The role of Maintenance treatment Appropriate endpoints according to ESMO consensus

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1 ESMO Preceptorship Programme Colorectal Cancer Singapore-October JY Douillard, MD, PhD, CMO ESMO The role of Maintenance treatment Appropriate endpoints according to ESMO consensus

2 MAINTENANCE THERAPY Most patients with mcrc have no hope for cure and will receive several lines of chemo +/-targeted therapies with a median Overall Survival of 30 months For patients fit for intensive induction chemotherapy, the optimal sequence and duration are unknown, reduction of treatment intensity is often required for toxicity or patient request Quantity of life has improved and Quality of life should be considered Maintenance treatment apply after induction to maintain benefit as long as possible With lower toxicity regimen Improvement of disease control (PFS) Not at the detriment of QoL Several strategies are available

3 Available strategies in clinical practice Disease Progression Continuous with dose reduction according to toxicity 2 nd Line Induction phase 4-6 months with controlled disease Intermittent with treatment breaks 2 nd Line Maintenance with less toxic drugs Re-induction

4 CONTINUED VS: INTERMITTENT CHEMO Comparison of intermittent and continuous palliative chemotherapy for advanced colorectal cancer: a multicentre randomised trial TS Maughan, MD, RD James, MRCP, DJ Kerr, FRCP, JA Ledermann, MD, MT Seymour, MD, C Topham, MD, C McArdle, FRCS, D Cain, PhD, Mr RJ Stephens CR06 Induction phase 12 w 5FU-based (GM, Lockich) Or Raltitrexed OR STB n=354 Maughan TS et al. The Lancet , The Lancet Volume 361, Issue 9356, Pages (February 2003) DOI: /S (03) Continue until PD STOP and restart PD Primary endpoint: Overall Survival (OS)

7 Folfiri Continuous vs Intermittent 2 months on/2months off -Stop and Go- 337 patients randomized 147 in the final analysis continuous Folfiri 146 in the final analysis Intermittent Folfiri ORR : 34 vs.42% (int/cont) (NS) DCR: 67 Vs. 76% (NS) Labianca R et al, Annals Oncol 22: , 2011

8 CONTINUED VS: INTERMITTENT CHEMO In this study, discontinuing chemotherapy resulted in: Similar PFS and OS Slightly better QoL Reduced toxicity 10 week less chemotherapy Same incidence of exposure to second line Interpretation: Our findings provided no clear evidence of a benefit in continuing therapy indefinitely until disease progression. They showed that it is safe to stop chemotherapy after 12 weeks and re-start the same treatment on progression in patients with chemosensitive advanced colorectal cancer. Lancet 2003; 361:

9 PFS 274 mcrc L1 = weeks Xelox or Folfox Response or stable disease R Capecitabine 2000mg/m2/d1-14 observation PD PFS 2 Primary endpoint: PFS from randomization H. Y. Luo et al. Ann Oncol 2016;27:

10 Capecitabine maintenance PFS from randomization PFS from induction treatment (PFS2) overall survival H. Y. Luo et al. Ann Oncol 2016;27:

11 Maintenance chemotherapy after induction vs. Continuous chemo until PD Christophe Tournigand et al. JCO 2006;24:

12 Chemotherapy regimens: (A) FOLFOX4; (B) FOLFOX7; and (C) simplified LV5FU2. OPTIMOX 1 A (Folfox 4) until PD A B (Folfox 7) (6 cycles) C (LV5FU2 x12) B (Folfox 7) B C B Primary End-Point. Duration of Disease Control Christophe Tournigand et al. JCO 2006;24:

13 Primary End-Point Duration of disease control Progression-free survival Overall survival Conclusion Oxaliplatin can be safely stopped after six cycles in a FOLFOX regimen. No difference in PFS and OS, less grade 3-4 toxicity in arm B Christophe Tournigand et al. JCO 2006;24:

14 Comparison of the proportion of patients who developed a grade 3 or 4 toxicity at each cycle. Drug exposure: n patients receiving each cycle N patients with G3-4 toxicity Neurotoxicity G3-4 Christophe Tournigand et al. JCO 2006;24: by American Society of Clinical Oncology

15 OPTIMOX 2 R n = 99 n = 103 mfolfox7 x 6, slv5fu2 maintenance, mfolfox7 mfolfox7 x 6, chemo-free interval, mfolfox7 mfolfox 7: Oxali 100mg/m 2 DDC mfolfox 7 reintroduced at progression Primary End-Point: DCC PFS Optimox 2: conclusion DCC and PFS are improved OS is not Similar toxicity in both arms OS Benoist Chibaudel et al. JCO 2009;27:

