Maintenance Therapy for Lung

Cancers: Get Off to the Right Start

and Stick With a Winner

Mark G Kris, MD

The William and Joy Ruane Chair in Thoracic Oncology

Member and Attending Physician

Memorial Sloan-Kettering Cancer Center

Professor of Medicine

Weill Cornell Medical College

New York, NY

Maintenance Therapy for Lung Cancers: Stick with a Winner

Disclosures

Consultant/Trial Support: Pfizer, Genentech/Roche, Novartis,

Clovis, Ariad

Stock/Royalties: None

Mark G. Kris, MD Maria C. Pietanza, MD Gregory J. Riely, MD, PhD Naiyer A. Rizvi, MD

Marjorie Zauderer, MD Alexander E. Drilon, MD

Helena A. Yu, MD

Stephen Veach, MD

Kenneth Ng, MD John Fiore, MD

Stephanie

Smith-Marrone, MD Afsheen Iqbal, MD

Lee M. Krug, MD

Paul K. Paik, MD Jamie Chaft, MD

Charles Rudin, MD, PhD Service Chief

Stefan Berger, MD Michael Fannuchi, MD

Memorial Sloan-Kettering Thoracic Oncology Service

Maintenance Therapy for Lung Cancers: Stick with a Winner

Introduction

• Make the right choice on day 1

• What drugs to continue

• What drugs to stop and when to do it

• Role of maintenance in personalizing care

NSCLCs Chemotherapy 1975-2013

No Chemotherapy 0% 10% 0%

Single Agent 15% 20% 10%

Two Drugs 25% 35% 20%

Three Drugs 35% 35%

20%

Two Drugs plus Cetuximab 36% 47% 20%

Two Drugs plus Bevacizumab 35% 51% 23%

Erlotinib with EGFR

Exon 19/21 Mutation 67% 90% 60%

Crizotinib with ALK

Rearrangement 57% 81% 61%

Response Rate 1 Year Survival 2 Year Survival

Lung Cancers

Memorial Sloan-Kettering 2000-2010

Squamous Cell Carcinomas

20%

Carcinoids 4%

Large Cell Neuroendocrine

Carcinomas 1% Small Cell Lung

Cancers 13%

Adenocarcinomas

60%

Large Cell

Carcinomas

2%

(N=14,418)

1% of Adenocarcinomas

Represents 1357 Cases

Annually in the USA

LCMC: Frequency of Oncogenic Drivers

733 Specimens with All 10 Drivers Assayed

NCCN Guidelines for NSCLCs:

Selection of Initial Chemotherapy

Agents by Histologic Type

Agent Adenocarcinoma Squamous

Cell

Small

Cell

Pemetrexed

Gemcitabine

Bevacizumab

Docetaxel

Cisplatin

Etoposide

Fossella J Clin Oncol 2003

Sandler NEJM 2006

Scagliotti J Clin Oncol 2008

Bevacizumab Works

A pearl in the SATURN and ATLAS oysters

Trial Initial Treatment Entered

(Randomized)

“Non-PD” After

4 Initial Cycles

SATURN

(Cappuzzo)

4 Cycles of First-Line

Platinum-Based

Doublet

1949

(889)

46%

P=0.0001

(Fishers Exact)

ATLAS

(Miller)

Bevacizumab plus

4 Cycles of First-Line

Platinum-Based

Doublet

1160

(768)

66%

11/6/2013 template 12 Cappuzzo et al and Miller et al Proc ASCO 2009

1. Roche, data on file; 2. Miller, et al. ASCO 2009

3. Reck, et al. Ann Oncol 2010; 4. Barlesi, et al. EMCC 2011

5. Patel, et al. IASLC 2012 (Chicago); 6. Belani, et al. ASCO 2010

7. Fidias, et al. J Clin Oncol 2009; 8. Paz-Ares, et al. Lancet Oncol 2012

How many patients with lung cancers get to

maintenance?

