Current Strategies for Adjuvant Therapy:  Ongoing and Future Trial Research

Current Strategies for Adjuvant Therapy: 

Ongoing and Future Trial Research

Tracey Evans, MDAbramson Cancer Center

University of Pennsylvania, Philadelphia

Current Status of Adjuvant Chemotherapy in NSCLC

It is STANDARD OF CARE

How did we get here?

Early Adjuvant Trials in NSCLC

No benefitBusulfan + Cyclophosphamide

726Girling 1985No benefitCCNU + Hydrea865Shields 1982No benefitCyclophosphamide +

MTX417Shields 1977

No benefitCyclophosphamide IV + IP

909Shields 1974

No benefit higher

recurrence in treatment

arm

Cyclophosphamide IV189Brunner 1973

No benefitCyclophosphamide orally

502Miller 1971No benefitNitrogen mustard IV +

IP1192Slack 1970

No benefitCyclophosphamide IV1035Higgins 1969

No benefitNitrogen mustard IV + IP

1002Hughes 1962

ResultsChemotherapy# ptsInvestigator

Limitations of Earlier Adjuvant Trials

• Regimens with marginal activity in advanced NSCLC

• Inclusion of patients with compromised PS and multiple co-morbidities

• Difficulty administering systemic therapy in the post-op setting

• Inadequate power/overly ambitious survival endpoints

BMJ Meta-analysis: Adjuvant Cisplatin-based Chemotherapy

Overall Survival

at risk Months706 590 462 371 295 206Surgery+CT

Surgery 688 548 433 353 258 177

Survival

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

1.00.9

0 12 24 36 48 60

Surgery 316 688298 706

Events Total Surgery+CT

Survival benefit with cisplatin-based chemotherapy:

3% at 2 years, 5% at 5 years

BMJ 311:899-901, 1995.

IALT Schema

Surgically resected non-small cell lung cancer

Observation

Cisplatin 300-400mg/m2 over 3-4 cycles

with

Etoposide, vinorelbine, vinblastine, or vindesine

Within 60 days post-op

Randomize

Radiation optional, predetermined by N stage for each center

IALT Results

Chemo (932) No Chemo (935)5 yr OS 44.5% 40.4%

5 yr DFS 39.4% 34.3%MS 50.8 mos 44.4 mosMDFS 40.2 mos30.5 mos

NEJM 350; 351-60, 2004.

935 775 619 520 447 372 282 208 125932 780 650 550 487 399 300 208 133

0%

20%

40%

60%

80%

100%

0 1 2 3 4 5 6 7 8 years

chemotherapy: 578 deaths - 495 deaths before 5 years - 83 deaths after 5 years

control 590 deaths - 534 deaths before 5 years - 56 deaths after 5 years

HR: 0.91 (0.81-1.02, P = 0.10)

Le Chevalier T, et al. J Clin Oncol. 2008(May 20 suppl). Abstract 7507.

IALT: 7.5-Year Median Follow-Up

NCIC-BR10

Select inclusion criteria:

•Stage IB-II NSCLC

•Complete surgical resection

•N=482

RANDOMIZE

Vinorelbine, IV, 25 mg/m2, weekly 16 wk

Cisplatin, 50 mg/m2, d 1, 8 q 4 wk 4 cycles

No chemotherapy

Overall Survival by Treatment Arm

Absolute improvement in 5 yr OS = 11% (67% vs. 56%); benefit persists at 9+ yrs

Vincent, Butts et al, 2009.

All Patients

Absolute improvement in 5 yr OS = 15% (69% vs. 54%) Winton et al. NEJM 2005.

HR 0.695 yr: 69% vs 54%MST 94 m vs 73 m

5 yr: 67% vs 56%MST 94m vs 72m

At RiskObservationVinorelbine

Stratified Log-Rank: p=0.04HR: 0.780(0.613, 0.993)

'

Observation Vinorelbine

Perc

enta

ge

0

20

40

60

80

100

0

240242

3

155182

6

117135

9Time(Years)

5867

12

912

15

00

NCIC-CTG JBR.10Elderly Analysis

• Elderly received less chemotherapy overall• Toxicity differences not seen in this trial by age

group• Adjuvant chemotherapy should be offered to the fit

elderly

Pepe, J Clin Oncol Vol 25: 1553-1561, 2007.

