HIGHLIGHTS DANS LE CANCER DU RECTUM

REGINA TRIAL

Dr Yeter Gökburun

Gastro-Entérologie et Oncologie Digestive

Centre Hospitalier Régional de Namur

Institut Jules Bordet

REUNION MEDICALE 29-04-2021

2e cancer le plus fréquent chez la femme après celui du sein

3e cancer le plus fréquent chez l’homme après ceux de la prostate et du poumon

CAUSES ET FACTEURS DE RISQUE

Age: > 50 ans dans 90% cas

Les habitudes de vie en cause :

alimentation riche, notamment en graisses animales; viande rouge;

Inactivité physique;

Surpoids;

Alcool;

Tabac

ATCD personnels et familiaux : polypes, CCR, MICI, PAF, Syndrome de Lynch

D+ abdominale ou anale

Sang dans les selles

Alternance diarrhée et constipation

Epreintes

TR: masse palpée

Amaigrissement , anorexie et fatigue

Test iFOBT

CLINIQUE

Glynne-Jones, Ann Oncol 2017

ESMO guidelines for nonmetastatic rectal cancer (2017)

Swedish Rectal Cancer Trial, N Engl J Med 1997

1. Roh et al, J Clin Oncol 2009

2. Sauer et al, N Engl J Med 2004

Sauer et al, N Engl J Med 2004

RCT NA

RCT A

Sauer et al, J Clin Oncol 2012

Pied de page à compléterDutch CKVO 95-04 TME TrialKapiteijnet al, N EnglJ Med 2001

Cochrane Database Syst Rev 2013

Erlandssonet al, Lancet Oncol 2017

2021: Where are we?

3-yr DFS

RAPIDO

30.4% [95%CI: 26.1-34.6]

for the CRT group

23.7% [95%CI: 19.8-27.6]

for the TNT group

3-yr DRTF

Total neoadjuvant therapy: RAPIDO and PRODIGE 23

CRT Surgery

High-risk

rectal cancer*

N=885

Optional CAPOX x8

or FOLFOX x12

SCRTCAPOX x6

or FOLFOX x9Surgery

R

PRODIGE 23

CRT Surgery

Stage II-III

rectal cancer

N=461

mFOLFOX x12

or Cape x8

mFOLFIRINOX x6 CRT Surgery

R

mFOLFOX x6

or Cape x4

Bahadoer, ASCO 2020; Bahadoer, Lancet Oncol 2020; Conroy, ASCO 2020

* ≥1 high-risk features: CRM+, T4, N2, lateral N+, EMVI

Treatment pCR p value

Standard 14.3% <0.001

TNT 28.4%

Treatment pCR p value

Standard 12.1% <0.001

TNT 27.8%

Total neoadjuvant therapy: RAPIDO and PRODIGE 23

Which sequence to choose?

- Improved DFS and MFS with Polychemo

- Improved compliance with chemoradiation therapy in group with

consolidation chemo (CAO/ARO/AIO-12: 97% vs 91%)

- DFS-3yr: similar results (75.7% Prodige 23 – 76,4% Rapido)

- No significant improvement in OS

- No significant improvement in local control in both studies

- Same results for pRC

- Tren_

SCRT or CRT

The new paradigm for stage II-III rectal cancer

The “treatment ceiling effect” in rectal cancer

TME

Neoadj RT

Neoadj CRT

Neoadj SCRT

Adj CT

TNT

The “treatment ceiling effect” in rectal cancer

TME

Neoadj RT

Neoadj CRT

Neoadj SCRT

Adj CT

TNT

Immunotherapy?

- Variation anormale du nombre de

séquences répétées dans l'ADN

tumoral comparé à l'ADN du même

patient provenant de tissu sain

- Décrite d’abord dans le syndrome de

Lynch ou syndrome HNPCC

(hereditary nonpolyposis colon

cancer) (95 % des cas)

- 15 % CCR sporadiques

- Recherche par PCR de 5 marqueurs

microsatellites répartis dans le

génome des cellules tumorales.

INSTABILITE DES MICROSATELLITES (MSI)

Why immunotherapy for rectal cancer?

Walle, Ther Adv Med Oncol 2018; Vanpouille-Box, Nat Comm 2017

The vast majority of rectal cancers are MSS/MMRp, but…

The immunomodulatory effects of RT may increase the therapeutic potential of ICIs

Immunotherapy for rectal cancer is now a hot topic

About 30 ongoing/planned

clinical trials (ie, >1700 pts)

with ICIs or other immuno-

modulatory agents

REGorafenib and nIvolumab iN rectAl cancer

(REGINA)

A phase II trial of neoadjuvant regorafenib in combination

with nivolumab and short-course radiotherapy in

intermediate-risk, stage II-III rectal cancer

The REGONIVO (EPOC1603) trial

Gastr(n=25)

Colon(n=25)

≥3 prior linesof tx

64% 80%

Prior ICIs 28% 0

MMRp/MSS 100% 96%

Median TMB 9.2 10.9

CPS ≤1 58% 67%

Phase Ib trial (JAPAN)

Median PFS 5.6 m (GC) and 7.9 m (CRC)1-year PFS 22.4% (GC) and 41.8% (CRC)

Median OS 12.3 m (GC) and NR (CRC)1-year PFS 55.3% (GC) and 68% (CRC)

ORR 44% ORR 36%

Fukuoka, J Clin Oncol 2020

REGorafenib and nIvolumab iN rectAl cancer (REGINA)

Single-arm phase II study

Simon’s two-stage design

+ early safety analysis

Primary endpoint: pCR

Sample size: max 60 pts

REGINA – Main inclusion criteria

Histologically or cytologically verified adenocarcinoma of the rectum

Tumour with distal border below the peritoneal reflection and within 15 from the anal verge

Intermediate-risk rectal cancer as defined by the followingcriteria on baseline pelvic MRI:

• cT3/T4a, Nany or cT1-2, N+

• No involvement/threatening of the mesorectal fascia

• No involvement of lateral pelvic lymph nodes

Absence of distant metastases at baseline CT scan of the thorax-abdomen and (PET)/CT scan

SurgeryDr Anguraj Sadanandam

Systems and Precision Cancer Medicine Team

Prof Jeroen RaesLaboratory of Molecular Bacteriology (Rega Institute)

S

ur

g

er

y

Prof Eleonora LeucciTrace Platform

Prof Diether Lambrecths VIB-KU Leuven Center for Cancer Biology

Dr Francesco SclafaniGUTS Lab

Prof François GhiringhelliGenetic and Immunotherapy Medical Institute

Center Georges Francois Leclerc

REGINA – TR plan

UZ ANTWERPENUZ GENT

AZ GROENINGESAINT-LUC

ERASME

BORDET

GHd CHARLEROI

CHR NAMURCHU NAMUR - GODINNE

CHIREC - DELTA

REGINA – Participating centres

Please, considering referring your

patients to the nearest study site!

TNT is a new standard of care for high-risk stage II and stage III cancers

A substantial proportion of locally-advanced rectal cancer patients still

experience treatment failure and tumour recurrence

Any further survival gain in this setting is likely to be achieved with alternative

treatment strategies

Preclinical data provide a sound rationale for the combination of ICIs, multi-

TKI and RT

The REGINA trial is a novel-design clinical trial that: will build on data from studies of ICIs with standard (C)RT

will provide an optimal in vivo platform for correlative biomarker analyses

Conclusions

THANKS

If you have any questions: yeter.gokburun@chrsm.be