27-30 September 2011 | Stockholm, Sweden ECCO-ESMO 2011

ECCO-ESMO 2011

Developed in association with the European Thoracic Oncology Platform

Supported by Eli Lilly & Company

27-30 September 2011 | Stockholm, Sweden

Special thanks to the ETOP reviewers

•  Enriqueta Felip, Barcelona, Spain •  Solange Peters, Lausanne, Switzerland

Table of contents

• Biomarkers • Early-stage/locally-advanced NSCLC • Metastatic NSCLC

– 1st line – Maintenance – Later lines – Elderly

• Trial design

BIOMARKERS

#9003: Biomarker analysis in BO21015, a Phase II randomized study of first-line bevacizumab combined with carboplatin-gemcitabine or carboplatin-paclitaxel in patients with advanced or recurrent non-squamous NSCLC – T Mok

•  Study objective –  To explore correlation between biomarker candidates and best overall

response to bevacizumab (BEV) plus chemotherapy in NSCLC •  Study type/design

–  ABIGAIL: randomized, multicentre, Phase II trial –  Up to 6 cycles (q21d) of BEV 7.5 mg/kg or 15 mg/kg combined with

carboplatin-gemcitabine (CG) or carboplatin-paclitaxel (CP) –  Primary endpoint: Correlation of baseline plasma biomarker levels with

best overall response to chemotherapy + BEV •  bFGF; E-selectin; ICAM; PLGF; VEGFA; VEGFR1; VEGFR2

•  Patients –  303 patients with advanced/recurrent non-squamous NSCLC

(biomarker evaluable population, n=287) –  Median age ∼60 years; ∼60% male; ~65% ECOG PS 1; 85% white; ~30/

~43/~27% never/former/current smokers Mok et al. EJC: 2011; (suppl; abstr 9003)

Key results

Mok et al. EJC: 2011; (suppl; abstr 9003)

Primary endpoint: overall response rate relative to baseline candidate biomarker status Low BM level High BM level Logistic regression

N Responders

(%) N Responders

(%) Odds ratio* 95% CI P-value

bFGF 142 45 141 43 1.07 0.63–1.80 0.813

E-selectin 142 39 141 48 1.81 1.06–3.08 0.029

ICAM 142 44 141 43 1.09 0.64–1.85 0.748

PLGF 146 44 56 43 1.16 0.58–2.33 0.676

VEGFA 140 44 140 45 1.22 0.72–2.09 0.460

VEGFR1 142 49 141 39 0.77 0.46–1.29 0.319

VEGFR2 143 39 140 49 1.44 0.85–2.45 0.176

Definition of candidate biomarker (BM) level: “low” ≤median; “high” >median; *Odds ratio: high vs. low BM level BEP population patients pooled; all patients received bevacizumab; covariates: treatment, biomarker level (dichotomized) and baseline prognostic factors; statistically significant if p≤0.007 (0.05/7 adjusted for multiple testing)

After adjustment for multiple testing, none of the candidate biomarkers correlated with overall response rate according to baseline plasma level

Key results


Exploratory analysis of PFS relative to candidate biomarker status Low BM level High BM level Cox regression

N

No. of events, n

(%)

Median PFS,

months N

No. of events, n

(%)

Median PFS,

months HR 95% CI P-value

bFGF 142 116 (82) 7.2 141 124 (88) 6.5 1.21 0.92–1.59 0.170

E-selectin 142 119 (84) 6.6 141 121 (86) 6.8 0.94 0.72–1.24 0.684

ICAM 142 118 (83) 7.0 141 122 (87) 6.3 1.18 0.89–1.56 0.250

PLGF 146 122 (84) 6.7 56 51 (91) 6.3 1.20 0.85–1.71 0.308

VEGFA 140 111 (79) 7.4 140 126 (90) 6.1 1.57 1.17–2.09 0.002

VEGFR1 142 119 (84) 7.2 141 121 (86) 6.2 1.14 0.87–1.49 0.351

VEGFR2 143 120 (84) 6.7 140 120 (86) 6.9 0.95 0.72–1.26 0.724

Biomarker evaluable population patients pooled: all patients received bevacizumab; covariates: treatment, biomarker level (dichotomized) and baseline prognostic factors; statistically significant if p≤0.007 (0.05/7 adjusted for multiple testing) N.B. Absence of control arm precludes determination of predictive and/or prognostic value of the tested BM candidate

