Jones, Jeremy C

e15626 Background: Studies have shown the effectiveness of immune checkpoint inhibition (ICI) in patients with tumors demonstrating microsatellite instability (MSI-H) and an associated defect in DNA mismatch repair (dMMR). In particular, KEYNOTE-177 demonstrated significant survival benefit for patients with unresectable or metastatic colorectal cancer with MSI-H or dMMR. Recently published case reports and series have demonstrated similar outcomes for patients with locally advanced and resectable rectal cancer. We report on the experience of patients with locally advanced, resectable rectal adenocarcinoma treated across the Mayo Clinic Health System. Methods: We conducted a retrospective analysis of patients treated at Mayo Clinic since 2015 A search of the Mayo Clinic database was done to include parameters for confirmed rectal adenocarcinoma, dMMR in pathology reports. Patients receiving ICI treatment including pembrolizumab, nivolumab/ipilimumab and durvalumab in any combination with chemotherapy and/or radiation were included. Patients with metastatic disease at the time of surgical intervention or ICI were excluded. Clinical data was assimilated. Results: Twenty-one patients met criteria for inclusion in our analysis. Fifteen patients had de novo disease. Six patients had local recurrence and had been treated previously with chemotherapy, radiation (RT) and surgery. None of the patients included had prior ICI therapy. Fifteen patients had Lynch syndrome. The median age of diagnosis was 41.5 years. Seven patients underwent surgical intervention. of the seven patients received surgery upfront followed by immunotherapy. The remaining six had neoadjuvant immunotherapy alone or in combination with chemotherapy and/or radiation. Prior to surgery, all patients demonstrated radiographic partial response (rPR). 67% of these demonstrated a pathologic complete response (pCR) while 33% had residual disease. The patient who received surgery upfront and adjuvant ICI continues to have radiographic stable disease after 1 year of treatment. For patients who did not have surgery, 50% had radiographic “complete or near complete” response (rCR), 43% had rPR and 7% had radiographic stable disease. Ten patients received RT and ICI with 70% demonstrating rCR and 30% rPR. Overall, the objective response rate was 90 Response to treatment was observed upwards of 75 months. Only 1 person in the study had progression of disease that occurred after 14 months of therapy. Conclusions: Similar to KEYNOTE-177, patients with locally advanced MSI-H/dMMR rectal cancer have significant and durable response to immunotherapy alone or in combination with chemotherapy, radiation and surgery. Further large prospective trials are needed to validate these findings and determine a standardized approach.

e15599 Background: Screening and removal of pre-malignant adenomas has reduced CRC incidence in adults older than 50 years (later onset CRC [LOCRC]), but EOCRC incidence has increased by 1-2% annually since the 1990s. The liver is the commonest site of CRC metastasis, and EOCRC presents with more advanced stage compared with LOCRC. Oligometastasis (OM) refers to potentially resectable CRC, and complete resection of CRC primary and OM is associated with improved survival and potential cure. Here, we examined treatment outcomes of EOCRC with synchronous liver oligometastases (sLiOM) at our institution. Methods: We performed a retrospective review of institutional electronic health records and identified 160 EOCRC patients with sLiOM treated with curative intent in the last decade. Demographics, treatment, and follow up data were recorded, and analysis for survival outcomes performed. The study protocol was exempt after review by Mayo Clinic institutional review board. Results: Of 160 patients, median age at diagnosis was 43 years. Primary tumor was in the left colorectum in 73% and right colon in 26% of patients. Metastasis was limited to the liver only in 64%, and liver metastasis was solitary in 14% of patients (table 1). Fluoropyrimidine doublet backbone (81%) was more commonly used compared to triplet (19%), with doublet + bevacizumab (41%) as the most common regimen. Hepatectomy only (59%), combined hepatectomy with ablation (32%), ablation only (5%), transarterial radioembolization (2%), and trans arterial embolization (1%) were the modalities employed for sLiOM. Of the 148 patients who underwent hepatectomy, R0 resection was achieved in 51%. After a median follow-up of 37 months, progression-free survival was 11.6 mos (95% CI 9-14mos) and median overall was 83.6 mos (95% CI 62-105mos). The median time to liver progression was 16 mos (95% CI 12-20 mos). At data cut off, 41 patients (26%) were alive and disease-free, and 60 patients (38%) were alive and disease free in the liver only. Conclusions: This multi-site, retrospective analysis of EOCRC patients demonstrates excellent survival outcomes with localized treatment of sLiOM. Median OS in this cohort compares favorably to previously reported mOS of 36 months in EOCRC patients (Arhin et al, 2021). Cure is not often achieved even after treatment of sLiOM in this cohort, suggesting aggressive disease biology and the need for improved patient selection. [Table: see text]

