Zemla, Tyler

AbstractBackgroundOne in three patients with stage III colon cancer will experience tumor recurrence. It is uncertain whether physical activity during and after postoperative chemotherapy for stage III colon cancer improves overall survival after tumor recurrence.MethodsA prospective cohort study nested within a randomized multicenter trial of patients initially diagnosed with stage III colon cancer who experienced tumor recurrence (N = 399) was conducted. Postoperative physical activity before tumor recurrence was measured. Physical activity energy expenditure was quantified via metabolic equivalent task hours per week (MET‐h/week). The primary end point was overall survival after tumor recurrence. Multivariable flexible parametric survival models estimated relative and absolute effects with two‐sided hypothesis tests.ResultsCompared with patients expending <3.0 MET‐h/week of physical activity (comparable to <1.0 h/week of brisk walking), patients with ≥18.0 MET‐h/week of physical activity (comparable to 6 h/week of brisk walking) had a 33% relative improvement in overall survival time after tumor recurrence (hazard ratio, 0.67; 95% CI, 0.42–0.96). The overall survival rate at 3 years after tumor recurrence was 61.3% (95% CI, 51.8%–69.2%) with <3.0 MET‐h/week of physical activity and 72.2% (95% CI, 63.1%–79.6%) with ≥18 MET‐h/week of physical activity (risk difference, 10.9 percentage points; 95% CI, 1.2–20.8 percentage points).ConclusionsHigher postoperative physical activity is associated with improved overall survival after tumor recurrence in patients initially diagnosed with stage III colon cancer. These data may be relevant to patients who, despite optimal postoperative medical therapy, have a high risk of tumor recurrence.

TPS5634 Background: The prognosis for women with recurrent or persistent EC after progressing on first-line chemotherapy is poor, with a median overall survival (OS) of 12 months, highlighting the need for more efficacious therapies for this population. Immune checkpoint inhibitors either as monotherapy or when combined with kinase inhibitors have recently demonstrated encouraging response rates in pts with microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) and MS-stable (MSS)/MMR-proficient (MMRp) EC, respectively. Atezo is a humanized monoclonal anti-programmed cell death ligand 1 (PD-L1) inhibitor that has demonstrated monotherapy antitumor activity with an acceptable safety profile in relapsed recurrent EC. Atezo has shown compelling clinical efficacy for pts with certain solid tumors (e.g., urothelial, NSCLC, triple negative breast cancer) as monotherapy and as part of combinatorial therapy. The AFT-50 EndoMAP trial is a platform trial designed to evaluate the efficacy and safety of Atezo in combination with biomarker-defined targeted agents in pts with recurrent or persistent EC. Recognizing pts may have either progressed through or received a checkpoint inhibitor in a prior line of therapy, a non atezo cohort will also be open to enrollment. Methods: This is a phase IB/II non-randomized, multicenter, multicohort, biomarker-driven platform study consisting of two cohorts: A (atezo containing) and B (non atezo). Eligible pts have recurrent or persistent EC and have received no more than 2 prior lines of therapy. FoundationOne CDx (F1CDx) NGS assay will be used for genomic tumor profiling. In cohort A, pts may be eligible for one of the following doublets: Atezo+ipatasertib (PIK3CA/PTEN/AKT1-altered cancers), Atezo+talazoparib (tumors with genomic loss of heterozygosity (LOH) ≥16%), Atezo+Trastuzumab emtansine (ERBB2/HER2 mutated and/or amplified tumors), Atezo+Tiragolumab (MSI-H and/or TMB>10 mut/MB), and Atezo+bevacizumab (biomarker unmatched). Pts will receive Atezo in addition to the targeted agent (at the study approved dosing schedule) until progression, unacceptable toxicity, pt or physician decision to withdraw from the study, death, or study termination. Pts in cohort B, will be eligible for inavolisib (PIK3CA/PTEN/AKT1-altered cancers) + letrozole. Each cohort will enroll ~20 pts; however, the exact size of the cohort may be adjusted. The primary endpoint for Cohort A is confirmed overall response rate (ORR) for each cohort, and for Cohort B is progression free survival at 6 months. Secondary endpoints include disease control rate, duration of response, OS, safety and tolerability, 6-month PFS (cohort A). As a platform study, additional arms may be added, as supported by evolving understanding of EC and molecular targets. EndoMAP is actively enrolling at 17 sites in the US with a target of 25 sites nationwide. Clinical trial information: NCT04486352 .