16 MAINTENANCE CHEMOTHERAPY CONCLUSION Treatment discontinuation STOP and GO: Similar PFS and OS Slightly better QoL Reduced toxicity Maintenance Capecitabine vs Observation: Improved PFS and PFS 2 No benefit on OS Maintenance with reduced toxicity regimen OPTIMOX Strategy No alteration or improved DCC and PFS Less toxicity with maintenance due to Oxaliplatin reduction No survival benefit

17 CONTRIBUTION OF TARGETED AGENT IN MAINTENANCE Bevacizumab Cetuximab

18 mcrc L1 = 4-6 months CT + bev Response or stable disease R bevacizumab 7.5 mg/kg/3 weeks pause Primary endpoint: TTP non inferiority D. Koeberle et al. Ann Oncol 2015;26:

19 SAKK 41/06 Kaplan Meier curves for time to progression from randomization. TTP 4.1 vs. 2.9 m HR 0.74 ( ) Non-inferiority not demonstrated OS 25.4 vs. 23.8m P=0.19 D. Koeberle et al. Ann Oncol 2015;26:

Maintenance with bevacizumab and capecitabine: CAIRO3 Phase III trial DCCG (Dutch Colorectal Cancer Group mcrc Non

CAPOXbevacizumab PFS2 CAPOXbevacizumab (6 cycles) SD or OR (n = 558) R Observation (n = 279) Capecitabine +

CAPOX-bevacizumab (n = 131 [47 %]) Progression * Capecitabine 625 mg/m 2 2 x/j en continu + bevacizumab 7,5 mg/kg

20 Maintenance with bevacizumab and capecitabine: CAIRO3 Phase III trial DCCG (Dutch Colorectal Cancer Group mcrc Non resectable 1 st line OMS 0-1 Primary endpoint PFS2 = Delay up to 2 nd progression after rechallenge with CAPOXbevacizumab PFS2 CAPOXbevacizumab (6 cycles) SD or OR (n = 558) R Observation (n = 279) Capecitabine + bevacizumab * (n = 279) PFS1 Progression Rechallenge CAPOX-bevacizumab (n = 212 [76 %]) Rechallenge CAPOX-bevacizumab (n = 131 [47 %]) Progression * Capecitabine 625 mg/m 2 2 x/j en continu + bevacizumab 7,5 mg/kg i.v. every 3 weeks Secondary endpoints : PFS1, TTP2, OS TTP2 : time to progression or death after first progression, whatever the treatment used

21 Figure 2 CAIRO 3: OUTCOMES PFS 1 PFS 2 Time to 2 nd PD OS The Lancet , DOI: ( /S (14) ) Simkens L et al. The Lancet 2015; 385:

22 Figure 1 The Lancet Oncology , DOI: ( /S (15)00042-X)

23 Figure 3 Failure of strategy PFS OS The Lancet Oncology , DOI: ( /S (15)00042-X)

25 MAINTENANCE TRIALS: COMBINED ANALYSIS, VS. NO THERAPY PFS PFS OS Koopman M, et al. J Clin Oncol. 2014;32(Suppl3): Abstract LBA388. Koeberle D, et al. J Clin Oncol 31;2013(Suppl); Abstract Presented by Dirk Arnold, et al. ASCO Abstract On behalf of the AIO CRC Study Group, Presented at 2014 ASCO Annual Meeting. Courtesy of Prof Arnold.

26 CONTRIBUTION OF TARGETED AGENT IN MAINTENANCE Bevacizumab Cetuximab

Wasan H et al The Lancet Oncology 2014; 15: 631-39 Phase II trial, Kras wt exon 2 (later retested for Kras,

the 12w induction, result will be expressed on per protocol population, not intent to treat Imbalanced

27 Wasan H et al The Lancet Oncology 2014; 15: Phase II trial, Kras wt exon 2 (later retested for Kras, Nras, Braf) n=78* n=91* Primary Endpoint: Failure-Free Survival at 10 months *14/78 and 25/91 did not complete the 12w induction, result will be expressed on per protocol population, not intent to treat Imbalanced population for Braf in defavor of the continued arm 13 patients received Xelox rather than Folfox (5 and 8 in the Contimued arm)

