Many patients with locally advanced rectal cancer receiving a preoperative regimen of standard chemoradiotherapy plus avelumab achieved pathological complete response and the majority of patients showed a major pathological response, according to findings from a phase II AVANA study presented at the ESMO World Congress on Gastrointestinal Cancer 2021 (30 June to 3 July).

Dr. Lisa Salvatore of the Comprehensive Cancer Center, Oncologia Medica, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Università Cattolica del Sacro Cuore in Rome, Italy and colleagues throughout Italy collaborated on the phase II AVANA study. AVANA evaluated the addition of avelumab, a monoclonal antibody targeting PD-L1, to preoperative chemoradiotherapy for the treatment of locally advanced rectal cancer.

She explained that the rationale for this study was based on the idea that preoperative chemoradiotherapy, which is considered the standard of care in the management of locally advanced rectal cancer, combined with immunotherapy could provide enhanced clinical benefit. According to Dr. Salvatore neoadjuvant chemoradiotherapy increases PD-L1 expression in the tumour cells of patients with locally advanced rectal cancer suggesting a PD-1/PD-L1 pathway blockade agent. Furthermore, radiotherapy can induce antigen release from a low neoantigen-burden tumour, such as is found in a mismatch repair proficient colorectal cancer, to activate dendritic cells leading to a CD8-positive T lymphocyte-mediated anticancer immune response.

AVANA was carried out in 10 centres across Italy that enrolled patients with resectable locally advanced rectal cancer, which was defined by the presence of at least one of the following features: lymph node-positive (cN+), invasion to the surrounding tissue (cT4), or high-risk cT3.

All 101 eligible patients received standard preoperative chemoradiotherapy comprising capecitabine at 825 mg/m2 twice daily for 5 days per week plus 50.4 Gy in 28 fractions over 5.5 weeks; in addition, avelumab was administered at 10 mg/kg every 2 weeks for 6 cycles. Surgery with total mesorectal excision was performed 8-10 weeks following chemoradiotherapy end.

The patients’ median age was 63 years (range, 23-82), the majority (61.4%) were male, and 93 (92%) patients had ECOG performance status 0. At baseline, 94 (93%) patients had cN+, and 16 (16%) cT4 locally advanced rectal cancer.

The primary endpoint was the pathological complete response (pCR) rate, defined as complete histological regression with no available tumour cells. Secondary endpoints included the R0 rate, tumour downstaging, local recurrence, sphincter preservation rate, progression-free survival (PFS), overall survival (OS), safety profile, and the evaluation of exploratory predictive and/or prognostic biomarkers.

The investigators planned further study of this experimental regimen if pCR was observed in at least 22 patients.

From April 2019 to November 2020, 101 patients were enrolled, which afforded the required sample size to detect an absolute increment of 10% in the pCR rate assuming a 15% pCR rate, a significance level of 5% (one-side), and a power of 80%. All of the patients completed the induction phase.

In total, 23 patients (23%) demonstrated a pCR, and 60 (60%) patients achieved a major pathological response.

As of the date of the analysis, microsatellite status was available for 62 patients, which revealed that just 2 patients had microsatellite instable high (MSI-H) status and from those 2 patients, one achieved pCR and one major pathological response. Among 60 patients with MSS tumours, 5 (8%) achieved pCR, 41 (69%) major pathological response and there were 14 patients (23%) with no response.  

The rates of grade 3-4 non-immune and immune-related adverse events were 8% and 4%, respectively.

Early interruption of avelumab therapy was reported in 9 patients, which was primarily due to toxicity.


The investigators remarked that the combination of standard preoperative chemoradiotherapy and avelumab showed promising activity and a feasible safety profile. They further concluded that their statistical considerations allowed consideration of the experimental regimen for further studies. Translational analyses on biological samples, in order to identify patients more likely to benefit from the combination of chemoradiotherapy plus avelumab are ongoing. They are awaiting for disease-free survival and OS results, after a longer follow-up.

Sponsorship by GONO and partial support from Merck Serono S.p.A., Rome, Italy, an affiliate of Merck KGaA, Darmstadt, Germany, as part of an alliance between Merck KGaA and Pfizer were disclosed.

Dr. Eric Deutsch of the Gustave Roussy in Villejuif, France, who discussed the study findings, commented about favourable safety profile of avelumab and preoperative chemoradiotherapy, no impact on surgery, interesting response rate, and responses observed in MSS rectal cancer. According to Dr. Deutsch, there is a need for randomisation and information on biomarkers, Immunoscore, RAS, RAF, PTEN, PI3K status.


O12 – Salvatore L, Bensi M, Corallo S, et al. Phase II Study of Preoperative (Preop) Chemoradiotherapy (CTRT) Plus Avelumab (AVE) In Patients (PTS) With Locally Advanced Rectal Cancer (LARC): The AVANA Study. ESMO World Congress on Gastrointestinal Cancer 2021 (30 June – 3 July).