Zemla, Tyler

LBA3509 Background: Systemic inflammation has been implicated in colon cancer progression. We examined whether intake of a proinflammatory diet is associated with survival among patients (pts) with stage III colon cancer. Methods: This prospective cohort study was nested within a randomized phase III trial of adjuvant therapy in pts with stage III colon cancer who had undergone curative-intent resection. EDIP score – a validated tool to classify the inflammatory nature of diets – was derived as a cumulative exposure using data from food-frequency questionnaires completed within 6 weeks of randomization and 14-16 months (mo) after randomization. Cox proportional hazards regression was used to assess the associations of EDIP with disease-free survival (DFS) and overall survival (OS). Results: Of 1625 included pts, the mean (SD) age was 60.9 (10.5) years (yrs). Compared to pts in the lowest EDIP quintile, pts in the highest quintile (a more inflammatory diet) were younger (58.7 ± 10.8 vs 61.3 ± 9.5 yrs old) and more likely to be female (64.0% vs 48.9%) and have worse performance status (ECOG 1-2: 35.7% vs 19.4%). Pts in the highest quintile were less likely to be White (76.6% vs 92.0 %) and more likely to be Black (15.4% vs 3.7%). Baseline aspirin use, assigned chemotherapy (3 mo vs 6 mo), and assigned pharmacotherapy (celecoxib vs placebo) were not significantly different across EDIP quintiles. Compared with pts in the lowest EDIP quintile, pts in the highest quintile had significantly worse OS (multivariable hazard ratio [HR] 1.87, 95% confidence interval [CI] 1.26-2.77, P trend =0.01), but not DFS (HR 1.36, 95% CI 0.99-1.86, P trend =0.22). Diet and physical activity jointly influenced OS. Those with lower EDIP scores (quintiles 1-4, 80% of the study population) and higher physical activity (≥9 MET-h/wk) had the best OS (HR 0.37, 95% CI 0.25-0.53) compared with pts in the highest EDIP quintile (20% of the study population) and lower physical activity (<9 MET-h/wk) ( P interaction <0.001). The association between higher EDIP and OS was consistent when analyzed by celecoxib and placebo treatment arms ( P interaction 0.54). The relationship between EDIP and OS did not differ significantly according to aspirin use, with HR 1.60 (95% CI 0.71-3.60) among aspirin users and HR 2.01 (95% CI 1.27-3.16) among aspirin non-users ( P interaction 0.06). Conclusions: Our findings suggest that greater intake of a proinflammatory dietary pattern is associated with worse OS in pts with stage III colon cancer. Regular physical activity may attenuate the association, and further investigation of diet and physical activity intervention is warranted. Support: U10CA180821, U10CA180882, U24CA196171, U10CA180863, CCS 707213, UG1CA233234, U10CA180820, U10CA180868, U10CA180888; https://acknowledgments.alliancefound.org. Pfizer; ClinicalTrials.gov Identifier: NCT01150045.

