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Total neoadjuvant therapy in rectal cancer may increase pathological complete response rates potentially allowing for a nonoperative approach.The objective was to identify patient and tumor characteristics that predict a complete response following total neoadjuvant therapy.This was a retrospective cohort study.This study was conducted at a university-based National Cancer Institute-designated Comprehensive Cancer Center.The patients include those with Stage 2 or 3 rectal adenocarcinoma.Total neoadjuvant therapy, total mesorectal excision, nonoperative management.Complete response was defined as patients with a clinical complete response undergoing non-operative management who remained cancer-free or patients undergoing surgery with a pathological complete response.Among 102 patients, median age was 54 years, 69% were male, median carcinoembryonic antigen level was 3.0 ng/mL, and the median distance of the tumor above the anorectal ring was 3 cm. 38 (37%) patients had a complete response which included 15 of 18 (83%) non-operative patients who remained cancer free at a median of 22 months (range 7-48 months) and 23 of 84 (27%) patients who underwent surgery and had a pathologic complete response. The incomplete response group consisted of 61 patients who underwent initial surgery and 3 non-operative patients with regrowth. There were no differences in gender, T-stage or tumor location between groups. Younger age (median 49 vs 55), normal carcinoembryonic antigen (71% vs 41%), clinical node-negative (24% vs 9%), smaller tumors (median 3.9 vs. 5.4 cm), and wild-type p53 (79% vs 47%) and SMAD4 (100% vs 81%) were more likely to have a complete response (all p0.05).This was a retrospective study and small sample size.In patients with rectal cancer treated with total neoadjuvant therapy, more than one-third will achieve a pathological complete response or sustained clinical complete response with non-operative management making oncological resection superfluous in these patients. Smaller, wild-type p53 and SMAD4, and clinically node-negative cancers are predictive features of a complete response. http://links.lww.com/DCR/B889.

85 Background: Rising rates of early-onset colorectal cancer (EOCRC) pose a dilemma for clinicians when deciding how to treat early-stage patients to maximize outcomes. While standard-of-care for Stage II colon cancer is largely surgical resection, evidence suggests that treatment selection may differ by patient age. We sought to determine whether rates of adjuvant chemotherapy administration differ between early and later-onset patients with Stage II CRC. Methods: Data were derived from the Flatiron National Database spanning 1/1/2003 to 8/1/2021. Patients 18 years or older with Stage II CRC were grouped into those aged 18-49 (EOCRC) and those aged 50 or older (LOCRC). Demographic characteristics, ECOG score, stage and site of tumor, and chemotherapy were included for all patients. Primary outcomes of interest included rates of adjuvant chemotherapy administration by age and ethnicity. Univariate and multivariable logistic regression models were used to evaluate relationships between chemotherapy administration, age groups, and ethnicity while adjusting for significant covariates. Results: Of 2133 patients with Stage II CRC, 1606 patients with complete data were included. A secondary analysis of 1065 patients with colon cancer was performed to address potential confounding factors related to neoadjuvant and/or adjuvant chemotherapy given in patients with stage II rectal cancer. Mean age of EOCRC patients was 45.0 years (range: 41.0-48.0) vs. 68.0 years (60.0-75.0) for LOCRC. Adjusting for ethnicity, gender, site, and ECOG score, multivariate analysis showed EOCRC patients received chemotherapy significantly more often than LOCRC patients for stage II CRC (adjusted odds ratio 1.85, 95% CI 1.32-2.60, p < 0.001). Similar findings were observed in the colon cancer only cohort (adjusted OR 2.02, 95% CI 1.31-3.09, p < 0.001). By ethnicity, non-Hispanic patients received chemotherapy at significantly lower rates than Hispanic patients in both cohorts (adjusted odds ratio 0.58, 95% CI 0.39-0.88, p = 0.009 and adjusted odds ratio 0.55, 95% CI 0.34-0.91, p = 0.018). In a subgroup analysis of Stage IIA patients, multivariate logistic regression adjusting for gender, ECOG, site, and ethnicity showed that patients with EOCRC were more likely to receive chemotherapy than patients with LOCRC (adjusted odds ratio 1.91, 95% CI 1.21-2.99, p = 0.005). Updated survival data will be presented. Conclusions: Adjuvant chemotherapy is given preferentially in Stage II EOCRC, even in Stage IIA disease, despite deviation from established guidelines. This may expose patients at low risk for recurrence to unnecessary toxicities and reveals potential provider bias in favor of younger patients in aggressively treating CRC, despite unclear evidence for any outcome benefit.

