Second Line Treatment for Second Line Treatment for Gastroesophageal Cancers:Gastroesophageal Cancers:Are We Helping People Feel Are We Helping People Feel

Better and Live Longer?Better and Live Longer?

Johanna Bendell, MDJohanna Bendell, MDDirector, GI Oncology ResearchDirector, GI Oncology Research

Associate Director, Drug Development UnitAssociate Director, Drug Development UnitSarah Cannon Research InstituteSarah Cannon Research Institute

Nashville, TNNashville, TN

Second Line Therapy for Second Line Therapy for Gastroesophageal Cancers – A Difficult Gastroesophageal Cancers – A Difficult

SituationSituation

After progression on first line therapy, only After progression on first line therapy, only roughly 20% of patients receive second-line roughly 20% of patients receive second-line therapy with a median overall survival of 5.6 therapy with a median overall survival of 5.6 months (Chau, GI ASCO 2004)months (Chau, GI ASCO 2004)

Patients are sickPatients are sick– Symptomatic – weight loss, anorexia, pain, difficulties Symptomatic – weight loss, anorexia, pain, difficulties

eating (with or without prior local intervention), N/Veating (with or without prior local intervention), N/V

Do we have data to show second line therapy Do we have data to show second line therapy can help?can help?

Randomized Second Line Trials Randomized Second Line Trials to Dateto Date

Study Treatment N OS Treatment

Group

OS Control Group

QoL

AIOThuss-

Patience 2011

Irinotecan vs. BSC

40 4.0 moHR 0.48

[0.25,0.92]

2.8 mo 50% vs. 7% improvement

in tumor-related

symptoms

Park2011

Irinotecan or docetaxel vs. BSC

202 5.1 moHR 0.63

[0.47,0.86]

3.8 mo N/A

WJOG4007Ueda 2012

Irinotecan vs.

Paclitaxel

219 9.5 mo (paclitaxel)

8.4 mo (irinotecan)

N/A

GRANITE-1Van Cutsem

2012

Everolimus vs. BSC

656 5.39 moHR 0.90

[0.75-1.08]

4.34 mo N/A

Trial Design

Adenocarcinoma of esophagus,

esophagus-gastric junction or

stomach refractory to platinum and fluoropyrimide

Arm A (n=84): Docetaxel 75mg/m2 IV every 3

weeks for up to 6 cycles+ ASC

Arm B (n=84): Active symptom control

May include: Radiotherapy, analgesia, anti-emetics,

steroids

Assess every 3 weeks for 18 weeks, then

every 6 weeks

RANDOMISE1:1

n=168

Stratified by:

1.Disease status (Locally advanced vs metastatic); 2. Site of disease (Esophagus vs GEJ vs Stomach); 3. Time to progression after previous chemotherapy ( 0 vs 0-3 vs 3-6 months); 4. ECOG PS ( 0/1 vs 2)

COUGAR-02COUGAR-02

Well-designed with good stratification factors Well-designed with good stratification factors

Screening vs. number enrolled show how Screening vs. number enrolled show how difficult these trials are to accruedifficult these trials are to accrue– Many are ineligible (sick population)Many are ineligible (sick population)– Refusal of study (vs. BSC)Refusal of study (vs. BSC)

Restaging at 3 and 6 cycles for docetaxel Restaging at 3 and 6 cycles for docetaxel patients, as indicated for BSC patients (no patients, as indicated for BSC patients (no TTP endpoint)TTP endpoint)

Included QUALITY OF LIFEIncluded QUALITY OF LIFE

This is a difficult population to This is a difficult population to treattreat

These patients are These patients are sicksick

Most do not complete Most do not complete treatment plantreatment plan

Docetaxel BSC

Completed 18 weeks

23% 36%

Reason off

Death 15% 38%

PD 40% 2%

Tox 31% N/A

Treatment N/A 14%

ToxicityToxicity

Toxicity rates relatively Toxicity rates relatively low for q 3 week low for q 3 week docetaxeldocetaxel

Only significant Only significant differences are differences are neutropenia and febrile neutropenia and febrile neutropenianeutropenia

Relatively low neuropathy Relatively low neuropathy and thrombocytopeniaand thrombocytopenia

Due to low amount of Due to low amount of chemotherapy given?chemotherapy given?