Lower plasma VEGFA at baseline was associated with a longer PFS

Conclusions •  None of the biomarkers studied correlated with overall

response rate •  Low baseline VEGFA levels were associated with longer PFS

in exploratory analysis (p=0.002) –  However, predictive and/or prognostic value cannot be

determined in this study due to lack of control arm •  Efficacy and safety profiles were similar to those observed in

previous studies of BEV in advanced non-squamous NSCLC •  Exploratory analyses for further biomarkers are ongoing


#26LBA: Results of a pilot external quality assurance scheme for somatic EGFR mutation testing in non-small cell lung cancer managed by EMQN, ESMO, ESP, and ETOP – N Normanno

•  Study objective –  To define the methodology and detect any inherent material problems in

assessing EGFR mutation analyses in the Pan-EU EQA –  Collaboration of experts in pathology (ESP), genetics (EMQN) and lung cancer

(ETOP, ESMO, AIOM) •  Study type/design

–  Pilot phase of the Pan-EU EQA for somatic EGFR mutation analyses (registration of open phase ends 30 September 2011)

–  25 laboratories across 13 countries: •  Provided with 10 formalin fixed paraffin embedded samples from NSCLC cell

lines with different EGFR mutations •  Registered with the EMQN •  Performed DNA extraction and analysis using their usual method

–  Laboratory results were scored for accuracy

Normanno et al. EJC: 2011; (suppl; abstr 26LBA)

ESP, European Society of Pathology; EMQN, European Molecular Genetics Quality Network; ETOP, European Thoracic Oncology Platform ESMO, European Society for Medical Oncology; AIMO, Italian Association of Medical Oncology; EQA, External Quality Assessment

Key results

0

1

2

3

4

5

6

1 2 3 4 5 6 7 8 9 10

Sample Number

Genotyping errors

25

20

15

10

5

0

Erro

r rat

e (%

)

Number of errors Error rate

17.4

20.8 21.7 20.8 20.8

4.2 4.2

0 0 0

42%

4% 4%

34%

4% 4%

8%

DxS / Therascreen kit / ARMS

Fragment length analysis

Pyrosequencing / Fragment length analysis / SNaPshot

Sequencing

Sequencing / Fragment length analysis / Tagman PCR

Sequencing / High Resolution Melt

Sequencing / Pyrosequencing / High Resolution Melt

Methodology used by participating labs

No.

of e

rror

s

Normanno et al. EJC: 2011; (suppl; abstr 26LBA)

42%

34%

Conclusions •  The standard of genotyping in EGFR mutation testing for

NSCLC is good, with a low level of “true” diagnostic errors •  Incidence of clerical errors was high suggesting that some

laboratories had failures in checking processes •  The standard of reporting is more variable with many

laboratories reporting the genotyping result in isolation of any interpretation

•  Robust EQA will harmonize reporting and analytical practices –  Benefit patients with NSCLC –  Transferable to future mutational testing

EQA, External Quality Assessment Normanno et al. EJC: 2011; (suppl; abstr 26LBA)

#9092: Efficacy of tyrosine kinase inhibitor for non-adenocarcinoma NSCLC patients with EGFR mutation – S Cho •  Study objective

–  To determine the incidence of EGFR mutations and evaluate the efficacy of EGFR TKIs in non-adenocarcinoma NSCLC patients with EGFR mutation

•  Study type/design –  Assessment of single centre data: assessment of patients with

non-adenocarcinoma NSCLC (n=250) –  Somatic mutation in exons 18 to 21 of EGFR were detected using a

polymerase chain reaction (PCR)-based assay

•  Patients –  Twenty patients had EGFR mutation –  Twelve of them were treated with EGFR-TKI: seven patients had

deletion mutation in exon 19 and one had L858R mutation

Cho et al. EJC: 2011; (suppl; abstr 9092)

•  No complete response in patients treated with TKI (n=12): –  Partial response in 6 patients (50%), stable disease in 3 patients (25%), disease

progression in 3 patients (25%)

•  Patients with deletion exon 19 or L858R mutation (n=8) –  Partial response in 5 patients (62.5%), stable disease in 2 patients (20%), disease

progression,in 1 patient (12.5%) –  Median PFS = 4.5 months, median OS = 30.2 months

Key results


Pro

gres

sion

-free

sur

viva

l (%

) 1.0

0.8

0.6

0.4

0.2

0.0 0 5 10 15

Months 0 10 20 30 40

Ove

rall

surv

ival

(%)

1.0

0.8

0.6

0.4

0.2

0.0

Months

mPFS = 3.67 mOS = 30.23

PFS OS

Conclusions •  Disease control rate was significant in non-adenocarcinoma

patients treated with EGFR-TKIs, although median PFS was lower than in patients with adenocarcinoma

