Overman, Michael J.

Abstract Purpose: Routine testing for mismatch repair deficiency (dMMR)/microsatellite instability (MSI) in colorectal cancers is recommended for Lynch syndrome screening, prognosis, and treatment guidance. In the metastatic setting, RAS/BRAF mutations guide treatment decisions. The impact of these mutations on the tumor immune microenvironment (TiME) in MSI/dMMR colorectal cancer is not known. Experimental Design: The study involved retrospective analysis of 448 patients with stage I to IV MSI/dMMR colorectal cancer profiled using next-generation sequencing (Tempus xT DNA sequencing of 595–648 genes at 500x coverage and Tempus xR whole-exome capture RNA sequencing). MSI status was determined by assessing 44 or 239 loci using next-generation sequencing. dMMR was determined using IHC. Tumor mutational burden, tumor neoantigen burden (NTB), PD-L1, immune infiltration, and canonical immune pathways (76 gene set signatures) were analyzed. Results: The median age at diagnosis was 67 years (range, 21–86); 59% of patients were female, and 70% were stage III to IV. Among the 448 patients, 100 (22%) harbored RAS mutations (RASmut), 119 (27%) a BRAFV600E mutation, and 229 (51%) were double wild type. RASmut exhibited lower NTB (median, 12 vs. 15 vs. 16; P = 0.003) and PD-L1 (3.6% vs. 13% vs. 24%; P < 0.001) than BRAFV600E and wild-type tumors, respectively. The RASmut TiME had lower overall inflammation and fewer infiltrating CD8+ T cells than wild-type or BRAFV600E tumors. In contrast, BRAFV600E tumors exhibited hyperproliferative characteristics associated with broad metabolic reprogramming but a similarly inflamed TiME compared with wild-type tumors. Conclusions: Our data suggest that MSI/dMMR colorectal cancers harboring RASmut are less immunogenic, and the TiME contains a lower inflammatory profile than wild-type or BRAFV600E tumors. Further analysis and validation are required to confirm these findings.

3569 Background: Immune checkpoint inhibitors (ICIs) are a standard treatment for gastrointestinal (GI) cancers with mismatch repair deficiency (dMMR) or microsatellite instability (MSI). However, around 50% of patients develop resistance to ICIs, during treatment or after discontinuation. In these patients, the efficacy of reuse an ICI in patients progressing during a previous ICI (rechallenge), or in patients who progressed after discontinuation (reintroduction), remains unknown. The INFLATE study evaluates the efficacy of ICI reuse in patients who progressed on or after discontinuing ICI. Methods: This is a multicenter international retrospective study from the IMMUNODIG cohort, including patients from 34 centers in France, the United States, Italy, Belgium and Spain. All patients received ICI for dMMR/MSI GI cancer. We analyzed patients who had progressed following initial ICI (ICI-1) and subsequently received a rechallenge or a reintroduction with ICI (ICI-2), either monotherapy (mono-ICI) or biotherapy (bi-ICI). Results: A total of 77 patients were included, receiving bi-ICI (N = 34) or mono-ICI (N = 43) during ICI-2. The majority (76%) had a metastatic colorectal cancer. The reason for discontinuing ICI-1 was disease progression in 53% of cases, end of treatment in 15%, toxicity in 5% and other reasons in 26%. Patients who discontinued ICI-1 due to progression received MONO-ICI-2 in 29% of cases and BI-ICI-2 in 71%, whereas those who stopped for other reasons received MONO-ICI-2 in 86% and BI-ICI-2 in 14% of cases. Efficacy results are shown in Table 1. The ORR and DCR were 26% and 79% with MONO-ICI-2, and 16% and 71% with BI-ICI-2. Among patients who discontinued ICI-1 due to progression, BI-ICI-2 (N = 29) achieved an ORR and DCR of 8% and 65%, with a median PFS of 5.5 months (95%CI 4.07-10.4). These