gefitinib in esophageal cancer: just the beginning of a spicy story

Taiwan 2000PETACC 3 ASCO 2009 ASCOscopy 2011

GEFITINIB IN ESOPHAGEAL CANCER:GEFITINIB IN ESOPHAGEAL CANCER:JUST THE BEGINNING OF A SPICY JUST THE BEGINNING OF A SPICY

STORYSTORY

A. D. Roth MD CC

Oncosurgery HUG Geneva

COG

Overall Survival

ESMO 29th Sept 2012 2

TreatmentHR= 0.90 (0.74 to 1.09)Log rank test p=0.285

0.00

0.25

0.50

0.75

1.00

Su

rviv

al P

rob

ab

ility

0 3 6 12 18 24Months from randomisation

Placebo - median OS=3.60m

Gefitinib - median OS=3.73m

By treatment

PS0 - HR=1.00PS1 - HR=1.40 (1.10, 1.78)PS2 - HR=2.98 (2.22, 3.98)Log rank test p<0.0001

0.00

0.25

0.50

0.75

1.00

Su

rviv

al P

rob

ab

ility

0 3 6 12 18 24Months from randomisation

PS0 - median OS=6.03m



By performance status

COG 2012

Gefitinib disc. ESMO 2012

Boring! Another negative study in esophageal cancer!

COG


Target recruitment=450

0

50

100

150

200

250

300

350

400

450

Num

ber

of patients

Months

Actual recruitment

Predicted recruitment

COG 2012

Predicted versus Actual recruitment

Recruitment from 51 UK sites from 30 Mar 2009 until 18 Nov 2011

Recrutement completed in 31 months,Congratulations!

COGProgression free survival


HR= 0.795 (95%CI, 0.657 to 0.962)Log rank test p=0.017

0.00

0.25

0.50

0.75

1.00S

urv

ival P

robability

222 51 21 6 3 0 0Placebo223 62 25 15 7 4 2Gefitinib

Number at risk

0 3 6 9 12 15 18Months from randomisation

Placebo - Median PFS=1.17mths

Gefitinib - Median PFS=1.60mths

COG 2012

Kaplan-Meier survival estimates

Days on protocol therapyPlacebo: median 35; IQR 27 to 62; range 0 to 372Gefitinib: median 42; IQR 27 to 91; range 0 to 680

COG COG Response rates: There is something behind the stage

Waterfall plots – Percentage change in longest diameter at 4 weeks from baseline, if measurable at both time points.

• RECIST 1.0 response rates (all PR): 0.4% placebo, 3.1% gefitinib • Disease control rate at 8 weeks: 16% placebo, 26% gefitinib (p=0.014)


Progressive disease

Stable disease

Partial response

Progressive disease

Stable disease

Partial response

-100

-50

-30

0

20

50

100

150

placebo gefitinibR

EC

IST

response a

t 4 w

eeks

COG 2012

COG patients with measurable disease at baseline

SPECTAColor 2012

Crizotinib Phase I-II clinical trial in NSCLC

• ≈ 1,500 patients screened => 82 (5.5%) enrolled!

• 2nd line treatment• Response rate: 57%!

Major screening effort.

Neg patients lost for this study

Kwak EL, NEJM 363:1693 2010

COG

Conclusions• COG is the first RCT in the second line setting in esophageal

cancer• The primary end point of OS was not met.• The dominant effect of PS on PFS and OS has been

demonstrated for the first time. • The trial demonstrated positive secondary end point of PFS

with HR 0.79, P = 0.017.• Significant relief of odynophagia (PRO data) in the gefitinib arm

(p=0.004) • The disease control rate was 26% at 8 weeks (P = 0.014) on

Gefitinib and durable responses were seen.• There were no new or worrying safety signals• The translational research project TRANSCOG will analyse

predictive biomarkers in over 300/450 patients biopsies and give guidance to identification of the patients most likely to benefit from this treatment modality. Sponsored by:



How to turn a negative trial into a nice story? Remember PETACC-3!