118 Background: To date, immune-checkpoint inhibition for microsatellite stable (MSS) mCRC has been ineffective, though targeted therapy combination strategies may be promising. This phase II, investigator-initiated trial (NCT03475004) was designed to evaluate the efficacy and safety of the three-drug combination of pembrolizumab (pembro), binimetinib, and bevacizumab in patients with advanced, MSS treatment-refractory colorectal cancer. Methods: Patients with mCRC locally determined to be MSS and whom have progressed on two prior lines of therapy were enrolled. Treatment consists of pembro (200 mg every 3 weeks), binimetinib (45 mg BID) and bevacizumab (7.5 mg/kg every 3 weeks) until disease progression or unacceptable toxicity. The primary endpoint is PFS using RECIST v1.1 by investigator review. Additional endpoints include objective response rate, disease control rate at time of first re-staging (2 mo), duration of response, and safety and tolerability. Results: 50 patients have been enrolled (accrual is completed). 53% of patients are male and the mean age is 53.6 (range 31-79). The mean number of prior therapies is 5.3. At the time of preliminary data review, 39 patients are evaluable for response data. The median PFS was 5.8 mo (95% CI 4.2 to 8.9). The objective response rate was 13% with 5 partial responses. 24 patients (62%) had stable disease and 10 (26%) had progressive disease as the best response. The disease control rate at the time of first re-staging was 74%. Median duration of response was 6.5 mo. 19 (40%) patients experienced serious adverse events; the most common grade ≥3 adverse events included transaminase elevation (15%), diarrhea (11%), acneiform rash (9%), hypertension (9%), and anemia (9%). Conclusions: Preliminary results from this phase II study indicate that this regimen of pembrolizumab, binimetinib, and bevacizumab has promising activity and acceptable tolerability in this heavily pre-treated population of patients with MSS metastatic colorectal cancer. Final results will be presented as well as ongoing correlative studies. Clinical trial information: NCT03475004.

e14559 Background: While TMB is very dependent on methodology, tissue TMB-H (≥10 mutations/megabase) may predict benefit with ICIs. Pembrolizumab received tissue-agnostic approval for TMB-H unresectable cancers in 2020, but little is known about TMB as a predictive biomarker in mGI cancers. We hypothesized that tissue TMB will correlate with efficacy of ICIs in mGI cancers. Methods: A retrospective chart review identified patients with mGI cancers who received an anti-PD-(L)1 drug and had known TMB at a single academic center from 2012 to 2020. The association of TMB with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) was analyzed using the Fisher’s exact and Log-rank tests. Survival curves were generated using the Kaplan-Meier method. Cox proportional hazard and logistic regression models were used to adjust for microsatellite status. Significance was prespecified at 0.05. Results: 83 patients were identified and included. The most common cancer types were colorectal adenocarcinoma (AC, n = 29), esophageal/gastric AC (n = 21) and SCC (n = 4), cholangiocarcinoma (n = 11), anal SCC (n = 7), and pancreas AC (n = 7). Average age was 61, average number of lines of prior systemic therapy for advanced disease was 1.3 (range 0-4), and 37% of patients were treated on a clinical study. All patients received an anti-PD-(L)1 drug; 6%, 2%, and 36% also received ipilimumab, cytotoxic chemotherapy, and other combinations, respectively. Among those with esophageal/gastric cancer, 76% had known PD-L1 CPS (84% ≥1, 63% ≥5, 42% ≥10). TMB was primarily determined by Foundation One CDx (87%). TMB ranged from 0 to 54; n = 22 (27%) were TMB-H (of these, n = 10 were microsatellite instability-high (MSI-H)), and n = 61 were TMB-L ( < 10 mutations/megabase; of these, n = 2 were MSI-H). The prevalence of TMB-H and microsatellite stable (MSS) was 14.4%. TMB-L, compared to TMB-H, was associated with inferior ORR (3.5% vs 55.6%; odds ratio (OR) 0.045; p < 0.001) and PFS (median 12.7 vs 29.3 weeks; hazard ratio (HR) 2.70; p = 0.001), but not OS (HR 1.20; p = 0.60). In patients with MSS disease, TMB-L, compared to TMB-H, was associated with inferior ORR (OR 0.13; p = 0.04) but not PFS (HR 1.76; p = 0.07) or OS (HR 0.89; p = 0.79). In subgroup analyses, ORR was not significantly associated to tumor type in all or MSS patients. TMB as a continuous variable, in patients with MSS disease, was positively correlated with ORR (p = 0.02) and PFS (p = 0.04), but not OS (p = 0.59). Among all patients, PFS and OS data is immature (median follow-up 13 and 31 weeks). Conclusions: In a single center retrospective study of patients with mGI cancers treated with ICIs, TMB-H was associated with improved ORR and PFS compared to TMB-L. In patients with MSS disease, ORR remained significant. PFS and OS data are immature. TMB as a biomarker of efficacy with ICIs in mGI cancers warrants further study to guide clinical use.