outcomes were 17%, 67%, and 3.7 months (95%CI 2.37-NA), respectively, with MONO-ICI-2 (N = 12). For patients who discontinued ICI-1 for reasons other than progression, BI-ICI-2 (N = 5) achieved an ORR and DCR of 60% and 100%, with a median PFS not reached (95%CI 11.5-NR), while MONO-ICI-2 (N = 31) achieved 29%, 82%, and 14.2 months (95%CI 11.2–NR), respectively. Conclusions: This is the first multicenter real-world study evaluating ICI reuse in dMMR/MSI GI cancers. In patients who discontinued ICI for reasons other than progression, reintroduction of ICI therapy upon progression achieves tumor control in 85% of cases. In cases of progression on mono-ICI, Bi-ICI re-challenge achieve tumor control in two-thirds of cases and might be to consider in some patients. ORR % DCR % PFS median (95%CI) OS median (95%CI) Overall N=77 21 76 7.65 months(5.5–11.5) 27.6 months(22.2–55.7) Discontinued ICI-1 due to Progression N=41 11 68 5.03 months(3.7–8.05) 26.7 months(21.1–NR) Discontinued ICI-1 for Other Reasons N=36 33 85 14.22 months(11.24–NR) 27.6 months(22.2–NR)

e16479 Background: Recent genomic data has demonstrated SBA to be a molecularly unique entity when compared to colon or gastric cancers. The ongoing SWOG 1922 randomized clinical trial is comparing FOLFIRI to ramucirumab/paclitaxel as the second-line treatment for metastatic SBA. We sought to further define the activity of taxane-based therapy in the largest collection of SBA patients treated with this therapy. Methods: A retrospective review of SBA patients treated with taxane-based chemotherapy from 1994 to 2024 at MD Anderson Cancer Center was performed. All patients had pathologic confirmation, received > 1 cycle of therapy, and had documented tumor response evaluation. Response was assessed by the treating physician based on the imaging studies and categorized as response, stable disease or progression. Patient demographics, clinical parameters, molecular data, and taxane treatment was reviewed. Kaplan-Meier survival analysis was performed to calculate time to progression (TTP) and overall survival (OS). Results: 70 SBA patients treated with taxane-based therapy were identified. The median age at diagnosis was 57 years (range 33-80 years), majority being male (59%) with primary tumor located at duodenum (44%), Jejunum (34%), Ileum (16%). The most common presenting metastatic site was peritoneum (39%), followed by liver (31%). The genomic status revealed mutations in the following genes: 62% TP53, 47% KRAS, 24% SMAD4, and 15% APC. Taxane treatment was single agent (nab-paclitaxel, paclitaxel, or docetaxel) in 29%, gemcitabine and taxane combination in 61% and other taxane-based combinations in 10%. Therapy was given in the metastatic setting as 2nd-line in 40%, 3rd-line in 33% and 4th-line or greater in 20%. Response status was response in 24%, stable disease in 26%, and progression in 50%. Median TTP was 3.1 months (95%CI: 2.0-4.2 months), and median OS was 8.7 months (95%CI: 7.4-10.1 months). Median TTP was similar between single agent (2.6 months) and gemcitabine-based combination (2.5 months) (p =0.75). Efficacy did not differ by line of therapy nor primary tumor site. Efficacy differed by TP53 mutation status: TP53 mutated vs wildtype (response 21% vs 43%, p = 0.02; median TTP 2.4m vs 4.9m, p = 0.013; median OS 7.3m vs 10.6m, p = 0.004). Conclusions: This retrospective study of 70 SBA patients confirms the activity of taxane-based therapy demonstrating a response rate of 24% and median TTP of 3.1 months. Though limited by sample size, TP53 mutations may represent a negative predictive marker for taxane-based therapy in SBA patients. These findings support the ongoing SWOG 1922 trial investigating taxane-based therapy as a second line for metastatic SBA.