3595 Background: PolyPEPI1018 is an off-the-shelf, multi-peptide vaccine containing 12 immunogenic epitopes derived from 7 tumor-specific antigens frequently expressed in patients with mCRC. Following early evidence of clinical activity of PolyPEPI1018 in first-line MSS mCRC, here we report the results of a phase Ib study of PolyPEPI1018 vaccine plus trifluridine/tipiracil (TAS-102) in late-stage mCRC patients. Methods: Patients with MSS mCRC who have progressed on ≤2 lines of prior chemotherapy regimen for mCRC received PolyPEPI1018 subcutaneously on days 1 and 15 and TAS-102 orally twice daily on days 1-5 and 8-15 of a 28-day cycle. Treatment continued for up to 7 cycles, until disease progression or unacceptable toxicity. Immunomonitoring was performed at both blood and tumor levels prior to and on study treatment. The primary endpoint of the study was safety and tolerability. Data on objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and correlation studies will be presented. Results: 15 patients started treatment. Median age was 55 years (range 31–71), 73% had liver metastases (mets), 73% had KRAS mutant tumors. The most common side effect related to PolyPEPI1018 was Grade (Gr) 1-2 local skin reactions in 93% of patients. Gr 3 events (n = 15) at least possibly related to treatment were fatigue, decreased white blood cell, lymphocyte and neutrophil counts, nausea, diarrhea, myalgia, and maculo-papular rash. There were no Gr 4 or 5 events. The ORR was 0%. The DCR was 53.3% in the overall population and 36% and 100% for the patients with liver mets and without liver mets, respectively. The mPFS was 4 months (95%CI 2.2-6.1) in the overall population and 2.3 months (95%CI 2.1-NE) and 7.6 months (95%CI 4.4-NE) for the patients with liver mets and without liver mets, respectively (HR = 5.73 (95%CI 1.21, 27.06); p = 0.015). At the data cut-off date (Feb 10, 2023), the mOS was 8.7 months (95%CI 6.9-NE; not mature) in the overall population and it was not reached in patients without liver mets. Patients with increased PFS (≥ 24 weeks) had more robust vaccine-specific humoral and T cell responses induced by higher number of vaccine peptides than patients with PFS < 24 weeks. Conclusions: To our knowledge, this is the first study investigating combination of a cancer vaccine with TAS-102 chemotherapy in advanced MSS mCRC. Our results show that PolyPEPI1018 plus TAS-102 was well-tolerated with few grade 3 AEs beyond what is expected with TAS-102 monotherapy. Despite no objective tumor responses could be detected, correlative data suggest contribution of PolyPEPI1018-induced immunological responses to the improved clinical benefit and the combination warrants further testing. Clinical trial information: NCT05130060 .

3533 Background: The BACCI trial (NCT02873195) randomized 133 mCRC pts to C+B+A (investigational) or C+B+placebo. Longer progression free survival (PFS) was observed in the investigational vs placebo arm. To investigate T-cell functional heterogeneity, we performed single-cell proteomic analyses on pts with either long or short PFS and evaluated T-cell function as a prognostic and predictive biomarker. Methods: Isolated CD8+ and CD4+ cells were analyzed at baseline and first restaging from pts with long ( > 6 mo, N = 14) or short ( < 2 mo, N = 13) PFS. Single-cell, functional proteomic analyses were conducted using the IsoLight system (Isoplexis), which assessed secretion of 32 cytokines from an average of 786 cells per sample. The cumulative readout was polyfunctional strength index (PSI), a composite score of frequency and magnitude of secreted cytokines. Cytokines are organized into effector (E), stimulatory, chemoattractive (CA), regulatory, and inflammatory (I) clusters. Differential expression analyses were done using Wilcoxon rank-sum tests. Potential predictive effects were assessed using logistic regressions with interaction between treatment and biomarkers. No multiple comparison control was done due to the exploratory nature of analyses. Results: Baseline CD8+ and CD4+ cells were stimulated ex vivo and single-cell cytokine analyses performed. Prognostic analyses indicated that CD8+ cells from pts with long PFS had ~3-fold higher PSI compared to pts with short PFS (p = 0.005). Further analysis identified that the E (p = 0.005) and CA clusters (p = 0.005) most impacted PSI, significant individual cytokines are listed in the table. Baseline CD8+ cell function was not predictive of outcome. Baseline CD4+ cell function was not prognostic or predictive of outcome. Analysis of CD8+ cells after treatment identified that changes in CA cluster was prognostic of long PFS (p = 0.024). Cytokine changes from CD4+ cells were not prognostic; however, early changes in the CD4+ CA cluster were predictive of outcome (p-int = 0.055). Similarly, early changes in the CD8+ I cluster were predictive of outcome (p-int = 0.073). Conclusions: These results reveal pts with long PFS had more functional CD8+ T-cells with a higher PSI than pts with short PFS. Predictive analyses suggested that early changes in the CD4+ CA and CD8+ I clusters were associated with benefit from immunotherapy. These preliminary results highlight the importance of single-cell functional proteomic analyses. [Table: see text]

