1. TERAPIA SEQUENZIALE E/O DI MANTENIMENTO DOPO UNA PRIMA LINEA: ANCORA UN TRATTAMENTO SPERIMENTALE?
Paolo Bidoli
S.C. Oncologia Medica
A.O. San Gerardo Monza

2. Sequential & Maintenance chemotherapy
Sequential administration of non–cross-resistant chemotherapy for a defined number of cycles. In a sequential regimen, the switch from one treatment to another does not require documented progression.
Maintenance/consolidation is prolongation of CT duration with administration of additional drugs at the end of a defined number of initial CT cycles, after maximum response

3. Maintenance, consolidation and sequential chemotherapy

4. Rationale for maintenance/sequential chemotherapy
In view of the Goldie & Coldman hypothesis, sequential non-cross-resistant agents increase the probability of killing more cancer cells before resistance arises
Patients who achieved a CR/PR/SD could benefit from additional therapy with one of drugs included in induction regimen

5. Sequential chemotherapy: Randomized phase II study
Bidoli P. Ann Oncol 2007

6. Sequential chemotherapy: ITT results
Bidoli P. Ann Oncol 2007

7. Sequential chemotherapy: OS
Bidoli P. Ann Oncol 2007

8. Single agent followed by a single agent
The sequential addministration of non-cross resistant single agent may theoretically reduce toxicity while potentially killing tumor cells subsets due to different sensitivity of CT agents
Grossi F, The Oncologist 2007

9. Consolidation Docetaxel 75 mg/m2 D1, Q21D, until PD or max. 6 cycles
Consolidation vs delayed docetaxel in advanced NSCLC
N=145
CR PR SD
Consolidation Docetaxel 75 mg/m2 D1, Q21D, until PD or max. 6 cycles
Patient Eligibility
Stage IIIB/IV
Chemonaive
ECOG PS 0-2
CNS metastases allowed
GC Phase:
Gemcitabine 1,000 mg/m2 D 1,8
Carboplatin AUC=5 D1
Q21D x 4 cycles
Delayed BSC, then start at PD, Docetaxel 75 mg/m2 D1, Q21D, until PD or max. 6 cycles
N=566
N=309
I: 153
D: 156
Endpoints:
N=98
Primary: OS
Secondary: Response, PFS, Toxicity, QoL
Fidias P, JCO 2008 10

10. Overall Survival (from randomization) Progression-Free Survival
Consolidation vs delayed docetaxel:
PFS and Survival
Overall Survival (from randomization)
Progression-Free Survival 2 4 6 8 10 12 14 16 18 20 22 24
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Survival
PFS, mo
153 72 27 11 5
154 28
C :
D :
Consolidation (n=153)
5.7 (4.4, 7.2)
20% (13, 26)
Median PFS, mo (95% CI)
1-y PFS (95% CI)
Delayed D (n=156)
2.6 (2.6, 3.4)
9% (5, 14)
Log-Rank p-value
<0.001 52
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Survival 4 8 12 16 20 24 28 32 36 44 48
OS, mo
153
111 56 27 5 2
154 98 45 22 9 3 62
IC:
D : 40
Consolidation (n=153)
12.5 (10, 13.7)
51.1% (39.9, 57.1)
Delayed D (n=156)
9.7
(8, 11.2)
38.3% (30, 4.5)
Log-Rank p-value
0.0853
Median survival, mo (95% CI)
1-y OS (95% CI)
Fidias P, JCO 2008 11

11. Consolidation vs delayed docetaxel:
Toxicity
Grade 3/4 Toxicity
Consolidation
Delayed
Thrombocytopenia
1.4
Neutropenia
26.1
28.6
Febrile neutropenia
2.8
1.1
Anemia
0.7
Fatigue
9.2
3.3
Diarrhea
4.4
Fidias P, JCO 2008 12

12. Consolidation vs delayed docetaxel:
Conclusions
Immediate use of docetaxel following
CBDCA+GEM:
Significantly improved PFS: mo
Allowed a trend toward improved survival: mo
Did not compromise quality of life
Did not lead to increased toxicity
Increased feasibility: 50% more patients than delayed
Fidias P, JCO 2008 13

13. Hanna JCO 2008

14. NSCLC stage III (inoperable): Docetaxel consolidation
Conclusions: consolidation docetaxel after PE/RT results in increased toxicities but does not further improved survival compared with PE/RT alone
Hanna JCO 2008