Bevacizumab + carboplatin/paclitaxel 66% E45991

Bevacizumab + platinum doublet (no pemetrexed) 66% ATLAS2

Bevacizumab + pemetrexed/cisplatin 67% AVAPERL4

Carboplatin/paclitaxel 52% E4599 control arm1

Gem/Carbo 53% Doc maintenance7

Pemetrexed/cisplatin 57% PARAMOUNT (S124)8

Bevacizumab + cisplatin/gemcitabine 64% AVAiL‡3

Cisplatin/gemcitabine 59% AVAiL control arm3

Gem/Carbo 49% Gem maintenance6

Bevacizumab + carboplatin/pemetrexed 66% POINTBREAK5

Bevacizumab + carboplatin/paclitaxel 67% POINTBREAK5

Sandler J Thorac Oncol 2010;4:1416

Adding Bevacizumab to Chemotherapy Patients with Lung Adenocarcinoma

Duration of Therapy Trials in NSCLCs: More Initial Cycles,

Continue Initial Agents, Add Agent Without Progression

Author, Year Median

Survival

“Shorter”

Median

Survival

“Longer”

Change

With

“Longer”

Duration of Initial Rx Smith, 2001 6 7 +1 month

Socinski, 2002 7 9 +2 months

Von Plessen,2006 7 8 +1 month

Park, 2007 16 15 -1 month

Barata, 2007 7 12 +5 months

Maintenance Westeel, 2005 12 12 0 month

Belani, 2003 15 19 +4 months

Brodowicz, 2006 8 10 +2 months

Add New Agent Fidias, 2007 9 12 +3 months

Without Progression Ciuleanu, 2008 10 13 +3 months

Stinchcombe and Socinski JTO 2009

Duration of chemotherapy treatment: Meta-analysis of 13 trials

No. of patients Hazard Ratio

(95% CI) P-value

Progression

Free

Survival

2570 0.75 (0.69–0.81) <0.00001

Overall

Survival 3079 0.92 (0.86–0.99) 0.03

Soon J Clin Oncol 2009

Two Sides of Maintenance

Continuation vs Switch to a New Agent

Continuation to Progression or

Toxicity

Switch to a New Agent

Bevacizumab Pemetrexed

Pemetrexed Docetaxel

Afatinib/Erlotinib/Gefitinib Erlotinib

Crizotinib

Gemcitabine

*Data supports continuation even after progression of disease by RECIST

Riely Clin Cancer Res 2008, Chmielecki Science Trans Medicine 2011

Continuation Maintenance

The Ultimate Targeted Therapy

Therapy only to the right patient

Demonstrated objective benefit

Proven subjective benefit

Tolerance assured

11/6/2013 18

PARAMOUNT: Study Design

Induction Therapy 4 cycles, q21d

Continuation Maintenance Therapy q21d until PD

Pemetrexed

Placebo

Pemetrexed

+ Cisplatin

CR/PR/SD per RECIST

R 2:1

Randomized, placebo-controlled, double-blind phase III study

Pemetrexed 500 mg/m2; Cisplatin 75 mg/m2

Folic acid and vitamin B12 administered to both arms

• Untreated

• PS 0/1

• Stage IIIB-IV

NS-NSCLCs

PARAMOUNT: Overall Survival from Randomization

Patients at Risk

Pemetrexed 359 333 272 235 200 166 138 105 79 43 15 2 0

Placebo 180 169 131 103 78 65 49 35 23 12 8 3 0

Time from Randomization (Months)

0 3 6 9 12 15 18 21 24 27 30 33 36

Su

rviv

al

Pro

bab

ilit

y

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Pem Placebo

OS Median (mo)

(95% CI)

14

(12.8-16.0)

11

(10.0-12.5)

Alive (%) 29 22

Survival Rate (%) (95% CI)

1-year 58 (53-63) 45 (38-53)

2-year 32 (27-37) 21 (15-28)

Log-rank P = 0.0195

Unadjusted HR: 0.78

(95% CI: 0.64–0.96)

PARAMOUNT: Overall Survival from Induction S

urv

ival

Pro

bab

ilit

y

Time from Induction (Months)

0 3 6 9 12 15 18 21 24 27 30 33 36

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Pemetrexed

Median OS =17 months (95% CI: 15.8–19.0)

Placebo

Median OS =14 months (95% CI: 12.9–15.5)

Log-rank P=0.0191

HR=0.78 (95% CI: 0.64–0.96)