Abstract Purpose: To assess whether higher plasma 25-hydroxyvitamin D [25(OH)D] is associated with improved outcomes in colon cancer and whether circulating inflammatory cytokines mediate such association. Experimental Design: Plasma samples were collected from 1,437 patients with stage III colon cancer enrolled in a phase III randomized clinical trial (CALGB/SWOG 80702) from 2010 to 2015, who were followed until 2020. Cox regressions were used to examine associations between plasma 25(OH)D and disease-free survival (DFS), overall survival (OS), and time to recurrence (TTR). Mediation analysis was performed for circulating inflammatory biomarkers of C-reactive protein (CRP), IL6, and soluble TNF receptor 2 (sTNF-R2). Results: Vitamin D deficiency [25(OH)D &lt;12 ng/mL] was present in 13% of total patients at baseline and in 32% of Black patients. Compared with deficiency, nondeficient vitamin D status (≥12 ng/mL) was significantly associated with improved DFS, OS, and TTR (all Plog-rank&lt;0.05), with multivariable-adjusted HRs of 0.68 (95% confidence interval, 0.51–0.92) for DFS, 0.57 (0.40–0.80) for OS, and 0.71 (0.52–0.98) for TTR. A U-shaped dose–response pattern was observed for DFS and OS (both Pnonlinearity&lt;0.05). The proportion of the association with survival that was mediated by sTNF-R2 was 10.6% (Pmediation = 0.04) for DFS and 11.8% (Pmediation = 0.05) for OS, whereas CRP and IL6 were not shown to be mediators. Plasma 25(OH)D was not associated with the occurrence of ≥ grade 2 adverse events. Conclusions: Nondeficient vitamin D is associated with improved outcomes in patients with stage III colon cancer, largely independent of circulation inflammations. A randomized trial is warranted to elucidate whether adjuvant vitamin D supplementation improves patient outcomes.

559 Background: Cabozantinib, a multikanase inhibitor, is approved by the Food and Drug Administration (FDA) for treatment of advanced stage hepatocellular carcinoma (HCC) following progression on sorafenib. The CELESTIAL study which demonstrated benefit from cabozantinib following sorafenib included only patients with Child Pugh class A liver function. Recently, bevacizumab plus atezolizumab has replaced sorafenib as the first line treatment for HCC. It is unclear whether there is benefit from using Cabozantinib following progression on immunotherapy as CELESTIAL trial included very few patients who received prior immunotherapy. We describe the outcomes of individuals with advanced stage HCC treated with Cabozantinib following progression on immunotherapy. Methods: This was a multicenter, retrospective analysis of patients with advanced HCC diagnosed between 2010-2021 at Mayo Clinic Arizona, Florida, and Minnesota. Progression free survival (PFS) and median overall survival analysis were performed using Kaplan-Meier method. Results: We identified a total of 26 patients with advanced stage HCC who received cabozantinib following progression on immunotherapy. The median age of patients was 61 years (range, 39 – 81) and the majority were male (85%). Eighteen (72%) patients had Child Pugh A at initiation of cabozantinib therapy. Four (15%) patients received cabozantinib as second line therapy, the rest received it as third line or later. PFS on cabozantinib was 2.1 months (95% CI: 1.3 – 3.9) and median overall survival from time of cabozantinib initiation was 7.7 months (95% CI: 5.3 – 14.9). PFS was shorter with Child Pugh Class B, 1.3 months (95% CI: 0.9 – NE) compared to those with Child Pugh Class A, 2.1 months (95% CI: 1.5 – 4); although this difference was not significant (p=0.55). Common adverse events included fatigue (50%), anorexia (35%), aspartate aminotransferase (AST) elevation (35%), and diarrhea (31%); 7 (26%) patients experienced Grade 3 or greater adverse events including hypertension, diarrhea, anorexia, and bowel obstruction. Two patients discontinued cabozantinib due to side effects including one for uncontrolled blood pressure elevations and the other due to fatigue. Conclusions: The optimal sequencing of therapy for patients with advanced HCC following progression on immunotherapy is unknown. Treatment with cabozantinib may improve clinical outcomes following progression on immunotherapy with similar adverse event profile. This study included patients with Child Pugh class B liver disease (28%) and heavily pretreated population and demonstrated mPFS and mOS similar to other work examining outcomes of cabozantinib in real world setting after progression on sorafenib. Further studies to determine optimal treatment sequencing for this patient population are needed.

