Immunotherapy In Locally Advanced Rectal Cancer

Summary

Preoperative CTRT is considered the standard of care in the management of LARC. Preoperative CTRT approach results in significant tumor downstaging and local control with a complete pathological response rate of about 15% even if additional therapeutic strategies should be explored to improve outcomes, expecially for T4 cancers.

Immunotherapy with PD-1/PD-L1 immunocheckpoint blockade (ICB), turned out a breakthrough in cancer treatment among different tumor types, including CRC. An ICB strategy could lead up to a 40% of response in metastatic CRC with deficient mismatch repair (MMR) status. Unfortunately, the activity of ICBs in MMR proficient mCRC is extremely low but it might be improved using immunomodulatory strategies as demonstrated by Bendell et al.

In this context, the role of RT in revert the tolerance to a low neoantigen-burden (such as in MMR proficient CRCs) by the induction of antigen release from the tumour and activation of dendritic cells leading to a CD8+ T lymphocyte-mediated anticancer immune response has been widely elucidated. Moreover, antineoplastic agents can be exploited to target other crucial cellular effectors of immunosuppressive tumor microenvironment (i.e. regulatory T cells and myeloid-derived suppressor cells).

In line with these evidences, Hecht et al. have recently reported that in rectal cancer patients, neoadjuvant CTRT increases PD-L1 expression in tumor cells, strongly suggesting a neoadjuvant combinatory strategy with RT and PD-1/PD-L1 pathway blockade. The integration of immunotherapy in the neoadjuvant setting (instead of adjuvant one) for the management of LARC is also supported by preclinical findings showing that in metastatic breast cancer mice models, neoadjuvant immunotherapy is superior in inducing long-term survivors, compared with adjuvant strategy with a greater magnitude of tumor-specific T cell expansion in neoadjuvant treated mice and a better anti-tumor T cell-mediated immune response.

On the basis of such considerations, there is a strong biological and clinical rationale for testing the addition of avelumab, an anti-PD-L1 moab, to capecitabine-based CTRT in patients with technically resectable, LARC. The aim of this strategy is to lead to significant improvements of pCR and, ultimately, patients' survival.

Conditions

• Colon Rectal Cancer

Interventions

DRUG

Avelumab

Eligible patients will receive: CHEMORADIOTHERAPY PLUS AVELUMAB: * CAPECITABINE 825 mg/sqm/bid p.o. 5 days/week * EXTERNAL-BEAM IRRADIATION 50.4 GY in 28 fractions over 5.5 weeks * AVELUMAB 10 mg/Kg ev over 1 hour every 2 weeks at days 1, 14, 28, 42, 56, 70 Surgery with TME must be performed at week 8-10 after the end of CTRT. The final choice of surgical procedure (ie, abdominoperineal surgery or anterior resection) is at the surgeon's discretion.

DRUG

Capecitabine

Eligible patients will receive: CHEMORADIOTHERAPY PLUS AVELUMAB: * CAPECITABINE 825 mg/sqm/bid p.o. 5 days/week * EXTERNAL-BEAM IRRADIATION 50.4 GY in 28 fractions over 5.5 weeks * AVELUMAB 10 mg/Kg ev over 1 hour every 2 weeks at days 1, 14, 28, 42, 56, 70 Surgery with TME must be performed at week 8-10 after the end of CTRT. The final choice of surgical procedure (ie, abdominoperineal surgery or anterior resection) is at the surgeon's discretion.

RADIATION

EXTERNAL---BEAM IRRADIATION 50.4 GY

Surgery with TME must be performed at week 8-10 after the end of CTRT. The final choice of surgical procedure (ie, abdominoperineal surgery or anterior resection) is at the surgeon's discretion.

Sponsors & Collaborators

• Gruppo Oncologico del Nord-Ovest

  lead OTHER

Study Design

Allocation

NA

Purpose

TREATMENT

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2019-04-01

Primary Completion

2021-02-15

Completion

2023-09-30

Countries

• Italy

Study Locations