e15628 Background: Total neoadjuvant therapy (TNT) with cytotoxic chemotherapy and chemoradiation followed by surgical resection is a standard treatment for locally advanced rectal cancer (LARC). In a limited number of LARC patients with deficient mismatch repair (dMMR), treatment with an immune checkpoint inhibitor (ICI) resulted in all patients achieving complete clinical response (cCR) (median follow-up of 29 months) such that radiotherapy and surgery were avoided. These and other data have resulted in the routine use of neoadjuvant ICI for dMMR LARC. Here we report a multicenter series of patients with dMMR LARC treated with neoadjuvant ICI. Methods: Adult patients (N = 21) with dMMR LARC who received neoadjuvant ICI at Mayo Clinic, MD Anderson Cancer Center, Duke University or University of Pittsburgh were identified from the electronic medical record (EMR) and relevant data were abstracted. All patients were staged with pelvic MRI; clinical response was evaluated by repeat pelvic MRI and sigmoidoscopy. Data were summarized using descriptive statistics. This study was approved by the Mayo Clinic IRB. Results: Patients with clinical stage I (n = 2), II (n = 3) or III (n = 15) dMMR LARC were treated with neoadjuvant PD-1 monotherapy (n = 20) or combination (n = 1, ipilimumab+ nivolumab). Median age was 46 years (IQR 39, 65), 15 (71%) were male, 10 (48%) had distal tumors, and 14 had Lynch Syndrome. Median duration of ICI treatment was 7 mos (IQR 6, 12); one patient remains on dostarlimab at data cut-off. Clinical complete response (cCR) was achieved in 11 (52%) patients, partial response (PR) in 7 (33%), stable disease (SD) in 1 (5%), and progressive disease (PD) in 2 (10%) patients. Median time from first dose of ICI to best clinical response was 6 mos (IQR 5, 8) months. All partial or non-responders received salvage TNT with (n = 6) or without (n = 3) surgery. At a median follow up of 19 mos (range 6 to 56), tumor regrowth occurred in 1 patient who was subsequently treated with TNT. Any grade immune-related adverse event occurred in 6 (29%) patients; one grade 3 hepatitis occurred in the patient on Ipi+Nivo (Table1). Conclusions: Neoadjuvant ICI treatment of dMMR LARC resulted in half of treated patients achieving cCR. Careful monitoring is necessary to identify non responders who will require salvage TNT. Patient characteristics and clinical response to ICI. ID Sex Age Stage ICI Response to ICI ID Sex Age Stage ICI Response to ICI 1 M 62 T3N+ Pembro cPR 12 M 37 T3N+ Pembro cCR 2 M 60 T2N0 Pembro cCR 13 M 41 T3N0 Pembro cCR 3 M 80 T2N0 Pembro cPD 14 M 46 T4N+ Pembro cPR 4 M 36 T3N+ Ipi+Nivo cCR 15 M 68 T3N+ Pembro cPR 5 M 57 T3N+ Dostarli cCR 16 M 77 T3N0 Pembro cPR 6 M 39 T3N+ Dostarli cPR 17 M 40 T4Nx Pembro cCR 7 F 44 T2N+ Dostarli cPD 18 F 35 T3N+ Dostarli cCR 8 M 74 T3N+ Pembro cCR 19 M 60 T2N+ Pembro cPR 9 M 43 T3N+ Nivo cCR 20 F 65 T3N+ Pembro cCR 10 F 81 T3N0 Dorstali cPR 21 F 39 T4N+ Dorstali cSD 11 F 32 T2N+ Pembro cCR

TPS311 Background: Approximately 45% of dMMR/MSI-H metastatic colorectal cancer (mCRC) in the immunotherapy arm progressed at 12 mos (KEYNOTE 177). We hypothesize that dMMR/MSI-H mCRC patients (pts) may be more effectively treated with the combination of PD-1/PD-L1 (PD-1) pathway blockade and mFOLFOX6/bevacizumab (bev) rather than with anti-PD-L1 therapy (atezo) alone. Preclinical work demonstrated synergistic effects between anti-PD-1/anti-VEGF as well as between oxaliplatin/anti-PD-1 in murine CRC models, and phase II data showed activity of anti-PD-1/anti-VEGF in chemotherapy refractory colon cancer. Within the AtezoTRIBE 8-pt dMMR CRC subgroup treated with FOLFOXIRI+bev+atezo, median PFS was not reached, with the first progression event at ~16 mos. Additionally, in other solid tumor malignancies, anti-PD-1 plus anti-VEGFr (i.e., HCC and RCC) as well as anti-PD-1 plus chemotherapy (i.e., gastroesophageal and lung cancers) combinations are standard first-line treatments. Methods: This two-arm prospective phase III open-label trial randomizes (1:1) mCRC dMMR/MSI-H to atezo monotherapy v mFOLFOX6/bev+atezo combination. Key inclusion criteria have been simplified on recent amendments