Age (N) HR OS(Chemo vs obs)

CI p

≤65 (327)

0.77 [0.54-1.09] 0.14

>65 (155)

0.61 [0.38-0.98] 0.04

>75 (23) 2.35 [0.84-6.58] 0.09

CALGB 9633: RCT of Adjuvant Chemotherapy in Stage IB NSCLC

T2N0MOstage IB NSCLC

COMPLETESURGICAL RESECTION

ADJUVANT CHEMOTHERAPY

Paclitaxel, 200 mg/m2

Carboplatin, AUC=6 mg/ml x min

4 cycles over 12 weeks

OBSERVATIONrandomization within 4 to 8 wks of resection

STRATIFIEDsquamous vs otherpoorly differentiated vs othermediastinoscopy: yes vs no Strauss GM, Herndon JE, Maddaus MA, et al. Adjuvant chemotherapy in stage IB

non-small cell lung cancer (NSCLC): update of Cancer and Leukemia Group B (CALGB) protocol 9633. Slides presented at: ASCO; June 2-6, 2006; Atlanta, GA. Presentation based on abstract 7007.

Overall Survival: THEN AND NOW

ASCO: 2004 ASCO: 2006

HR=0.62; 90% CI: 0.44-0.89; P=0.01

HR=0.80; 90% CI: 0.60-1.07; P=0.10

Reproduced with permission (pending) from Strauss et al. Slides presented at: ASCO; June 2-6, 2006; Atlanta, GA. Presentation based on abstract 7007.

0 2 4 6 8

Survival Time (Years)

0.0

0.2

0.4

0.6

0.8

1.0

Prob

abili

ty

ObservationChemo

0 1 2 3 4 5 6 7 8 9 0 2 4 6 8

Survival Time (Years)

0.0

0.2

0.4

0.6

0.8

1.0

Prob

abili

ty

ObservationChemo

0 1 2 3 4 5 6 7 8 9

Disease-Free Survival: Then and Now

ASCO: 2004 ASCO: 2006

HR=0.69; 90% CI: 0.51-0.92; P=0.02

HR=0.74; 90% CI: 0.57-0.96; P=0.03

Reproduced with permission (pending) from Strauss et al. Slides presented at: ASCO; June 2-6, 2006; Atlanta, GA. Presentation based on abstract 7007.

0 2 4 6 8

Survival Time (Years)

0.0

0.2

0.4

0.6

0.8

1.0

Prob

abili

ty

ObservationChemo

0 1 2 3 4 5 6 7 8 9 0 2 4 6 8

Survival Time (Years)

0.0

0.2

0.4

0.6

0.8

1.0

Prob

abili

ty

ObservationChemo

LACE* Meta-analysis• 5 trials including 4,584 patients• Median follow-up: 5.1 years (3.1 – 5.9)• 80% male • Median age 59 years, 9% > 70 years old • Pathological Stage: IA: 8%, IB: 30%, II: 35%, III: 27%• Surgery: 31% pneumonectomy• Histology: 49% squamous cell, 39% adenocarcinoma, 12% other

*Lung Adjuvant Cisplatin Evaluation Pignon Proc ASCO 2006 abs 7008.

Pignon J et al. JCO 2008;26:3552-3559.

The absolute effect of chemotherapy at 5 years was a decrease of 6.9% for lung cancer death and an increase of 1.4% for non–lung cancer death.

LACE Meta-analysis

Overall Survival (%) Disease-free Survival (%)

Overall Survival (%)

LACE Meta-analysis

P=.005 P<.001

0.89 (0.82-0.96)

0.84 (0.78-0.91)

Pignon J et al. JCO 2008;26:3552-3559.

NCCN Guidelines

Controversies

• Which regimen?– Cisplatin vs Carboplatin?

• Stage IB?

• Predictive/prognostic biomarkers?

• Post-operative XRT (PORT)?

Which regimen?

Regimens: LACE Meta-analysis

• Cisplatin/vinorelbine: regimen for 41% LACE pts– Regimen for Anita and JBR10– 86% patients received >300mg/m2 cisplatin– 13% of IA’s cis/vinorelbine vs. 43% other stages

• Drugs used with cisplatin other studies– IALT: vinorelbine, vindesine, vinblastin, etoposide– BLT: vinorelbine, vindesine, mitomycin/vindesine,

mitomycin/ifosfamide– ALPI: vindesine/mitomycin

.04

.02

.10

.09

Extrapolating Stage IV: Not Vinorelbine?

Survival Time (Mos.)

Cum

ulat

ive

Prob

abili

ty1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

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

DocetaxelCisplatin

VinorelbineCisplatin

P = 0.044(adjusted log-rank)

Fossella FV et al. JCO 22, 2003.

Schiller et al. NEJM.2002; 346:92-98.

Extrapolating Stage IV: It’s all the Same?

Ardizzoni A et al. JNCI J Natl Cancer Inst 2007;99:847-857.

Extrapolating stage IV: Cisplatin ≠ Carboplatin:

Response Rate

Extrapolating Stage IV: Cisplatin ≠ Carboplatin:

Overall Survival

Ardizzoni A et al. JNCI J Natl Cancer Inst 2007;99:847-857.

