Old dogmas, new tricks:

the changing treatment of advanced non-small cell lung cancer

Boone Goodgame, MD

Division of Medical Oncology

Washington University School of Medicine

Faculty Disclosures

Dr Goodgame has received:

- Consulting fees from Abraxis Bioscience.

- Honoraria from Lilly Oncology

Old dogmas– Locally advanced NSCLC with pleural dissemination is

considered “wet” IIIB and is treated as stage IV disease.

– A platinum doublet is the standard of care for medically fit patients with advanced disease.

– Distinction between histologic subtypes of NSCLC is inconsequential and has no direct bearing on therapy.

– All third-generation platinum doublets are equivalent in terms of efficacy and are distinguished only by differing toxicity profiles.

– There is no benefit to continuing chemotherapy beyond 4 to 6 cycles and patients should be observed until progression.

– Median survival is 8 to 9 months and only very rare patients survive to two years.

– Cetuximab has no role in the treatment of NSCLC.

New tricks– Updated staging system

– IPASS trial of 1st line gefitinib

– Pemetrexed in the first line setting

– “Maintenance” docetaxel or pemetrexed

– Cetuximab studies

Goldstraw P, et al. J Thorac Oncol. 2007;2:706-714.

IASLC Staging Project: Proposed Changes

Sixth Edition T/M and Descriptor Proposed T/M

T1 (≤2 cm) T1a

T1 (>2-3 cm) T1b

T2 (≤5 cm) T2a

T2 (>5-7 cm) T2b

T2 (>7 cm) T3

T3 invasion T3

T4 (same lobe nodules) T3

T4 (extension) T4

M1 (ipsilateral lung) T4

T4 (pleural dissemination) M1a

M1 (contralateral lung) M1a

M1 (distant) M1b

IASLC Staging Project: Proposed Changes

Sixth Edition T/M and Descriptor Proposed T/M

T1 (≤2 cm) T1a

T1 (>2-3 cm) T1b

T2 (≤5 cm) T2a

T2 (>5-7 cm) T2b

T2 (>7 cm) T3

T3 invasion T3

T4 (same lobe nodules) T3

T4 (extension) T4

M1 (ipsilateral lung) T4

T4 (pleural dissemination) M1a

M1 (contralateral lung) M1a

M1 (distant) M1b

Goldstraw P, et al. J Thorac Oncol. 2007;2:706-714.

IASLC Staging Project: AJCC 2009

Proposed T/M Stage Based on Proposed T/M Definitions

N0 N1 N2 N3

T1a IA IIA IIIA IIIB

T1b IA IIA IIIA IIIB

T2a IB IIA IIIA IIIB

T2b IIA IIB IIIA IIIB

T3 IIB IIIA IIIA IIIB

T3 IIB IIIA IIIA IIIB

T3 IIB IIIA IIIA IIIB

T4 IIIA IIIA IIIB IIIB

T4 IIIA IIIA IIIB IIIB

M1a IV IV IV IV

M1a IV IV IV IV

M1b IV IV IV IV

Goldstraw P, et al. J Thorac Oncol. 2007;2:706-714.

IASLC Staging Project: Survival by pathologic stage

Ove

rall

S

urv

ival

A = Sixth EditionTNM (Current)

B = IASLCProposal

Goldstraw P, et al. J Thorac Oncol. 2007;2:706-714.

IPASS (Iressa Pan-Asia Study)

Mok T, et al. Ann Oncol. 2008;19(suppl 8):viii1-viii4. Abstract LBA2.

IPASS Patients

IPASS Results

• All patients: Gefitinib associated with increased PFS (HR=0.74; 95% CI, 0.65-0.85; P<.0001)1

Mok T, et al. Ann Oncol. 2008;19(suppl 8):viii1-viii4. Abstract LBA2.

IPASS bottom line

– Phase III data to support empiric use of EGFR TKI’s in patients with increased likelihood of having an EGFR mutation.

