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TPS283 Background: Colorectal cancer (CRC) is among the top three most commonly occurring cancers globally. CRC is now routinely classified as MSI-high (MSI-H) or microsatellite-stable (MSS) based on the detection or absence of molecular markers of genetic instability, respectively. The efficacy of checkpoint inhibitor immunotherapy in MSI-H CRC has not been replicated in MSS CRC. Therefore, additional interventions are needed to convert immunologically “cold” MSS CRC to “hot” tumors resembling MSI-H tumors. PolyPEPI1018 is an off-the-shelf, multi-peptide vaccine containing 12 immunogenic epitopes derived from 7 cancer testis antigens (CTAs) frequently expressed in patients with CRC. PolyPEPI1018 successfully restored and boosted pre-existing anticancer immunity of MSS mCRC subjects and triggered recruitment and infiltration of cytotoxic T cells into the tumor. In first line metastatic MSS CRC, PolyPEPI1018 in combination with fluoropyrimidine/bevacizumab vaccine was safe and demonstrated early evidence of clinical activity. Therefore, we hypothesized that the combination of PolyPEPI1018 and atezolizumab will convert a “cold” MSS mCRC to a “hot” tumor and may increase the likelihood of inducing favorable antitumor immunity and subsequent clinical benefit. Methods: The study is a phase 2, multicenter, single-arm clinical trial of PolyPEPI1018 vaccine (1.2 mg, sc, every 3 weeks) and atezolizumab (1200 mg, iv, every 3 weeks) for patients with advanced or metastatic MSS CRC who have progressed on 2 or 3 lines of prior standard regimens. 28 patients will be enrolled at 3 US sites with a primary objective to assess the safety and tolerability of multiple doses of PolyPEPI1018 in combination with atezolizumab. Secondary endpoints include objective response rate (ORR) assessed by RECIST v1.1, vaccine induced immunological response rate (IRR), progression-free survival and overall survival. Correlative aims include assessing blood and tissue biomarkers (PD-L1, Immunoscore®IC, ctDNA, clinical tumor markers) for association with clinical benefit. An exploratory study is being conducted for co-development of a companion diagnostic based on HLA-genotype and computational personal epitope (PEPI) prediction test. A Simon 2-stage design will be used for the initial assessment of ORR. If pre-specified activity goal for the first stage of accrual (n = 18) is met, additional 10 participants will be enrolled to the second stage. A formal review of safety will be performed after the initial 6 participants have received at least 2 cycles of study therapy. The study is open with 10 patients enrolled at time of submission. Clinical trial information: NCT05243862 .

57 Background: Metastatic colorectal cancer (mCRC) with deficient DNA mismatch repair (dMMR) or microsatellite instability-high (MSI-H) show frequent and durable responses to programmed cell death -1 (PD-1) blockade. While the majority of these tumors are sporadics and observed in elderly patients, first-line data are limited to the KEYNOTE-177 study. Here, we report a consecutive series of elderly patients with dMMR mCRC treated with pembrolizumab in routine clinical practice that includes analysis of clinical outcome based on metastatic site. Methods: Patients with dMMR mCRC received first-line pembrolizumab (200 mg every 3 weeks) (N = 41) at Mayo Clinic and Mayo Clinic Health System (2015-2022). Clinicopathological features including metastatic site and molecular data ( BRAFV600E, KRAS) were analyzed in relationship to tumor response rate (RECIST version 1.1). Furthermore, these variables were also analyzed in relationship to patient progression-free survival (PFS) using Kaplan-Meier methodology and multivariable stepwise Cox regression. Results: Among patients with dMMR mCRC, 29/41 (70.7%) were female, 30 (78.9%) harbored BRAFV600E, and 32 (80%) were sporadic. Median age at start of treatment was 80.6 years (IQR of 75.9, 85.9) and median number of treatment cycles was 9 (IQR: 4, 20). At a median follow-up of 23 months (range, 3.0 to 88.5), patient median PFS was 21.3 months (95% CI: 6.4, 38.5). An overall response was observed in 48.8% (20 of 41) of patients including 13 (31.7%) complete (CR) and 7 (17.1%) partial responses (PR). The median duration of response was 42.2 months (95%CI: 8.6, NR). Patients with metastases that included liver had significantly poorer PFS compared to those with non-liver metastases (HRadj 3.40 (95%CI: 1.27-9.13); Padj= 0. 01). In this regard, responses (CR, PR) to pembrolizumab were observed in 3 (21.4%) patients with liver metastasis compared to 17 (62.9%) of those with non-liver metastases. Treatment-related grade 3 or 4 adverse events were observed in 9 (22.0%) patients of whom two discontinued therapy, and there was one treatment-related death. Conclusions: First-line therapy with pembrolizumab for dMMR mCRC significantly prolonged survival in an elderly patient population with manageable toxicity in routine clinical practice. Moreover, the survival benefit of pembrolizumab was significantly attenuated in patients with liver vs non-liver metastases.