Randomized Phase 2 Trial on Refinement of Early Stage NSCLC Adjuvant Chemotherapy with Cisplatin and Pemetrexed

(CPx) vs. Cisplatin and Vinorelbine (CVb) - TREAT

M. Kreuter, J. Vansteenkiste, J. Fischer, W. Eberhardt, H. Zabeck, J. Kollmeier, M. Serke, N. Frickhofen, M. Reck, W. Engel-Riedel, S. Neumann, M. Thomeer, C. Schumann, P. De Leyn, T. Graeter, G. Stamatis, I. Zuna, F. Griesinger and M.

Thomas on behalf of the TREAT investigators

LACE-Metaanalysis NCIC-JBR .10No treatment 9% 4.5%Treatment incomplete 24 %

(≤ 2 cycles)50%

(< 4 cycles)• early death or progression 9% 5%• toxicity 34% 13%• patient refusal 35% 29%Therapy delay 55%Dose reductions 77%

Pignon, JCO, 2008 ; Winton, N Engl J Med, 2005; Alam, Lung Cancer, 2005; Vogelzang, JCO, 2003; Scagliotti, JCO, 2008; Schmid-Bindert, ASCO, 2009.

TREAT Rationale:• Adjuvant CTX: mainly Cisplatin / Vinorelbine • Need: reduction of toxicity, improvement of dose delivery & compliance• Cisplatin / Pemetrexed in thoracic malignancies: high dose intensity, low toxicities

Rationale: Dose delivery: Adjuvant CTX

TREAT: Design

Cisplatin / Vinorelbine (CVrb)

Cisplatin / Pemetrexed (CPx)

50 mg/m2 d1+8 / 25 mg/m2 d1, 8, 15, 22 q d 29 x 4

75 mg/m2 d1 / 500 mg/m2 d1 q d 22 x 4

R0Winton et al., N Engl J Med (2005) 352: 258

Inclusion • NSCLC stages IB, IIA, IIB, T3N1M0 • ≤ 42 days postoperative, R0, systematic LN-dissection • ECOG 0, 1 • amenable to Cisplatin treatment

Stratification • Center • Nodal status (N0 versus N1) • Surgical procedure (lobectomy versus pneumonectomy)

Study conduct:• Study concept 2005, Inclusion 10/2006-12/2009 (16 sites,

132 patients)• Treatment until 2/2010, primary endpoint analysis 12/2010

Primary endpoint:Clinical Feasibility considered promising if > 80%• No death due to cancer, toxicity, comorbidity• No Non-acceptance by patients leading to premature

withdrawal• No observation of DLT

Neutropenia grade 4 > 7 d Neutropenia grade 3/4 with fever/infection Thrombocytopenia grade 4 > 7 d Thrombocytopenia any grade with bleeding Non-hematologic toxicity grade 3/4 related to CTX

Secondary endpoints:Dose delivery, safety, TTTF, RFS, OS, DMFS, LRFS, site of

relapse

TREAT: Conduct / Endpoints

Characteristics CPx(n=67)

CVb(n=65)

Total(n=132)

Age (years [range]) 58 [40-73] 60 [38-74] 59 [38-74]Gender (%)• male • female

7228

77 23

7426

Smoking status (%)• Smoker • Ex-smoker• Non-smoker • Not available

336160

26711.5 1.5

29664 1

Stage (%)IB 37 38 38IIA 12 8 10IIB 46 48 47T3N1 5 6 5

TREAT: Characteristics

Characteristics CPx(n=67)

CVb(n=65)

Total(n=132)

Surgical procedures (%)Lobectomy 84 82 83Pneumonectomy 12 15 14Complex resections 4 3 3

Histology (%)Squamous cell carcinoma 45 42 43Non-squamous 55 58 57• Adenocarcinoma 37 44 41• Large cell carcinoma 9 9 9• Mixed cell carcinoma 9 5 7

TREAT : Characteristics

CPx CVb

Feasibility rate (%) 95.5

(CI 87.5-99.1)75.4

(CI 63.1-85.2)Death (%) 1.5 3.1Withdrawal of consent (%) 0 6.2DLT (%) 3.0 15.4

Reasons for DLT (events) * patients (n=2) patients (n=10)G4 neutropenia >7d 0 4G4 thrombocytopenia >7d 0 0G3/4 febrile neutropenia 1 5Thrombocytopenia with bleeding 0 0

G3/4 non-hematologic toxicity 2 1

Results: Primary Endpoint - Feasibility

* multiple reasons possible

p = 0.0010

EOT CPx CVbRegular EOT (%) 77.6 36.9

Earlier termination of therapy (%) 22.4 63.1

Reasons for earlier termination (events)*

patients (n=15)

patients (n=41)

