TRANSITIONING SURVIVAL FROM MONTHS TO YEARS IN

ADVANCED NSCLC

H. Jack West, MDSwedish Cancer InstituteSeattle, WA

Global Resource for Advancing Cancer Education (GRACE)www.cancerGRACE.org

Metastatic NSCLC in a Historical Context

• Treatment is not curative: goal is to prolong survival survival with minimal treatment-related toxicity and risk, also hoping to reduce cancer-related symptoms

• Debate through 1990s: is treatment “worth it” for what was typically a two month benefit?

• This was with a platinum-based doublet that was widely considered toxic (cisplatin-based)

• Can we do better?

• One year OS? ~30%

MedianOS

Searching for the “Best Doublet”

Schiller, NEJM 2004

1 yr OS – 33%2 yr OS – 11%

Second Line Therapy?• ~2000, docetaxel, followed by erlotinib and

pemetrexed, are all tested and demonstrate comparable survival benefit in previously treated patients with advanced NSCLC.

• This is despite response rates below 10% and is largely driven by up to 50% of patients achieving minor tumor shrinkage or stable disease.

Optimizing Survival by Histology

• Over last 6-8 years, we begin to see value in distinguishing between NSCLC histologies (squamous and non-squamous, primarily)

• Cisplatin-pemetrexed vs. cisplatin-gemcitabine

Scagliotti, JCO 2008

Tailoring Regimen by Histologyto Approach a 1 Year Median OS

• As we approach a median survival of 1 year, this means that half of patients are living beyond a year

MedianOS

Adding Bevacizumab & Integrating Maintenance Therapy

Advanced NSCLC,Non-squamous carbo/

paclitaxel/bevx 6 cycles

carbo/paclitaxelx 6 cycles

Maintenance bev until progression

Sandler, NEJM 2006

Response rate: 15% with chemo alone, vs. 35% with chemo/bev

New Era of Targeted Therapies and Maintenance Therapy

• With ECOG 4599, we now have nearly ¼ of patients living 2 yrs

MedianOS

“Down-Shifting” to a Less Challenging

but Still Effective Therapy

Two Basic Mechanisms (neither proven better or

worse)

First Line Chemo

First Line Chemo

Continuation Maint

Continuation Maint

“Continuation” maintenance: after 4-6 cycles 1st line, drop >1 drug,

keep others going until progression

Switch MaintSwitch Maint“Switch” maintenance:

after 4-6 cycles 1st line, stop all,switch directly to new drug(s)

Both approaches less intensive than first line

combo therapy

First Line Chemo

First Line Chemo

Refining Maintenance Therapy: Switch Maintenance with Pemetrexed

Advanced NSCLC,Not progressing after

4 cycles non-pem doublet Placebo infusion every 3 weeks

Switch maintenance pemetrexedevery 3 weeks

Ciuleanu, Lancet 2009

24% censored

HR = 0.599 (95% CI: 0.49–0.73)

p < .00001

Time (mos)

PF

S P

rob

abili

ty (

%)

0 3 6 9 12 15 18 21 24

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Pemetrexed: 4.04 mos (95% CI: 3.06–4.44)

Placebo: 1.97 mos (95% CI: 1.54–2.76)

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Su

rviv

al P

rob

abili

ty (

%)

Time (mos)

HR = 0.79 (95% CI: 0.65–0.95)

p = .012

HR = 0.79 (95% CI: 0.65–0.95)

p = .012

Pemetrexed 13.4 mos Placebo 10.6 mos

Pemetrexed 13.4 mos Placebo 10.6 mos

Progression-Free Survival

Overall Survival

Non-Squamous (n = 481) Squamous (n = 182)

JMEN: OS by Histology

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

HR = 0.70 (95% CI: 0.56–0.88)

p = .002

HR = 1.07 (95% CI: 0.49–1.73)

p = .678

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Su

rviv

al P

rob

abil

ity

(%)