199 Background: The progression of neoplasia in colorectal cancer (CRC) has been well characterized, with the evolution typically involving mutations in APC, KRAS, and p53, among others. POLE/POLD1 genes encode for proteins essential in enzymatic DNA polymerase function, yet POLE/POLD1 mutations in tumors are poorly characterized. Pathogenic mutations in POLE/POLD1 lead to decreased fidelity of DNA replication, resulting in a high tumor mutational burden (TMB-H) independent of deficient mismatch repair (dMMR) and high microsatellite instability (MSI-H). Studies have shown associations between this hypermutated phenotype and susceptibility to immune checkpoint inhibition, which may be attributable to neoantigen creation. As such, these tumors are a clinically relevant phenotype requiring further investigation. Here, we characterized POLE/POLD1 alterations in a large, real-world cohort of patients with CRC. Methods: We retrospectively analyzed de-identified records of 9,136 primary CRC patients profiled with the Tempus xT assay. The assay includes DNA-seq of 595-648 genes at 500x to evaluate single-nucleotide variants, insertions/deletions, and copy number changes. Immunological markers analyzed included tumor mutational burden (TMB), MSI, and dMMR. MSI-H was determined by the assay through assessment of 239 loci. dMMR was determined by immunohistochemistry. Results: A total of 217 patient tumors harbored somatic POLE/POLD1 mutations (n = 203 POLE, n = 13 POLD1, and n = 1 POLE and POLD1; none germline), with no differences noted in baseline demographics including gender and age. Among the POLE/POLD1-mutant cohort, POLE copy number losses accounted for most mutations (n = 127, 59%), with short variants and copy number amplifications accounting for 35% (n = 76). The remainder of tumors exhibited POLD1 copy number changes (n = 14), including one with both POLE and POLD1 copy number loss. POLE/POLD1-mutated tumors presented with a lower frequency of MSI-H compared to wild-type (1.8% vs 6.1%, P= 0.018). Conversely, there was a higher frequency of TMB-high cases ( > 10 mut/Mb) for POLE/POLD1-mutated compared to wild-type tumors (22% vs 9.9%, P< 0.001). Differences between POLE/POLD1-mutated and wild-type tumors were also observed among many co-mutated genes, including APC (80% vs 65%, P< 0.001), ALK (31% vs 11%, P< 0.001), ATM (12% vs 3.6%, P< 0.001), BRCA2 (12% vs. 3.2%), and RET (24% vs 8.9%, P< 0.001). Conclusions: Patients with POLE/POLD1 mutations exhibited significant differences across immunological markers and molecular co-alterations. POLE/POLD1 mutations in CRC have been previously described to present with a hypermutated phenotype; however, 78% of tumors exhibited low TMB despite POLE/POLD1 mutations. Thus, these results have identified POLE/POLD1-mutated tumors as a unique genomic subpopulation, and further studies are needed to better characterize POLE/POLD1 mutations in CRC.

Abstract Background Despite multiple randomized trials, the role of perioperative chemotherapy in colorectal cancer liver metastasis (CRLM) is still under debate. In this systematic review and network meta-analysis (NMA), we aim to evaluate the efficacy of perioperative systemic therapies for patients with CRLM. Methods We searched various databases for abstracts and full-text articles published from database inception through May 2021.We included randomized controlled trials (RCTs) comparing the addition of perioperative (post, pre, or both) systemic therapies to surgery alone in patients with CRLM. The outcomes were compared according to the chemotherapy regimen using a random effects model. Outcomes of interest included disease-free survival (DFS) and overall survival (OS). Results Seven RCTs with a total of 1504 patients with CRLM were included. Six studies included post-operative treatment and one evaluated perioperative (pre- and postoperative) therapy. Fluoropyrimidine-based chemotherapy was the most used systemic therapy. NMA showed benefit of adding perioperative therapy to surgery in terms of DFS (HR 0.73, 95% CI 0.63 to 0.84). However, these findings did not translate into a statistically significant OS benefit (HR 0.88, 95% CI 0.74 to 1.05). NMA did not show any advantage of one regimen over another including oxaliplatin or irinotecan. Conclusions This systematic review and NMA of 7 RCTs found that the addition of perioperative systemic treatment for resectable CRLM could improve disease-free survival but not overall survival. Based on the findings, addition of perioperative treatment in resectable CRLM should be individualized weighing the risks and benefits.