Integrated analysis of molecular

and clinical prognostic factors in

stage II/III colon cancerA. Roth et al JNCI 2012 (in press)


ATP

Ras-Raf-MAPKProliferation

Pi3K-AKTSurvival

Ligand

Extracellular domain

Trans-membrane domain

Tyrosine kinase domain

Tyrosine phosphorylation

EGFR internalisationDegradation/recycling

EGFR signals for longerat the cell membrane

Wild Type EGFR Mutant EGFR

EGFR mutation causes conformational change and increased activation (at least in NSCLC)

Arteaga 2006, Gadzar et al 2004, Hendricks et al 2006, Sordella et al 2004


181921 20

N-lobe

Transmembraneregion

Extracellulardomain

ATP binding cleft

C-lobe

A-loop Chelix P-loop

TK domain

Regulatory domain

Common mutation sites in the EGFR gene in NSCLC


“IPASS”: Comparison of progression-free survival by mutation status within treatment arms

GEFITINIB, HR=0.19, 95% CI 0.13, 0.26, p<0.0001No. events M+ = 97 (73.5%)No. events M- = 88 (96.7%)

Carboplatin / paclitaxel, HR=0.78, 95% CI 0.57, 1.06, p=0.1103No. events M+ = 111 (86.0%)No. events M- = 70 (82.4%)

0 4 8 12 16 20 24

Time from randomisation (months)

0.0

0.2

0.4

0.6

0.8

1.0Probabilityof PFS

GEFITINIB EGFR M+ (n=132)GEFITINIB EGFR M- (n=91)

Carboplatin / paclitaxel EGFR M+ (n=129)Carboplatin / paclitaxel EGFR M- (n=85)

Hazard ratio <1 implies a lower risk of progression in the M+ group than in the M- groupM+, mutation positive; M-, mutation negative

Mok et al 2009, Fukuoka et al 2009


And what about esophageal cancer?

• 50 -70% of esophageal cancers overexpress EGFR protein

• EGFR exon 19 and 21 mutations are infrequent in esophageal cancer

• No relation between gefitinib and erlotinib efficiency and EGFR status established in esophageal cancer so far


Why should esophageal cancer behave like NSCLC when treated by anti-EGFR TKIs?

• CRC does not respond to cisplatin!• KRAS negative predictive value is restricted

so far to CRC!• BRAFmutated melanoma and CRC do not

respond the same way to vemurafenid!• …..etc.


We need to go deeper into the biology of esophageal cancer!


What should be looking for?

• Mutations or other DNA abnomalities can be without any biological consequence

• Biological consequences can be assessed by:– Genomic expression profiling (mRNA)– Proteomic studies (endproduct)

BRAFmut vs BRAF and KRAS wild type in CRC: Differentially expressed probesets with fold

change > 2 and <1% FDR (53 probesets)

Adjusted for MSI status and BRAF/MSI interactions

S. Tejpar et al, ASCO 2010, V. Popovici JCO 30;1288, 2012

SAR according to BRAF mutation statusPetacc3 – SAKK 60-00 (CRC)

Median survivals (95% CI):

- BRAF mut: 7.49 m (4.8-11.2)- BRAF wt: 25.2 m (21.1-29.5) (p = 1.9e-11)

A. Roth ASCO 2010


BRAFmut-like signature in CRC • If average(Gene1) < average(Gene2) then predict 'BRAF-positive'



Survival after relapse (SAR) in CRC:BRAFmut-like patients behave like BRAF mutated!



Translational research in this study

• Do not loose to much time at looking for discret mutations predicting response to gefitinib

• Analyse the responding subpopulation by genomic profiling and examine if they correspond to a particular subtype

• Validate findings in relatively small clinical studies


CONCLUSIONS

• Gefitinib does not improve OS in second/third line treatment of esophageal cancer

• A study of this size is a fantastic opportunity to learn more about esophageal cancer biology

• Better knowledge in molecular biology in this disease might help to select patients who might benefit from anti-EGFR TKIs

• Investigators should be encouraged in the conduct of this TR program

gefitinib in esophageal cancer: just the beginning of a spicy story

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