Options for firstline treatment of advanced NSCLC: what should the standard of care be

1
Options for first-line treatment of advanced
NSCLC what should the standard of care be?

• Enriqueta Felip and Mark A Socinski
• Vall dHebron University Hospital, Barcelona,
  SpainLineberger Comprehensive Cancer Center,
  University of North Carolina, USA

2
The lung cancer epidemic in Europe and the USA
1995 data 2006 data In European women,
breast cancer, colorectal cancer and stomach
cancer were ranked 13, respectively in the USA,
the top two most common sites of cancer in women
are breast and colorectal cancer
Bray F, et al. Eur J Cancer 20023899166 Jemal
A, et al. CA Cancer J Clin 20065610630
3
E1594 randomised trial comparing modern
platinum-based chemotherapy regimens
1.0 0.8 0.6 0.4 0.2 0
Cisplatin/paclitaxel Cisplatin/gemcitabine Cisplat
in/docetaxel Carboplatin/paclitaxel
Survival ()
0 5 10 15 20 25 30
Months
Schiller JH, et al. N Engl J Med 2002346928
4
Response rate and survival with single-agent,
doublet and triplet chemotherapy regimens
Ratio is either an odds ratio or median
ratioThe two odds ratios were significantly
different (plt0.001)The two odds ratios were
significantly different (p0.04)Data not
possible to calculate
Delbaldo C, et al. JAMA 200429247084
5
More effective treatment strategies are needed

• Chemotherapy in advanced NSCLC has reached a
  plateau
• Triplet chemotherapy regimens do not appear to
  improve survival substantially, and are
  associated with increased toxicity1
• Novel chemotherapy combinations are not likely to
  confer substantial improvements in survival
• Chemotherapy results in unacceptable levels of
  toxicity for patients with poor PS (gt2), thus
  outweighing potential improvements in survival2
• Quality of life and symptom improvement are
  crucial aspects to consider in lung cancer
  patient management

1Delbaldo C, et al. JAMA 200429247084 2National
Comprehensive Cancer Network (NCCN) clinical
practice guidelines in oncology. Non-small cell
lung cancer, version 1 2007. Available at
http//www.nccn.org/professionals/physician_gls/PD
F/nscl.pdf
6
Treatment options for advanced NSCLC pre-2006
(stage IIIB with pleural effusion/stage IV)
Suitable for chemotherapy?
Yes
No (PS 34)
Platinum doublet chemotherapy/ third-generation
non-platinum doublet
Best supportive care
Single-agent chemotherapy (elderly)
OR
First line
Tarceva monotherapy or chemotherapy (docetaxel or
pemetrexed)
Second line
Tarceva monotherapy or best supportive care
Third line
Best supportive care
7
Treatment of advanced NSCLC in the USA

• NCCN guidelines recommend chemotherapy for
  advanced/recurrent NSCLC
• Platinum combinations are superior to best
  supportive care
• No specific new agent-platinum combination is
  clearly superior
• First-line therapy cisplatin or carboplatin in
  combination with
• paclitaxel
• docetaxel
• gemcitabine
• vinorelbine
• irinotecan
• etoposide
• vinblastine

NCCN clinical practice guidelines in oncology.
Non-small cell lung cancer, version 1 2007.
Available at http//www.nccn.org/professionals/ph
ysician_gls/PDF/nscl.pdf
8
First-line treatment of advanced NSCLC in the USA
Carboplatin/paclitaxel (CP)
Carboplatin/docetaxel
Carboplatin/gemcitabine
Cisplatin/docetaxel
Other platinum-based
Single agents
Tarceva
Other
Source Tandem/Synovate US Oncology Monitor (MAT
Q4 2006)
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Phase III trial of Avastin in NSCLC (E4599)
trial design
CP ? 6 (n444)
PD
Previously untreated stage IIIB/IV non-squamous
NSCLC (n878)
Avastin (15mg/kg) every 3 weeks CP ? 6 (n434)
Avastin every 3 weeks until progression
PD

• Primary endpoint overall survival
• Avastin 15mg/kg i.v. every 3 weeks
• Carboplatin i.v. to AUC 6mg/mL and paclitaxel
  200mg/m2 i.v. every 3 weeks
• Patients in the Avastin plus CP arm received
  single-agent Avastin until disease progression

No cross over permitted
Sandler A, et al. N Engl J Med 2006355254250
10
Phase III trial of Avastin in NSCLC (E4599)
eligibility criteria

• Histologically or cytologically confirmed,
  measurable or non-measurable, non-squamous NSCLC
• Disease must be advanced (stage IIIB with
  malignant pleural effusion, stage IV or recurrent
  disease)
• Adequate haematologic, hepatic and renal function
• ECOG PS 0 or 1
• No central nervous system (CNS) metastases
• No anticoagulation
• No history of gross haemoptysis (?½ teaspoon)

Sandler A, et al. N Engl J Med 2006355254250
11
E4599 trial improvement in overall survival when
Avastin is added to standard first-line therapy
1.0 0.8 0.6 0.4 0.2 0
Probability
HR0.79 (0.670.92) p0.003
10.3
12.3
0 6 12 18 24 30 36 42
Months
In this milestone trial, Avastin-based
therapy extended median overall survival beyond 1
year
Sandler A, et al. N Engl J Med 2006355254250
12
E4599 trial improvement in PFS when Avastin is
added to standard first-line therapy
1.0 0.8 0.6 0.4 0.2 0
CP Avastin CP
HR0.66 (0.570.77) plt0.001
Probability
4.5
6.2
0 6 12 18 24 30
Time (months)
Sandler A, et al. N Engl J Med 2006355254250
13
E4599 trial response rate (measurable disease)
Sandler A, et al. N Engl J Med 2006355254250
14
E4599 trial haematological toxicity
NS not significant
Sandler A, et al. N Engl J Med 2006355254250
15
E4599 trial non-haematological toxicity
Sandler A, et al. N Engl J Med 2006355254250
16
E4599 trial bleeding events
Sandler A, et al. N Engl J Med 2006355254250
17
E4599 trial causes of death
One patient in the CP Avastin group who had a
grade 5 AE was considered to be ineligible
because of undocumented advanced disease data on
this patient are not included in the table (but
were included in the analysis of AEs)NR not
reported
Sandler A, et al. N Engl J Med 2006355254250
18
E4599 trial summary

