Hot topics in lung cancer: Adjuvant chemotherapy

1
Hot topics in lung cancerAdjuvant chemotherapy

• ESMO Conference, Lugano 2007
• Enriqueta Felip
• Vall dHebron University Hospital
• Barcelona, Spain

2
Five-year survival for resected stage I-II NSCLC
Complete surgical resection the most effective
treatment for potential cure

Systemic relapse occurs in up to 60 of resected
patients
Mountain CF. Chest 1997
3
(No Transcript)
4
Post-1995 meta-analysis adjuvant/platinum trials
5
LACE Meta-analysis

• Randomized trials cisplatin-based vs no CT
• Sample size gt 300 patients
• Five randomized trials / 4584 patients

Pignon, ASCO 2006 7008
6
Adjuvant chemotherapy / stages

• Insufficient evidence for use with stage IA
  patients
• Retrospective analyses
• IALT, greater benefit in stage IIIAN2
• JRB.10, survival benefit in stage II not in
  stage IB
• ANITA, survival benefit in stage II-III not in
  stage IB
• CALGB 9633, negative study survival benefit in
  Tgt4 cm
• Subset analyses should be viewed cautiously

7
(No Transcript)
8
LACE meta-analysis
9
Adjuvant chemotherapy in NSCLC standard approach

• Adjuvant cisplatin-based CT is recommended after
  complete resection in stage II-IIIA patients with
  good PS
• What can be done for patients?
• PS 2
• Elderly patients
• With stage IB disease

10
PS 2 patients enrolled

• ALPI NR
• IALT 7.3
• JBR-10 0
• ANITA 3

Less benefit subgroups. IALT PS 2 gt 65 years old
11
JBR-10 patients gt 65 years

• Older patients received less chemotherapy
• Similar toxicities
• CT prolonged survival for elderly patients
  (HR0.61)
• Despite receiving less CT, elderly patients
  derive a similar survival benefit from adjuvant
  CT
• Patients over 75 require further study (only 23
  assessable patients)

Pepe et al, JCO 2007
12
CALGB 9633

• 5-yr survival 59 in CT arm vs 57 in control
  arm (HR, 0.80 p0.10)
• Why was the CALGB study negative? Too few
  patients?
• Total accrual only 344 patients / initial accrual
  target 500 patients
• For an HR of 0.80 to be significant, over 1,000
  patients required

13
Is carboplatin inferior to cisplatin? Cisca
meta-analysis (Ardizzoni et al, JNCI 07)

• 2968 patients (9 trials) randomized to cis or
  carbo
• Cis gt carbo in RR (30 for cis 24 for carbo)
• Overall, no significant differences in survival
• Subgroup analyses cis gt carbo in survival when
  combined with third generation agents and in
  non-squamous tumors
• Cisplatin-based chemotherapy the cornerstone of
  adjuvant chemotherapy

14
(No Transcript)
15
Adjuvant chemotherapy lines of investigation

• Neoadjuvant vs adjuvant
• Integration new targeted drugs
• Customized adjuvant chemotherapy

16
S9900 Overall Survival by Treatment Arm
05/17/07, median F/U 53 mo
HR0.81 0.60-1.10, p0.19
Courtesy K Pisters, ASCO 2007
17
MRC LU22 / NVALT 2 /EORTC 08012

• No differences in survival HR1.02

Gilligan et al Lancet 2007
18
(No Transcript)
19
NATCH preliminary findings in the neoadjuvant arm

• Survival data expected in 2009
• 203 patients included in the neoadjuvant arm
• grade 3-4 neutropenia 11
• radiographic response 59
• complete resection rate 94
• pathologic complete response 8.8
• Neoadjuvant chemotherapy in early stage NSCLC has
  proven feasible and safe

E Felip, ASCO 2007
20
Phase III randomized trial of adjuvant
chemotherapy with / without bevacizumab in
completely resected stage IB-IIIA NSCLC
(ECOG1505/BO19731)

• ELIGIBLE
• Resected
• IB (gt4cm)-IIIA
• Lobectomy
• No prior chemo
• No planned XRT
• No h/o CVA/TIA
• No ATE w/in 12 mo

RANDOM I Z E
STRATIFIED Stage Histology Gender Type of
Chemo
Chemotherapy X 4 cycles
Chemotherapy x 4 cycles Plus Bevacizumab X 1 year

• Primary Endpoint Overall Survival

21
RADIANT Erlotinib adjuvant trial
Erlotinib 150mg p.o. once daily for 2 years

• Stage Ib-IIIa
• EGFR ve
• Complete resection
• No radiotherapy
• N 1730

4 cycles of standard platinum-based chemotherapy
(optional)
Stratified by country adjuvant CT histology
stage smoking status EGFR status
2 1
R
Placebo