to better mirror clinical practice for pts receiving mFOLFOX6/bev+atezo: One cycle of FOLFOX or CAPOX, with or without bev (or biosimilar) prior to enrollment allowed, dMMR tumor determined by local CLIA-certified IHC assay (MLH1/MSH2/MSH6/PMS2) or MSI-H by local CLIA-certified PCR or NGS panel; pts with total bilirubin ≤4.0 x ULN; duration of therapy for up to two years for both arms; imaging frequency on post-treatment follow-up has been reduced; as has measurable disease per RECIST. Primary endpoint is PFS. Assuming the atezo monotherapy control arm has a 48% PFS at 24 mos as assessed by site investigator, we have 80% power to detect a hazard ratio of 0.6 (equivalent to 64.4% PFS at 24 mos) with alpha 0.025 one-sided. Stratification factors include BRAFV600E status, metastatic site, and prior adjuvant CRC therapy. Secondary endpoints include overall survival, objective response rate, safety profile, disease control rate, and duration of response. Archived tumor tissue and blood samples will be collected for correlative studies. Harmonization of translational analyses is planned between GI004 (COMMIT) and A021502 (ATOMIC). Sample size has been modified with the accrual goal of 120 pts randomized between the two immunotherapy arms needed for study completion. Enrollment actively continues at U.S. sites. Current accrual (as of 9-20-2024): 100/120. Clinical trial information: NCT02997228 .

801 Background: SBA is a rare, poorly understood gastrointestinal malignancy. Adenocarcinomas are often grouped with other small bowel cancer histologies in epidemiologic and outcomes reports, which limits the ability to detect SBA-specific trends. Recent studies in European populations show increasing SBA incidence, but there are limited published data in American cohorts. Identifying trends in SBA can improve understanding of the population most at risk for developing SBA. This study describes U.S. trends in SBA incidence and outcomes from 2000 to 2019. Methods: Using the 2022 SEER research-limited dataset, we identified SBA cases and measured the incidence change from 2000-2019. We built linear regression models to evaluate changes in annual incidence by groups, including sex, race, and age of diagnosis, separately. We then compared the overall incidence and trends between subgroups. We investigated overall survival (OS) through the SEER research case listings for SBA patients diagnosed during the study period. Results: An average of 0.67 cases/100,000 SBA cases were reported annually from 2000-2019, with a median diagnosis age of 69 years. SBA incidence has increased annually by 0.3% per year from 2000-2019 (p=0.05). From 2000-2019, men were at a higher risk for SBA compared to women (p=0.02). In men, SBA cases increased at a rate of 0.004 cases/100,000/year from 2000-2019 (p=0.01) and a nonsignificant decrease in women of 0.00012 cases/100,000/year. There were no statistically significant differences in incidence or the change in incidence of SBA by race. The age-adjusted incidence was significantly higher each year between 2000 and 2019 in the > 70 cohort compared to the <70 cohort (p=0.02). Cases of SBA increased at a rate of 0.02 cases/100,000/year in adults >70 years (p=0.02). There were no differences in incidence rates in patients <70 years. There was no significant difference in OS for patients diagnosed with SBA in 2000, 2005, 2010, 2015, and 2019 (p=0.21). Conclusions: The overall annual incidence of SBA is increasing in the U.S. population. The most significant rate increases are in men and adults older than 70. In the SEER population, trends in SBA contrast with the recent rise of colorectal cancer in the young adult population, highlighting the unique nature of SBA compared to other gastrointestinal malignancies. Additionally, survival outcomes in patients diagnosed with SBA have remained stable over the past 20 years, while other malignancies have shown improvement in the same period. The small cohort size and the lack of a universal U.S. cancer registry limited this evaluation. Improved reporting of SBA cases and further research to identify risk factors are urgently needed to reduce the growing impact of SBA.