e16276 Background: Appendiceal adenocarcinoma is relatively rare and often diagnosed incidentally during operations for acute appendicitis. It is commonly associated, either at time of initial presentation or upon recurrence, with peritoneal metastases. A typical treatment strategy for patients with peritoneal disease includes cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC). Extrapolating largely from literature in colorectal cancer, chemotherapy is frequently given before and/or after CRS/HIPEC though high-level evidence to support this is lacking. We sought to evaluate the effect of systemic chemotherapy on survival. Methods: Utilizing a database of CRS/HIPEC procedures at University of Colorado Hospital from 2008 to present we retrospectively reviewed cases of appendiceal adenocarcinoma. Data collected included staging, histologic grade, chemotherapy given, surgical outcomes, and time to disease recurrence. Patients without adequate information regarding treatment, or without at least 1 year of clinical follow-up, were excluded. Associations between administration of chemotherapy or histologic grade and 1-year DFS were analyzed using Fisher’s exact test, and logistic regression was used to assess whether 1-year DFS were different in chemotherapy-treated patients when adjusted for histologic grade. Results: In total, 117 cases reviewed indicated an appendiceal pathology. Of these, 54 cases in a total of 51 patients met the specified criteria for pathology and completeness and length of follow-up information. The average age was 58 years (range 26-81 years). Adenocarcinoma was graded as low in 15 (28%) cases, intermediate in 18 (33%) cases, and high in 21 (39%) cases. 23 (43%) patients received no chemotherapy while 31 (57%) received chemotherapy before and/or after surgery. In the overall population, there was no significant effect of chemotherapy on survival, with 1-year DFS demonstrated in 74.2% of patients receiving some chemotherapy and 70% in patients not receiving chemotherapy (p = 0.765). One-year DFS was achieved in 86% of low-grade cases, 61% of intermediate-grade cases, and 71% of high-grade cases, though this was also not statistically significant (p = 0.254). Furthermore, when 1-year DFS between chemotherapy and non-chemotherapy patients was adjusted for grade, there was again no significant interaction (odds ratio = 0.48, 95% C.I. (0.13-1.64), p = 0.763). Conclusions: In this small, single-institution experience of patients with peritoneal appendiceal adenocarcinoma, there was no significant effect of chemotherapy administration on 1-year DFS. These findings are likely affected by significant confounding with the small sample size and retrospective nature of the data. Further investigation on a larger scale is warranted.

64 Background: The management of locally advanced rectal cancer has historically included preoperative chemoradiation followed by surgery and then adjuvant chemotherapy. Recently there has been an increasing utilization of preoperative chemotherapy in addition to standard chemoradiation, a strategy known as total neoadjuvant therapy (TNT). TNT has been offered to patients at the University of Colorado Cancer Center since 2015. Methods: Records of all patients presenting to the University of Colorado colorectal multidisciplinary clinic since 2015 were screened for treatment with TNT. Data collected on these patients included demographic information, diagnosis and initial staging, preoperative treatment received, and surgical outcomes including treatment response and pathological stage. TNT included preoperative chemotherapy with oxaliplatin combined with either 5-FU (FOLFOX) or capecitabine (CAPOX) as well as chemoradiation, generally given with concurrent capecitabine. Patients then underwent surgical resection; if a complete clinical response was achieved with TNT, non-operative management (NOM) was offered. Results: A total of 81 patients thus far have undergone TNT followed by resection or, if complete clinical response and preferred by the patient, NOM. The mean age of patients was 56 years, ranging from 23 to 87, and 60% of patients were male. The majority of patients (67) had stage III disease at presentation while 1 had stage 1 (T2N0) disease, 11 had stage II disease and 2 patients had oligometastatic disease. Ultimately 13 patients (16%) opted for non-operative management after being found to have a complete clinical response following TNT. Of the 68 patients who underwent surgical resection, 21 (31%) had a pathological complete response, with another 14 (21%) with near-complete response. 28 patients (41%) had a partial treatment response and 5 (7%) had no treatment response. In total, the rate of complete clinical or pathologic response was 42%. Treatment was overall well-tolerated with 90% of patients receiving the full planned dose of radiation and 98% of patients completing all planned cycles of chemotherapy, though most of them with typical dose reductions needed. Of the patients who underwent surgery, 49 (72%) had low anterior resection and 19 (28%) had an abdominoperineal resection. Of patients with temporary ileostomies, 85% of them had their ileostomy reversed within 10 weeks of surgery. Conclusions: Treatment of locally advanced rectal cancer by a total neoadjuvant approach is well-tolerated and results in a high rate of clinical and pathological complete response.

