JY Douillard MD, PhD Professor of Medical Oncology

Transcription

1 ESMO Preceptorship Colorectal Cancer Colorectal ESMO Cancer Preceptorship Vienna Program October 2015 Prague May 22-23rd 2014 Review of the ESMO Consensus Conference on metastatic colo-rectal cancer Basic strategy and groups (RASwt/mut, BRAF mut) JY Douillard MD, PhD Professor of Medical Oncology Integrated Center of Oncology R Gauducheau Nantes France

2 Disclosure JY Douillard Compensated participations in: Advisory Boards and Symposia: Amgen Bayer Boehringer Ingelheim Merckserono Roche/Genentech Sanofi Takeda Research Funding Merckserono

3 Adapted from E Van Cutsem Year Survival Rate for Stage IV CRC Remains Only 6% Saltz Douillard Saltz Douillard Goldberg Hurwitz Falcone Saltz Bokemeyer Van Cutsem Douillard Falcone/Heinemann Douillard Heinemann Falcone Van Cutsem Venook 5-FU/LV bolus 5-FU/LV infusion IFL LVFU2/irinotecan FOLFOX IFL + bevacizumab FOLFOX/FOLFIRI 12,6 XELOX/FOLFOX + bevacizumab FOLFOX + cetuximab FOLFIRI + cetuximab FOLFOX + panitumumab FOLFIRI + bevacizumab FOLFOX + panitumumab FOLFIRI + cetuximab FOLFOXIRI + bevacizumab FOLFIRI + cetuximab 14,1 14, Overall Survival (months) *KRAS wild type tumors; **Extended RAS wild type population. Note: Informal comparison as these are not head-to-head clinical trials. 1. Saltz. N Engl J Med. 2000; 2. Douilliard. Lancet. 2000; 3. Goldberg. J Clin Oncol. 2004; 4. Hurwitz. N Engl J Med. 2004; 5. Saltz. J Clin Oncol. 2008; 6. Falcone. J Clin Oncol. 2007; 7. Bokemeyer. Ann Oncol. 2011; 8. Van Cutsem. J Clin Oncol. 2011; 9. Douilliard. ASCO Abstract 3510; 10. Heinemann. ASCO Abstract LBA3506; 11. Stintzing and Heinemann. ESMO Abstract LBA17; 12. Falcone. ASCO Abstract 3505; 13. Douillard JY, et al. New Engl J Med. 2013;369(11): ;14. Van Cutsem et al. Ann Oncology ESMO GI 2014 A. 15. Venook P, et al. ASCO Abstract LBA3; Plenary presentation. 17,4 FOLFOX/FOLFIRI + cetuximab or bevacizumab 19,5 20,3 21,3 22,6 22.8*

4 Unresectable mcrc treatment in 2015 Median expected OS: about 30 months Most of the patients will receive several lines of treatment From 100 in 1st line will receive a 2 nd line will receive a 3rd Line 15-20% will receive 4+ lines

5 ESMO Guidelines Package

6 ESMO 2015 Consensus on Advanced Colorectal Cancer Presentation at ESMO GI/WCGIC July 4, Barcelona Manuscript in preparation Eric Van Cutsem, Andres Cervantes, Dirk Arnold

7 Groups according to clinical presentation ESMO Consensus Conference 2011 Schmoll H J et al. Ann Oncol 2012;23:2479 Groups Clinical Criteria Group 0 Group 1 Group 2 Upfront resectable metastasis, Goal: cure, reduced relapse rate Potentially resectable metastasis Goal: Objective Response, tumor shrinkage. Multiple metastasis, rapid progression, associated symptoms even in patients without major co-morbidities Goal: Disease control, symptom improvement. Group 3 Multiple metastasis or organ involved, definitely never resectable, Mild symptoms associated, co-morbidities Goal: Disease control, increased survival with preserved quality of life, regimen with mild toxicity profile prefered..

8 Clinical Groups 0 and 1 Clinical presentation Treatment aim Treatment intensity

9 Clinical Groups 2 and 3 Clinical presentation Treatment aim Treatment intensity

10 Hierarchy of factors for definition of treatment aim/group. Schmoll H J et al. Ann Oncol 2012;23:

11 Factors influencing the choice of 1st-line treatment in group 1, 2 and 3

12 Factors influencing the choice of 1st-line treatment in group 1, 2 and 3

13 1st-line options according to clinical groups Group RAS wild-type Recommendation a RAS mutant Recommendation a FOLFIRI + Pan/Cet +++ FOLFOX/XELOX + Bev +++ FOLFOX + Pan/Cet +++ FOLFOXIRI ++(+) b 1 FOLFOX/XELOX + Bev ++(+) FOLFIRI/XELIRI + Bev ++(+) c FOLFOXIRI ++(+) b FOLFOX/XELOX + FOLFIRI/XELIRI + Bev ++(+) c FOLFIRI/XELIRI + FOLFOX/XELOX + IRIS + FOLFIRI/XELIRI + IRIS + FOLFIRI + Cet +++ FOLFOX/XELOX + Bev +++ FOLFOX + Pan/Cet +++ FOLFIRI/XELIRI + Bev ++(+) c 2 3 FOLFOX/XELOX + Bev +++ FOLFOX/XELOX ++ FOLFIRI/XELIRI + Bev ++(+) c FOLFIRI/XELIRI ++ FOLFOXIRI +(+) b FOLFOXIRI ++ b FOLFOX + Cet +(+) IRIS + FOLFOX/XELOX + FOLFIRI/XELIRI + IRIS + FUFOL/Cape (mono) +++ FUFOL/Cape (mono) +++ FUFOL/Cape + Bev +++ FUFOL/Cape + Bev +++ XELOX/FOLFOX ++ XELOX/FOLFOX ++ FOLFIRI/XELIRI ++ FOLFIRI/XELIRI ++ IRIS + IRIS + Cet/Pan (mono) (+) watchful waiting + selected pts. d Watchful waiting + selected pts. d triplets (±Bev) + option for spec. situation Triplets (+/ Bev or Cet/Pan) + option for spec.