• Unacceptable toxicity according to protocol** 4 19

• Unacceptable toxicity perceived by patient 6 7• Relapse of disease 0 2• Withdrawal of consent 0 4• Death (therapy related) 1 (0) 2 (0)• Non-compliance to protocol 0 2• Medical decision by investigator 4 5• Major protocol violation 0 1• Other reasons 0 4

Results: End of Therapy

*multiple reasons possible**delay >2 weeks due to toxicity or in case of G3/4 non-hem toxicity

Toxicity CPx CVbMean Number(AE / SAE) 6.8 / 0.3 6.9 / 0.2

HematologicToxicity G3/4 (%) 10.5 76.5

Non-hematologic Toxicity G3/4 (%) 33 31

Hematologic Toxicity (%) G3/4 G3/4

Anemia 0 1.5Thrombocytopenia 0 0

Neutropenia 9 69Febrile Neutropenia 1.5 6

TREAT: Toxicity

p<0.0001

p=0.7988

TREAT: Time to Treatment Failure

TtTF:Time from surgery to withdrawal due to • AE• progression /

relapse / death• failure to return

to therapy• refusal of treatment

/ withdrawal of consent

p<0.001W

ithdr

awal

pro

babi

lity

• CPx safe and feasible less toxicity compared to CVb superior dose delivery compared to CVb high dose density (mg/m2/week)

• Dose delivery failure in CVb mostly due to Vb (delivery d15, d22)

• Efficacy: longer follow up to be awaited

TREAT: Conclusions

E1505 Chemotherapy Regimens

• Therapy to start 6-12 weeks post-operatively– Investigator Choice of Chemo - 4 cycles (12

wks)• Cisplatin/Vinorelbine

– Cis 75 mg/m2 d 1, Vin 25 mg/m2 d1,8 q21 d• Cisplatin/Docetaxel

– Cis 75 mg/m2 d 1, Docetaxel 75 mg/m2 d 1 q21 d• Cisplatin/Gemcitabine

– Cis 75 mg/m2 d 1, Gem 1250 mg/m2 d1,8 q 21 d• Cisplatin/Pemetrexed

– Cis 75 mg/m2 d 1; Pem 500 mg/m2 d 1 Q 21 d

• Bevacizumab 15 mg/kg q 21 days x 12 months

ECOG 1505: Adjuvant Bevacizumab

RANDOM IZE

STRATIFIED:

StageHistologyGenderChemo regimen*

ChemotherapyX 4 cycles

ELIGIBLE:

Resected IB^-IIIA

Squamous Allowed!³ LobectomyNo prior chemoNo planned XRTNo h/o CVA/TIANo ATE w/in 1 yr

Chemotherapyx 4 cyclesPlusBevacizumabX 1 year

^ Now revised to exclude IB < 4cmCompleted accrual/study closed Sept 20, 2013

ECOG 4599: Overall Survival

0.0

0.2

0.4

0.6

0.8

1.0

Prop

orti

on S

urvi

ving

0 6 42 4818 3012 24 36Months

HR=0.80; P=0.013

BV/PC 12.3 moPC 10.3 mo

Median Survival

1-year survival51% vs. 44%

2-year survival23% vs. 15%

Sandler, et al. NEJM. 355;24. Dec 14 2006.

Stage IB

LACE Meta-analysis: Stage Effects

CT may be detrimental for stage IA, but stage IA patients were generally not given the potentially best combination cisplatin + vinorelbine (13% of stage IA patients versus ~43% for other stages)

Stage IA 102 / 347 1.41 [0.96;2.09]

Stage IB 509 / 1371 0.92 [0.78;1.10]

Stage II 880 / 1616 0.83 [0.73;0.95]

Stage III 865 / 1247 0.83 [0.73;0.95]

CategoryNo. Deaths

/ No. EnteredHazard ratio

(Chemotherapy / Control) HR [95% CI]

Test for trend: p = 0.051Chemotherapy better | Control better

0.5 1.0 1.5 2.0 2.5

Stage IA 102 / 347 1.41 [0.96;2.09]

Stage IB 509 / 1371 0.92 [0.78;1.10]

Stage II 880 / 1616 0.83 [0.73;0.95]

Stage III 865 / 1247 0.83 [0.73;0.95]

CategoryNo. Deaths

/ No. EnteredHazard ratio

(Chemotherapy / Control) HR [95% CI]