•  In patients with exon 19 or L858R mutations, there was a more prolonged median PFS, suggesting that these active mutations may support positive treatment outcome in patients with non-adenocarcinoma

•  A further large study is warranted to confirm these findings


EARLY-STAGE LOCALLY-ADVANCED NSCLC

METASTATIC NSCLC 1st line

#9001: A retrospective subgroup analysis of EGFR immunohistochemistry (IHC) expression by Histo-Score correlated to outcomes from the BMS099 1st line phase III NSCLC trial of cetuximab (Cet) plus carboplatin/taxane – T Lynch

•  Study objective –  To investigate the predictive role of tumour EGFR expression levels in

the efficacy of cetuximab plus first-line chemotherapy in advanced NSCLC

•  Study type/design –  BMS099: Phase III trial –  Tumour EGFR expression levels measured in tumour tissue specimens

using EGFR IHC Histo-Score (H-Score) –  Subjects were classified into high (≥200) and low (<200) EGFR

expression groups •  Patients

–  676 patients with advanced NSCLC –  Tissue specimens were available for 148 of 676 subjects

Lynch et al. EJC: 2011; (suppl; abstr 9001)

Key results

EGFR H-Score <200 EGFR H-Score ≥200 CT + Cetuximab

(n=39) CT

(n=36) CT + Cetuximab

(n=35) CT

(n=33)

PR or CR, n 8 9 14 6

ORR (%) 95% CI

20.5 9.3–36.5

25.0 12.1–42.2

40.0 23.9–57.9

18.2 7.0–35.5

A higher ORR was observed for the high-EGFR expression group compared with the low group in the cetuximab treated-arm, but not in the chemotherapy alone arm

Test for interaction of ORR and biomarker status; p=0.087


Secondary endpoint: ORR (by IRC evaluation)

Conclusions •  Addition of cetuximab to patients with high EGFR H-Score results in

greater ORR benefit compared with those with low EGFR H-Score (p=0.087)

•  No significant interaction between ORR and biomarker status was seen for OS or PFS

•  Further work is required to understand the role of EGFR H-Scores in selecting NSCLC patients who will receive increased benefit from cetuximab therapy

•  The small sample size of the BMS099 biomarker data set limits the interpretation of this analysis


#9028: Gemcitabine and cisplatin followed by concurrent gemcitabine and radiotherapy or sequential radiotherapy alone in unresectable stage III NSCLC – G Kerner •  Study objective

–  To evaluate the outcome of concurrent and sequential chemoradiotherapy in unresectable stage III NSCLC

•  Study type/design –  2-arm study

•  Arm A: Gemcitabine (G) + cisplatin (C) followed by concurrent G+ radiotherapy •  Arm B: G + C followed by radiotherapy alone

–  Doses •  Concurrent: initially G 1125 mg/m2 on days 1/8 and C 80 mg/m2 on day 1 of each 21-

day cycle; then weekly G 300 mg/m2 with 5 weeks of radiotherapy (60 Gy) •  Sequential: 2–4 cycles of chemotherapy then 5 weeks of radiotherapy alone

–  Endpoints: PFS and OS •  Patients

–  214 patients received concurrent chemoradiation and 69 received sequential chemoradiation

–  Median age 62-64 years ; 70-74% male; patients on sequential therapy had lower PS at baseline than concurrent therapy group (majority ECOG 1 vs ECOG 0); 2-7/40-41/52-58% never/former/current smokers

Kerner et al. EJC: 2011; (suppl; abstr 9028)

Key results: efficacy

Kerner et al. EJC: 2011; (suppl; abstr 9028)

Median PFS is 16 months for concurrent and 14 months for sequential approach

OS is 26.1 months for concurrent and 17.8 months for sequential approach

PFS OS

Pro

gres

sion

free

sur

viva

l

1.0

0.8

0.6

0.4

0.2

0.0 0 20 40 60 80 100 120

Time (months)

Concurrent chemoradiotherapy Sequential chemoradiotherapy

Ove

rall

surv

ival

1.0

0.8

0.6

0.4

0.2

0.0 0 20 40 60 80 100 120

Time (months)

Key results: safety

Concurrent (%) Sequential (%)

CTC grade dysphagia 0–1/2/3 69/20/12 93/3/4

CTC grade esophagitis 0–1/2/3/4/5 73/17/9/1/1 93/3/3/1/0

CTC grade radiation pneumonitis 0/1/2/3/4/5 34/46/19/1/0/1 38/48/11/2/0/2

Radiation-related adverse events

Kerner et al. EJC: 2011; (suppl; abstr 9028) CTC, common toxicity criteria

Conclusions •  Concurrent chemoradiotherapy with gemcitabine as

radiosensitizer gives comparable results as reported for high-dose chemoradiotherapy regimens

