Adjuvant/neoadjuvant systemic treatment of colorectal cancer

Transcription

1 5th ESO-ESMO Eastern Europe and Balkan Region Masterclass in Medical Oncology Belgrade, June 19 th 2018 Adjuvant/neoadjuvant systemic treatment of colorectal cancer Carlotta Antoniotti Polo Oncologico Azienda Ospedaliero-Universitaria Pisana Università di Pisa

2 My agenda Early CRC: current state of art The IDEA collaboration Future perspectives

3 Pills of adjuvant therapy Why? To kill residual tumour cells TO CURE! For whom? Stage III and high-risk stage II pts. When? Within no more than 8-10 weeks from surgery.

4 Controversies: stage II O Connor, J Clin Oncol 2011

5 Adjuvant chemo for stage II: what to expect? Overall Survival Surgery + chemo 15% 3-5% Surgery alone 80% No benefit from adjuvant chemo Cured by surgery + chemotherapy Already cured by surgery Exposed to toxicities Years

6 Stage II: high and low risk STAGE II III Low risk Microsatellit e status High risk Fluoropyrimidine Or consider FOLFOX or XELOX T4 tumors Poor differentiation (G3) <12 lymph nodes examined bowel obstruction or perforation lymphovascular invasion

7 Stage II: high and low risk STAGE II III Low risk High risk Follow up in MSI-H Fluoropyrimidine consider Fluoropyrimidine in MSS/MSI-L consider FOLFOX or XELOX

8 Stage III STAGE II III Low risk High risk FOLFOX or XELOX Follow up in MSI-H Fluoropyrimidine consider Fluoropyrimidine in MSS/MSI-L consider FOLFOX or XELOX

9 Adjuvant chemo for stage III: what to expect? DFS % Surgery alone surgery+ chemo 15-20% 20% 60% No benefit from adjuvant chemo Cured by surgery + chemotherapy Already cured by surgery Exposed to toxicities years

10 3 positive phase III trials for oxaliplatin Δ 3y DFS Δ 5y DFS Δ 5-6y OS Mosaic + 5.3% + 5.9% C % + 5.2% + 4.3% HR 0.84 (median FU: 120 m) + 4.2% HR 0.85 (median FU: 67 m) Xelox + 4.5% + 6.3% + 3.4% HR 0.85 (median FU: 84 m) André T, et al. J Clin Oncol 2015 Yothers et al, J Clin Oncol 2011

11 MOSAIC trial study design 2246 Patients R A N D O M FOLFOX-4 LV5FU2 Stage II / III ratio = 40 / 60% 2.3 year enrollment (10/ /2001) Expected 3-year DFS: 79% for test arm and 73% for control arm or 25% reduction in risk of recurrence N = 2200 for a statistical power of 90% (a=0.05) André T, et al. NEJM 2004, J Clin Oncol 2009

12 MOSAIC trial DFS primary endpoint André T, et al. NEJM 2004, J Clin Oncol 2009

13 André T, et al. J Clin Oncol 2015 MOSAIC study - Stage III - OS 4.3% 8.1%

14 André T, et al. J Clin Oncol 2009 Oxaliplatin: the other side of the coin Grade 3 peripheral sensory neuropathy during treatment was 12.5% (0.2% of the patients in the LV5FU2 group) At 48 months: 15,4 % had symptoms of any grade 0.7% reporting grade 3 symptoms

15 how to face the problem?

16 A world wide effort SCOT Idea France TOSCA C HORG ACHIEVE

17 The IDEA collaboration What is the IDEA Collaboration? Prospective Pooled Analysis 6 Phase III Trials For Patients with Stage III Colon Cancer

18 Grothey et al, N Eng J Med 2018 IDEA: pooled analysis design 12,834 pts

19 Grothey et al, N Eng J Med 2018 Rationale for the non-inferiority margin IDEA Consensus (Oncology and Patient Advocates) Non-Inferiority Margin: DFS HR=1.12