Median number of cycles Median number of cycles of docetaxel given was 3of docetaxel given was 3

Overall survival

Median survival: 5.2 months (95% CI 4.1-5.9) for Docetaxel 3.6 months (95% CI 3.3-4.4) for ASC

Hazard ratio 0.67 (95% CI 0.49-0.92), p=0.01

0

25

50

75

100

0 2 4 6 8 10 12 14 16 18

Perc

enta

ge su

rviv

ing

Months from randomisation

DocetaxelASC

No. at Risk:Docetaxel 84 69 53 33 25 17 10 8 5 4 ASC 84 70 38 19 13 9 6 2 1 1

Who really received benefit???Who really received benefit???Patients who had disease progression 3-6 Patients who had disease progression 3-6 months after first line therapymonths after first line therapy– Longest disease free intervalLongest disease free interval– Selection of patients who respond to therapy Selection of patients who respond to therapy

betterbetter

Patients with ECOG 0Patients with ECOG 0

We Help Them Live Longer, But Do We Help Them Live Longer, But Do We Help Them Feel Better?We Help Them Feel Better?

QoL forms (EORTC QLQ-C30, STO22, EQ5D) QoL forms (EORTC QLQ-C30, STO22, EQ5D) planned in both arms q 3 weeks for 18 weeks, planned in both arms q 3 weeks for 18 weeks, then q 6 weeksthen q 6 weeks

Number of QoL forms expected/returned lower Number of QoL forms expected/returned lower in the control arm – potential source of bias, but in the control arm – potential source of bias, but common in these types of studiescommon in these types of studies

  Arm A (Docetaxel) Arm B (ASC)QLQ-C30 Form

Number Received

  

n(%)*

Number Expected

Number died/not

expecting QOl n(%)~

Number Received

  

n(%)*

Number Expected

Number died/not

expecting QOl n(%)~

Baseline 82(98) 84 0 76 (90) 84 03 weeks 62 (81) 77 7 (8) 50 (68) 73 11 (13)6 weeks 49 (68) 72 12 (14) 38 (57) 67 17 (20)9 weeks 45 (68) 66 18 (21) 25 (45) 55 29 (35)12 weeks 34 (55) 62 22 (26) 29 (64) 45 39 (46)18 weeks 29 (60) 48 36 (43) 13 (45) 29 55 (65)24 weeks 17 (52) 33 51 (61) 11 (65) 17 67 (80)Total 318 (72) 442   242 (65) 370  

Quality of life (EORTC QLQ-C30)• Standardised AUC analysis• Comparison using O’Brien global rank procedure• No significant differences in function or global health scale• Symptom score for pain significantly better in chemotherapy arm

CT ASC

Global health Pain

p=0.53 p=0.0008

COUGAR-2COUGAR-2Chemotherapy benefits patients in the second Chemotherapy benefits patients in the second line settingline setting– We now see docetaxel and irinotecan workWe now see docetaxel and irinotecan work– But overall benefit is still around 1.5 moBut overall benefit is still around 1.5 mo

But need to think about who will really benefitBut need to think about who will really benefit– Can we get better at selecting the appropriate Can we get better at selecting the appropriate

patient?patient?– Longer PFI, better PSLonger PFI, better PS– Patients who respond better and feel better live Patients who respond better and feel better live

longerlonger

COG

ASCO GI 24th Jan 2013

Gefitinib in advanced esophageal cancer progressing after

chemotherapy

Patients progressing following

chemotherapy

Planned: 18 months to recruit 450 patientsPrimary endpoint: Overall survival - powered to detect an increase in 1 year survival from 10 to 18%, 82.5% power, 5% significance level.Secondary endpoints: PFS, toxicity & PROs 13

Gefitinib 500mg od(n=225)

Gefitinib 500mg od(n=225)

Placebo (n=225)Placebo (n=225)

Simple randomisation

• Multi-centre• Double-blind – patients,

clinicians and trial office staff blinded to trial treatment

• Treated until progression

• Regular CT scans

COGCOGNo benefit for overall survivalNo benefit for overall survival– 3.73 vs. 3.6 mo, HR 0.90 [0.74,1.09]3.73 vs. 3.6 mo, HR 0.90 [0.74,1.09]

PFS PFS – 1.60 vs. 1.17 mo, HR 0.795 [0.657,0.962]1.60 vs. 1.17 mo, HR 0.795 [0.657,0.962]– Was there a subgroup who had benefit?Was there a subgroup who had benefit?