LBA1 Background: Standard adjuvant chemotherapy of stage III colon cancer consists of a fluoropyrimidine plus oxaliplatin. In patients (pts) with stage III colon cancer and deficient mismatch repair (dMMR), the benefit of an immune checkpoint inhibitor combined with adjuvant chemotherapy is unknown. The phase III ATOMIC trial (NCT02912559) was conducted to determine whether atezolizumab (atezo), an anti-PD-L1 antibody, can improve pt outcomes when added to adjuvant 5-fluorouracil, leucovorin plus oxaliplatin (mFOLFOX6) in pts with stage III dMMR tumors. Methods: We conducted an NCI-sponsored, multicenter and randomized phase III trial in pts with surgically resected stage III dMMR colon adenocarcinoma (any T, N 1,2 M 0 ). Pts, age > 12 years (yr), were accrued at NCTN sites and the German AIO. Tumor dMMR was determined by local immunohistochemistry and centrally verified. Pts were randomized 1:1 to mFOLFOX6 plus atezo (840 mg IV q2 weeks) for 12 cycles (6 months)[mo] followed by atezo monotherapy for 13 cycles (12 mo total) versus mFOLFOX6 alone for 12 cycles. Randomization stratification factors were N-stage (N 1 /N 1c vs N 2 ), T-stage (T 1 -T 3 vs T 4 ) and site (proximal vs distal). The primary endpoint was disease-free survival (DFS); secondary endpoints were overall survival and adverse event (AE) profile (CTCAE, PRO-CTCAE). Primary efficacy analysis was done in the intent-to-treat population; DFS was compared by arm (stratified log-rank test). Hazard ratio (HR) and 95% confidence interval (CI) were calculated using a stratified Cox model; 3-yr DFS was determined by Kaplan-Meier method. Among 700 pts., 165 DFS events with two interim analyses (50% , 75% of events) yielded 90% power to detect HR 0.6 (3-yr DFS 75% vs. 84.2%) assuming exponential survival and 1-sided alpha (0.025). Results: From 9/2017 to 1/2023, 712 pts were randomized (1 pediatric) to either atezo plus mFOLFOX6 (n= 355; atezo arm) or mFOLFOX6 (n= 357). Median pt age was 64 yr. 55.1% were female. Among tumors, 83.8% were proximal, 46.1% were clinical low risk (T 1-3 N 1 ) and 53.9% high risk (T 4 and/or N 2 ). At the second interim analysis, median pt follow-up was 37.2 mo (interquartile range, 24.2 to 55.5) and 124 DFS events were observed. Three-year DFS was 86.4 % (95% CI, 81.8 to 89.9) in the atezo arm and 76.6 % (95% CI, 71.3 to 81.0) in the mFOLFOX6 arm (HR, 0.50; 95% CI, 0.35 to 0.72). Stratified log-rank p-value was <0.0001, crossing the pre-specified efficacy boundary of 0.009. Efficacy for the atezo arm was consistent across subgroups, including pts >70 yr and low- and high-risk groups. Treatment-related > grade 3 AEs occurred in 71.7 % of pts in the atezo arm vs 62.1 % in the mFOLFOX6 arm. Conclusion: The addition of atezolizumab to mFOLFOX6 significantly improved DFS and should be considered the new adjuvant standard of care for patients with dMMR stage III colon cancer. Support: U10CA180821, U10CA180882, U24CA196171; Genentech, a member of the Roche group; https://acknowledgments.alliancefound.org. Clinical trial information: NCT02912559 .

4020 Background: In previously treated patients (pts) with advanced extra-pancreatic NET (epNET) or pancreatic NET (pNET), cabozantinib (cabo) demonstrated improved progression-free survival compared to placebo (pbo) in the CABINET trial (NCT03375320). Here we present HRQOL data from CABINET. Methods: Pts with previously treated unresectable, locally advanced or metastatic epNET or pNET were randomized (2:1) in separate cohorts to receive cabo 60 mg daily vs pbo. HRQOL was an exploratory endpoint measured using the EORTC QLQ-C30, QLQ-GI.NET21, Patient Global Impression of Change (PGIC), and PRO-CTCAE questionnaires. Optional participation was by paper surveys at baseline and every 12 weeks (wks) until disease progression or new anticancer therapy. Mean changes from baseline were compared between treatment arms at wk12 using general linear mixed models. Minimally important within-arm improvements and between-arm differences were defined as 8 points on the C30 Global Health Status (GHS)/QOL Scale. PGIC was dichotomized as improved vs unchanged/worsened and compared using Chi-squared tests. Rates of pt-reported adverse events (AEs) by PRO-CTCAE were baseline-adjusted and compared using Fisher’s exact tests. Results: 172 pts (113 cabo, 59 pbo) with epNET and 81 pts (53 cabo, 28 pbo) with pNET consented for survey participation. Pts completed 524 (82%) of 640 expected