•  24% of patients were not fit enough to be treated with concurrent chemoradiotherapy schedules

•  Concurrent chemoradiotherapy is associated with more (low CTC grade) dysphagia and oesophagitis complaints

CTC, common toxicity criteria Kerner et al. EJC: 2011; (suppl; abstr 9028)

METASTATIC NSCLC Maintenance

#34LBA: Final efficacy outcomes for patients with advanced non-squamous non-small cell lung cancer randomized to continuation maintenance with bevacizumab or bev+pemetrexed after first-line bev-cisplatin-pemetrexed treatment – F Barlesi

•  Study objective –  To investigate the use of pemetrexed (Pem) in addition to standard

bevacizumab (BEV) continuation maintenance therapy in NSCLC •  Study type/design

–  AVAPERL study: randomized, open-label Phase III trial –  4 cycles (q3w) of BEV 7.5 mg/kg + Pem 500 mg/m2 + cisplatin 75 mg/

m2 followed by randomization to maintenance therapy: •  Arm A: BEV q3w until PD •  Arm B: BEV + Pem q3w until PD

–  Endpoint: PFS from beginning of induction therapy •  Patients

–  125 patients randomized to BEV, 128 patients to Bev+Pem –  Median age 60 years; ~57% male; 46-55% ECOG PS 1; 86-92%

adenocarcinoma; ~26/~50/~24% never/former/current smokers

Barseli et al. EJC: 2011; (suppl; abstr 34LBA)

AVAPERL trial designa

nsNSCLC, nonsquamous non–small cell lung cancer aRandomized, open-label, phase III study; bDose of bevacizumab = 7.5 mg/kg; dose of pemetrexed = 500 mg/m2; dose of cisplatin = 75 mg/m2. RECIST-related end points measured from the preinduction phase

Stratification factors: • Gender • Smoking status • Response at randomization

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


Key results PFS subgroup analysis

Favours combination Favours BEV alone

ITT population (n=253)

Age <65 y (n=176)

Age ≥65 y (n=77)

ECOG PS 0 (n=118)

ECOG PS 1 (n=126)

Never smoker (n=64)

Current/past smoker (n=188)

Adenocarcinoma (n=225)

SD prior to randomization (n=116)

CR/PR prior to randomization (n=137)

0.54

0.53

0.57

0.43

0.60

0.40

0.59

0.52

0.64

0.46

Hazard Ratio (95%) Cl

Hazard ratio BEV+Pem 10.2 months (81 events)

BEV 6.6 months (104 events) HR, 0.50 (0.37–0.69); p<0.001

Pro

gres

sion

-fre

e su

rviv

al (%

)

Time (months)

100

75

50

25

0

Patients at risk

BEV+Pem BEV

128 125

126 122

103 73

66 38

25 12

4 2

0 0

0 3 6 9 12 15 18

PFS from inductiona

a Randomized patients, intent-to-treat population

0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0

Pem + BEV maintenance treatment was associated with a marked increase in PFS over BEV alone


Positive effect on PFS was observed in all subgroups studied

Conclusions •  Continuation maintenance with BEV+Pem achieved a PFS

benefit of unprecedented magnitude (10.2 months; HR, 0.50; p<0.001) over BEV alone

•  Both regimens were well tolerated but AEs occurred more frequently in the combination treatment group, with some differences due to toxicities commonly attributed to chemotherapy

•  OS data available so far favour BEV+Pem maintenance treatment

•  Overall, the AVAPERL results strongly favour the use of BEV+Pem as continuation maintenance therapy in patients with non-squamous NSCLC


•  Study objective –  To investigate efficacy of BEV maintenance therapy on OS and PFS after induction with

BEV and first-line chemotherapy (CT) in NSCLC •  Study type/design

–  Observational cohort study in which choice of CT, BEV dose and schedule is based on investigator’s decision

–  Analysis between •  No BEV maintenance population: induction period (IP) defined as 12–18 weeks of CT

(∼4–6 cycles) within 18 weeks of initial BEV+CT treatment •  BEV maintenance population: treated with BEV beyond the IP

•  Key results –  1967 BEV-treated patients with advanced NSCLC were enrolled (to Feb 2011) –  1213 patients survived progression-free beyond their IP –  6 month PFS and 1-year OS were higher in the BEV maintenance population than the

group who did not receive BEV beyond the IP (44 vs 33%, p=0.001; 59 vs 47%, p<0.001) •  Key conclusion

–  In this real-world population, maintenance therapy with BEV beyond induction with first-line CT+BEV improves OS and PFS