Test for trend: p = 0.051Chemotherapy better | Control better

0.5 1.0 1.5 2.0 2.5

Stage-Specific Hazard RatiosRecent Adjuvant Trials

Trial IB II IIIAIALT 0.95 0.93 0.79BR-10 0.94 0.59 N/AANITA 1.10 0.71 0.69CALGB 0.8 N/A N/ALACE 0.92 0.83 0.83

Negative Positive

Indeterminate Not studied

Stage-Specific Hazard RatiosRecent Adjuvant Trials

Trial IB < 4 cm IB > 4 cm

II IIIA

IALT 0.95 0.93 0.79BR-10 1.73 0.66 0.59 N/AANITA 1.10 0.71 0.69CALGB 1.02 0.66 N/A N/ALACE 1.41* 0.91* 0.83 0.83

Negative Positive

Indeterminate Not studied* Using 3 cm as cut off

UICC6 T/M Descriptor Proposed T/M N0 N1 N2 N3

T1 (< 2 cm) T1a IA IIA IIIA IIIB

T1 (> 2-3 cm) T1b IA IIA IIIA IIIB

T2 ( 3 to < 5 cm) T2a IB IIA IIIA IIIB

T2 (>5-7) T2b IIA IIB IIIA IIIB

T2 (> 7 cm) T3 IIB IIIA IIIA IIIB

T3 invasion T3 IIB IIIA IIIA IIIB

T4 (same lobe nodules) T3 IIB IIIA IIIA IIIB

T4 (extension) T4 IIIA IIIA IIIB IIIB

M1 (ipsilateral Lung) T4 IIIA IIIA IIIB IIIB

T4 (pleural effusion) M1a IV IV IV IV

M1 (contralateral lung) M1a IV IV IV IV

M1 (distant) M1b IV IV IV IV

New Staging System (IASLC ’07)

Staging alteration

Prognostic/Predictive Biomarkers

• Using prognostic data to treat fewer patients who are probably cured, more who are probably not

• Using predictive data to treat only those likely to benefit with drugs most likely to work

ERCC-1• DNA repair mechanisms important for

resistance to cisplatin• Excision repair cross-complementation

group 1 (ERCC1) enzyme plays rate-limiting role in the nucleotide excision repair pathway

ERCC-1 Negative

ERCC-1 Positive

IALT: ERCC-1 Survival

Olaussen et al, NEJM 2006; 355: 983-991

Prospective Biomarker NSCLC Studies

Stage Therapy BiomarkerSWOG 0720 I (>2cm) +/- chemo

(cis/gemcitabine)

ERCC1/RRM1

ITACA I-IIIA cis/pemetrexed ERCC1/TSTASTE I-IIIA cis/erlotinib ERCC1/EGFR

mutSCAT I-IIIA Platinum/

docetaxelBRCA1/RAP80

• Evaluation of 16 commercially available ERCC1 antibiodies could not distinguish between active and inactive ERCC1 isoforms.

8F1 antibody in IALT data set

Friboulet, et al, NEJM 2013; 368: 1101-1110.

Erlotinib

CDDP-Pemetrexed

Observation

ERCC1-

ERCC1+

EGFR wt

Experimental ArmCustomized

Control ArmCDDP - pemetrexed

EGFRmutated

TASTE: TAilored Post-Surgical Therapy in Early stage NSCLC:

Non-squamous cell NSCLC stage II and IIIA (non-N2)

[TITLE]

Presented By Jean-Charles Soria, MD, PhD at 2013 ASCO Annual Meeting

[TITLE]

Presented By Jean-Charles Soria, MD, PhD at 2013 ASCO Annual Meeting

[TITLE]

Presented By Jean-Charles Soria, MD, PhD at 2013 ASCO Annual Meeting

Spanish Customized Adjuvant Treatment (SCAT)

Resected NSCLCpN1/pN2

Control

Experimental

Q 1 BRCA1

Q 2,3 BRCA1

Q 4 BRCA1

Docetaxel/Cisplatin

Gemcitabine/Cisplatin

Docetaxel/Cisplatin

Docetaxel

RANDOMIZE

StratificationAge (</>65)Histology (squam vs non-squam)Extent of surgery (lobe vs pneumo)Nodal involvement (pN1/pN2)

PORT mandatory N2

3

1

BRCA1: mismatch repair pathway, High levels sensitize to apoptosis by antimicrotubulin agents (taxanes) and inhibit apoptosis with platinum

[TITLE]

Presented By Rafael Rosell, MD at 2013 ASCO Annual Meeting.

[TITLE]

Presented By Rafael Rosell, MD at 2013 ASCO Annual Meeting.

[TITLE]

Presented By Rafael Rosell, MD at 2013 ASCO Annual Meeting.