Background Immune checkpoint inhibitors (ICIs) are recommended to treat patients with deficient mismatch repair/microsatellite instability high (dMMR/MSI-H) metastatic colorectal cancer (mCRC). Pivotal trials have fixed a maximum ICI duration of 2 years, without a compelling rationale. A shorter treatment duration has the potential to improve patients' quality of life and reduce both toxicity and cost without compromising efficacy. Here we examine whether early treatment discontinuation (ETD) before 13 months in patients without progressive disease (PD) can lead to similar long-term disease control compared with a longer treatment duration (LTD). Methods To assess whether ETD is associated with similar outcomes compared with LTD, we assembled an international cohort of patients with dMMR/MSI-H mCRC treated with ICIs who stopped treatment for a reason other than PD within 395 days (ETD group) and compared them to those who continued for >395 days (LTD group). Outcomes were adjusted for patient/tumor characteristics. Primary endpoint was progression-free survival (PFS) and secondary endpoints were objective response rate (ORR), overall survival (OS) and safety. Results Of 976 patients, 137 and 394 were allocated to the ETD and LTD groups, respectively. In the ETD group, treatment was discontinued due to toxicity (n=56), objective response (n=43), surgery (n=28), patient decision (n=2) or other reasons (n=8). Baseline characteristics were well balanced between the two groups: 22% in both groups received both anti-programmed death-(ligand) 1 (anti-PD-(L)1) + anti-cytotoxic T-lymphocyte antigen-4 (anti-CTLA-4); all others received anti-PD-(L)1 monotherapy. ORR to ICIs was 81% in both groups. Median duration of treatment was ~7 months in the ETD and ~24 months in the LTD group. After a median follow-up of 44 months (IQR: 30–67), similar PFS (HR: 0.92, 95% CI: 0.60 to 1.40, p=0.69) and OS (HR: 1.15, 95% CI: 0.66 to 1.99, p=0.62) from the start of ICIs were observed in ETD and LTD patients. In the ETD group, 28 (20%) patients had a PFS event and 9 restarted ICIs with a disease control rate of 66%. Conclusions In our international series of dMMR/MSI-H mCRC, ETD of ICIs in the absence of PD did not seem detrimental in terms of PFS and OS compared with continuing treatment beyond 1 year. Randomized clinical trials to compare short and long treatment duration are now warranted.

Background Underserved patient populations characterized by low income, lack of insurance, low levels of education, and minoritized status face significant barriers when accessing clinical trials. To better understand these challenges, patients from a safety-net county hospital were surveyed on their perspectives on clinical trials, barriers to care, and facilitators of participation. Methods Patients ≥ 18 years old with histologically confirmed non-Hodgkin lymphoma (NHL) who received care at Lyndon B. Johnson Hospital, a safety-net county hospital in Houston, Texas, were invited to participate regardless of treatment status. A self-administered questionnaire was used and offered in English or Spanish. The questionnaire included a total of 53 items with an additional 13 demographic items assessing patient sociodemographic factors and knowledge of clinical trials. Questions also addressed barriers/facilitators of trial participation and respondent willingness to participate in a trial based on certain scenarios. Results Of the 136 patients invited to participate, a total of 49 participants diagnosed with NHL consented to the study and all completed the survey (participation rate 36%). Twenty-seven (55%) surveys were completed in Spanish. Participants self-identified as Hispanic (N=35, 71.4%), African American (N=6, 12.2%), non-Hispanic white (N=7, 14.3%), and Asian/Pacific Islander (N=1, 2%). This cohort included Diffuse Large B-cell lymphoma NOS (DLBCL) [32%], Follicular Lymphoma (FL) [28%], Marginal Zone lymphoma (12%). There were several patients with rare histologies such as Burkitt's lymphoma (4.2%); Mantle Cell lymphoma (4.2%), Plasmablastic lymphoma (4.2%) and T-cell lymphoma (4.1%). The majority of participants reported a commute of less than an hour away to the doctor's office (83%) with almost all participants commuting less than 2 hours (98% with 2% missing an answer). Participants were a median age of 55 years old (range 22-80), majority female (51%), less than a bachelor's degree as highest education (91.8%) and earning &lt; $35,000 (49%). Among respondents, 89.8% had not participated in a clinical trial for their cancer. Only 36.7% of respondents reported that they understood what a clinical research study as “somewhat well,” while 30.6% reported their understanding as “not very well.” Regardless, a majority were very willing (38.8%) or somewhat willing (36.7%) to participate in a trial as their initial course of treatment. Respondents' biggest concerns were the cost of a clinical trial (61.2%), not being able to contact the research team with questions (38.8%), and frequency of clinic visits (32.7%). The most helpful resources that participants identified to reduce participation burden were educational resources such as written materials (77.6%), videos (67.3%), an explanation of the study in their language (65.3%), insurance aid (75.5%), and flexible study visit times (65.3%). Notably, 26.5% of participants responded that they believed they had received medication from a doctor as part of an experiment without their permission. When asked which outcome would most influence their decision to participate in a trial, 79.6% of participants rated the possibility of improving quality of life by decreasing pain and increasing activity levels as very important. Fewer patients (55%) rated other outcomes such as types of side effects (55%) and possibility of pain/discomfort (59%) as very important. Conclusions The majority of patients with NHL who participated in this observational study had little or no previous exposure to or understanding of cancer clinical trials. We identified common barriers to participation including out-of-pocket costs, the ability to contact the research team, and the frequency of clinic visits that should be addressed with specific identified resources to reduce participation burden. Interventions guided by these data should be implemented and evaluated to improve clinical trial participation for patients with lymphoma.