surveys across baseline, wk12, and wk24. For epNET, C30 GHS/QOL was significantly improved at wk12 in pts receiving cabo (mean change 9.5, standard error (SE) 2.2, p < 0.001) but not pbo (mean change 0.2, SE 3.1, p = 0.95) resulting in significantly different mean changes from baseline between arms (p = 0.02). For pNET, C30 QHS/QOL was significantly improved at wk12 in pts receiving cabo (mean change 8.0, SE 3.0, p = 0.008) but not pbo (mean change 6.8, SE 4.4, p = 0.12); mean changes from baseline did not statistically differ between arms (p = 0.82). No significant differences in mean changes from baseline at wk12 in C30 Physical, Role, Emotional, Cognitive and Social Function were observed between arms in the epNET or pNET cohorts. In both cohorts at wk12, pts on cabo reported improved overall status as measured by PGIC more often than those on pbo (epNET: 38% vs 19%, p = 0.04; pNET: 57% vs 18%, p = 0.006). Rates of pt-reported AEs were statistically significantly higher in cabo for diarrhea (68% vs 53%), hand-foot syndrome (57% vs 26%), mouth or throat sores (47% vs 27%), and dysgeusia (67% vs 37%) [all p < 0.05]. GI.NET21 data will be presented. Conclusions: Although cabo is associated with pt-reported AEs consistent with its known safety profile, global HRQOL was maintained. A higher proportion of patients receiving cabo reported improved overall status. Results support cabo as a treatment option for pts with previously treated advanced NET that preserves patient HRQOL. Clinical trial information: NCT03375320 .

TPS4616 Background: Osseous metastases (OM) occur in approximately 30% patients with advanced RCC. Despite therapeutic advances, OM are associated with poor survival and risk of symptomatic skeletal events (SSEs). Cabozantinib targets multiple tyrosine kinases, including vascular endothelial growth factor (VEGF) receptors and MET (Mesenchymal-Epithelial Transition factor), which are overexpressed in OM, contributing to cabozantinib’s enhanced bone activity. Radium-223, an alpha-emitting bone-seeking radioisotope, prolongs survival in men with metastatic castration-resistant prostate cancer to the bone. Building on this therapeutic approach targeting OM, our pilot study of radium-223 with VEGF inhibition in RCC with OM has also shown safety, improvement in circulating bone turnover markers, and early efficacy (McKay et al, CCR 2018). To address the unmet need to improve SSE rates and outcomes in RCC and OM, we designed a study investigating cabozantinib with or without radium-223 in patients with RCC with OM (NCT04071223). Methods: This is an open-label, multicenter randomized phase-2 study. Key inclusion criteria include metastatic RCC of any histology with ≥1 OM, at least 1 OM without prior radiation, any number of prior therapies, and Karnofsky performance status ≥ 60%. Use of a bone protecting agent is required unless contraindicated. Patients are randomized 1:1 to cabozantinib with (Arm A) or without (Arm B) radium-223. The starting dose of cabozantinib for Arm A is 40 mg by mouth daily to be escalated to 60 mg daily after cycle 1 (1 cycle = 28 days) if no persistent grade 2 or grade ≥3 toxicity. Radium-223 is administered at a fixed dose of 1.49 microcurie/kg IV every 28 days x 6 doses. The starting dose for cabozantinib in Arm B is 60 mg daily. The primary endpoint is SSE-free survival. Secondary endpoints include safety, progression-free survival, overall survival, time to first SSE, objective response rate, time to subsequent anti-cancer therapies, quality of life (QoL) measures, and correlative analyses including liquid biopsy and tumor tissue analysis. The study is designed to have 85% power to detect an improvement in 6-month SSE-free survival rate from 65% to 78% with one-sided α = 0.05 significance. To ensure 124 evaluable patients, target accrual is 134 (67 per arm). The group-sequential design includes a safety run-in and an interim analysis for futility when 50% of the expected number of events have been observed. The safety run-in, performed in the first 12 patients randomized to combination therapy, did not demonstrate dose limiting toxicities. Final data analysis will occur when 99 events have been observed. The study was activated in July 2020 and accrual is ongoing throughout the National Clinical Trials Network (NCTN). Continued site participation and enrollment are essential to evaluate this therapeutic strategy. Clinical trial information: NCT04071223 .