#9020: Use of bevacizumab after induction therapy is associated with survival benefit in patients with NSCLC in the ARIES observational cohort study (OCS) – MP Kosty

Kosty et al. EJC: 2011; (suppl; abstr 9020)

METASTATIC NSCLC Later lines

#27LBA: A Phase II study of sorafenib in patients with locally advanced and/or metastatic (stage IIIB or IV) non-small cell lung cancer (NSCLC) with a K-Ras mutation – A Dingemans

•  Study objective –  To investigate the use of sorafenib in NSCLC with K-Ras mutation

•  Study type/design –  Single arm Phase II study –  Inclusion criteria: stage IV NSCLC with proven K-Ras mutation; progression after ≥1

platinum doublet; ECOG 0-2; asymptomatic brain metastasis allowed –  All patients were treated with sorafenib (400 mg, bid) –  Primary endpoint: rate of no progression at 6 weeks –  Secondary endpoint: PFS

•  Patients –  57 patients with stage IV NSCLC received at least one dose of sorafenib –  Mean age 58.5 years; 28% male; 21/77% former/current smokers –  ECOG PS 0/1/2: 40/53/7% –  2nd/3rd/≥4th line of treatment: 54/28/18% –  81% adenocarcinoma –  Median duration of treatment 9 weeks (range 0-61 weeks)

Dingemans et al. EJC: 2011; (suppl; abstr 27LBA)

Key Results


Primary endpoint: No progression at 6 weeks

Secondary efficacy endpoint: PFS

Efficacy

Partial response 9 (16%)

Stable disease 21 (37%)

Progressive disease 27 (47%)

No progression at 6 weeks 53%

0 5 10 15

PFS (months)

0.0

0.2

0.4

0.6

0.8

1.0

Cum

ulat

ive

surv

ival

Median PFS: 2.3 months (95% CI: 1.6-3.0)

Primary endpoint was achieved Sorafenib treatment was associated with a PFS of 2.3 months

Conclusions •  Sorafenib shows activity in K-Ras mutated NSCLC

–  Primary endpoint was achieved with no progression within 6 weeks observed in 53% of patients

–  Treatment was associated with median PFS of 2.3 months •  Sorafenib was well tolerated with few cases of grade 3 or more toxicity •  WHO-PS 2 patients showed rapid deterioration (PFS of 1.2 months) •  Further work is required to

–  Identify subgroup of patients who will show prolonged benefit to treatment

–  Understand the effect of specific K-Ras mutation


#9012: A Phase Ib study to evaluate the PI3-kinase inhibitor GDC-0941 with paclitaxel (P) and carboplatin (C), with and without bevacizumab (BEV), in patients with advanced non-small cell lung cancer (NSCLC) – H. Groen

•  Study objective –  To establish the safety and tolerability of GDC-0941 with paclitaxel (P)

and carboplatin (C), with and without bevacizumab (BEV) •  Study type/design

–  2-arm phase Ib study •  Arm A: GDC-0941 + C + P ineligible for BEV •  Arm B: GDC-0941 + C + P eligible for BEV

–  Doses: GDC-09411, 60 to 330 mg PO qd days 1-14 of a 21-day cycle; P, 200 mg/m2 for 4-6 cycles; C, AUC 6 mg/mL.min for 4-6 cycles; BEV, 15 mg/kg every 3 weeks

•  Patients –  22 first-/second-line patients with advanced NSCLC –  Median age 60 years; 68% male; 68% ECOG 1; 77% nonsquamous;

73% first line therapy; 5/68/27% never/former/current smoker

Groen et al. EJC: 2011; (suppl; abstr 9012)

Key results •  Tolerability

–  Treatment-related adverse events seen in ≥20% of patients (n=20, safety cutoff 25 Feb 2011) were alopecia, asthenia, nausea, stomatitis, neutropenia, rash, decreased appetite (anorexia), leukopenia, peripheral neuropathy, paresthesia, epistaxis and arthralgia

–  All were grade 1 or 2 except for neutropenia. •  Efficacy

–  Partial responses were seen in 4 of 5 squamous patients, including 1 patient with a pathologic complete response

–  Partial responses were seen in 7 of 20 non-squamous patients


Conclusions •  GDC-0941, P and C (±BEV) combination was well tolerated at doses

consistent with preclinical activity •  Evaluation of 330 mg GDC-0941 + C + P±BEV is ongoing •  Randomized studies are planned


#9014: Randomized Phase II trial of NGR-hTNF and chemotherapy in chemo-naive patients with non-small cell lung cancer (NSCLC) - preliminary results – V. Gregorc •  Study objective