Despite numerous breakthroughs in the understanding of colorectal cancer and identification of many oncogenic mutations, the treatment of metastatic colorectal cancer remains relatively more empiric than targeted. Testing for mutations in rat sarcoma virus (RAS) and rapidly growing fibrosarcoma (RAF) are routinely performed, though identification of these mutations currently offers little more than a negative predictive marker for response to EGFR inhibitor treatment and, in the case of RAF mutation, a poor prognostic indicator. Next-generation sequencing has identified both common and rare mutations in colorectal cancer that offer options for more advanced, targeted therapy. With so much research invested in these targets, the treatment of metastatic colorectal cancer stands to become much more personalized in the near future. This review describes several of the more promising targets that are currently being investigated in advanced colorectal cancer.

258 Background: Patients with clinical stage II or III locally advanced rectal cancer may be treated with the total neoadjuvant therapy (TNT) approach; chemotherapy with 4 mths of FOLFOX followed by chemoradiation (chemo/XRT) with capecitabine for 5 wks administered before surgery. We hypothesized that full dose intensity is not necessary for treatment benefit. Methods: A retrospective chart review was conducted on patients with newly diagnosed rectal cancer recommended to receive TNT by the multidisciplinary (multiD) colorectal cancer tumor board at the University of Colorado Cancer Center (UCCC). The primary objective was to evaluate dose intensity of TNT and its impact on response assessed by biopsy and/or imaging (MRI). Results: Between January 31, 2016 and January 31, 2019, 80 patients were recommended the TNT approach for cancer management by the multiD team. Of those, 48 completed their neoadjuvant treatment at UCCC and were included in the analysis. The average age was 55 years (range 23-80) and 61% were male. Thirty-one patients had an ECOG of 0 and 17 had an ECOG of 1. Overall responses were 44% complete response (CR, n = 21), 15% near complete response (nCR, n = 7), 35% partial response (PR, n = 17), and 6% no response (NR, n = 3). See Table for responses seen by dose intensity for chemotherapy. Two patients did not receive their full planned XRT course, and 9 patients had their capecitabine doses held/decreased during chemoradiation. Conclusions: This single center retrospective analysis of patients receiving the TNT approach for rectal cancer provides data supporting that achieving full dose intensity is not necessary to achieve treatment benefit. [Table: see text]

848 Background: The current standard treatment for locally advanced rectal cancer (LARC) is neoadjuvant chemoradiation followed by surgery, and then adjuvant chemotherapy. An alternative approach currently being offered to patients at University of Colorado is total neoadjuvant therapy (TNT), in which patients receive all of their planned treatment, including systemic chemotherapy, preoperatively. Methods: Records of patients from the University of Colorado multidisciplinary colorectal clinic between 2/2015 and 5/2017 were retrospectively reviewed. Treatment plans for included patients involved 8 cycles of preoperative chemotherapy with FOLFOX (5-fluoruracil, oxaliplatin, leucovorin), followed by chemoradiation with concurrent capecitabine, and then resection. Patient data collected includes demographic information, initial staging, chemotherapy and radiation received, adverse effects, surgical outcomes, and clinical and pathological response to treatment. Results: At the time of our analysis, 14 patients have completed TNT and undergone surgical resection, with either abdominoperineal resection or low anterior resection (LAR), at the University of Colorado. Patients ranged in age from 39 to 74 years (mean age 56) with 8 patients (57%) female sex. All 14 patients received 5-fluorouracil with all 8 cycles, though 4 (29%) required omission of oxaliplatin by cycle 8. Toxicities from preoperative treatment were as expected, without significant delays in surgery. Of the 14 patients, 4 (29%) showed a pathologic complete response (grade 0, no residual tumor) on their surgical pathology, with 8 (57%) having either grade 0 or 1 (minimal residual tumor) response. Of the 5 patients who underwent LAR with diverting loop ileostomies, mean time to ostomy reversal was 53.6 days (range 49-61). No patients developed clinically-apparent metastatic disease during preoperative therapy. Conclusions: The use of preoperative chemotherapy in addition to standard chemoradiation for locally advanced rectal cancer is well-tolerated, results in a high rate of pathologic complete response, and allows for early reversal of diverting ileostomies.