• Primary endpoint disease-free survival (all
  patients, IHCve and/or FISHve)
• Co-primary DFS in FISHve (US) TBC in Europe
• Secondary endpoints OS, safety, biomarkers
• Status 1st patient entered 09/2006, 1. interim
  1Q11, 2. interim 2Q12, final analysis 3Q13

22
Study design
Screened N1089 / MAGE-A3 N363 / Enrolled
N182

• MAGE-A3 Immunotherapeutic
• Induction q3w x 5
• Maintenance q3m x 8
• Total duration 27 mo

Double-blind
N 122

• Pathological stage IB or II NSCLC
• MAGE-A3 () tumors
• Complete surgical resection
• PS 0-1

R
N 60

• Placebo
• Same schedule

J. Vansteenkiste ASCO 07
23
Disease-free Interval (DFI)
HR 0.73 (95 CI 0.44-1.20)one-sided logrank p
0.107
DFI Interval from the date of surgical resection
to the date recurrence) HR Hazard ratio
calculated by Cox analysis
24
Molecular markers predictive / prognostic
factors in resected NSCLC
25
A genomic strategy to refine prognosis
Potti et al, NEJM 2006
26
Five-gene signature clinical outcome

• Used both microarray analysis and RT-PCR to
  studied gene expression in frozen samples from
  125 resected NSCLC patients
• 16 genes correlated with survival selected 5
  genes (DUSP6, MMD, STAT1, ERBB3, LCK) for RT-PCR
  and decision tree-analysis
• The 5 gene signature was an independent predictor
  of relapse and overall survival in 3 independent
  patient cohorts

Chen et al, NEJM 07
27
Molecular signatures in resected
patientsPotential clinical implications

• Prognosis assessment
• Objective selection of patients for adjuvant CT
• No adjuvant chemotherapy in patients with
  low-risk gene signature
• Adjuvant chemotherapy in patients with high-risk
  gene signature
• However predictive value of molecular signatures
  remains to be proven!

28
Molecular signature profiles comments

• Limitations associated with microarray
  techniques
• Frozen samples
• Reproducibility
• Not yet standardized
• Molecular signatures should be validated in
  adjuvant therapy trials
• How to integrate molecular signatures with single
  gene prognostic and predictive markers should be
  explored

29
Predictive markers in resected patients

• JBR. 10 adjuvant cis / vin benefit appears
  greater
• in patients with high class III ß-tubulin (Seve
  et al, CCR 07)
• In patients with P53 IHC (gt15) (Tsao et al,
  ASCO 07)

30
IALT Bio (Olaussen et al, NEJM 06)
ERCC1 is a prognostic factor in CT-naïve patients
31
ERCC1 comments

• This is a retrospective analyses
• These results do not imply that ERCC1 is a
  marker for all CT agents
• Further prospective trials needed

32
NSCLC patients with p27-negative tumors benefit
from adjuvant cisplatin-based chemotherapy
Fig 2. Kaplan-Meier analyses of overall survival
according to treatment (A) in patients with
p27Kip1-negative tumors and (B) in patients with
p27Kip1-positive tumors
Filipits, M. et al. J Clin Oncol 252735-2740
2007
33
RRM1 and ERCC1 in resected NSCLC

• Disease-free Survival and Overall Survival among
  184 Patients with AQUA Scores for RRM1 and ERCC1
  (Zheng et al NEJM 07)

Zheng Z et al. N Engl J Med 2007356800-808
34
Gene expression analysis was performed in frozen
tumor samples from 126 completely resected Polish
NSCLC patients.
Increased BRCA1 mRNA an independent prognostic
variable in completely resected chemonaive NSCLC
patients
NRnot reached Survival data is not available
for some patients. Gene amplification was not
successfully performed in all samples for all
genes.
Rosell et al ASCO 07
35
Adjuvant chemotherapy summary

• Early-stage NSCLC, potentially curable after
  surgery, but with a wide spectrum of survival
• Adjuvant cisplatin-based CT, the standard of care
  in stage II-III
• The role of adjuvant chemotherapy for stage I
  remains controversial
• Integration of targeted agents in adjuvant
  setting

36
Adjuvant chemotherapy summary

• Gene expression profiles can identify patients
  with higher risk of recurrence (stage I disease)
• Molecular markers needed to guide customized
  treatment
• ERCC1 the most studied predictive marker, not
  yet validated in prospective trials
• Customized adjuvant CT, the way to go