2248P - Capecitabine-based concomitant chemoradiation followed by durvalumab as a neoadjuvant strategy in locally advanced rectal cancer (PANDORA trial): Molecular profiling and translational results

Background

The combination of preoperative chemo- and radiotherapy (CRT) is the standard treatment in locally advanced rectal cancer (LARC). The benefit of the addition of immunotherapy in the neoadjuvant treatment is under investigation. However, a wide genomic characterization is needed to better stratify LARC patients (pts) for the most adequate treatment.

Methods

We analysed cancer tissues from 48 pts enrolled in the PANDORA trial (NCT04083365) in which a capecitabine-based concomitant CRT followed by durvalumab was administrated. DNA was extracted from bioptic chemo-naïve formalin-fixed paraffin-embedded samples. Genetic alterations of more than 500 genes, microsatellite instability (MSI) and tumor mutational burden (TMB) status were characterized using TSO500HT panel on an Illumina Novaseq 6000 instrument. PD-L1 expression was evaluated by the combined positive score (CPS). Pathological response was centrally determined on surgical specimens and was evaluable for 46 pts. A pathological complete response (pCR) was defined as ypT0N0M0.

Results

Pathogenic variants on APC, TP53, KRAS, FBXW7, PIK3CA, SMAD4, AMER1 and ARID1A genes were the most frequent mutations. Overall, 17/46 (37%) pts achieved a pCR. Interestingly, ARID1A and SMAD4 alterations occur only in patients without a pCR, being mutated in the 17% and 21% of pts, respectively. In particular, a more significant association was reached for SMAD4 when either pathogenetic variants and variants of uncertain significance (VUS) were considered (p=0.019). Only 4% and 31% of pts had MSI and high TMB, respectively, but no significant association with response was found. High TMB status was significantly related to ARID1A, FBXW7, MYC and RICTOR1 mutations. SMAD4 mutations resulted significantly associated with low levels of PD-L1 expression (p=0.017). Indeed, 75% of the mutated pts as compared to the 27% of the wild type pts reported PD-L1 CPS values less than 10.

Conclusions

SMAD4 mutations are related to the absence of complete response and to a low PD-L1 expression. SMAD4 alterations should need further investigation in LARC pts treated by combined CRT followed by durvalumab.

Clinical trial identification

NCT04083365.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.