666 Background: In the phase 3 CABINET trial (NCT03375320), cabozantinib (CABO) significantly prolonged median progression-free survival (PFS) compared to placebo (PB) in patients with advanced, previously treated, progressive extrapancreatic NET (epNET) [HR 0.38 (95% CI, 0.25-0.59, P<0.0001)] and pancreatic NET (pNET) [HR 0.23 (95% CI, 0.12-0.42, P<0.0001)] (Chan et al., NEJM, 2024). In this analysis, we focus on outcomes of patients with epNET arising in the GI tract. Methods: Patients with locally advanced or metastatic epNET or pNET were randomized 2:1 in separate cohorts to receive CABO 60 mg daily vs PB. The epNET cohort included patients with tumors arising in the GI tract (not including pancreas), lung, unknown primary, and other rare primary sites. In this subgroup analysis of the epNET cohort, patients with GI NET were included. Eligibility included progression by RECIST within 12 months (mo) prior to registration, ≥ 1 prior systemic therapy. Primary endpoint: PFS by blinded independent central review (BICR). Secondary endpoints: objective response rate, overall survival, safety. Results: 116 of the 203 patients in the epNET cohort had GI NET (CABO, n=70; PB, n=46). Median age was 66 yrs; females: 46%; G1/G2/G3/unknown grade: 35%/57%/6%/2%. ECOG performance status: 0/1-2: 43%/57%. White race: 86%. The most common primary tumor locations were ileum/cecum (54%), small intestine with location not specified (20%); non-cecum colon or rectum (11%), stomach (4%); duodenum (3%); jejunum and nonspecified midgut site (3% each). Prior systemic therapies included somatostatin analogs (SSA) (100%), everolimus (59%); Lu-177 dotatate (77%); temozolomide +/- capecitabine (16%). In patients with GI NET, CABO was associated with improved PFS by BICR compared to PB (stratified HR, 0.50; 95% CI: 0.28-0.88, 1-sided stratified log-rank P=0.007). Median PFS with cabozantinib was 8.5 mo (95% CI, 6.0-16.7) compared to 5.6 mo (95% CI, 3.9-11.0) with PB. CABO demonstrated potential benefit in patients with midgut GI NET and across clinical factors including grade, functional status related to hormone secretion, concurrent SSA use, and prior therapy with Lu-177 dotatate or everolimus. The most frequent grade 3/4 adverse events attributed to therapy with CABO included hypertension (19%), diarrhea (13%), fatigue (10%). Conclusions: CABO is associated with improvement in PFS compared to PB in patients with advanced GI NET. Potential benefit was observed across clinical factors including grade, functional status, concurrent SSA, and prior treatment. The safety profile for CABO in patients with GI NET is consistent with that previously reported. Support: U10CA180821, U10CA180882; U10CA180820 (ECOG-ACRIN), U10CA180868 (NRG Oncology), U10CA180888 (SWOG); Exelixis; https://acknowledgments.alliancefound.org . Clinical trial information: NCT03375320 .

