Efficacy and safety of combining short-course neoadjuvant chemoradiotherapy with envafolimab in locally advanced rectal cancer patients with microsatellite stability: a phase II PRECAM experimental study

Abstract

Background: Conventional neoadjuvant chemoradiotherapy (nCRT) yields a pathologic complete response (pCR) rate of 15-30% for locally advanced rectal cancer (LARC). This study ventures to shift this paradigm by incorporating short-course nCRT with immunotherapy, specifically Envafolimab, to achieve improved treatment efficacy and possibly redefine the standard of care for LARC.

Materials and methods: The PRECAM study is a prospective, single-arm, phase 2 clinical trial for LARC in patients with microsatellite stable (MSS) tumors. Participants received short-course radiotherapy (25Gy/5f), followed by two cycles of CAPEOX chemotherapy and six weekly doses of Envafolimab, a PD-L1 antibody, before total mesorectal excision surgery. The primary endpoint was the pCR rate.

Results: From April to December 2022, 34 patients were enrolled, of whom 32 completed the study, each diagnosed with an MSS rectal adenocarcinoma. All patients underwent preoperative CRT combined with Envafolimab. Remarkably, a pCR rate of 62.5% (20/32) was attained, and a significant pathologic response rate of 75% (24/32) was achieved. Additionally, 21 of 32 participants achieved a neoadjuvant rectal (NAR) score below 8, suggesting an effective treatment response. Common adverse events included tenesmus (78.1%), diarrhea (62.5%), and leukocyte decrease (40.6%). Two Grade 3 adverse events were noted, one related to liver function abnormality and the other to a decrease in platelet count. Surgical procedures were performed in all cases, with minor complications, including ileus, infections, and anastomotic leakage. As of this report, there have been no reported cases of recurrence or death during the follow-up period, ranging from 12 to 20 months.

Conclusion: In LARC patients exhibiting MSS tumors, combining short-course nCRT with Envafolimab demonstrated favorable efficacy, leading to a significant pCR rate. Minor adverse effects and surgical complications were observed. These preliminary but promising results underscore the potential of this approach and call for further exploration and validation through a randomized controlled trial.

Figure 1

Workflow of the study. Flowchart in Figure 1A details the process from patient enrollment to the implementation of our treatment protocol. Figure 1B delineates the treatment strategy employed in this study.

Figure 2

Comprehensive analysis of treatment response in MSS-type LARC. Figure 2A illustrates the changes in T-stage before and after the treatment. Figure 2B depicts the shifts in N-stage as a result of the treatment. Figure 2C compares the tumor diameters measured on MRI images before and after the treatment. Figure 2D categorizes patients based on their post-treatment pathological TRG. Figure 2E focuses on the MR-TRG grouping post-treatment. Figure 2F displays the distribution of NAR scores for each sample, quantifying the degree of response to the neoadjuvant therapy.

Figure 3

Evolution of endoscopic, radiographic, and pathological responses in representative cases across TRG groups. This figure provides a detailed visual representation for each TRG subgroup, illustrating the treatment’s impact. For each subgroup, we present a set of images: endoscopic images and MR images taken before and after treatment, alongside corresponding postsurgical pathological findings.

Figure 4

Genetic mutation profiles in study samples. Figure 4A offers a comprehensive overview of the mutations identified across all samples, illustrating the range and frequency of genetic alterations. Figure 4B presents a focused comparison of mutations between the pCR and non-pCR groups.