Is there a biomarker? Studies ongoing…Is there a biomarker? Studies ongoing…

Did anyone feel better?Did anyone feel better?– EORTC QLQ-C30EORTC QLQ-C30– EORTC QLQ-OG25EORTC QLQ-OG25

Quality of LifeQuality of LifePlanned assessments at baseline, 4, 8, Planned assessments at baseline, 4, 8, and 12 weeks then until progressionand 12 weeks then until progression

Prespecified PRO: global QoL, dysphagia, Prespecified PRO: global QoL, dysphagia, difficulty eating, odynophagiadifficulty eating, odynophagia

Primary evaluation at 4 weeksPrimary evaluation at 4 weeks– Not surprisingly for this patient population, Not surprisingly for this patient population,

only 70% alive and progression free at 4 only 70% alive and progression free at 4 weeks (82.5% placebo vs. 74.7% geftinib weeks (82.5% placebo vs. 74.7% geftinib compliance)compliance)

0

10

20

30

40

50

Me

an O

dyn

opha

gia

Baseli

ne

4 wee

ks

8 wee

ks

12 w

eeks

Placebo

GefitinibOdynophagia is improved in Odynophagia is improved in the gefitinib arm at 4 weeks, the gefitinib arm at 4 weeks, and stays consistently better and stays consistently better with time out to 12 weekswith time out to 12 weeks

This points to a group of This points to a group of patients who appear to benefit patients who appear to benefit from gefitinibfrom gefitinib

There was a group with tumor There was a group with tumor shrinkage at 4 weeksshrinkage at 4 weeks– RR 3.1 vs 0.4%RR 3.1 vs 0.4%– DCR (8 weeks) 26 vs. 16% (p = DCR (8 weeks) 26 vs. 16% (p =

0.014)0.014)

Can we identify who they are?Can we identify who they are?Progressive disease

Stable disease

Partial response

Progressive disease

Stable disease

Partial response

-100

-50

-30

0

20

50

100

150

placebo gefitinib

RE

CIS

T r

esponse a

t 4 w

eeks

COG 2012

COG patients with measurable disease at baseline

It always comes down to the It always comes down to the biomarker question…biomarker question…

But what are the biomarkers?But what are the biomarkers?

REAL-3 REAL-3 – Mutations/pathway dysregulation not commonMutations/pathway dysregulation not common– EXPAND biomarkers pendingEXPAND biomarkers pending

Though we do see EGFR overexpression (50-70%)Though we do see EGFR overexpression (50-70%)

Squamous vs. adenocarcinomaSquamous vs. adenocarcinoma– Different responses to EGFR inhibitors?Different responses to EGFR inhibitors?– SCC head and neck respondSCC head and neck respond– Lordick, et al, R ph II SCC esophagus, Lordick, et al, R ph II SCC esophagus,

RR 19 vs. 13%, RR 19 vs. 13%,

PFS 5.7 vs. 3.6 mo, PFS 5.7 vs. 3.6 mo,

OS 9.5 vs. 5.5 moOS 9.5 vs. 5.5 mo

Chau 2011

Randomized Second Line Trials to DateRandomized Second Line Trials to Date

Study Treatment N OS Treatment

Group

OS Control Group

QoL

AIOThuss-

Patience 2011

Irinotecan vs. BSC

40 4.0 moHR 0.48

[0.25,0.92]

2.8 mo 50% vs. 7% improvement in tumor-related

symptoms

Park2011

Irinotecan or docetaxel vs.