15. Study XRP6976B2506 R A N D O M I S E Doc 75 mg/m2 Gem 1200 mg/m2
Cis 75 mg/m2
d 1 q 21
3 cycles
Gem 1200 mg/m2
d 1,8 q 21
3 cycles
84 NSCLC
Stratification:
stage IIIB vs IV
Doc 25 mg/m2
Cis 25 mg/m2
d 1,8,15 q 28
3 cycles
Gem 1200 mg/m2
d 1,8 q 21
3 cycles
Grossi F, ELCC 2008

16. Best response at EOT
Grossi F, ELCC 2008

17. Overall Survival B (qw)= 7.7 months (95%CI: 6.3-10.4)
A (q3w)= 12.1 months (95%CI: )
B (qw)= 7.7 months (95%CI: )
Grossi F, ELCC 2008

18. Vinorelbine maintenance
Maintenance VNR
25 mg/mq weekly x 6 months
plus BSC
N=573
N=90
Patient Eligibility
Stage IV NSCLC
CR/PR/SD after MIC x 2-4 cycles (N: 227)
BSC only
N=91
Primary endpoint: Median TTP
Westeel JNCI 2005 19

19. Vinorelbine maintenance:
PFS
p = 0.32

20. Vinorelbine maintenance:OS
p = 0.48

21. Gemcitabine maintenance
Maintenance GEM
1250 mg/mq 1-8 q21
plus BSC
N=352
N=138
Patient Eligibility
Stage IV NSCLC
CR/PR/SD after CDDP/GEM (N: 206)
BSC only
N=68
Primary endpoint: Median TTP
Brodowicz Lung Cancer 2006 22

23. Pemetrexed sequential/maintenance

27. R Phase III Trial: Lilly H3E-EW-S124
1st line treatment for advanced NSCLC (non squamous)
Pemetrexed 500 mg/m2 Q 3 weeks until to PD
CDDP + PEM
4 cycles
OR or SD R
Placebo
N= 600 Random 2:1
Primary endpoint: PFS
Secondary endpoints: OS, RR, QoL, Tox

28. Systematic review on optimal duration of CT in NSCLC
13 RCTs including 2416 pts
Results: continuing CT for more then 3-4 cycles induces delayed disease progression, not statistically significant improvement in overall survival, increase adverse events, and may impare QoL
Further trials should determine if extended treatment with targeted agents rather than CT can improve PFS and OS without increasing toxicity
Soon YY et al, ASCO 2008

29. Not designed to address the maintenance role
Maintenance with targeted agents: agent already present in the induction phase
Author
Phase
Regimen
Results
Sandler 2007
III
CBDCA and TAX plus bevacizumab until progression (vs chemotherapy alone)
Bevacizumab prolonged survival
Manegold 2008
CDDP and GEM plus bevacizumab until progression (vs chemotherapy alone)
Bevacizumab prolonged progression-free survival
Pirker 2008
CDDP and VNR plus cetuximab until progression (vs chemotherapy alone)
Cetuximab prolonged survival
Giaccone 2004
CDDP and GEM plus concurrent gefitinib followed by gefitinib until progression (vs placebo)
No survival and progression-free survival improvement
Gatzmeier 2004
CDDP and GEM plus concurrent erlotinib followed by erlotinib until progression (versus placebo)
Not designed to address the maintenance role

30. Maintenance with a biological agent
SWOG S0023
Maintenance with a biological agent
N=571
N=429
CR PR SD
Patient
Eligibility
Selected Stage IIIA (N2)
Stage IIIB
CDDP+VP-16 with
concurrent
chemoradiation
Consolidation
Docetaxel
1 q 21 x 3 cycles
CR,PR,SD
N=118
N=125
Maintenance
GEFITINIB
PLACEBO
Kelly JCO 2008 31

31. SWOG S0023: OS
p = 0.013
Kelly JCO 2008

32. Sequential/ Maintenance
conclusions
Future strategies seem to be based on prolungation of
treatment until to disease progression
Targeted therapies or CT agents (i.e. pemetrexed)
with good safety are the best option for manteinance
treatment
In my opinion further phase III randomized trials are warranted before the sequential/maintenance therapy will become standard therapy

33. LEV NIKOLAEVIC TOLSTOJ
“Benchè i dottori lo curassero,
gli cavassero sangue e
gli facessero prendere molte medicine,
tuttavia guarì”.
LEV NIKOLAEVIC TOLSTOJ