Abstract Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide including sub-Saharan Africa. The GALAD score, derived from Gender, Age, Lens culinaris agglutinin-reactive fraction of alpha fetoprotein, Alpha fetoprotein, and Des-carboxy-prothrombin, has high accuracy in diagnosing HCC in Asia, Europe, and North America; however, it has not been validated in an African cohort. The aim of this study was to assess the performance of the GALAD score in the diagnosis of HCC in sub-Saharan Africa. Clinical data from patients with cirrhosis (n = 93) or HCC (n = 78) from outpatient hepatology clinics at three teaching hospitals in Ghana were abstracted, and serum samples were analyzed. A logistic regression model predicting HCC status based on the GALAD score was constructed to obtain the ROC curve for GALAD. The AUC with 95% confidence interval (CI) was calculated. The median GALAD score was higher among patients with HCC versus cirrhosis controls (8.0 vs. −4.1, P &lt; 0.01). The AUC of the GALAD score for HCC detection was 0.86 (95% CI, 0.79–0.92). At a cut-off value of −0.37, the GALAD score had a sensitivity of 0.81 and a specificity of 0.86. The AUC (95% CI) was 0.87 (0.80–0.95) and 0.81 (0.67–0.94) in hepatitis B virus–positive and hepatitis B virus–negative patients, respectively. The GALAD score has a high accuracy for HCC detection. It has great potential to improve HCC surveillance in sub-Saharan Africa where imaging resources are limited. Significance: The GALAD score or its relevant modifications have the potential to aid in improving HCC surveillance efforts in low-resource settings in sub-Saharan Africa. This could enhance early detection rates of HCC and potentially improve survival rates in resource-limited settings.

50 Background: A+B is commonly used as first line systemic therapy in HCC patients with CP-B liver function, although in the IMbrave150 clinical trial, its efficacy was only assessed in patients with CP-A liver function. We evaluated outcomes in patients with CP-B liver function and compared to those with CP-A. Methods: We completed a multi-institution, retrospective review of patients with HCC from Mayo Clinic and University Hospitals Seidman Cancer Center, who had received A+B in the first line setting between March 2018 and November 2023. CP score was calculated at time of treatment, response was assessed, and progression free (PFS) and overall (OS) survival were determined using the Kaplan Meier method. Results: Among 322 patients with HCC, median age was 66.5 years, 78.6% were male, and 82.6% were white. Eighty-six patients (27%) had CP-B liver function, while 226 (70%) had CP-A and 10 (3%) had CP-C. Etiology of liver disease in patients with CP-B included hepatitis B in 7.0%, hepatitis C in 38.4%, alcohol use in 30.2%, and metabolic associated steatohepatitis in 20.9%. Median OS in patients with CP-B liver function was 6.4 months, while mOS was 21.6 months for those with CP-A ( p<0.0001). Further stratifying, mOS in those with CP-B7 was 9.1 months, CP-B8 was 5.5 months, and CP-B9 was 4.0 months. 12-month OS in patients with CP-B was 32.4%, compared to 69.3% in CP-A. Median PFS was 4.8 months in those with CP-B and 8.9 months in those with CP-A. Median PFS in those with CP-B7, -B8, and -B9 was 6.4 months, 2.7 months, and 2.7 months, respectively. Among those with CP-B, 1 patient had a complete response, 17 (19.8%) had a partial response, 29 (33.7%) had stable disease, and 37 (43.0%) had progressive disease. Adverse events in CP-B patients included hypertension in 14.0% (grade 3 in 1 patient), bleeding in 16.3% (grade 3 or greater in 11.6%), fatigue in 38.4%, and an immune-related adverse event in 17.4% (grade 3 in 5.8%). Conclusions: Patients with advanced HCC and CP-B7 liver function may still benefit from A+B. Importantly, no additional safety risks were identified in this subgroup. Those with CP-B8 and CP-B9 have significantly worse survival than those with CP-B7 and the likelihood of benefit from systemic therapy is minimal. It is important for providers to address the impact of baseline liver function on expected outcomes in patient with HCC.