• The addition of Avastin to a standard
  platinum-based chemotherapy regimen significantly
  improved overall survival, PFS and response rate
  in patients with non-squamous NSCLC and a good
  performance status
• Some increased toxic effects were associated with
  the addition of Avastin
• the hypertension, proteinuria and headache
  observed in this study (AEs previously associated
  with Avastin) were generally manageable and did
  not require permanent discontinuation of Avastin
• these risks must be considered within the context
  of the survival benefit conferred by the addition
  of Avastin to standard treatment for NSCLC

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Avastin-based therapy is the first regimen to
extend overall survival beyond the historical
benchmark of 1 year
CP
INTACT-2
CP gefitinib 250mg/day
CP gefitinib 500mg/day
CP
SPIRIT-2
CP bexarotene
CP
ISIS-3521
CP aprinocarsen
CP
E4599
CP Avastin
0 5 10 15
Overall survival (months)
12 months
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Avastin changing treatment practice in the USA

• Based on the positive results of the E4599 trial,
  Avastin plus CP became the ECOG reference
  standard for the first-line treatment of advanced
  non-squamous NSCLC1
• Avastin plus chemotherapy is also recommended as
  first-line therapy in the NCCN Clinical Practice
  Guidelines in Oncology for NSCLC (v.1.2007)1
• The E4599 trial formed the basis for the filing
  of Avastin in the USA
• in October 2006, the US FDA approved the use of
  Avastin plus CP as first-line treatment for
  patients with advanced non-squamous NSCLC

1NCCN clinical practice guidelines in oncology.
Non-small cell lung cancer, version 1 2007.
Available at http//www.nccn.org/professionals/ph
ysician_gls/PDF/nscl.pdf
21
Treatment options for advanced NSCLC (stage IIIB
with pleural effusion/stage IV) addition of
Avastin
Suitable for chemotherapy?
Yes
No (PS 34, elderly)
Suitable for Avastin?
Yes
No
Best supportive care
Platinum doublet
Single-agent chemotherapy (elderly/poor PS)
Platinum doublet Avastin
OR
First line
Tarceva monotherapy or chemotherapy (docetaxel or
pemetrexed)
Second line
Tarceva monotherapy or best supportive care
Third line
Best supportive care
NCCN clinical practice guidelines in
oncology.Non-small cell lung cancer, version 1
2007. Available athttp//www.nccn.org/profession
als/physician_gls/PDF/nscl.pdf
22
Treatment of advanced NSCLC in the EU

• Chemotherapy use in the EU differs from that in
  the USA
• Common doublet regimens cisplatin/gemcitabine,
  cisplatin/vinorelbine
• these two account for 31 of chemotherapy
  regimens used for first-line treatment of NSCLC
• CP regimen was used in the USA E4599 trial
• represents only 8 of first-line therapy for
  patients in the EU
• It is clinically relevant to establish whether
  the survival benefits of Avastin are also
  observed when Avastin is combined with other
  chemotherapy doublets

23
First-line treatment of advanced NSCLC in the EU
BO17704
E4599
Source Synovate EU Oncology Monitor (Q1Q4 2006)
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Phase III trial of Avastin in NSCLC in the EU
BO17704 trial design
No Avastin after progression
PD
Cis/Gem ? 6 placebo
Previously untreated, stage IIIB, IV or recurrent
non-squamous NSCLC (n1,050)
Cis/Gem ? 6 Avastin 7.5mg/kg every 3 weeks
PD
Cis/Gem ? 6 Avastin 15mg/kg every 3 weeks
PD

• Cisplatin 80mg/m2 i.v. every 3 weeks gemcitabine
  1,250mg/m2 on days 1 and 8 of each 3-week cycle
• Primary endpoint PFS
• Secondary endpoints overall survival, time to
  treatment failure, response rate
• Recruitment completed final results expected Q2
  2007

Cis/Gem cisplatin/gemcitabine
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Safety of Avastin in NSCLC MO19390 trial design
Locally advanced, metastatic or recurrent
non-squamous NSCLC (n2,000)
Chemotherapy Avastin 15mg/kg every 3
weeks (up to six cycles)
Avastin maintenance therapy
PD

• Primary endpoint safety profile of Avastin when
  combined with chemotherapy
• Secondary endpoints time to disease progression,
  overall survival, safety of Avastin in patients
  who develop CNS metastases
• 2,000 patients from 400 centres worldwide
  recruitment started Q3 2006

Standard-of-care first-line NSCLC chemotherapy
regimen
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Conclusions

• Avastin-based therapy is the first regimen to
  extend median overall survival beyond the
  historical benchmark of 1 year
• Avastin has already modified treatment practice
  in the USA
• Avastin may change the standard of care in the EU
  if a survival benefit is also observed in the
  BO17704 trial, in which Avastin is combined with
  a cisplatin-based chemotherapy doublet commonly
  used in Europe