RRMI > 40.5AND

ERCC1> 66.0

Active Monitoring

All Others (RRM1< 40.5 OR ERCC1 < 66.0 )

Cisplatin-Gemcitabine

S0720: Biomarker-directed Adjuvant Therapy of Stage I

NSCLC

Assignment

Good Prognosis Less benefit from Chemotherapy

Poor Prognosis More benefit from Chemotherapy

Primary Endpoint = Feasibilty (>75% of patients assigned)

High

Low

TS

TS

Low

Low

High

High

Profile 4

Profile 3

Profile 2

Profile 1

Taxane

Pemetrexed

Cis/Gem

Cis/Pem

Control*

Control*

Control*

Control*High/Low ERCC1 & TS selected according to median level of mRNA expression in historical series ; * Control arm – Investigator choice of a DDP-based doublet

ERCC1

ITACA* : Pharmacogenomic-Driven Adjuvant Study Assessing ERCC1 &

TS

* International TAilored Chemotherapy Adjuvant Trial

• Completely resected stage II-IIIA• Primary endpoint: overall survival• Secondary endpoints: recurrence free

survival, therapeutic compliance, toxicity profile, comparative evaluation of ERCC1 and TS mRNA vs protein

• Plan for 700 pts (90% power to detect 30% improvement in survival)

• As of ASCO 2011 annual meeting, 180 patients enrolled from 24 institutions (mostly Italy and Germany)

ITACA Pharmacogenomic-Driven Adjuvant Study Assessing ERCC1 &

TS

Novello et al, 2011 ASCO Annual Meeting, abstract e17514.

CALGB 30506: Phase III Randomized Study of Adjuvant Chemotherapy vs. Observation in Patients with Stage I

NSCLCD. Harpole, PI

Stage I NSCLC (2-6 cm, node negative)N=1525

Primary Outcome:• Overall survival chemo vs observation• Collection of high-quality fresh frozen tissue for gene expression array generationSecondary• Evaluate selected genomic-based prognostic models using data from the patients randomized to observation after resection.• Rate of toxicity for different chemo regimens.• QOL and impact of chemo on QOL

Cisplatin with vinorelbine, gemcitabine, docetaxel, pemetrexed x 4 cycles

Observation

RANDOMIZE

Start date: 3/09Estimated completion: 1/2014

SELECT Trial: Phase II Trial of Adjuvant Erlotinib in Patients with Resected, Early Stage NSCLC with EGFR Mutations

PI L Sequist

Resected stage IA-IIIA NSCLC

Screen tumor for activating EGFR mutations (del_19, L858R)

Adjuvant erlotinib x 2 years

+/- adjuvant chemo

Enroll if: screen + or documented EGFR mutation positive –and-No evidence recurrence on baseline CT scans

Surveillance CT scans and CTC analysis q 6 mos x 3 years then q 12 mos x 2 years

Biopsy at recurrence, sequence EGFR gene for new mutations, FISH for EGFR and MET copy number

surveillance

SCREENING PHASE TREATMENT PHASE

N=100Primary Endpoint: Two year disease-free survival

SELECT*: First 36 Patients Characteristic Patients

(n=36)Percentage

Median age, years 63 Range, 43-82Sex     Male 9 25% Female 27 75%Smoking     Never 20 56% <=10 pack years 6 17% >10 pack years + current

10 28%

Ethnicity     Non-Asian 32 89% Asian 4 11%

Surgically resected EGFR mutant Lung cancer with adjuvant Erlotinib Cancer Treatment

Neal et al, ASCO 2012, abstract 7010.

SELECT: Stage and Mutation Distribution

Stage EGFR Mutation

SELECT: Toxicities

ToxicityAny (%)

Grade 3 (%)

Grade 4 (%)

Rash * 89 17 -Diarrhea * 78 3 -Fatigue * 61 6 -Nausea/vomiting 39 - -Dry skin 39 - -Cough (unrelated except 1 gr 2) 42 3 -Nail changes 36 - -Dyspnea (unrelated) 28 - -Alopecia/Scalp irritation 25 - -Eye irritation 25 - -

(Any relationship, >25% frequency or grade 3+)

* Toxicities leading to dose reductions

SELECT: Toxicities (cont)

ToxicityAny (%)

Grade 3 (%)

Grade 4 (%)

Pruritis 19 3 -Mucositis 19 - -Transaminitis* 19 - -Hyperbilirubinemia* 17 3 -Anorexia/dysguesia 14 - -Nosebleed 14 - -Constipation 14 - -Neuropathy 14 - -Urticaria* 3 3 -Venous thrombosis (unrelated) 3 3 -Pneumonitis (none observed) - - -

(Any relationship, 10-25% frequency or grade 3+)

