634P - The ave-rec phase II trial of PD-L1/PD-1 blockade with avelumab plus chemoradiotherapy for resectable ESMO high risk rectal cancers

Background

Long course chemoradiotherapy (LCCRT) for locally advanced rectal cancer (LARC) results in a complete pathological CR in 10-30% of patients (pts). Radiotherapy (RT) is immuno-stimulatory by enhancing tumour cell death, but also immunosuppressive stimulating PDL1 production and myeloid-derived suppressor cells. PDL1 inhibition may be required to enhance RT immuno-stimulatory effects. Hypothesis: In pts with resectable LARC, Avelumab given post LCCRT may enhance tumour response rates whilst reducing relapses.

Methods

Phase II single arm trial. Pts had LCCRT (50.4Gy + 5FU [225mg/m²/day/CI] or Capecitabine [825mg/m² BID]/5.5 weeks). Post LCCRT pts received 4 cycles Avelumab (AV) (10mg/kg, q2 weeks), then resection 10-12 weeks post LCCRT. Fresh tumour biopsy/ctDNA sampling taken at pre LCCRT, pre AV and at surgery. Response by FDG PET and pelvic MRI. Inclusion Criteria: pts with MRI stage T3b-4/N1-2/M0 LARC , tumoural lower border <12cm from anal verge, measurable disease, ECOG 0-1, adequate organ function. Endpoints: (a) Primary; Complete pathological response rate (Target ≥ 35%) reported centrally, (b) Secondary; Imaging responses, Toxicity. (c) Exploratory; Tumoural immune cell subsets/checkpoint expression and ctDNA analysis, Distant relapse-free survival and the sites of relapse.

Results

37 pts entered. Baseline TNM: T3b-d 75%, T4a-b 25%. 33 pts completed LCCRT, 31 pts (83%) had all 4 cycles of AV and 32 pts (86%) had surgery. ORR Pelvic MRI (N=33): 2 CR, 14 PR, 31 DCR. FDG PET: 10 CMR, 18 PMR.. 10 pts Grade 3 AEs, 3 pts with treatment-related G3 and no G4 AEs. No immune-related G3 AEs. Post-operative complications as expected. Pathological response (Modified Ryan Score) (N=32): Complete pathCR (18.7%), near CR (15.7%), in MSI-H (N=4), 50% and 25% resp. Median followup 3.1 yrs: 3 yr est. time to progression 82%, distant relapse free survival 80%, disease free survival 80%.

Conclusions

The Ave-Rec phase II study has shown Avelumab post LCCRT is safe with significant imaging responses and complete/near-complete path response rate of 34.3% in pts with ESMO high risk rectal cancers. Parallel translational studies are ongoing. The addition of immune checkpoint inhibitors warrants further evaluation in LARC.

Clinical trial identification

NCT03299660.

Editorial acknowledgement

Legal entity responsible for the study

M. Michael.

Funding

Merck Pty Ltd.

Disclosure

All authors have declared no conflicts of interest.