28 The Lancet Oncology , DOI: ( /S (14) ) Copyright 2014 Wasan et al. Open Access article distributed under the terms of CC BY Terms and Conditions COIN B Failure Free Survival (Primary Endpoint) All Wild-type population: Median FFS (months): Intermittent: 12.3 m Continued: 14.5 m

29 The Lancet Oncology , DOI: ( /S (14) ) Copyright 2014 Wasan et al. Open Access article distributed under the terms of CC BY Terms and Conditions COIN B Overall Survival All Wild-type population: Median OS (months): Intermittent: 18.8 m Continued: 21.7 m

30 COIN B Intermittent Folfox-Cetuximab with Cetuximab maintenance: conclusion In COIN-B, planned maintenance with cetuximab was associated with a greater failure-free survival, a greater progression-free survival, a greater overall survival, an improved disease control at 24 weeks, and a longer chemotherapy-free interval than was intermittent cetuximab. These benefits occurred despite an imbalance of prognostic factors at baseline COIN-B was designed as an exploratory, hypothesis generating study to complement COIN.

31 Switch maintenance with another EGFR targeting agent Bevacizumab with or without erlotinib as maintenance therapy in patients with metastatic colorectal cancer (GERCOR DREAM; OPTIMOX3): a randomised, openlabel, phase 3 trial Prof Christophe Tournigand, MD, Benoist Chibaudel, MD, Benoit Samson, MD, Prof Werner Scheithauer, MD, Dewi Vernerey, PhD, Paul Mésange, PhD, Gérard Lledo, MD, Frédéric Viret, MD, Jean-François Ramée, MD, Prof Nicole Tubiana-Mathieu, MD, Jérôme Dauba, MD, Olivier Dupuis, MD, Yves Rinaldi, MD, May Mabro, MD, Nathalie Aucoin, MD, Jean Latreille, MD, Prof Franck Bonnetain, PhD, Prof Christophe Louvet, MD, Annette K Larsen, PhD, Prof Thierry André, MD, Prof Aimery de Gramont, MD The Lancet Oncology Volume 16, Issue 15, Pages (November 2015) DOI: /S (15) Copyright 2015 Elsevier Ltd Terms and Conditions

32 33 Maintenance: Bev + erlotinib DREAM Induction, N=700 Maintenance, N=446 R E G I S T R A T I O N mfolfox7 bevacizumab (59%) XELOX2 bevacizumab (30%) FOLFIRI bevacizumab (10%) 6 MONTHS No Progression R Bevacizumab (7.5 mg/kg /21d) + erlotinib (150 mg/d) until progression N=222 Bevacizumab (7.5 mg/kg /21d) until progression N=224 Primary Endpoint: PFS after maintenance randomisation ( m)

34 Berry SR et al, Annals Oncol 26: , 2015

35 If maintenance is prefrerred: ESMO Highlights Copenhagen J.Taïeb

36 Abst 462

37 PFS HR 0.63 ( )

38 Van Cutsem E et al. 41

39 Van Cutsem E et al. 42

40 MAINTENANCE THERAPY Individualisation and discussion with the patient is essential: For patients receiving FOLFOX or CAPOX plus bevacizumab-based therapy, consider maintenance therapy after 6 8 cycles with a combination of a fluoropyrimidine plus bevacizumab Patients receiving FOLFIRI can continue on induction therapy for as long as tumour shrinkage continues and the treatment is tolerable Bevacizumab as monotherapy is not recommended as maintenance therapy As overall survival has not been improved by maintenance strategies, treatment holidays are a valid option and should be discussed with the patient Pause remains useful in patients with: Normalisation of CEA Slow-growing tumours Good response to initial therapy For patients receiving initial therapy with a single agent fluoropyrimidine (plus bevacizumab) induction therapy should be maintained

RECONSIDERING THE BENEFIT OF INTERMITTENT VERSUS CONTINUOUS TREATMENT IN THE MAINTENANCE TREATMENT SETTING OF METASTATIC COLORECTAL CANCER

RECONSIDERING THE BENEFIT OF INTERMITTENT VERSUS CONTINUOUS TREATMENT IN THE MAINTENANCE TREATMENT SETTING OF METASTATIC COLORECTAL CANCER SUNAKAWA, Y, 1 BEKAIISAAB, T, 2 AND STINTZING, S. 3 SELECTED HIGHLIGHTS