Abstract Objectives Peritoneal metastasis (PM) from appendiceal cancer or colorectal cancer (CRC) has significant morbidity and limited survival. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a minimally invasive approach to treat PM. We aim to conduct a dose-escalation trial of mitomycin C (MMC)-PIPAC combined with systemic chemotherapy (FOLFIRI) in patients with PM from appendiceal cancer or CRC. Methods This is a multicenter Phase I study of MMC-PIPAC (NCT04329494). Inclusion criteria include treatment with at least 4 months of first- or second-line systemic chemotherapy with ineligibility for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). Exclusion criteria are: progression on chemotherapy; extraperitoneal metastases; systemic chemotherapy intolerance; bowel obstruction; or poor performance status (ECOG>2). Escalating MMC-PIPAC doses (7–25 mg/m 2 ) will be administered in combination with standard dose systemic FOLFIRI. Safety evaluation will be performed on 15 patients (dose escalation) and six expansion patients: 21 evaluable patients total. Results The primary endpoints are recommended MMC dose and safety of MMC-PIPAC with FOLFIRI. Secondary endpoints are assessment of response (by peritoneal regression grade score; Response Evaluation Criteria in Solid Tumors [RECIST 1.1], and peritoneal carcinomatosis index), progression free survival, overall survival, technical failure rate, surgical complications, conversion to curative-intent CRS-HIPEC, patient-reported outcomes, and functional status. Longitudinal blood and tissue specimens will be collected for translational correlatives including pharmacokinetics, circulating biomarkers, immune profiling, and single-cell transcriptomics. Conclusions This Phase I trial will establish the recommended dose of MMC-PIPAC in combination with FOLFIRI. Additionally, we expect to detect an early efficacy signal for further development of this therapeutic combination.

10588 Background: Detection of pathogenic germline variants (PGVs) has implications for cancer screening, prognostication, treatment selection, clinical trial enrollment and family testing. Published guidelines provide indications for PGV testing, determined by clinical and demographic factors, but these leave a significant number of cases missed by guideline-directed testing (incremental PGV). We have previously shown that 50% of patients with PVGs would not have been detected with guideline-based testing alone. In this project, we aimed to determine the feasibility and generalizability of this approach within a more racially/ethnically diverse cohort from a community cancer practice. Methods: We completed a prospective study of proactive germline genetic sequencing among patients with solid tumor malignancies at a community-based oncology practice in downtown Jacksonville, FL between June 2020, and September 2021. The patients were unselected for cancer type, stage, family history, race/ethnicity, and age. PGVs identified using an 84-gene NGS platform were stratified by penetrance. National Comprehensive Cancer Networks (NCCN) guidelines were used to determine incremental PGV rates. Results: 221 patients were enrolled, median age 63.0 years, 21.7% male. 56.6% of patients were white (non-Hispanic), 32.6% were black/African American, 5.4% were Hispanic. 39.8% of patients were commercially insured, 52.4% insured by Medicare/Medicaid and 2.7% uninsured. The cohort was comprised predominantly of breast cancer (61.5%), lung cancer (10.4%) and colon cancer (7.2%) patients. A total of 27 PGVs were identified in 23 patients. We found no significant difference in the rate of PGVs based on race/ethnicity. The overall rate of variants of uncertain significance (VUS) was numerically higher in black/African American patients (61.1%) compared with other ancestry (45%). 13 of 23 (56.5%) patients with detected PGVs did not meet NCCN guidelines for germline genetic screening (incremental PGVs). Conclusions: This prospective study found that universal multi-gene panel testing among patients from a racially/ethnically diverse cohort from a community cancer practice was associated with an increased detection of heritable variants with treatment implications over the predicted yield of targeted testing based on guidelines. This study is the first to evaluate this approach in an exclusively community-based practice. Clinical trial information: NCT04456140.