–  To investigate effect of the vascular targeting agent NGR-hTNF on PFS in NSCLC •  Study type/design

–  Ongoing recruitment into randomized Phase II trial of chemo-naïve patients with stage IIIb-IV NSCLC (including those with brain metastasis), stratified by histology (nonsquamous vs squamous) and PS (0 vs 1) •  Arm A: Chemotherapy for up to 6 cycles plus NGR-hTNF 0.8 µg/m2 day 1 until progression •  Arm B: Chemotherapy alone

•  Key results –  112 patients enrolled to date and data from 100 (n=50 per group) have been analyzed –  Tolerability was similar between the groups except for higher incidence of chills (Grade 1) in the

combination group –  No difference was seen in PFS between the two treatment arms:

•  Nonsquamous histology; 6.2/5.4 months in Arms A/B •  Squamous histology; 4.5/2.7 in Arms A/B

•  Key conclusion –  NGR-hTNF and chemotherapy can be given together without safety issues –  Efficacy data are immature but currently do not appear promising

Gregorc et al. EJC: 2011; (suppl; abstr 9014) NGR-hTNF=tumour-homing peptide with human tumour necrosis factor

#9017: Initial detection of the double EGFR mutation (L858R or deletion in exon 19 [del 19] plus T790M) in NSCLC patients with brain metastases and the influence of first-line chemotherapy on outcome to erlotinib - C. Rolfo

•  Study objective –  To investigate PFS achieved with erlotinib treatment in NSCLC harbouring dual activating mutation and

T790M and according to site of metastasis •  Study type/design

–  Assessment of T790M mutations by TaqMan assay •  Key results

–  129 patients with advanced NSCLC –  De novo T790M mutations were identified in 35% (45 of 129) of EGFR-mutant patients before

receiving erlotinib –  PFS was 12 months for patients with T790M mutation and 18 months for those without (p=0.05) –  Among patients with the T790M mutation, PFS was lower in those with brain metastasis than those

without (1 vs 13 months, p=0.002) –  In patients without the T790M mutation, PFS was not significantly affected by brain metastasis –  T790M mutation status had no effect on PFS in patients with bone, lung, liver or pleura metastases

•  Key conclusion –  The T790M mutation in EGFR-TKI naïve patients is a marker for poor prognosis, particularly in patients

with brain metastases –  Initial chemotherapy can play a role in the management of these patients

Rolfo et al. EJC: 2011; (suppl; abstr 9017)

#9069: Randomized Phase II study of maintenance enzastaurin following whole brain radiation therapy in the treatment of brain metastases from lung cancer - the MENZA study – B. Grønberg

•  Study objective –  To determine if maintenance enzastaurin (E) improves outcome of

whole brain radiation therapy (WBRT) in lung cancer with brain metastases (BM)

•  Study type/design –  MENZA trial: randomized, double-blind Phase II study of patients who

had received WBRT (20 or 30 Gy) •  Arm A: E (1125 mg on day 1 followed by 500 mg qd until progression) •  Arm B: Placebo until progression

–  Primary outcome measure was time to progression (TTP) of BMs •  Patients

–  109 patients enrolled at 11 hospitals (Dec 2006 to April 2010) –  Median age 61-65 years; 60% male; ~70/~30% ECOG 0-1/2

Grønberg et al. EJC: 2011; (suppl; abstr 9069)

Key results

TTP, time to progression; BM, brain metastases Grønberg et al. EJC: 2011; (suppl; abstr 9069)

TTP of BMs OS

Median TTP is 6.9 months with enzastaurin and 4.9 months with placebo

Median OS is 3.8 months with enzastaurin and 5.1 months with placebo

Sur

viva

l pro

babi

lity

1.0

0.8

0.6

0.4

0.2

0.0 0 3 6 9 12 15 18 21 24 27 30

Overall survival time (months) No. at risk Enzastaurin 55 24 11 3 1 0 0 0 0 0 0 Placebo 54 28 8 3 2 2 1 1 0 0 0

Sur

viva

l pro

babi

lity 0.8

0.6

0.4

0.2

0.0 0 3 6 9 12 15 18 21 24 27 30

Overall survival time (months) No. at risk Enzastaurin 55 32 18 10 6 3 1 1 1 1 0 Placebo 54 37 19 11 5 4 2 1 0 0 0

Enzastaurin (n = 55, censored = 35) Placebo (n = 54, censored = 32) Censored observations 1.0

Enzastaurin (n = 55, censored = 3) Placebo (n = 54, censored = 5) Censored observations

HR: 0.93 (95% CI: 0.51–1.71; p=0.82)