20 Safety profile Qian Shi, et al, ASCO 2017

21 Grothey et al, N Eng J Med 2018 Primary endpoint - DFS 3 years DFS 74.6% vs 75.5% HR: % CI ( ) P for not inferiority=0.11

22 Primary endpoint - DFS Qian Shi, et al, ASCO 2017

23 What is the IDEA message?

24 Subgroups analyses Risk group P for interaction 0.11 T1-3 N1 T4 and/or N2 Grothey et al, NEJM 2018

25 Subgroups analyses Regimen P for interaction Grothey et al, NEJM 2018

26 Grothey et al, NEJM 2018 IDEA Recommendations In the low risk group, 3 months appeared to be sufficient, especially when CAPOX was chosen; In the high risk group, a longer treatment may be appropriate, especially when FOLFOX was chosen.

27 Pending questions What about discontinuation of oxaliplatin at 3 months while continuing a fluoropyrimidine? OS data?

28 My clinical practice in stage III 6 months of oxa for all stage III patients HIGH RISK patients Try to do everything! If neurotoxicity LOW RISK patients After at least 3 months, considering stop OXA and prosecution of fluoropyrimidine

29 How to improve the absolute benefit of adjuvant therapy?

30 Irinotecan? Biologic agents? Study Phase N pts Investigational drugs Primary endpoint Outcome AVANT III 3451 FOLFOX/XELOX +/- bevacizumab DFS NEGATIVE NSAPB-C08 III 2719 FOLFOX +/- bevacizumab DFS NEGATIVE NCCTG NO147 III 2686 FOLFOX+/- cetuximab DFS NEGATIVE PETACC-8 III 1602 FOLFOX+/- cetuximab DFS NEGATIVE CALGB III FU/LV+/-Irinotecan OS/DFS NEGATIVE FNCLCC Accord02 III 397 5FU/LV+/-Irinotecan DFS NEGATIVE PETACC-3 III FU/LV+/-Irinotecan DFS NEGATIVE De Gramont et al, Lancet Oncol 2012; Allegra et al, J Clin Oncol 2011; Alberts S, JAMA 2012; Taieb J, Lancet Oncol 2014; Saltz L, J Clin Oncol 2007; Ychou M, J Clin Oncol 2009; Van Cutsem E, J Clin Oncol 2009

31 Prognostic markers in stage III CRC CLINICAL AND PATHOLOGICAL pt and pn status Tumor side Lymphnode ratio Grading Lymphovascular and perineural invasion Pre-operative CEA Lymphocyte infiltration Immunoscore MOLECULAR CIMP MSI BRAF (in MSS) KRAS (in MSS) HER-2 CDX2 Circulating tumor DNA Molecular signatures CMS subgroups None of these factors today impacts on the indication of adjuvant l-ohp+fluoropyrimidine in stage III

32 Who to treat? unmeet clinical needs 50% cured by surgery alone Adjuvant chemo (fp+oxa) 25% cured by surgery and chemo Stage III CRC pts fit for fluropyrimidine+oxaliplatin 25% relapsed despite surgery and chemo Adapted from Meyerhardt et al, ASCO Ann Meet

33 News: liquid biopsy Use of liquid biopsy for treatment strategy in various stages of cancer EARLY DETECTION Diagnosis of cancer or pre-cancer earlier through screening. LOCALIZED DISEASE Prognostication; Detection of residual disease and treatment personalization in macroscopically resected patients. METASTATIC DISEASE Molecular profiling and replacement of tumor tissue analyses; Prognostication. REFRACTORY DISEASE Monitoring response and tracking resistance; Identification of mechanisms of acquired resistance. adapted from Wan et al, Nature Rev 2017; adapted from Heitzer et al, Precision Oncology 2017

34 Tie et al, ASCO Ann Meeting 2018; abst #3516 ctdna in stage III CRC Disease Free Survival according to ctdna status

35 Take home message - In stage III: plan 6 months of oxaliplatin-based adjuvant therapy. - In low risk of stage II, the oncologists can discuss potential trade-offs between side effects and efficacy of adjuvant therapy. - ctdna could be superior to clinicopathological factors to guide the adjuvant chemo decision.

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