14 ESMO consensus patients groups Additional predictive biomarkers should be incorporated in treatment decision Ras phenotype allows to select for anti-egfr therapy Braf phenotype for chemotherapy intensification?

15 ESMO Group 2 mcrc Need for an active regimen for an agressive tumor to stop tumor growth Doublets or Triplets chemo-regimen are preferred To be selected according to tolerance profile/pre-existing conditions Targeted agents may be used in combination with chemotherapy for improved efficacy Decision should be based on RAS phenotype and contra-indications In some cases, patient file should be reviewed in a MDT to discuss possible resection.

16 Preceptorship program: colorectal cancer Group 3 patients

17 Clinical Group 3 for 1st-line treatment stratification Clinical presentation Treatment aim Treatment intensity

18 1st-line options according to clinical groups Group RAS wild-type Recommendation a RAS mutant Recommendation a FUFOL/Cape (mono) +++ FUFOL/Cape + Bev +++ XELOX/FOLFOX ++ FUFOL/Cape (mono) FUFOL/Cape + Bev XELOX/ FOLFOX FOLFIRI/XELIRI ++ FOLFIRI/XELIRI ++ 3 IRIS + IRIS + Cet/Pan (mono) (+) Watchful waiting watchful waiting + selected pts. d triplets (±Bev) + selected pts. d + option for spec. situations Triplets (+/ Bev or Cet/Pan) + option for spec.

19 Proposal for sequence of salvage-chemotherapy. Schmoll H J et al. Ann Oncol 2012;23: The Author Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please journals.permissions@oup.com.

20 ESMO Group 3 mcrc Multiple strategies are possible Several lines will be used The important points are: To try to use all available agents Drug re-introduction may apply To improve survival and preserve quality of life Stop and Go strategies are convenient and may allow longer treatment overall

21 ESMO Group 3 mcrc Targeted agents + Chemotherapy Bevacizumab is active in combination with chemotherapy Survival benefit is not constantly seen but PFS is Risk factors should be considered If used, should be preferred in early lines No activity as single agent To be discussed if maintenance is used

22 ESMO Group 3 mcrc Anti-EGFR Monoclonal Antibodies are generally used at a later line of treatment in this patients population Patients should be selected according to K and N RAS wt No sequential trials in this group of patients are available Upfront use of anti EGFR MoAb has been reported in small trial with high efficacy Most frequently used in 3rd or 4th line

23 State of Art for treatment strategy in mcrc ESMO consensus guidelines as a reference in clinical practice Each individual patient should be referred to 1 of the 4 groups Treatment goal will be stated upfront Treatment options will be identified for discussion

24 Metastatic Colorectal cancer Basic strategy and groups (RASwt/mut, BRAF mut) Based on present molecular profile and treatment availability mcrc should be split according to: Mutational status of RAS and Braf Metastatic spread Single organ (LLD) potentially resectable Multiple organs never resectable Treatment strategy should be offered accordingly After MultiDisciplinary Team discussion Patients characteristics and desire Taking into consideration the Goal of treatment, the possibility of several lines and also Quality of Life.

25 Modification possibly to be added after the 2014 consensus conference

26 Treatment of metastatic disease It is clear that treatment stratification according to ESMO Groups 0, 1, 2 and 3 is no longer representative of what occurs in everyday clinical practice, there can be no clear distinction made between group 1 and 2 patients or between group 2 and 3 patients. Increasingly often patient desire in terms of treatment goal is the main driver of treatment decisions.

27 Treatment of metastatic disease Drivers for decison making in 1st line treatment Table 4. Treatment drivers for first-line treatment Tumour characteristics Clinical presentation: Tumour burden Tumour localisation Patient characteristics Age Treatment characteristics Toxicity profile Tumour biology Performance status Flexibility RAS mutation status Organ function Socio-economic factors BRAF mutation status Comorbidities Quality of life, patient expectation and preference

28 Treatment of metastatic disease CLINICAL CONDITION OF THE PATIENT Fit *a Unfit a (but may be suitable) Unfit a GOAL FP+/- bevacizumab; reduced dose doublet; anti-egfr BSC NED Patients with clearly resectable metastases Surgery alone Surgery with perioperative/ postoperative CT Cytoreduction (Shrinkage) MOLECULAR PROFILE RAS wt RAS mt BRAF mt Doublet + anti-egfr Combination + bevacizumab Triplet + bevacizumab Disease control (Control progression) RAS wt RAS mt BRAF mt CT + biological agent MOLECULAR PROFILE CT + bevacizumab Unusual, see text Re-evaluation/assessment of response every 2months* Re-evaluation/assessment of response every 2-3 months* GOAL Progressive disease Second-line Progressive disease Second-line Surgery Cytoreduction (Shrinkage) Continue Disease control Continue; maintenance; or pause Continue; maintenance; or pause

29 Review of the ESMO Consensus Conference on metastatic colorectal cancer CONCLUSION Metastatic colorectal cancer is a fast-moving field New drugs regularly registered (Regorafenib, TAS-102) Changing label (anti-egfr MoAbs restricted to RASwt) New technologies outside of medical oncology (Sirflox) More than ever a multidiscplinary approach is needed Guidelines need regular updates Consensus is not easy to fine ORR, Progression-free and Overall survival are improving