227 Background: Circulating tumor DNA (ctDNA) consists of small fragments of DNA released into the plasma from cancer cells. Tumor informed ctDNA testing by whole exome sequencing of the primary tumor coupled with multiplex polymerase chain reaction (PCR)-based next generation sequencing of cell free DNA in serum, can detect and quantify ctDNA, allowing for detection of minimal residual disease (MRD). Methods: We conducted a retrospective analysis of 120 patients with colorectal cancer who had at least one tumor-informed ctDNA MRD assay completed between May 6, 2019, and July 1, 2022, at Mayo Clinic, Rochester. Disease recurrence was defined as radiographic evidence consistent with recurrence with or without biopsy confirmation. Data are presented descriptively, including number of ctDNA assays completed, ctDNA positivity prior to disease recurrence, and ctDNA concordance with carcinoembryonic antigen (CEA). The study protocol was exempt after review by the Mayo Clinic Institutional Review Board. Results: One-hundred twenty patients were included in the study with median age at initial disease diagnosis of 67.0 years. Sixty-four percent were male and 94% were white. At time of initial diagnosis, 10 had stage I, 23 stage II, 60 stage III, and 25 stage IV disease. In 120 patients, 476 ctDNA assays were performed, and 110 recurrences were observed among 62 patients. There were 39 instances in which ctDNA was obtained prior to clinical detection of recurrence and of these, at least one ctDNA assay was positive in 28 cases (72%). CEA was obtained prior to recurrence in 88 instances and was elevated in only 39 cases (44%). Among 37 instances where both ctDNA and CEA testing were obtained prior to recurrence, ctDNA was positive in 27 cases (73%) while CEA was positive in 14 cases (38%). ctDNA was positive in 83% of recurrences involving liver and 62.5% of recurrences involving only the lungs. ctDNA and CEA positivity are shown by location of recurrence. ctDNA and CEA were discordant in 44% of instances in which the assays were completed within 2-weeks of each other. Results of a ctDNA assay impacted management decisions in 16% of cases. Conclusions: ctDNA detected 72% of recurrences with higher rates of detection in liver versus lung metastasis. ctDNA performed superiorly to serum CEA in detection of recurrence, suggesting a role in disease surveillance. However, ctDNA impacted disease management in only 16% of patients, suggesting need for better patient selection and further study for ctDNA-based disease management strategy (more details will be reported). [Table: see text]

