N1 disease showed significant RFS and DMFS in 2007 • Improvements at 7.6 years are no longer statistically significant

• Stage III N1 disease showed significant RFS and DMFS in 2007 • Improvements at 7.6 years are no longer statistically significant

Outcome in N1 Population

2007 2012

HR PValue

HR(99% CI)*

PValue

RFS 0.73 .016 0.82 (0.61-1.10)

.08

DMFS 0.75 .034 0.86 (0.63-1.17)

.22

OS 0.88 .43 0.86 (0.62-1.21)

.26

• Patients with stage III N2 show no significant benefit in any endpoint• Patients with stage III N2 show no significant benefit in any endpoint

EORTC 18991: N2 population lacks benefit at either 3.8 or 7.6 yrs. evaluation

EORTC 18991: N2 population lacks benefit at either 3.8 or 7.6 yrs. evaluation

Outcome in N2

2007 Evaluation 2012 Evaluation

HR PValue

HR(99% CI)*

PValue

RFS 0.86 .12 0.89 (0.71-1.13)

.21

DMFS 0.94 .53 0.96 (0.76-1.22)

.66

OS 1.01 .91 1.00(0.78-1.29)

.97

EORTC 18991: Stage III N1, Ulcerated DiseaseEORTC 18991: Stage III N1, Ulcerated Disease

• Greatest benefit of Peg IFN in Stage III N1 subset, ulcerated primary

– Median OS peg IFN vs. observation: > 9 vs. 3.7 years

• EORTC 18081 trial compares Peg IFN x 2 yrs vs.

observation in patients with ulcerated primary tumors

• Greatest benefit of Peg IFN in Stage III N1 subset, ulcerated primary

– Median OS peg IFN vs. observation: > 9 vs. 3.7 years

• EORTC 18081 trial compares Peg IFN x 2 yrs vs.

observation in patients with ulcerated primary tumors

Outcome in 2007 in Patients With

Stage III N1, Ulcerated Primary

HR(99% CI)

P Value

RFS 0.72 (0.46-1.13)

.06

DMFS 0.65 (0.41-1.04)

.02

OS 0.59 (0.35-0.97)

.006

EORTC 18991: Primary Tumor Ulceration**

EORTC 18991: Primary Tumor Ulceration**

• Primary tumor ulceration is associated with trend to IFN benefit:*• Primary tumor ulceration is associated with trend to IFN benefit:*

OS Outcome in 2011 Based on

Primary Tumor Ulceration

HR(99% CI)

P Value

Ulcerated 0.81 (0.58-1.14)

.11*

Not ulcerated 1.05 (0.79-1.41)

.64

*not significant at maturity in 2012;

**US Intergroup trials have never shown this correlation

Study/PI Stage N Treatment agent/ dosage/duration

Median Follow up

(year)

Impact on (%) Toxicity Attrition

Rate

CommentPFS

 OS

E1684Kirkwood

 T4, N+

 287

IFNα2b 20 MU/m2/D IV for 1 month. Then, 10 MU/m2 SC TIW for 11 months vs. Observation

 6.9

0.61;p=.001

 

0.67;p=.01

  

26

At 12.6 yr, the impact of competing causes of death on OS cannot be ignored

 12.6

0.72;p=.02

0.82;p=.18

E1690 Kirkwood

 T4, N+

 642

IFNα2b 20 MU/m2/D IV for 1 month. Then, 10 MU/m2 SC TIW for 11 months vs.  3 MU/D given SC TIW for 2 years vs. Observation

 4.3

0.78;p=.05

 

1.0    

13

Cross over of observation pts to HDI at nodal relapse (n=38 pts) is expected to affect OS analysis

 6.6  0.81;p=0.09

1.0

E1694 Kirkwood

 T4, N+

 880

IFNα2b 20 MU/m2/D IV for 1 month. Then 10 MU/m2 SC TIW for 11 months vs. GMK vaccine for 96 wks

 1.3

0.67;p=.0004

 

0.72;p=.023

   

10

Symmetrical impact upon RFS, OS for IFN over GMK led to early

closure for vaccine futility at 2 yr 

 2.1

0.75;p=.006

0.76;p=.04

EORTC 18991

 Eggermont

 

N1-2

 

1256

PegIFNα2b given SC at 6 µg/kg/week (8 weeks) then 3 µg/kg/week (5 years) vs. Observation

 3.8

0.82;P=.011

 

0.98 

   

37

No impact upon OS, or DMFS at initial

reporting or mature publication 

 7.6

0.87;P=0.055

.96

Summary of IFNα trials leading to regulatory approval Summary of IFNα trials leading to regulatory approval

Tarhini and Kirkwood J Clin Oncol 2012

Biomarkers of Risk & Benefit are Needed to Tailor and Improve Adjuvant Therapy

Biomarkers of Risk & Benefit are Needed to Tailor and Improve Adjuvant Therapy

Risk/Prognosis•S100B may add to risk assessment (Tarhini et al., J. Clin Onc 2008)

Benefit: Predictors of IFN clinical benefits•Autoimmunity (Gogas, et al., NEJM 2006)

•Cytokine profile in serum (Yurkovetsky, 2007)

•Ulceration of primary tumor (Ives, 2007)

•Inflammatory profile in tumor (Gajewski, 2011)

Risk/Prognosis•S100B may add to risk assessment (Tarhini et al., J. Clin Onc 2008)

Benefit: Predictors of IFN clinical benefits•Autoimmunity (Gogas, et al., NEJM 2006)

•Cytokine profile in serum (Yurkovetsky, 2007)

•Ulceration of primary tumor (Ives, 2007)

•Inflammatory profile in tumor (Gajewski, 2011)

Conclusions: IFNα Adjuvant TherapyConclusions: IFNα Adjuvant Therapy

• Relapse-free survival benefit HR ~.70 correlates with overall survival benefit

– Disease/stage burden predicts PegIFN benefit, but not HDI benefit

– Duration of therapy feasible with HDI & PegIFN are both ~1 year

– Dose-response relationship still unclear

• Adjuvant recommendation should be HDI

• If HDI not tolerated, and disease is of stage <IIIA, PegIFN is a fallback option

• Relapse-free survival benefit HR ~.70 correlates with overall survival benefit

– Disease/stage burden predicts PegIFN benefit, but not HDI benefit

– Duration of therapy feasible with HDI & PegIFN are both ~1 year

– Dose-response relationship still unclear

• Adjuvant recommendation should be HDI

• If HDI not tolerated, and disease is of stage <IIIA, PegIFN is a fallback option