Time (mos) Time (mos)

Pemetrexed 15.5 mos

Placebo 10.3 mos

Pemetrexed 9.9 mos

Placebo 10.8 mos

Ciuleanu, Lancet 2009

Continuation Maintenance Pemetrexed

advanced non-squam

NSCLC, no prior systemic Rx

placebo every 3 weeks

continuation maintenance pemetrexed every 3 weeks

Paz-Ares, J Clin Oncol 2013

Progression-Free Survival (from rand)

Overall Survival (from 1L chemo)

cis/pemetrexedx 4 cycles

1 yr OS: 58% vs. 45%; 2 yr OS: 32% vs.21%

AVAPERL: Continuation Maintenance Therapy after Chemo/Bevacizumab

advanced non-squam

NSCLC, no prior systemic Rx

continuation maintenancebevacizumab

continuation maintenance pemetrexed/bevacizumabcis/pem/bev

x 4 cycles

Progression-Free Survival (from rand)

Overall Survival (from 1L chemo)

Rittmeyer, Proc ASCO 2013

AVAPERL: Continuation Maintenance Therapy with Pemetrexed vs. Pemetrexed/Bevacizumab

0

2

4

6

8

10

12

14

16

18

20

Natural Hx Plat Doublet Doublet +2L Histol Specific Bv + Maint Switch/Cont Maint Maint w/Bev

2 yr. survival now up to 1/3 of patients

MedianOS

EGFR Mutations & Molecular Oncology

Sequist, JCO 2007

Before & after gefitinib (2 mo)

Courtesy of Dr. D. Gandara

Before & after gefitinib (2 mo)

Courtesy of Dr. D. Gandara

IPASS: Molecular Oncology Overrides Clinical Features

advanced lung adenocarcinoma,

Asianno prior systemic Rx

Never or light ex-smokerGefitinib daily until

progression

Carbo/paclitaxel x 6 cycles

Mok, NEJM 2009

IPASS: Objective Response Rate by EGFR Mutation Status

0

10

20

30

40

50

60

70

80

Mutation positive patients Mutation negative patients

Gefitinib Carboplatin / paclitaxel

EGFR M+ odds ratio (95% CI) = 2.75(1.65, 4.60), p=0.0001

EGFR M- odds ratio (95% CI) = 0.04(0.01, 0.27), p=0.0013

Overallresponserate (%)

(n=132) (n=129) (n=91) (n=85)

Odds ratio >1 implies greater chance of response on gefitinib

71.2%

47.3%

1.1%

23.5%

Mok, NEJM 2009

Prospective Trials of EGFR TKIs vs. Chemo in EGFR Mutation (Exons 19, 21) PopulationTrial N Rx

RR PFS (mo) OS (mo)

TKI Chemo TKI Chemo TKI Chemo

MaemondoNEJ002

230Gefitinib vs. Carbo/Pac

74% 31% 10.8 5.4 30.5 23.6

MistudomiWJTOG3405

172Gefitinib vs.

Cis/Doce62% 32% 9.2 6.3 30.9 N.R.

Zhao OPTIMAL

165Erlotinib vs. Carbo/Gem

83% 36% 13.1 4.6 22.6 28.8

Rosell EURTAC

174Erlotinib vs.

Plat Doublet

58% 15% 9.4 5.2 19.3 19.5

Sequist LUX-Lung 3

345Afatinib vs.

Cis/Pem56% 23% 13.6 6.9 NR NR

Wu LUX-Lung 6

364Afatinib vs.