4145 Background: Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer death. Outcomes remain poor, due to irresectability at diagnosis for many and sub-optimal responses to systemic therapy. Cytotoxic chemotherapy remains the standard of care. High microsatellite instability (MSI-H) predicts response to immune checkpoint inhibition (ICI) in many cancers. Detecting high MSI is rare in PDAC (incidence <2%), but case reports demonstrate potential therapeutic benefit with ICI. Here, we present multi-institutional data to characterize the clinical behavior of MSI-H PDAC, with special attention to response to ICI. Methods: Cases of MSI-H PDAC were obtained by reviewing data of all PDAC patients from our tertiary cancer center who had undergone genomic sequencing by one commercially available platform. The resulting cohort was supplemented with MSI-H PDAC cases identified by GI oncology specialists at multiple institutions. De-identified patient data were compiled and analyzed. Results: 15 MSI-H PDAC patients were identified. 20% had stage II disease at diagnosis, 27% stage III, and 53% stage IV. 73% of patients received ICI (n=11); 40% as 1st line and 33% as 2nd line. These patients demonstrated 100% overall response rate; 45% complete response (1 pathologic CR, 4 radiographic CR) and 55% partial response. No patient that received ICI had lost response or died after a median follow-up of 18 months (range 6-89 mos). 1 patient had oligoprogression of a single hepatic lesion after 7 mos that was then irradiated; this patient retained radiographic CR for 17 subsequent mos (ongoing). In this cohort, we observe poor responses to cytotoxic chemotherapy. In total, 12 regimens were trialed among 9 patients. Overall response rate was 0%. 42% achieved disease stability, with median duration of response of 2 mos; only 2 cases maintained disease stability for >5 mos. 4 patients did not receive ICI; all patients died, with a median survival of 7.5 mos. Conclusions: MSI-H PDAC represents a rare but important subtype of PDAC with unique clinical behavior. Given its rarity, large-scale analyses and trials are unlikely to be performed, making case series such as ours crucial. In our cohort, we observe impressive, durable responses to ICI, along with very poor responses to cytotoxic chemotherapy. Our data argues for consideration of ICI in any patient presenting with MSI-H PDAC, including in the first-line and neoadjuvant settings.

3590 Background: Co-occurring alterations (COAs) in the HER2 and MAPK pathway are rare in mCRC. RAS, HER2 and BRAF alterations have been associated with resistance to EGFR inhibitor therapy (EGFR-mab). Typical co-occurring mutually exclusive gene mutations such as in KRAS and BRAF have been reported. This study aims to evaluate the prevalence of co-occurring alterations in the MAPK pathway or across MAPK/ HER2 and correlate to outcomes in patients with mCRC treated with EGFR-mab. Methods: This is a retrospective study of patients with mCRC within the Mayo Clinic database who have available blood-based NGS Guardant 360 data (September 2017-November 2021) and contained co-alterations in the MAPK pathway or across MAPK/ HER2. MSI-high cases were excluded. Typical-RAS was defined as alterations in codons 12, 13, 59, 61, 117, and 146 of KRAS, HRAS, and NRAS. Atypical-RAS alterations were considered mutations at other codons of these genes. Patient characteristics, specific mutations, and outcome data were assessed. Results: 692 patients (pts) with mCRC were identified and 66 (9.5%) of those had COAs detected. 59/66 pts had clinical data available. Median age was 52 years, 55.9% were male, and 61.0% had left-sided tumors. The frequency of detected alterations was: BRAF-V600E (7.3%), BRAF-non-V600E (7%), BRAF-amplification (3.04%), RAS-typical (39.5%), RAS-atypical (2.1%), HER2 amp (0.5%), HER2-mutation (1.2%) and PIK3CA (13%). COAs are described in the table. Twenty-three pts received EGFR-mab; COAs developed in 19 of them after progression on EGFR-mab. Four pts received EGFR-mab with documented COAs at baseline with none of them responding to treatment. Conclusions: COAs in MAPK and MAPK/ HER2 pathway are not uncommon in pts with mCRC emphasizing on the importance and feasibility of blood based NGS vs. selected gene testing. In pts with prior EGFR-mab treatment, COAs were detected after progression on treatment in the majority of pts, suggesting a mechanism of secondary treatment resistance. Further data including prospective validation is warranted. [Table: see text]