Patients at Risk

Pemetrexed 359 335 276 234 200 164 138 106 77 42 15 2 0

Placebo 180 168 132 103 78 63 49 35 23 12 8 3 0

ASCO 2010 Abstract 7507 – Perol

Continuation and Switch Maintenance

ASCO 2010 Abstract 7507 – Perol

Switch Maintenance: Erlotinib

ASCO 2010 Abstract 7507 – Perol

Continuation Maintenance: Gemcitabine

Phase III Trial of Bevacizumab

in Lung Adenocarcinoma: ECOG 4599

Paclitaxel 200 mg/m2

Carboplatin AUC = 6

(q 3 weeks) x 6 cycles

Paclitaxel 200 mg/m2

Carboplatin AUC = 6

(q 3 weeks) x 6 cycles

+

Bevacizumab

(15mg/kg q 3 wks)

Continue to Progression

Eligibility:

• No squamous

• No hemoptysis

• No CNS metastases

Stratification Variables:

• RT vs no RT

• Stage IIIB or IV vs recurrent

• Wt loss <5% vs >5%

• Measurable vs non-measurable

Sandler A, et al. New Engl J Med 2006;355(24):2542-2550

ECOG 4599 Phase III Trial of Chemotherapy +/-

Bevacizumab in NSCLC

Carboplatin

-plus-Paclitaxel

Only

Bevacizumab

15 mg/kg

+ Carboplatin

–plus- Paclitaxel

p

Entered 444 434

CR/PR Rate 15% 35% <0.0001

1 Yr Survival 44% 52%

Median Survival 10.2 months 12.5 months 0.007

• Randomized phase III trial in 878 patients – JUL 01- APR 04

• No prior therapy for stage IIIB/IV lung adenocarcinoma

Sandler NEJM 2006

PEM+CBP+BEV---PEM+BEV vs

PTX+CBP+BEV---BEV

PEM+CBP+BEV

---BEV+ PEM

PTX+CBP+BEV---

BEV

Entered 472 467

Median Overall Survival-1° Endpoint 13 mo 13 mo

Median Progression Free Survival 6 mo 6 mo

CR+PR Rate 34% 33%

Maintenance Overall Survival 18 mo 16 mo

Maintenance Progression Free Survival 9 mo 7 mo

Discontinuations due to AEs 3% 3%

Drug-Related Deaths 2% 2%

Patel J Clin Oncol 2012; 7(Suppl 4):S336

28

AVAPERL: Trial design

Barlesi Proc ESMO 2011

Previously

untreated

stage IIIB–IV

nsNSCLC

Arm A:

bevacizumab

Arm B:

bevacizumab +

pemetrexed

Bevacizumabb

+ pemetrexedb

+ cisplatinb

CR/PR/SD

per RECISTc

First-line induction

4 cycles, q3w

R

PD

Continuation maintenance

q3w until PD

Follow-up

29

AVAPERL

PFS from induction (1°Endpoint) Bev+pem 10.2 months (81 events)

Bev 6.6 months (104 events)

HR, 0.50 (0.37–0.69); P <.001

Pro

gre

ss

ion

-fr

ee

su

rviv

al (%

)

Time (months)

128 126 103 66 25 4 0

125 122 73 38 12 2 0

100

75

50

25

0

0 3 6 9 12 15 18

Pts at risk Bev+pem

Bev

Cont. maintenance bev+pem (n=128)

Cont. maintenance bev (n=125)

30

AVAPERL

Overall Survival from induction O

ve

rall

su

rviv

al (%

of p

atie

nts

)

100

75

50

25

0

0 3 6 9 12 15 18 21

128 127 120 103 56 20 3 0

125 123 110 96 45 17 2 0

Time (months)

Bev+pem NR (34 events)

Bev 15.7 months (42 events)

HR, 0.75 (0.47–1.20); P=0.23

Pts at risk Bev+pem

Bev

Cont. maintenance bev+pem (n=128)

Cont. maintenance bev (n=125)

“Switch Maintenance” Trials

Overall Survival Trial N Agent Median

Survival

“Control”

Median

Survival

“Agent

Added”

Survival

Benefit With

“Agent

Added”

Ciuleanu - All 633 pemetrexed 10.6 mo 13.4 mo +2.8 mo

(p=0.01)

Ciuleanu - AdenoCa 328 pemetrexed 11.5 mo 16.8 mo +5.3 mo

(p=0.03)

Fidias 566 docetaxel 9.7 mo 12.3 mo +2.6 mo

(p=0.08)

Cappuzzo 889 erlotinib 11 mo 12 mo +1 mo

(p=0.01)

Miller 743 erlotinib NR NR NR

NS

Results in EGFR mutation positive and negative

patients ( All Asian, 94% Never Smokers)