– In such without EGFR mutations, gefitinib was inferior to chemotherapy.

– 1st line TKI should be considered in select patients.

– Screening for mutations is ideal.

ECOG 1594: All third generation platinum doublets are equivalent

Schiller JH, et al. N Engl J Med. 2002;346:92-98.

1.0

0.8

0.6

0.4

0.2

0

10 15 25

Months0 5 20 30

Cisplatin/PaclitaxelCisplatin/GemcitabineCisplatin/DocetaxelCarboplatin/Paclitaxel

Phase 3 Study Evaluating Cisplatin + Phase 3 Study Evaluating Cisplatin + Gemcitabine vs Cisplatin + PemetrexedGemcitabine vs Cisplatin + Pemetrexed

Cisplatin 75 mg/m2 day 1 +Pemetrexed 500 mg/m2 day 1 (n=862)

RandomizationFactors • Stage • Performance status • Gender • Histologic vs cytologic

diagnosis• History of brain

metastases

Cisplatin 75 mg/m2 day 1 +Gemcitabine 1250 mg/m2 days 1,8 (n=863)

Vitamin B12, folate, and dexamethasone given in both arms

Each cycle repeated q 3 wk up to 6 cycles

Scagliotti GV, et al. J Clin Oncol. 2008;26:3543-3551.

RANDOM IZATION

Cis + Gem vs Cis+ Pem: Overall SurvivalCis + Gem vs Cis+ Pem: Overall Survival

Scagliotti GV, et al. J Clin Oncol. 2008;26:3543-3551.

1.00.90.80.70.60.50.40.30.20.10.0

0 6 12 18 24 30

Su

rviv

al P

rob

abil

ity

Survival Time, mo

Median (95% CI)Cisplatin/pemetrexed 10.3 (9.8-11.2)Cisplatin/gemcitabine 10.3 (9.6-10.9)CP vs CG Adjusted HR (95% CI)

0.94 (0.84-1.05)

Pre-specified subset analysis by histology:overall survival

Scagliotti GV, et al. J Clin Oncol. 2008;26:3543-3551.

2 year survival of 25% in adenocarcinoma treated with cis-pemetrexed

“Maintenance” chemotherapy after 4 – 6 cycles of a platinum doublet

• Immediate vs delayed docetaxel

• Pemetrexed vs best supportive care

• Continuation of pemetrexed-bevacizumab after first line bevacizumab.

Immediate vs delayed docetaxel

Fidias, et al. J Clin Oncol 27:591-598. 2009

p=0.001 p=0.085

Pemetrexed vs best supportive care

Ciuleanu, et al. ASCO 2008

Continuation of pemetrexed-bevacizumab after first line bevacizumab

Patel, et al. ASCO 2008

“Cetuximab has no role in the treatment of NSCLC”FLEX Study

Cisplatin 80 mg/m2 on day 1 +Vinorelbine 25 or 30 mg/m2 on

days 1 and 8 q3wk for a maximum of 6 cycles +

Cetuximab 400 mg/m2 on d 1 250 mg/m2/wk thereafter

(n=557)

Cisplatin 80 mg/m2 on d 1 +Vinorelbine 25 or 30 mg/m2 on

d 1, 8 q3wk 3 for amaximum of 6 cycles

(n=568 )Eligible: • Stage IIIB/IV,

EGFR-positive NSCLC by IHC

(N=1125)

Stratified by ECOG performance score 0/1 vs 2

CetuximabMaintenanceUntil disease progression

or unacceptable toxicity

Pirker, et al. ASCO 2008

FLEX Study: Results

Pirker, et al. ASCO 2008

PFS = 4.8 mo’s in both arms

Conclusions

We don’t have to say “wet IIIB” any more.

We need to know the histologic subtype to guide chemo choices and bevacizumab use.

With modern treatments, in adenocarcinoma, 25% of patients survive to two years.

“Maintenance” therapy with docetaxel or pemetrexed may be effective.

Cetuximab may not be completely ineffective.