HR: 1.16 (95% CI: 0.78–1.71; p=0.47)

Conclusions •  Efficacy

–  Enzastaurin did not delay disease progression or improve survival of lung cancer patients after WBRT

–  It was not associated with any benefit in quality of life

•  Tolerability –  Enzastaurin was well tolerated in this population

WBRT, whole brain radiation therapy Grønberg et al. EJC: 2011; (suppl; abstr 9069)

#9011: Survival in patients with non-small cell lung cancer which is clinically acquired resistance to gefitinib – natural history since progression – H Kim •  Study objective

–  To investigate factors which affect survival of patients with NSCLC who have clinically-acquired resistance to tyrosine kinase inhibitors (TKIs)

•  Study type/design –  Retrospective review of 81 advanced NSCLC patients who experienced disease

progression following tumour response and durable (≥ 6 months) disease stabilization from first-line or second-line gefitinib •  Arm A: Resumed TKIs •  Arm B: TKIs not resumed

–  Primary outcome measure was post-progression survival (PPS) •  Patients

–  16 patients resumed TKIs (gefitinib n=11; erlotinib n=5) and 65 did not –  Most patients were female never-smokers with adenocarcinoma at stage IV with

ECOG PS 0-1

Kim et al. EJC: 2011; (suppl; abstr 9011)

Key results

•  Median overall PPS was 10.3 months (95%CI; 7.458–13.142) •  Resuming TKIs increased PPS in the univariate analysis (shown here) but not the multivariate analysis •  Age, gender, smoking history, histology, ECOG PS at the start of gefitinib, initial stage and platinum-based

chemotherapy after gefitinib were not significant predictors for PPS •  Using pemetrexed after gefitinib showed significantly longer PPS (18.5 vs 8.6 months, HR=0.45, p=0.008)


OS since disease progression (PPS)

PPS, post-progression survival

Cum

ulat

ive

surv

ival

1.0

0.8

0.6

0.4

0.2

0.0

OS since PD (months) 0 10 20 30 40 50

TKI resumed (n = 16) TKI not resumed (n = 65) p=0.004

Cum

ulat

ive

surv

ival

1.0

0.8

0.6

0.4

0.2

0.0

OS since PD (months) 0 10 20 30 40 50

Pemetrexed used (n = 28) Other regimen used (n = 53) p<0.001

Conclusions •  Resuming treatment with TKIs who are believed to have

clinically-acquired resistance can have benefits on survival in some NSCLC patients

•  Pemetrexed may improve outcome in patients with acquired resistance to gefitinib

•  Further work is required to improve our management of this patient group


#9018: Prospective assessment of combined pemetrexed and erlotinib or gefitinib therapy after the relapse to erlotinib or gefitinib in patients with advanced non-small cell lung cancer having an active epidermal growth factor receptor mutation – K Okishio

•  Study objective –  To evaluate the efficacy and toxicity of pemetrexed combined with erlotinib or

gefitinib after the relapse to erlotinib or gefitinib in patients with advanced NSCLC who have an active EGFR mutation

•  Study type/design –  Phase II trial –  Treatment: Pemetrexed (500 mg/m2) was administered on day 1, followed by

erlotinib or gefitinib on days 2–16 (cycle repeated every 3 weeks until disease progression)

–  Primary outcome measure was disease control rate (DCR) •  Patients

–  27 patients with stage IV NSCLC (population evaluable for toxicity and efficacy, n=22)

–  Median age 67 years; 74% female; 74% ECOG PS 1; 96% adenocarcinoma; median number of prior chemotherapy regimens was 2

Okishio et al. EJC: 2011; (suppl; abstr 9018)

Key results

Okishio et al. EJC: 2011; (suppl; abstr 9018)

Disease control rate 77.8% Median PFS of 7.1 months

Response N %

Complete response 0

Partial response 7

Stable disease 14

Progressive disease 6

Total 27

Response rate 7 25.9

Disease control rate 21 77.8 P

roba

bilit

y

1.0

0.8

0.6

0.4

0.2

0.0

1-year PFS rate = 13.7% 6-month PFS rate = 61.8%

0 50 100 150 200 250 300 350 400 450 Time (day)

Conclusions •  Pemetrexed plus erlotinib or gefitinib combination treatment

leads to a high DCR in patients with advanced NSCLC who have an active EGFR mutation

•  Combination treatment showed acceptable toxicity, with Grade 3/4 toxicities neutropenia, leucopenia, and anemia occurring in 22, 14 and 7% of patients, respectively

•  A Phase III trial for pemetrexed alone versus pemetrexed plus EGFR-TKI after relapse to EGFR-TKI is warranted