* Toxicities leading to dose reductions

SELECT: Treatment LengthTreatment duration and dose reductions

1 Travel precluded participation2 Diarrhea 3 Rash/Diarrhea4 Diarrhea/fatigue5 Prostate cancer radiotherapy

Mon

ths

on E

rlot

inib

6 Patient preference7 Rash8 Disease progression9 Patient preference10 Rash

Reasons for discontinuation

Disease Free Survival

Disease Free Survival, by Stage

Overall Survival

SELECT: Conclusions• Feasible, some patients required dose reduction or

discontinuation

• Primary endpoint of 2 year DFS > 86% met. • Observed 2 year DFS: 94%• Only one patient progressed while receiving adjuvant

erlotinib• Ten patients progressed ≥6 months after stopping adjuvant

erlotinib• 6 of 8 rebiopsies did not identify a TKI resistance mechanism

• All 5 evaluable patients were sensitive to further treatment with erlotinib

• Taken together, this suggests that adjuvant erlotinib has, at least, a cytostatic effect on micrometastatic disease

• Based on the demonstrated role of EGFR TKIs in advanced NSCLC with EGFR mutations, this trial has been expanded to 100 patients total

RADIANT: Adjuvant Erlotinib in Resected NSCLC

Stage IB, II, or IIIA NSCLC*Complete surgical resectionAnd subsequent adjuvant chemoNo prior or concurrent neoadjuvant or adjuvant

N=945

Arm AErlotinib qd 2 years

Arm BPlacebo qd 2 years

RANDOMIZE

*Enriched Population: FISH and/or IHC (+)

•Primary endpoint: disease free survival•240 sites (US, Canada,Europe, Asia, Argentina) •Completed enrollment 4/2010•Interim results expected soon

2

1

BR 19: Adjuvant Trial of Gefitinib

in NSCLCStage IB, II, or IIIA NSCLCComplete surgical resectionNo prior or concurrent neoadjuvant or adjuvant N=1242

Modified 2004 to allow adjuvant ٭chemotherapy

Arm AGefitinib qd 2 years

Arm BPlacebo qd 2 years

CAN-NCIC-BR19, CTSU, ECOG-CAN-NCIC-BR19, SWOG-CAN-NCIC-BR19 Protocol. Clinical Trials (PDQ®). At: www.cancer.gov. Commenced October 2002.

RANDOMIZE٭

BR 19: Results

Arm BSC Gefitinib P valueNo 252 251Female 46% 46%Adenoca 59% 60%Stage IB 50% 53%MS NR 5.1 y 0.14

[HR1.24]DFS NR 4.2 0.15 [HR

1.22]• Trend toward impaired outcome for EGFR mutation pts receiving Gef [HR of OS: 1.5]

Goss et al, ASCO 2010, abstract LBA7005.

Vaccines

MAGE-A3 Antigen(melanoma antigen family A, 3)

• Truly tumor-specific–Not expressed on normal cells (RT-PCR)–Expressed by various tumor types

• Lung 35-50%• Bladder 35%• Head & Neck 49%• Melanoma 74%

• May be associated with poor prognosis(Bolli et al.,2002; Gure et al.,2005)

• Member of a large family of genes (portfolio)

MAGE A3 ASCI* Randomized Phase II

• stage pIB or pII were 2:1, double-blind, randomly assigned to postoperative MAGE-A3 vaccination or placebo.

• Vaccination was started >6 weeks after surgery, with 5 vaccinations at 3-week intervals, followed by 8 vaccinations every 3 months.

• Other anti-cancer adjuvant therapy was not allowed.

• Primary endpoint was disease-free interval, other endpoints were recurrence rates at different times, and survival.

• N=182 * antigen-specific cancer immune therapeutic

Vansteenkiste et al, J Thorac Oncol 2008; 3(4):S55.

Safety Status

• 182 patients / 1214 MAGE-A3 doses administered

• Overall well tolerated• Mild grade 1 or 2 • Local or systemic reactions, 48 hours

• 29 grade 3 or 4 adverse events in 21 patients

• Three grade 3 events, possibly related to treatment

• Leading to withdrawal of 2 patients – (local pain, COPD exacerbation)

• Median follow up 44 mos• Induction of anti-MAGE-A3 IgG antibody

response observed in >98% of pts immunized (8% pts with baseline anti-MAGE-A3 antibody response)

• T cell response in 41% immunized pts, 14% placebo

• No correlation of immune response and clinical outcome

MAGE-A3 Vaccine Phase II:Efficacy Endpoints Overview

Hazard Ratio 95% CI p

Disease-free interval

0.75 [0.46-1.23] 0.127

Disease-free survival

0.76 [0.48-1.21]

Overall survival

0.81 [0.47-1.40]

Vansteenkiste et al, J Thorac Oncol 2008; 3(4):S55.