Abstract Background Atezolizumab plus bevacizumab is the standard of care for advanced hepatocellular carcinoma (HCC) in the first-line setting, although was only evaluated in patients with Child-Pugh (CP) A liver function in the IMbrave150 trial. We sought to determine the outcomes of these patients based on CP score and ALBI grade in the US population. Methods This multicenter cohort study included patients with HCC who received atezolizumab with bevacizumab as first-line systemic therapy between March 2018 and November 2023. Overall survival (OS) was determined using the Kaplan-Meier method and multivariate analyses were performed using Cox proportional hazard regression method. Results Among 322 patients, 226, 86, and 10 patients had CP-A, CP-B, and CP-C liver function, respectively. Median age was 66.5 years, 78.6% were male, and 82.6% were White. Median OS (mOS) was 21.6 months for those with CP-A, 9.1 months for those with CP-B7, and 4.7 months for those with CP-B8-C12 (P &lt; .0001). Among patients with CP-A, those with ALBI grade 1 had an mOS of 34.9 months versus 14.2 months in those with grade 2. In multivariate analyses, CP score, ALBI grade, hepatitis B, performance status, and macrovascular invasion were significantly associated with survival. Conclusions CP score is an important prognostic tool for patients with HCC receiving atezolizumab plus bevacizumab, and this regimen remains a viable option for patients with CP-B7 with no additional safety concern, although the benefit is significantly less than those with CP-A. ALBI score has independent predictive value in patients with CP-A liver function.

TPS5642 Background: The landscape in the management of recurrent or persistent endometrial cancer (EC) continues to evolve. Anti-PD-1/PD-L1 immune checkpoint inhibitors (ICI) as monotherapy or when combined with the VEGF-targeted tyrosine kinase inhibitor, lenvatinib, have demonstrated promising response rates in patients (pts) with microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) and MS-stable (MSS)/MMR-proficient (MMRp) EC, respectively. Recent studies have also shown a benefit with adding ICI to standard of care chemotherapy in the frontline setting. Pts with MSI-H/dMMR tumors seem to derive the greatest benefit. Approximately, 30% of recurrent EC pts fall into this category. Pairing ICI with targeted therapies carries the potential to elicit prolonged anti-tumor effects. Atezolizumab (Atezo) is a humanized monoclonal PD-L1 inhibitor that has demonstrated monotherapy antitumor activity in relapsed recurrent EC, and other solid tumors (e.g. NSCLC, HCC) as monotherapy and as part of combinatorial therapy. The AFT-50/EndoMAP study is a phase IB/II non-randomized, multicenter, 2-arm, multi-cohort platform trial designed to evaluate the efficacy and safety of biomarker-driven combination regimens, both with Atezo (AFT-50A) and without Atezo (AFT-50B) with biomarker-defined targeted agents in pts with recurrent or persistent EC. Methods: Eligible pts have recurrent or persistent EC with no more than 2 prior lines of therapy. FoundationOne CDx (F1CDx) NGS assay will be used for genomic tumor profiling. In AFT-50A, pts may be eligible for one of the following doublets: Atezo+talazoparib (tumors with genomic loss of heterozygosity (gLOH ≥16%), Atezo+Trastuzumab emtansine (ERBB2/HER2 mutated or amplified tumors), and Atezo+Tiragolumab (MSI-H and/or TMB-H). The Atezo+bevacizumab (biomarker unmatched) and Atezo+ipatasertib (PIK3CA/PTEN/AKT1-altered tumors) cohorts have completed accrual. Each cohort will enroll ~20 pts with potential adjustment to account for statistical and clinical considerations. AFT-50A pts will receive Atezo in addition to a targeted agent (per study-approved dosing schedule) until progression, unacceptable toxicity, pt withdrawal, death, or study termination. AFT-50B pts will be eligible for inavolisib (PIK3CAm/PTEN and AKT1wt-altered tumors) + letrozole or giredestrant + abemaciclib (RB1wt, estrogen receptor positive tumors). The primary endpoint for AFT-50A is confirmed overall response rate (ORR) for each arm, and for AFT-50B is 6-month progression free survival. Secondary endpoints include disease control rate, duration of response, OS, safety and tolerability. As a platform study, additional arms may be added, as supported by evolving understanding of EC and molecular targets. EndoMAP is actively enrolling at 20 sites in the US with a target of 25 sites nationwide. Clinical trial information: NCT04486352 .