Rectal cancer is treated with induction chemotherapy followed by chemoradiationand subsequentsurgery. Most patients who have undergone this sequential treatment approach have significant tumor downstaging , and up to 30% achieve complete clinical and pathologic responses. Approximately 5-10%of all rectal cancers are deficient in mismatch repair (dMMR) and tumors with this genetic defect respond poorly to standard therapy. Studies in metastatic patients with dMMR have demonstrated durable response to checkpoint inhibition, with nearly 20% achieving a complete clinical response with PD-1 blockade. We seek to improve outcomes in dMMR rectal cancers by treatment with upfront PD-1 blockade with or without standard chemoradiotherapy, with the goal of increasing the number of complete clinical responses and improving the chances of organ preservation and reduction in morbidity. Our proposed clinical trial incorporates neoadjuvant PD-1 blockade in patients with dMMR locally advanced rectal cancer. Utilizing collected biospecimens from patients enrolled in this trial we will use genomic assessments to determine if the intrinsic features of these dMMR rectal tumors can predict for resistance or response to PD-1 blockade (Aim 1) and determine if we can predict which patients will achieve long-term benefit from neoadjuvant PD-1 blockade using circulating tumor DNA (ctDNA) to monitor tumor response (Aim 2).
We will perform an in-depth analysis of the effects of neoadjuvant PD-1 blockade in locally advanced rectal cancer with mismatch repair deficiency to expand on the biology behind response and resistance to this therapy as well as to evaluate the use of ctDNA as a marker for tumor response. Our trial will change the wa y these patients are treated, and this proposal will deliver an improved understanding of the fundamental mechanisms behind response to PD-1 blockade and noninvasive monitoring of response, which are vital steps towards improving patient outcomes.
