1. F. Maindrault-Gœbel, G. LLedo, B. Chibaudel, L. Mineur, T. André, M. Bennamoun, M. Mabro, P.Artru, C. Louvet, A. de Gramont OPTIMOX2, a large randomized phase II study of maintenance therapy or chemotherapy-free intervals (CFI) after FOLFOX in patients with metastatic colorectal cancer (MRC). A GERCOR study.

2. Rationale Chemotherapy-free intervals (CFI) have previously been studied in patients receiving 5FU- based therapy: Hejna et al (Br J Cancer (1998) have shown that patients can benefit from 5FU reintroduction after a CFI following 6 months of therapy. Maughan et al (Lancet 2003) have show in a larger phase III that 3 months 5FU-based chemotherapy followed by CFI achieved the same survival than 5FU until progression. New combination therapies have improved survival but also increased toxicity, especially the cumulative toxicities like the oxaliplatin sensory neuropathy. The need to preserve the quality of life is the clinical rationale to evaluate CFI. Plantade et al have shown in a retrospective study presented at ASCO 2006 that patients with MCRC an benefit from CFI, especially in first-line therapy.

3. Rationale: OPTIMOX 1 Oxaliplatin Stop and Go Better tolerance Same efficacy results Tournigand, JCO 2006

4. RANDOMIRANDOMISATSATIONIONRANDOMIRANDOMISATSATIONION maintenance therapy vs chemotherapy-free interval mFOLFOX7 x 6 cy sLV5FU2 until baseline progression mFOLFOX7 reintroduction mFOLFOX7 x 6 cy No maintenance until baseline progression mFOLFOX7 reintroduction OPTIMOX 2 Study design A B OPTIMOX2 : chemotherapy-free interval OPTIMOX1 : maintenance therapy

5. A FOLFOX7 x 6 cy AAAAA FOLFOX7 x 6sLV5FU2 Baseline progression FOLFOX7 x 6 cy AAAA FOLFOX7 x 6 Chemotherapy-free interval Baseline progression LV 400 5-FU 3000 mFOLFOX7 Oxali 100 H0 H2 H24 H48 LV 400 5-FU 3000 sLV5FU2 H0 H2 H24 H48 5FUb 400 Cycles every 14 days, d ose mg/m² CHEMOTHERAPY OPTIMOX 1 OPTIMOX 2 A A

6. Baseline Progression t T size FOLFOX ProgressionBaseline progression Progression at reintroduction Chemotherapy-free Interval

7. Histologically proven colorectal cancer Unresectable metastases Mesurable or evaluable metastasis No prior CT except adjuvant CT if ended  6 months before study entry 18 - 80 years alk. ph. 100 10 9, creatinin <3 UNL WHO PS  2 No peripheral sensory neuropathy Inclusion criteria

8. Randomisation using minimization technique Stratification by center, PS (0-1 vs 2), number of sites (1 vs > 1), age (18 - 50 vs 51-75 vs 76 - 80), Alk Ph. (  3x UNL vs  3 - 5 ULN), adjuvant chemo or not Initial sample size was 600, downgraded to 200 when bevacizumab was approved in France Primary objective was duration of disease control, no formal hypothesis were done between the two arms Statistics

9. Duration of Disease Control t T size FOLFOX PFS 1 ProgressionBaseline progression PFS 2 Progression at reintroduction DDC = PFS 1 + PFS 2 (if no PD) ASCO 2001, 146a

10. Patients Characteristics Arm A OPTIMOX1 N = 100 Arm B OPTIMOX2 N = 102 Median age, years (range)67 (35 - 81)67 (32 - 80) Male/Female60% / 40%59% / 41% WHO PS 0 / 1-258% / 42%59% / 41% LDH N / > ULN / Missing35% / 48% / 17%30% / 45% / 25% Colon/Rectum/Both63% /36% / 1%69% /26% / 5% Prior adjuvant CT/RT (oxali)17% (0%)18% (2%) Synchronous metastasis25%27% Nb metastatic sites 1/  2/Uk 46% / 51% / 3%52% / 47% / 1% 202 patients enrolled from 12 centers

11. Response was evaluated at 4 and 6 cycles then every 2 months. OPTIMOX 2 Responses OPTIMOX1OPTIMOX2 CR3% PR58% PR+CR61% Stable27%32% Prog11%6% NE0%1% Too early11 patients12 patients

