Short-course radiation followed by mFOLFOX-6 plus avelumab for locally-advanced rectal adenocarcinoma

Abstract

Background Current standard practice for locally advanced rectal cancer (LARC) entails a multidisciplinary approach that includes preoperative chemoradiotherapy, followed by total mesorectal excision, and then adjuvant chemotherapy. The latter has been accompanied by low compliance rates and no survival benefit in phase III randomized trials, so the strategy of administering neoadjuvant, rather than adjuvant, chemotherapy has been adapted by many trials, with improvement in pathologic complete response. Induction chemotherapy with oxaliplatin has been shown to have increased efficacy in rectal cancer, while short-course radiation therapy with consolidation chemotherapy increased short-term overall survival rate and decreased toxicity levels, making it cheaper and more convenient than long-course radiation therapy. This led to recognition of total neoadjuvant therapy as a valid treatment approach in many guidelines despite limited available survival data. With the upregulation (PDL-1) expression in rectal tumors after radiotherapy and the increased use of in malignant melanoma, the novel approach of combining immunotherapy with chemotherapy after radiation may have a role in further increasing pCR and improving overall outcomes in rectal cancer. Methods The study is an open label single arm multi- center phase II trial. Forty-four recruited LARC patients will receive 5Gy x 5fractions of SCRT, followed by 6 cycles of mFOLFOX-6 plus avelumab, before TME is performed. The hypothesis is that the addition of avelumab to mFOLFOX-6, administered following SCRT, will improve pCR and overall outcomes. The primary outcome measure is the proportion of patients who achieve a pCR, defined as no viable tumor cells on the excised specimen. Secondary objectives are to evaluate 3-year progression-free survival, tumor response to treatment (tumor regression grades 0 & 1), density of tumor-infiltrating lymphocytes, correlation of baseline Immunoscore with pCR rates and changes in PD-L1 expression. Discussion Recent studies show an increase in PD-L1 expression and density of CD8+ TILs after CRT in rectal cancer patients, implying a potential role for combinatory strategies using PD-L1- and programmed-death- 1 inhibiting drugs. We aim through this study to evaluate pCR following SCRT, followed by mFOLFOX-6 with avelumab, and then TME procedure in patients with LARC. Trial registration Trial Registration Number and Date of Registration: ClinicalTrials.gov NCT03503630, April 20, 2018.

Total Neoadjuvant Therapy vs Standard Therapy in Locally Advanced Rectal Cancer

“…In addition, immune checkpoint inhibitors such as durvalumab, avelumab, and nivolumab and other novel agents such as peposertib, a DNA protein kinase inhibitor, and aflibercept, an angiogenesis inhibitor, are being investigated in a TNT setting. 32 , 33 , 34 , 35 , 36 A list of recent and ongoing TNT trials that are yet to be published is included in eTable 2 in the Supplement . 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 …”

Clinical evidence for synergy between immunotherapy and radiotherapy (SITAR)

“…Shamseddine et al conducted a phase 2 trial for locally advanced rectal cancer (T2N+ or T3 or T4a) of short-course radiation (25 Gy in five fractions) followed by six cycles of FOLFOX plus avelumab and total mesorectal excision and found a CR rate of 25%. 22 Rahma et al reported on 185 rectal cancer patients, CR after neoadjuvant CRT +/À pembrolizumab did not show any difference, although long-term survival data are awaited. Grade 3-4 adverse events were slightly increased in the pembrolizumab arm (48.2%) vs the control arm (37.3%) during CRT.…”

“…Shamseddine et al . conducted a phase 2 trial for locally advanced rectal cancer (T2N+ or T3 or T4a) of short‐course radiation (25 Gy in five fractions) followed by six cycles of FOLFOX plus avelumab and total mesorectal excision and found a CR rate of 25% 22 . Rahma et al .…”

Neoadjuvant chemotherapy and radiotherapy followed by resection/ablation in stage IV rectal cancer patients with potentially resectable metastases

“…However, there were still 34.6% of patients who had disease progression after treatment. Immunotherapy, targeted therapies and triplet chemotherapy which might facilitate the removal of potential micrometastasis and the strategy of total neoadjuvant therapy could be considered, to improve the treatment efficacy [ 31 , 32 ].…”