Oral Abstract DiscussionRectal cancer

Abstracts # 62 VOLTAG Study and # 556 CAO/ARO/AIO-12

Ali Shamseddine,MD,FRCP

Professor of Clinical Medicine

Director GI&GU Cancer Programs

NK Basile Cancer Institute, AUBMC

Disclosure

• Advisory Boards:Roche, Sanofi, Pharmamed,MSD,Bayer,Lilly,Janssen,

Pierre Fabre,Merck

• Research Grants:Roche, Sanofi, Novartis,GSK, Merck, BMS

• Educational Materials and Honoraria:Roche, Sanofi,MSD,Amgen, Merck,Pierre Fabre

Current Outcome for Stage II/III Rectal Cancer

•5 year local relapse rate 5-10%

• pCR rates < 20%

•Deaths occur from distant metastatic disease

- Good local control (TME and RT)- Neoadjuvant chemoRT (reduced toxicity)

- Surgery still required for most patients

- 5 year DFS ~ 65%- 5 year OS ~ 75%

Sauer R, et al. N Engl J Med 2004;351:1731-40Roh M, et al. J Clin Oncol 2009;27:5124-30Allegra CJ, et al. J Natl Cancer Inst 2015 Sept 14;107(11)

Hypothesis: Can Chemoradiation Modulate Microenviroment in MSS Rectal Cancer Patients?

Can we convert noninflamed tumors to become inflamed?

Increase number of antigen-specific T cells or

increase antigen presentation

Chemoradiation

Bring T cells in contact with cancer cells

Accelerate or remove brakes on T cell response with the use of

check point inhibitors

MSS (>95% of CRC)

Increases tumor infiltration with dendritic, CD+ T cells, Treg cells

Releases of neoantigens and inflammatory cytokines

Kim JM, et al. Ann Oncol. 2016;27(8):1492-1504. Hegde PS, et al. Clin Cancer Res. 2016;22(8):1865-1874Weichselbaum RR, et all. Nature Reviews 2017.

Stimulates PD-L1 production and immune- suppressive activity MDSCs

Hypothesis: Can Chemoradiation Modulate Microenviroment in MSS Rectal Cancer Patients?

Can we convert noninflamed tumors to become inflamed?

Increase number of antigen-specific T cells or

increase antigen presentation

Chemoradiation

Bring T cells in contact with cancer cells

Accelerate or remove brakes on T cell response with the use of

check point inhibitors

MSS (>95% of CRC)

Increases tumor infiltration with dendritic, CD+ T cells, Treg cells

Releases of neoantigens and inflammatory cytokines

Kim JM, et al. Ann Oncol. 2016;27(8):1492-1504. Hegde PS, et al. Clin Cancer Res. 2016;22(8):1865-1874Weichselbaum RR, et all. Nature Reviews 2017.

Stimulates PD-L1 production and immune- suppressive activity MDSCs

Abstracts :TPS3620 (NSABP FR-2) & TPS3622 ( The Ave-Rec Trial) ASCO 19

VOLTAGE Study

-Design:

-Primary endpoint: pCR by ICA using TRG score

-Secondary end point: pCR by LA, ORR, RFS, OS, Safety, RCPT, RRR

-Patients and statistical method: Cohort A1 (MSS) 37 pts to achieve 30% pCR(10%) , Cohort A2 (MSI) 5 pts, exploratory

-Results: Cohort A1 pCR (TRG 0) 11/37 (30%) , 3/37 (8%) (TRG1) with MPR 14/37 (38%)

-VOLTAGE study for advanced T/N stage: MPR 42% in T3/or N+ and for stage III (44%) compared to stage II (37%)

-PD-L1 expression and elevated CD8/eTreg ratio performed on biopsy before CRT and not after CRT may be better predictive of CPI benefit

ChemoRT Nivolumab x5 Surgery Adj Chemo

Rectal Cancer(cT3-T4,any N M0,(<12cm)

Translational Research

WGS, immune cell infiltration, HLA Haplotyping, T cell receptor and Enteric bacteria

Interpretation of the study outcome

• A positive study for the primary end point

But several questions should be answered in future trials

• Can we achieve the same results with different approach?

• What is the best modality of radiation therapy (SCRT vs LCCR) in combination with CPI?

• Weather adding CPI to LCCR or delaying surgery beyond 8 weeks after LCCR contributes to increasing pCR ?

• What is the best tool to measure the effect of CPI after LCCR, is it TNM and TRG or immunoscore and LNR?

Total Neoadjuvant Therapy (TNT)A Multicenter Phase II Trial

Gracia-Aguilar J.Lancet Oncol 2015;16:957-66Marco MR, et al. Dis Colon Rectum 2018:61:1146-1155

Disease-free survival was significantly associated withstudy group, ypTNM stage, and pathological complete response

(p = 0.004)

Median F/U 59 mo(Range, 9-125 mo)

OS in Rectal Cancer

Swedish Trial13 year follow up

Flkesson J, et aj. J Clin Oncol 2005

908 pts P= 0.008

38%

30%

OS at 3yA: 73% P=0.046B: 65%

AB

Bujko K et al. Ann of Oncol 2016;27:834-842

POLISH II Trial

541 pts

Tumor response takes time after completion of neoadjuvant therapy (CRT)

(OSTRiCh Consortium)Probst CP,et al. JACS 2015;221(2):430-440

National Cancer Data Base

Prognostic Value of Clinical vs Pathologic Stage in Rectal Cancer Patients Receiving Neoadjuvant Therapy

Delitto D, et al. JNCI Natl cancer Inst, 2018;110(5)