TPS3632 Background: Approximately 45% of dMMR/MSI-H mCRC in the immunotherapy arm progressed at 12 mos (KEYNOTE 177). We hypothesize that dMMR/MSI-H mCRC patients (pts) may be more effectively treated with the combination of PD-1/PD-L1 (PD-1) pathway blockade and mFOLFOX6/bevacizumab (bev) rather than with anti-PD-L1 therapy (atezo) alone. Preclinical work demonstrated synergistic effects between anti-PD-1/anti-VEGF as well as between oxaliplatin/anti-PD-1 in murine CRC models, and phase II data showed activity of anti-PD-1/anti-VEGF in chemotherapy refractory colon cancer. Upon AtezoTRIBE subgroup analysis of the 8 pts with dMMR mCRC treated with FOLFOXIRI+bev+atezo, median PFS was not reached, with the first pt having progression ~16 mos. Additionally, in other solid tumor malignancies, anti-PD-1 plus anti-VEGFr (i.e., HCC and RCC) as well as anti-PD-1 plus chemotherapy (i.e., gastroesophageal and lung cancers) combinations are standard first-line treatments. Methods: This two-arm prospective phase III open-label trial randomizes (1:1) mCRC dMMR/MSI-H to atezo monotherapy v mFOLFOX6/bev+atezo combination. Key inclusion criteria have been simplified on recent amendments to better mirror clinical practice for pts receiving mFOLFOX6/bev+atezo: One cycle of FOLFOX or CAPOX, with or without bev (or biosimilar) prior to enrollment allowed, dMMR tumor determined by local CLIA-certified IHC assay (MLH1/MSH2/MSH6/PMS2) or MSI-H by local CLIA-certified PCR or NGS panel; pts with total bilirubin ≤4.0 x ULN; duration of therapy for up to two years for both arms; imaging frequency on post-treatment follow-up have been reduced; as has measurable disease per RECIST. Primary endpoint is PFS. Assuming the atezo monotherapy control arm has a 48% PFS at 24 mos as assessed by site investigator, we have 80% power to detect a hazard ratio of 0.6 (equivalent to 64.4% PFS at 24 mos) with alpha 0.025 one-sided. Stratification factors include BRAFV600E status, metastatic site, and prior adjuvant CRC therapy. Secondary endpoints include overall survival, objective response rate, safety profile, disease control rate, and duration of response. Archived tumor tissue and blood samples will be collected for correlative studies. Harmonization of translational analyses is planned between GI004 (COMMIT) and A021502 (ATOMIC). Sample size has been modified with the accrual goal of 120 pts randomized between the two immunotherapy arms needed for study completion. Enrollment actively continues. Current accrual (as of 02-02-2024): 96/120. NCT02997228. Support: U10CA180868, -180822, -180888, UG1CA189867, U24CA196067; Genentech, Inc. Clinical trial information: NCT02997228 .

Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and the second leading cause of cancer death in the United States. Management of disseminated metastatic CRC involves various active drugs, either in combination or as single agents. The choice of therapy is based on consideration of the goals of therapy, the type and timing of prior therapy, the mutational profile of the tumor, and the differing toxicity profiles of the constituent drugs. This manuscript summarizes the data supporting the systemic therapy options recommended for metastatic CRC in the NCCN Guidelines for Colon Cancer.