• Median follow up 44 mos• Induction of anti-AMGE-A3 IgG antibody

response observed in >98% of pts immunized (8% pts with baseline anti-MAGE-A3 antibody response)

• T cell response in 41% immunized pts, 14% placebo

• No correlation of immune response and clinical out

MAGE-A3 Vaccine Phase II:Efficacy Endpoints Overview

Hazard Ratio 95% CI p

Disease-free interval

0.75 [0.46-1.23] 0.127

Disease-free survival

0.76 [0.48-1.21]

Overall survival

0.81 [0.47-1.40]

Vansteenkiste et al, J Thorac Oncol 2008; 3(4):S55.

Resectable NSCLC

Surgery

Pathological stage IB, II, IIIA

N=2,270*

R

MAGE-A3 +AS15 Placebo

No chemotherapy

Chemotherapy

Up to 4 cyclesplatinum based chemotherapy

R

MAGE-A3 +AS15 Placebo

MAGRIT: Phase III

*MAGE-A3 as Adjuvant non-small cell LunG Cancer ImmunoTherapy

PEARL

• Randomized, double blind phase II study of PRAME (PReferentially Expressed Antigen of MElanoma Immunotherapy) after resection in NSCLC

• Recombinant PRAME protein combined with AS15 adjuvant system, 13 doses

• N= 220 , stage IA-T1b, IB, II, IIIA, PRAME positive (~30-40%)

• Open 6/13, primary endpoint DFS

Post-operative Radiation Therapy

Adjuvant Radiotherapy:Meta-analysis 1998

• Individual data from 9 randomized trials including 2128 patients

• Treatment details (staging, surgery, RT) highly variable among series

• PORT: better local control: 29% fewer local recurrences - 195 LR vs 276 LR for no RT

• Overall HR = 1.21 (1.08-1.34) ~ survival decrement of 7 % at two years (55% vs 48%)

• Increase risk greater for early stage patients(Stage I/II vs. III)

Lancet 25 July 1998.

PORT Meta-analysisSurvival Curves

Stewart et al Lancet 1998.

PORT – Results by Stage/Nodal Status

• No increased risk for patients with N2 disease

• Patients with the least to gain have the most to lose

Stewart et al Lancet 1998

PORT Meta-analysisMethodologic Flaws

• Variable and unspecified staging• Variable and unspecified interval between

resection and PORT• Inadequate RT

– Suboptimal doses; large fields– Poor treatment planning– Outmoded techniques (e.g.: use of low-energy photons

or 60Co for a substantial proportion of patients)• Inclusion of node negative patients• Unpublished data (2 of 9 studies)• Relatively short follow up (< 4 yrs)

Risks of PORT Modern Technology

• Retrospective review– 202 patients treated with surgery

and PORT for Stage II and III disease

– Median dose 55 Gy– Actuarial rate of death from

intercurrent disease was 13.5% compared to expected rate of 10%

Machtay et al JCO 2001.

ANITA - PORT Evaluation• PORT: 33% on obs, 22% on chemo• For all Chemo > XRT = chemo/XRT > 0• For N2 Chemo/XRT > chemo > XRT > 0

XRT No No Yes YesChemo No Yes No YesAll pts MST 26mo 93mo 50mo 46mo

N2 MST 13mo 24mo 23mo 47mo

Rosell, IASLC 11, Abs Pr3, 2005.

CT RTCTRTOBS

0.00

0.25

0.50

0.75

1.00

DURATION OF SURVIVAL (MONTHS)

0 20 40 60 80 100 120

IASLC 2005

ANITA TRIAL: N2 Disease – Influence of RT

Lally, B. E. et al. J Clin Oncol; 24:2998-3006 2006.

Plot of Overall Survival for N2 pts Stratified by Postoperative Radiotherapy

(PORT) use SEER Data

“Lung ART”P.I. Dr Cécile Le Pechoux

Completely resected N2 NSCLC

SURGERY

Conformal RT

No post-op RT

54 Gy/27-30 fxs

Primary end-point: DFS (Sample size: 700 patients)

Pre or post-op chemotherapy allowedConcomitant chemo not allowed

Sponsors: FNCLCC, IFCT, LARS-G, EORTC

Controversies• Which regimen?

– Cisplatin vs Carboplatin?Cisplatin with vinorelbine, gemcitabine, docetaxel, pemetrexed (non-squam), or

nab- paclitaxel, carboplatin regimens if not cis candidate

• Stage IB? If at least 4 cm. • Predictive/prognostic biomarkers?

Not ready for prime time, clinical trials ongoing

• Post-operative XRT (PORT)? Consider if N2 disease