EGFR mutation positive EGFR mutation negative

HR (95% CI) = 0.48 (0.36, 0.64)

p<0.0001

No. events gefitinib: 97

No. events Chemo: 111

Gefitinib (n=132)

Carboplatin / paclitaxel (n=129)

HR (95% CI) = 2.85 (2.05, 3.98)

p<0.0001

No. events gefitinib: 88

No. events Chemo: 70

132 71 31 11 3 0 129 37 7 2 1 0

108 103

0 4 8 12 16 20 24

Gefitinib C / P

0.0

0.2

0.4

0.6

0.8

1.0

Pro

bab

ilit

y o

f p

rog

ressio

n-f

ree s

urv

ival

At risk : 91 4 2 1 0 0 85 14 1 0 0 0

21 58

0 4 8 12 16 20 24

0.0

0.2

0.4

0.6

0.8

1.0

Pro

bab

ilit

y o

f p

rog

ressio

n-f

ree s

urv

ival

Gefitinib (n=91)

Carboplatin / paclitaxel (n=85)

Months Months

Gefitinib CR/PR Rate 71%

CBP/PTX CR/PR Rate 47%

Gefitinib CR/PR Rate 1%

CBP/PTX CR/PR Rate 24%

Changes in FDG-PET SUVmax after discontinuation at

RECIST PD and re-introduction of EGFR TKI

-50%

0%

50%

100%

EGFR TKI stop re-start

3 weeks 3 weeks

20%

Ch

an

ge

fro

m b

ase

lin

e

Median Change in SUVmax +23% -11%

RECIST

PD

Disease “flare” post-TKI in EGFR-

mutant lung cancers with AR

• Pts with EGFR- mutant cancers on trials for treatment of AR

• “Flare” defined as hospitalization or death during TKI washout (7-21

days)

• 14 of 61 pts (23%, 95% CI 14-35%) experienced a flare

• Median time to flare was 8 days (range 3-21)

• Characteristics associated with flare:

– Shorter TTP on TKI (Median 9 vs 15 mo, p=0.002)

– Pleural disease (p=0.02) or CNS disease (p=0.01)

• Flare was not associated with T790M, type EGFR mutation, or prior

cytotoxic chemotherapy

Chaft Clin Cancer Res 2011

RECIST Criteria for Progression

A Signal to Stop the EGFR TKI?

EGFR TKI

1cm 5cm 1.3cm

EGFR TKI

EGFR TKI

Resistance

by RECIST

Stop

EGFR TKI?

Mok IASLC Santa Monica 2011

Local Therapy Outcomes

• The median time to progression after local therapy was 10 months (95% CI: 2-27).

• The median time from local therapy until a change in systemic therapy was 22 months (95%CI: 6 - 30).

• The median overall survival from local therapy was 41 months (95% CI: 26-not reached).

0 12 24 36 480

20

40

60

80

100

0 12 24 36 48 600

20

40

60

80

100

Time to Progression

Overall Survival

% P

rogr

essi

on

-fre

e %

Su

rviv

al

Time (months)

Time (months)

Yu, J Thorac Oncol 2012

Maemondo, NEJM 2010

Maintenance Therapy for Lung Cancers: Stick with a Winner

Conclusions

• Maintenance chemotherapy (a. k. a. continuing

successful drugs)

– Improves survival. Period

– The ultimate targeted therapy

– Results better than erlotinib for EGFR WT

• Continue bevacizumab until progression

• Continue erlotinib/gefitinib/afatinib and crizotinib (likely

all targeted therapies) until progression……and beyond

Efficacy Outcomes by Treatment Group in ECOG 4599

Patients Progression Free After 6 Cycles

CP nonprogressors

(n=134)

Bev maintenance

(n=217)

Median postinduction PFS, mo

3 4

p<.001

Median PFS, mo 7 9

Median postinduction OS, mo

11 13

p=0.03

Median Overall Survival, mo 16 17

1-year PFS rate, % (95% CI) 17 (11–25) 32 (26–39)

1-year OS rate, % (95% CI) 69 (61–77) 75 (69–81)

2-year OS rate, % (95% CI) 25 (18–34) 34 (28–42)

Sandler Proc IASLC 2011

ECOG 4599

Postinduction progression-free survival

Sandler Proc IASLC 2011

ECOG 4599

Postinduction overall survival

Sandler Proc IASLC 2011