12. OPTIMOX1 PD 10 no Prog. 40 > 6 mths 20 (surg. 7) >12 mths 10 (surg.5) OPTIMOX 2 Status of the study A B Median follow-up 70 weeks Prog on maintenance 49 Reintro. 31 Line 2 18 Dead 26 Dead 35 OPTIMOX2 PD 5 no Prog. 30 > 6 mths 15 (surg. 6) >12 mths 7 (surg.5) Prog on CFI 64 Reintro. 52 Line 2 12

13. OPTIMOX1 N = 100 OPTIMOX2 N = 102 Nb of cycles with oxaliplatin 649783 Nb of cycles with and without oxaliplatin 1218783 Median nb of cycles with oxaliplatin (range) 6 (1-18) 6 (1-18) Median nb of cycles with or without oxaliplatin (range) 12 (1-32) 6 (1-18) OPTIMOX 2 Number of Cycles +21% -36 %

14. Response was evaluated at 4 and 6 cycles then every 2 months. OPTIMOX 2 Responses Reintroduction 1 OPTIMOX1OPTIMOX2 N3045 CR0 (0%) PR4 (13%)14 (31%) Stable13 (43%)11 (24%) Prog12 (40%)18 (40%) NE1 (3%)2 (5%) Too early1 patient6 patients

15. Neuropathy Grade 1 9.7 % 2 32.2 % 3 3.2% Grade 1 21.7 % 2 30.4 % 3 8.7 % Grade 1 4.4 % 2 19.1 % 3 4.4 % Grade 1 27.0 % 2 16.2 % 3 13.5 % Optimox 1Optimox 2 After the first reintroduction 2 months after FOLFOX Grade 1 69.9 % 2 17.2 % 3 0% Grade 1 71.7 % 2 17.3 % 3 0% During C1-C6

16. Toxicity Grade 3-4 (%) per Patient OPTIMOX 1 OPTIMOX 2 C1-C6 maintenance R1 C1-C6 R1 Neutropenia 17.2 6.6 3.4 11.9 6.8 Anemia 1 0 0 0 1 Thrombopenia 6.4 1.7 0 3.2 2.2 Mucitis 1 3.3 0 1 2.2 Vomiting 2.1 0 0 4.3 4.4 Diarrhea 2.1 0 0 4.3 2.2 HFS 0 3.3 0 0 0

17. Progression-free Survival 8.7 months 6.9 months

18. Duration of Disease Control 12.9 months 11.7 months

19. Chemotherapy-free Interval 4.6 months

20. CFI according to Initial Response 5.1 months 3.9 months

21. CFI according to Pc factors 8.0 months 4.6 months PS 2 LDH ↑ Alk Ph >3ULN > 1 site

22. PFS of Reintroduction 3.7 months 4.1 months

23. Conclusions (1) Maintenance therapy improves PFS but not DDC Median duration of chemotherapy-free interval is 20 weeks (4.6 months), 35 weeks (8 months) in patients without adverse prognostic factors Results in the OPTIMOX 1 arm are comparable to the previous study except DDC, 12.9 vs 10.6 months, which can be explained by a higher reintroduction rate, > 60% vs 40%. Response rate after reintroduction of FOLFOX could be higher in patients who did not receive maintenance therapy

24. Conclusions (2) A break in therapy can be proposed in patients who achieved a response or a stable disease with first-line FOLFOX therapy, especially those without adverse prognostic factors The next GERCOR study, DREAM, will evaluate maintenance therapy with targeted drugs alone.

25. Acknowlegments: Dr Lledo Gérard – Lyon Pr de Gramont Aimery – Paris Dr Mineur Laurent – Avignon Pr André Thierry – Paris Dr Bennamoun Mustapha – Montfermeil Dr Mabro May – Suresnes Dr Carola Elisabeth – Senlis Dr Flesch Michel- Dijon Dr Ganem Gérard – Le Mans Dr Colin Philippe – Reims Dr Auby Dominique - Libourne For the GERCOR : Benoist Chibaudel Valentine Songeur Nourredine Ait Rahmoune Nora Zeghib Gaelle le Guludec Katia Neveu Laurence Renaud