e14576 Background: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of many solid malignancies. ICI appears particularly effective when tumors exhibit high microsatellite instability (MSI-H) and/or mismatch repair deficient (dMMR) status. Although the response is typically quite good in this setting, there are scenarios where benefit is less than anticipated. In this study, we aimed to explore the efficacy of ICIs in patients with MSI-H/dMMR cancers with peritoneal metastasis (PM). Methods: We conducted a retrospective chart review to identify patients (pts) with PM from primary MSI-H/dMMR cancers treated with immunotherapy between 2010 and 2022 at Mayo Clinic. Data was collected to include pt demographics, tumor characteristics, pathology, tumor markers, imaging, mutational profile, and previous and subsequent treatments. The primary endpoint was disease control rate (DCR), defined as objective response rate (RECIST v1.1 criteria) or stable disease. Results: Forty-six pts with MSI-H/dMMR and PM treated with ICIs. Most of our cohort were female (61%) with a median age at diagnosis of 61 years. Colorectal cancer was the most common primary site (69.6%), followed by endometrial (6.5%). Most pts received treatment with PD-1 antibodies as second-line therapy following systemic chemotherapy. DCR of the PM was 71.6 % (n= 13 PR, 9 CR, and 9 SD), with a median duration of response of 12.6 months. Thirteen pts (28.4%) had progressive peritoneal disease on ICI with a median PFS of 2.2 months. Ascites was a poor prognosticator and predicted a lack of benefit from ICI (HR 6.6, 95% CI=2.24-19.9, p= 0.006). Mucinous and signet ring histology were common in pts with peritoneal progression (61.5%); however, this was not statistically significant (HR=1.6; 95%CI= 0.4383 to 3.899, p 0.5). Multivariate analysis for the presence or absence of BRAF and/or RAS mutations was not statistically significant in predicting response. Neither was the specific MMR gene mutation(i.e., MLH1 or PMS2). Interestingly, discordant responses between the peritoneum and other sites of metastasis to immunotherapy were seen in 13 pts (28.4%), primarily as primary peritoneal progression compared to other tumor sites. Conclusions: In our cohort, the DCR of metastatic peritoneal disease in MSI-H/dMMR tumors was approximately 71%. The presence of ascites was identified as a poor prognosticator in this setting and was associated with a lack of response/benefit from ICIs. Histologic subtype (i.e., mucinous/signet ring) did not show statistical significance in predicting ICI response. The subpopulation with discordant response to ICI suggests that peritoneal immunobiology may differ from other sites. Further research on immunotherapy response in the peritoneum is needed for this special subset of pts.

Abstract Hereditary factors play a role in the development of several cancers. Identification of germline predisposition can have implications for treatment and cancer prevention. While previous studies have found that universal multigene panel testing in patients with cancer yields increased detection of actionable heritable variants compared to targeted testing, patients belonging to racial and ethnic minority groups have been underrepresented in these studies. We undertook a prospective multi-site study of germline alternations among solid tumor cancer patients from under-represented minority (URM) populations receiving care at Mayo Clinic Comprehensive Cancer Centers between January 2020 and November 2022. Patients with a new or active cancer diagnosis (all stages) not selected for family history of cancer were tested with a >80-gene next generation sequencing panel. Of 532 patients (mean [SD] age, 57.2 [12.7] years; 320 (60.2%) female), 247 (46.4%) were Hispanic/Latino, 130 (24.4%) Black/African American, 80 (15.0%) Asian, 66 (12.4%) American Indian/Alaskan Native, 2 (0.4%) Native Hawaiian/Pacific Islander, and 7 (1.3%) other. PGV were found in 43 patients (8.1%), including 29 moderate- or high- penetrance cancer susceptibility genes. Variants of uncertain significance (VUS) were found in 272 patients (51.1%). Of those with a PGV, 29 (67.4%) had incremental clinically actionable findings that would not have been detected by established testing criteria, of which 16 were moderate- or high-penetrance variants. Younger age of diagnosis, gender, race, ethnicity, and stage of disease were not predictive of PGV. In this study of under-represented minority cancer patients, universal genetic testing found that 1 in 12 patients harbor a PGV, more than two-thirds of whom would remain undetected using current guidelines. The paucity of genomic data in URM populations also results in a large proportion of VUS which may lead to under-estimation of disease associated variants. Table 1. Clinical and Demographic Characteristics of Included Patients Positive Negative VUS Total N (%) 43 217 272 532 (8.1%) (40.8%) (51.1%) Age - mean (SD) 53.7 57.0 57.8 57.2 (12.7) (12.6) (12.8) (12.7) Gender - Female 26 132 162 320 (60.5%) (60.8%) (59.6%) (60.2%) Race/Ethnicity Hispanic/Latino 24 110 113 247 (55.8%) (50.7%) (41.5%) (46.4%) Black/African 5 56 69 130 American (11.6%) (25.8%) (25.4%) (24.4%) Asian 10 (23.3%) 23 (10.6%) 47 (17.3%) 80 (15.0%) American Indian/Alaskan Native 4 (9.3%) 26 (12.0%) 36 (13.2%) 66 (12.4%) Native Hawaiian/Pacific Islander 0 (0.0%) 0 (0.0%) 2 (0.7%) 2 (0.4%) Other 0 (0.0%) 2 (0.9%) 5 (1.8%) 7 (1.3%) Tumor Types Breast 19 (44.2%) 80 (36.9%) 110 (40.4%) 209 (39.3%) CNS 1 (2.3%) 2 (0.9%) 1 (0.4%) 4 (0.8%) GI 7 (16.3%) 46 (21.2%) 58 (21.3%) 111 (20.9%) GU 8 (18.6%) 57 (26.3%) 62 (22.8%) 127 (23.9%) GYN 0 (0.0%) 8 (3.7%) 10 (3.7%) 18 (3.4%) Head/Neck 5 (11.6%) 8 (3.7%) 6 (2.2%) 19 (3.6%) Lung 0 (0.0%) 6 (2.8%) 11 (4.0%) 17 (3.2%) Melanoma 0 (0.0%) 2 (0.9%) 1 (0.4%) 3 (0.6%) Sarcoma 2 (4.7%) 4 (1.8%) 4 (1.5%) 10 (1.9%) Other 1 (2.3%) 4 (1.8%) 9 (3.3%) 14 (2.6%) Citation Format: Kevork A. Khadarian, Sailaja Pisipati, Jeremy C. Jones, Gerardo Colon-Otero, Donald W. Northfelt, Lindsey Gary, Idara U. Ekpoh, Giovanna G. Moreno, Edward D. Esplin, Robert Nussbaum, Brandie Heald, Margaret A. Klint, Kathleen A. Barrus, Tanios S. Bekaii-Saab, Aleksandar Sekulic, Michael A. Golafshar, Katie L. Kunze, Cheryl L. Willman, Konstantinos N. Lazaridis, Niloy Jewel Samadder. Universal genetic testing for hereditary cancer syndromes in an under-represented minority population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1921.