147 Background: 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 colorectal cancer (CRC). PolyPEPI1018 successfully induced anticancer immunity and triggered recruitment and infiltration of cytotoxic T cells into the tumor of MSS mCRC subjects demonstrating also early evidence of clinical activity, in first-line mCRC. Here we report the initial results of the phase Ib study of PolyPEPI1018 vaccine plus trifluridine/tipiracil (TAS-102) in late-stage mCRC patients. Methods: Patients with MSS mCRC who have progressed on ≤2 lines of prior chemotherapy regimen for mCRC received PolyPEPI1018 subcutaneously on days 1 and 15 and TAS-102 orally twice daily on days 1-5 and 8-12 of a 28-day cycle. Treatment continued for up to 7 cycles until disease progression or unacceptable toxicity. Immunomonitoring was performed at both blood and tumor levels prior to- and on study treatment. The primary endpoint of the study was safety and tolerability. Data on objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and correlation studies will be also presented. Results: 15 patients (67% male) started treatment. At baseline, median age was 55 years (range 31–71), 73% had liver metastases and the primary tumor site was colon-sigmoid in 40% and rectum in 33%. The combination was well-tolerated; most common side effect related to PolyPEPI1018 was Grade (Gr) 1-2 local skin reactions in 93% of patients. Gr 3 events. There were no Gr 4 or 5 events. The ORR was 0% and the DCR was 50%. The mPFS was 2.5 months (95%CI 2.1-NR). At the data cut-off (September 7, 2022), the mOS has not been reached; median follow-up was 4.0 months (95% CI 2.2-4.4). Post-treatment, vaccine-specific T cell responses were detected ex vivo in the PBMC of 4/5 subjects tested. In addition, one subject who had no detectable T cell response at peripheral level, responded at the tumor level with more than 300% increase of both CD3+ and CD8+ tumor-infiltrating lymphocytes compared to baseline. Patients with increased PFS (≥ 16 weeks) had robust vaccine-specific T cell responses. Conclusions: To our knowledge, this is the first phase Ib study investigating combination of a cancer vaccine with TAS-102 chemotherapy in advanced MSS mCRC. Our results show that PolyPEPI1018 plus TAS-102 was well-tolerated with few grade 3 AEs beyond what is expected with TAS-102 monotherapy. PolyPEPI1018 induced immunological responses at both peripheral and tumor level, albeit no objective tumor responses could be detected. The study is on-going for the collection of overall survival data. Clinical trial information: NCT05130060 .

139 Background: The fibroblast growth factor receptor (FGFR) pathway plays a key role in cellular proliferation, migration, survival and angiogenesis. Aberrant signaling through FGFR in colorectal cancer and other malignancies results from gene amplification or mutation, chromosomal translocation or ligand-dependent activation of the receptors. Pemigatinib is an oral inhibitor of FGFR1-3 with proven efficacy in FGFR-altered cholangiocarcinoma and myeloid/lymphoid neoplasms, among others. We hypothesized that pemigatinib would improve response rates compared to historical controls in patients with refractory FGF/FGFR-altered mCRC. Methods: ACCRU-GI-1701 was a multicenter, single-arm, Simon’s two-stage phase II clinical trial (NCT04096417) of the FGFR inhibitor pemigatinib in patients (pts) with FGF/FGFR-altered mCRC. Eligible pts had received prior fluoropyrimidine, oxaliplatin, irinotecan, and anti-VEGF/anti-EGFR/anti-PD-1 if eligible. Pts received pemigatinib 13.5 mg once daily on d1-21 of each cycle, with option to escalate to 18 mg in c2 if well tolerated. The primary endpoint was (unconfirmed) objective response (OR). A sample size of 21 evaluable pts would provide 82% power to detect a true OR rate of 20% or greater compared to a historical control of 5 % with a one-sided type I error rate of 0.1. A prespecified interim analysis for futility was planned after 12 evaluable patients. Results: A total of 14 patients were enrolled in the first stage of the study, and all were evaluable for the primary endpoint. No OR were observed (out of 12) crossing the futility boundary and resulting in permanent closure of the study. Among all enrolled patients, median age was 60.5 years, 71.4% were male, 92.9% Caucasian, 42.9% with no prior exposure to TAS-102 or regorafenib, and 64.3% with left-sided primary tumors. Treated patients all had tumors with FGFR1-4 mutations and/or FGF/FGFR amplifications by tissue- and/or blood-based molecular testing; no FGFR translocations were present. OR rate for this study was 0% (95% CI, 0-23.2%), with one patient achieving stable disease as best response. Median progression-free survival was 9.1 weeks (95% CI, 7.9-not evaluable [NE]), and median overall survival was 7.9 months (95% CI, 3.4-NE). Grade 3+ adverse events (AE) were seen in 42.9% of treated patients (including 1 grade 5 AE). Most commonly occurring AEs of any grade were anemia, hyperphosphatemia, alkaline phosphatase increased, aspartate aminotransferase increase, and fatigue. Conclusions: Pemigatinib demonstrated evidence of safety but not clinical activity in this population of patients with FGF/FGFR-altered mCRC. It is unknown whether pemigatinib would be active in mCRC patients with FGFR translocations/fusions as these were not represented in our trial. Translational studies are planned to investigate mechanisms of resistance to this therapy. Clinical trial information: NCT04096417 .