P=0.18P=0.12

P=0.44P=0.22

P<.001P=0.26

P<.001P=0.79

NCDB 2004-2014/ 44,320 pts with Rectal Cancer

Survival in Rectal Cancer is Driven by Post Therapy Pathologic Stage

Immunoscore in Patients with Rectal cancer

Anitei MG,et al. Clin Cancer Res 2014;20(7):1891-9

Tumor immune infiltrates in biopsies before surgery are predictive of response to chemoradiation

Abstract # 556CAO/ARO/AIO-12

• PhaseII,randomized for stage II&III rectal cancer: ↑pCR 15-25%

• Other end points: treatment compliance, toxicity, pathologic downstagingTRG, surgical complications, R0 and sphincter sparing surgery rates, CRM negativity, locoregional and distant recurrence, OS and QOL beside translational research

306 pts

156 pts 150 pts

Chemotherapy→CRT→SurgeryFOLFOX x 3 TME, W18

A B

CRT→Chemotherapy→SurgeryFOLFOX x 3 TME, W18

Pick the-winner

Randomisation

Up to 12 cm from anal verge⬧<6 cm : cT3 ⬧6-12 cm: cT3c-d, cT4 and N+

If the Compliance to Adjuvant Chemotherapy is Suboptimal, Why not to Give it Preoperatively?

• 27% of eligible patients with LARC never start adjuvant chemotherapy

• Delaying adjuvant chemotherapy beyond 12 weeks post-op will have a negative impact on outcome, any additional 4 weeks delay will result in 14% increase in mortality

• <50% receive the full dose and course without interruptions or delays owing to postoperative complications, delayed recovery, or interference caused by the need for a temporary ostomy closure (5-FU dose is <30% of the planned)

• No impact on OS in all randomized trials using preoperative CRT followed by TME followed by adjuvant chemotherapy

Khrizman P, et al. J Clin Oncol 2013;31(1):30-38

Adjuvant Chemotherapy in Rectal CancerMeta-analysis of Individual Patient Data

1196 patients,4 European randomized controlled phase III trials comparing observationwith adjuvant chemotherapy after preoperative chemoradiation and surgery

OSHR 0.97P=0.775

I-CNR-RT trial

CHRONICLE trial

PROCTOR-SCRIPT trial

EORTC 22921 trial

Patients at 10-15cmDFS : HR 0.59

P=0.005Distant recurrence

HR 0.61P=0.025

Breugom AJ.Lancet Oncol 2015;16:200-07

Which factors influence the choice of local or systemic therapy?

CRM+

T3 >5mm

or T4

T3 low lying tumour or

T4

N+

EMVI+

Local recurrence Distant recurrence

Abstract # 556CAO/ARO/AIO-12

Group A Group B

pCR* 17% P=0.210 25% P< 0.001

Compliance to CRT 78% 91%

CRT G3&4 toxicity 37% 27%

Full dose of XRT 91% 97%

Concomitant 5-FU 78% ( mean 90 ± 27% ) 87% ( mean97 ± 15% )

Concomitant OX 76% ( mean 87 ± 28% ) 93% ( mean 97 ± 14% )

Completed 3 cycles of OXCompleted 3 cycles of FU

92% ( mean 94 ± 17% )

93% ( mean 96 ± 14% )

85% ( mean 87 ± 28% )

90% ( mean 91 ± 26% )

Results

*Statistical calculation: each group versus 15% expected after standard CRT

Abstract#556CAO/ARO/AIO-12

• The study is positive for the primary end point with a TNT sequence that fulfilled the predefined trial hypothesis of an increased pCR rate of 25% as compared to historical pCR after preoperative chemoXRT alone set at 15%, whereas the inverse sequence did not. No increase on toxicity or surgical complications with a better compliance with CRT and less compliance with chemotherapy , but longer F/U is needed (limitation for survival) BUT:

• In group B , increasing pCR may be due to delaying surgery up to 90 days compared to group A with average 45 days(other factors: patient cohort, lack of central pathology review and of random assignment)

• The routine use of oxaliplatin with radiation is not recommended and may be contributing to increasing toxicity and decreased compliance with chemotherapy in group B

• To identify who will benefit from adding oxaliplatin to 5-FU with radiation ( patient < 60y as in 04 trial beside excluding stage II patients)

• What about SCRT vs LCCR in TNT?

Discussion

CAO/ARO/AIO-04 Trial

• Not a standard of care although fulfilled the primary end point DFS (P=0.038)

• Increased grade 3&4 GI toxicity during neoadjuvantchemoXRT 21%(OX) vs 15%(FU) with diarrhea 12% vs 8%

• 21% and 22% of patients did not initiate adjuvant chemotherapy

• 36% of patients in both arms had G 3&4 toxicity

• Minimal improvement in resection rate 95% in both with pCR 17% (OX) vs 13 (FU) NS

Forest plots of comparison between short-term versus long-term treatments on other outcomes. (a) death

rate; (b) recurrence rate; (c) complications; (d) distant metastasis

BUT

Short Course Radiation vs Chemoradiation

Chen et al. Journal of Cancer Research and Therapeutics - Volume 14 - Supplement Issue 1 - 2018

Surgery

Postoperativedoublet

chemotherapy

PreoperativeSCRT or LCCRfollowed by

chemotherapy

PreoperativeRT or CRT

Node positive

A suggested risk-adapted therapeutic strategy

Age <75 years

Good PS

CRM+

T3 low lyingtumour

T3c/d (>5mm)T4

Dependent on

pathology

On-going Clinical Trials (TNT)

• Short course (RAPIDO Trial)

• Chemo alone with elimination of RT (BACCHUS Trial)

• Selective elimination of RT (PROSPECT and FAVORE Trials)

• Selecive elimination of surgery (OPERA trial)

• Testing new agents with RT ( NRG GI-002 Trial)

THANK YOU