Cis/Gem67% 23% 11.0 5.6 NR NR

Maemondo, NEJM 2010; Mistudomi, Lancet Oncol 2010; OPTIMAL, Lancet Oncol 2011; Rosell, Lancet 2012Sequist, JCO 2013; Wu, Lancet Oncol 2014

NR = not reported

EML4-ALK Translocations in NSCLCEML4-ALK Translocations in NSCLC

EML4-ALK frequency:

~4% (64/1709) Primarily adenoCa, minimial or no smoking

history

EML4-ALK frequency:

~4% (64/1709) Primarily adenoCa, minimial or no smoking

history

Soda et al., Nature 448: 561-566, 2007 Soda et al., Nature 448: 561-566, 2007

Bang, NEJM, 2010

New Mutation ROS-1 Identified in ~1% of NSCLC Tumors

Bergethon, J Clin Oncol 2012

Response to Crizotinib in ROS-1 Patients

• 67% response rate in T790M+ patients (WCLC, 2013)• Dosing 900 mg PO BID

• No rash (c/w absence of systemic wt EGFR inhibition)

Soria, WCLC 2013, Sydney

CO-1686: Oral Inhibitor of EGFR Mutations & T790M Mutations (not EGFR

wild type)

89 patients with documented radiological PD while on EGFR-TKINo DLTs at 20-160 mg/d (dosing to 240 mg/d)No dose reductions

AZD9291: Best % change from baseline in target

lesions

Ranson, WCLC 2013, Sydney

Ceritinib: Activity in Patients with Advanced ALK+ NSCLC

Shaw, NEJM 2014

Ceritinib: Approved for Crizotinib-Pretreated ALK-Positive NSCLC April 29,

2014

…but $13,500/month!…but $13,500/month!

A mutation found in 54% of tumors completely tested

HER 2

LCMC: Incidence of mutations detected

LCMC: Protocols linked to specific mutations

HER 2

Crizotinib (complete)BKM120

GSK2118434

Erlotinib + ARQ197

MM-121Dacomitinib

GSK1120212

Crizotinib STA-9090

Erlotinib + OSI906

BRAF V600E Mutations in NSCLCBRAF V600E Mutations in NSCLC

Response rate – 40%, disease control 60%

Planchard, Proc ASCO, 2013

Before and After Dabrafenib in BRAF V600E Mutation-Positive NSCLC

Planchard, Proc ASCO, 2013

Next Generation Sequencing to Broadly Test Patients for Wide Array of Mutations

• Fast• Accurate• Relatively cheap• Scalable• Able to detect heterogeneity

Molecular Oncology Offers Survival of Years To More & More Advanced NSCLC Patients

0

5

10

15

20

25

30

35

Natural Hx Plat Doublet Doublet +2L Histol Specific Bv + Maint Switch/ContMaint

Maint w/Bev Targeted Rx

MedianOS

Conclusions: Transitioning Survival from Months to Years in Advanced

NSCLC

Conclusions: Transitioning Survival from Months to Years in Advanced

NSCLC• 15 years ago, we were asking the question of whether

treatment of advanced NSCLC was worth it at all, providing an improvement in median OS of only weeks to a couple of months.

• Since then, treatments have become less toxic, and we have identified several minimally toxic agents that can improve survival further, following first line.

• Selection of optimized chemo by histology, and addition of bevacizumab, has improved median OS to a year in broad population.

• Maintenance therapy and second and third line therapies have improved survival, especially in patients who haven’t progressed early, to a median OS of 15-18 months.

• About 1/3 are living 2 years and longer, even independent of targeted therapies.

Conclusions (2): Transitioning Survival from Months to Years; Molecular

Oncology• Detection of driver mutations such as EGFR mutations or ALK rearrangements profoundly increase the response rate to 60-75% and median survival to 2-3 years.

– Some are beginning to have new agents for “acquired resistance”, to extend response and survival further

• While this applies to only a minority of patients now, other targets, such as ROS1, BRAF, and HER2 are being identified and have agents with potential to bring this unprecedented efficacy to an ever-growing population of patients.

• We are just now moving to next generation genomic sequencing, which will lead to a new ability to detect these populations and facilitate studies for the 1-5% populations. These groups will add up.

• The new era will lead to delivery of targeted therapies to targeted populations, with an expectation that these patients will live YEARS.