Importance Metastatic colorectal cancer (mCRC) with deficient DNA mismatch repair (dMMR) shows frequent and durable responses to programmed cell death 1 blockade. While most of these tumors are sporadic and observed in older patients, first-line pembrolizumab data are limited to findings from the KEYNOTE-177 trial (A Phase III Study of Pembrolizumab [MK-3475] vs Chemotherapy in Microsatellite Instability-High [MSI-H] or Mismatch Repair Deficient [dMMR] Stage IV Colorectal Carcinoma). Objective To investigate outcome with first-line pembrolizumab monotherapy in mostly older patients with dMMR mCRC at a multisite clinical practice. Design, Setting, and Participants This cohort study included consecutive patients with dMMR mCRC who received pembrolizumab monotherapy between April 1, 2015, and January 1, 2022, at Mayo Clinic sites and the Mayo Clinic Health System. Patients were identified from review of electronic health records at the sites, which included the evaluation of digitized radiologic imaging studies. Intervention Patients with dMMR mCRC received first-line pembrolizumab, 200 mg, every 3 weeks. Main Outcomes and Measures The primary study end point was progression-free survival (PFS), which was analyzed using the Kaplan-Meier method and a multivariable stepwise Cox proportional hazards regression model. Clinicopathological features, including metastatic site and molecular data ( BRAF V600E and KRAS ), were also analyzed along with tumor response rate, which was determined using Response Evaluation Criteria in Solid Tumors, version 1.1. Results The study cohort included 41 patients (median [IQR] age at treatment initiation, 81 [76-86] years; 29 females [71%]) with dMMR mCRC. Of these patients, 30 (79%) had the BRAF V600E variant and 32 (80%) were classified as having sporadic tumors. Median (range) follow-up was 23 (3-89) months. Median (IQR) number of treatment cycles was 9 (4-20). Overall response rate was 49% (20 of 41 patients), including 13 patients (32%) with complete responses and 7 (17%) with partial responses. Median (IQR) PFS was 21 (95% CI, 6-39) months. Liver as a site of metastasis was associated with significantly poorer PFS vs nonliver metastasis (adjusted hazard ratio, 3.40; 95% CI, 1.27-9.13; adjusted P = .01). Complete and partial responses were observed in 3 patients (21%) with liver metastasis vs 17 patients (63%) with nonliver metastases. Treatment-related grade 3 or 4 adverse events were observed in 8 patients (20%), 2 of whom discontinued therapy; there was 1 treatment-related death. Conclusions and Relevance This cohort study found a clinically significant prolongation of survival in older patients with dMMR mCRC who were treated with first-line pembrolizumab in routine clinical practice. Furthermore, liver vs nonliver metastasis was associated with poorer survival in this patient population, which suggests that the metastatic site has implications for survival outcome.

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.