DCR, disease control rate Okishio et al. EJC: 2011; (suppl; abstr 9018)

METASTATIC NSCLC Elderly

#9072: Pemetrexed (Pem) maintenance therapy in elderly patients with good performance status (PS) - analysis of PARAMOUNT Phase III study of Pem versus placebo in advanced nonsquamous NSCLC – C Gridelli

•  Study objective –  To further investigate efficacy and safety of Pem maintenance therapy in elderly advanced

nonsquamous NSCLC patients with good PS •  Study type/design

–  PARAMOUNT: A Phase III, randomized, double-blind, placebo-controlled study of Pem maintenance (followingPem induction) therapy

–  Subgroup analysis of patients aged ≥70 and <70 years •  Key results

–  Median age 73 years in the older group (n=92) and 60 years in the younger group (n=447) –  Patient characteristics were comparable except for PS (PS 0/1 in ≥70: 20%/79%; <70: 34%/66%) and

sex (M/F ≥70: 66%/34%; <70: 56%/44%) –  For the ≥70 cohort, Pem reduced the risk of progression by 65% (p=0.00041); median PFS was 6.4

months for Pem and 3.0 months for placebo. –  For the <70 cohort, Pem reduced the risk of progression by 31%; median PFS was 4.0 months for Pem

and 2.8 months for placebo –  Incidence of grade 3/4 toxicities was higher in the Pem arms than the placebo arms in both age cohorts –  Patients in the ≥70 cohort experienced a higher incidence of Grade 3/4 toxicities than those in the

<70 cohort •  Key conclusions

–  Pem maintenance treatment is effective in elderly patients with good PS –  Grade 3/4 hematologic toxicities were more common in older patients

Gridelli et al. EJC: 2011; (suppl; abstr 9072)

TRIAL DESIGN

Trial in preparation #9035: A national, multi center, randomized, open-label, Phase II study of erlotinib versus gemcitabine (GEM) plus cisplatin as neoadjuvant treatment in stage IIIA-N2 NSCLC patients with activating EGFR mutations (C-TONG 1103) – W. Zhong

•  Study objective –  To investigate the efficacy and safety of erlotinib versus GEM plus cisplatin

(GC) as neoadjuvant treatment in NSCLC •  Study type/design

–  Randomized, open-label Phase II study in stage IIIA-N2 NSCLC with activating mutations •  Arm A: Erlotinib (150 mg qd for 42 days) •  Arm B: GC (GEM 1250 mg/m2 IV on days 1/8, and cisplatin 75mg/m2 on

day 1 of a 3-week schedule for 2 cycles) –  Thoracotomy will take place after 6 weeks of treatment –  Post-surgery treatment: erlotinib 150 mg/day for 1 year or 2 further cycles of GC –  Primary endpoint: objective response rate (ORR) in neoadjuvant treatment

•  Patients –  Target of 90 patients will be recruited over 18 months

Zhong et al. EJC: 2011; (suppl; abstr 9035)

Study design

•  Treatment naïve •  IIIA-N2 NSCLC •  N2 confirmed by

mediastinoscopy/ EBUS/PET-CT

•  EGFR activating mutation

•  ECOG 0–1 •  Age ≥18 Y

(n=90)

EBUS, endobronchial ultrasound; GEM, gemcitabine; Cis , cisplatin Zhong et al. EJC: 2011; (suppl; abstr 9035)

Erlotinib 150 mg/day x 6 weeks

GEM 1250 mg/m2 Days 1/8 +

Cis 75 mg/m2 Day 1 q3w x 2 cycles

R

Non-PD Surgery

Erlotinib 150 mg/day

1 year

Non-PD Surgery

GEM/Cis q3w x 2 cycles

Primary endpoint • ORR Secondary endpoint •  Lymph node

downgrade rate • Complete

resection rate •  pCR Exploratory research •  24 & 48 week DFS rate • Biomarker profile

•  PFS •  OS •  QoL •  Safety

1:1

Conclusions •  Induction erlotinib therapy in IIIA-N2 NSCLC with EGFR

activating mutation is a promising strategy

•  The study is planned to start in September 2011

Zhong et al. EJC: 2011; (suppl; abstr 9035)

ECCO-ESMO 2011

Developed in association with the European Thoracic Oncology Platform

Supported by Eli Lilly & Company

27-30 September 2011 | Stockholm, Sweden

27-30 September 2011 | Stockholm, Sweden ECCO-ESMO 2011

Documents

Transcript of 27-30 September 2011 | Stockholm, Sweden ECCO-ESMO 2011