Neoadjuvant Botensilimab and Balstilimab for the Treatment of Advanced Resectable Colorectal Cancer NEST3

PRIMARY OBJECTIVE: I. To estimate the two-year disease-free survival (DFS) rate when treating advanced mismatch repair proficient (pMMR)/microsatellite stable (MSS) colorectal cancer with botensilimab (BOT)/balstilimab (BAL) followed by surgery. SECONDARY OBJECTIVES: I. To determine the major pathologic response rate for patients with advanced mismatch repair proficient or microsatellite stable (pMMR or MSS) colorectal cancer treated with botensilimab (BOT) + balstilimab (BAL) followed by surgery. II. To evaluate the safety of treating advanced pMMR/MSS colorectal cancer with BOT/BAL followed by surgery. III. To estimate the pathologic response rate when treating advanced pMMR/MSS colorectal cancer with BOT/BAL followed by surgery. IV. To estimate the three-year disease-free survival rate when treating advanced pMMR/MSS colorectal cancer with BOT/BAL followed by surgery. V. To estimate the median recurrence free survival in patients with advanced pMMR/MSS colorectal cancer with BOT/BAL followed by surgery, among patients who are disease free at the time of surgery. VI. To describe the proportion of patients that get all four doses of BAL. VII. To describe the quality of life of patients with advanced pMMR/MSS colorectal cancer with BOT/BAL followed by surgery. VIII. To describe the time to surgery after treating advanced pMMR/MSS colorectal cancer with BOT/BAL followed by surgery. IX. To describe the percent of pMMR/MSS colorectal cancer patients treated with BOT/BAL followed by surgery in which adjuvant therapy is recommended, amount and type received, as well as patient refusal rate. EXPLORATORY OBJECTIVES: I. To examine changes in tumor microenvironment in response to BOT/BAL when treating advanced pMMR/MSS colorectal cancer. II. To explore the serial changes in circulating tumor deoxyribonucleic acid (ctdna) when treating advanced pMMR/MSS colorectal cancer with BOT/BAL followed by surgery. III. To explore markers on baseline imaging that correlate with response and long-term outcomes. IV. To determine ctDNA and cell free deoxyribonucleic acid (cfDNA) detectability before, during and after neoadjuvant BOT/BAL and curative-intent surgical resection. V. To describe the association between detectable ctDNA and cfDNA measured before, during and after neoadjuvant post-neoadjuvant treatment and surgery with DFS and pathologic response. VI. To describe the difference in time between ctDNA and cfDNA detection (molecular recurrence) and radiographic evidence of disease recurrence following definitive treatment among patients who achieved undetectable ctDNA and/or cfDNA levels after surgery. VII. Among patients that get presurgical standard of care (SOC) imaging, to describe the presurgical radiologic response. OUTLINE: Patients receive botensilimab intravenously (IV), over 30 minutes, on day 1 and balstilimab IV, over 30 minutes, on days 1, 15, 29 and 43 in the absence of disease progression or unacceptable toxicity. 5-16 weeks later, patients then undergo standard of care resection surgery. Patients undergo computed tomography (CT) scan and/or magnetic resonance imaging (MRI) and blood sample collection throughout the study. After completion of study treatment, patients are followed up at 2 weeks, 4 weeks and every 3 months for 2 years then every 6 months for 1 year.