BSC

202 5.1 moHR 0.63

[0.47,0.86]

3.8 mo N/A

WJOG4007Ueda 2012

Irinotecan vs. Paclitaxel

219 9.5 mo (paclitaxel)

8.4 mo (irinotecan)

N/A

COUGAR-2Ford 2013

Docetaxel vs. BSC

168 5.3 moHR 0.67

[0.49,0.92]

3.6 mo No diff global QoL but pain improvement

GRANITE-1Van Cutsem

2012

Everolimus vs. BSC

656 5.39 moHR 0.90

[0.75-1.08]

4.34 mo N/A

COGDutton 2013

Gefitinib vs. BSC

450 3.73 moHR 0.90

[0.74,1.09]

3.6 mo Improvement in odynophagia, social function

MOVING FORWARD…MOVING FORWARD…

T-DM1 structureT-DM1 structureT-DM1 is a novel ADC

Average drug:antibody ratio 3.5:1≅

Highly potent cytotoxic agent

Monoclonal antibody: Trastuzumab

Systemically stable

Target expression: HER2

Cytotoxic agent: DM1

Linker: MCC

T-DM1

Trastuzumab

* Dose selection based on PK/safety/efficacy ** Investigator’s choice between paclitaxel 80 mg/m2/wk and docetaxel 75 mg/m2 q 3 wk

• Phase II: 3 arm; 2:2:1 randomization; endpoints: safety, PK, PFS, ORR; n=100• Phase II: 3 arm; 2:2:1 randomization; endpoints: safety, PK, PFS, ORR; n=100

2L Her2 positive mGCPS: 0 -1IHC 3+ or IHC 2+/ISH+Prior Ctx + prior HER2 N=412

Chemotherapy**

T-DM1 2.4 mg/kg/wk

T-DM1 3.6 mg/kg q3 wk

Phase IIn=100

22

22

11

Trastuzumab Emtansine: Phase II Study of 2L treatment for HER2+ Metastatic Gastric

Cancer

Stratified by: region, PS, prior gastrectomy, prior HER2-targeted tx

REGARD: Randomized Phase REGARD: Randomized Phase III Trial 2III Trial 2ndnd Line Ramicirumab Line Ramicirumab

vs. Placebovs. Placebo

1:1

Second line metastatic gastric

and GEJ adenocarcinoma

R

Ramucirumab IVq 2 weeks

Placeboq 2 weeks

22

Primary EP: OSN = 355

Press release 10/12: met primary endpointof OS and secondary endpoint of PFSPress release 1/23/13: OS 5.2 vs. 2.6 moPFS 2.1 vs. 1.3 mo

RAINBOW: Randomized Phase RAINBOW: Randomized Phase III Trial 2III Trial 2ndnd Line Paclitaxel +/- Line Paclitaxel +/-

RamicirumabRamicirumab

1:1

Second line metastatic gastric

and GEJ adenocarcinoma

R

Paclitaxel 80 mg/m2 d1, 8, 15 +

Ramucirumab IVq 2 weeks

Paclitaxel 80 mg/m2 d1, 8, 15 +

Placeboq 2 weeks

23

Primary EP: OSN = 665

Second Line Treatment of Second Line Treatment of Gastroesophageal CancersGastroesophageal Cancers

Consistent trials showing some benefit to chemotherapyConsistent trials showing some benefit to chemotherapy

COUGAR trial shows docetaxel is an appropriate chemotherapy COUGAR trial shows docetaxel is an appropriate chemotherapy choicechoice

COG trial shows gefitinib overall does not improve survival COG trial shows gefitinib overall does not improve survival endpointsendpoints

However, both trials show suggestion of subpopulations that may However, both trials show suggestion of subpopulations that may benefit morebenefit more– COUGAR – longer PFI, better PSCOUGAR – longer PFI, better PS– COG – subpopulation with improved QoL factorsCOG – subpopulation with improved QoL factors

Drug development in this setting needs to be more targeted to the Drug development in this setting needs to be more targeted to the right populationright population– We are doing thisWe are doing this– TDM1 for HER2 positive patientsTDM1 for HER2 positive patients– Inclusion of biomarker studies and QoL in trials for this populationInclusion of biomarker studies and QoL in trials for this population