Vijayvergia, Namrata

Importance In a phase 2 randomized clinical trial, high-dose vitamin D 3 added to standard treatment improved progression-free survival (PFS) compared with standard-dose vitamin D 3 in patients with metastatic colorectal cancer (mCRC). Objective To determine if high-dose vitamin D 3 added to standard chemotherapy improves outcomes in patients with previously untreated mCRC. Design, Setting, and Participants Double-blind phase 3 randomized clinical trial enrolling 455 patients with previously untreated mCRC, conducted in the US through the National Clinical Trials Network from October 2019 to December 2022 (database freeze: July 15, 2024). Interventions mFOLFOX6 (modified FOLFOX6 [5-fluorouracil, leucovorin, oxaliplatin]) or FOLFIRI (5-fluorouracil, leucovorin, irinotecan) plus bevacizumab every 2 weeks with either high-dose vitamin D 3 (8000 IU daily × 14 days as loading dose followed by 4000 IU daily) or standard-dose vitamin D 3 (400 IU daily) until disease progression, intolerable toxicity, or withdrawal of consent. Main Outcomes and Measures The primary end point was PFS assessed by the unstratified log-rank test. Secondary end points included objective response rate, overall survival, and toxicity. Prespecified subgroup analyses of PFS were performed according to known prognostic factors. Results Among 455 randomized patients (median age, 59 years; 181 [40%] female) with median follow-up 20 months, the median PFS for high-dose vitamin D 3 (n = 228) was 11.8 months (95% CI, 10.3-13.3) vs 10.3 months (95% CI, 9.4-12.2) for standard-dose vitamin D 3 (n = 227) (1-sided log-rank P = .25). There were no significant differences in objective response rate between high-dose and standard-dose vitamin D 3 (51% [95% CI, 44%-58%] vs 44% [95% CI, 37%-50%], respectively; P = .12), or in overall survival (median, 25.6 vs 27.0 months; 1-sided log-rank P = .66). There were no clinically meaningful differences in the most common grade 3 or greater adverse events between the high- and standard-dose groups, including neutropenia (n = 67 [32%] vs n = 62 [30%]) and hypertension (n = 42 [20%] vs n = 49 [23%]) or in incidence of vitamin D–associated toxicities. Conclusions and Relevance Among patients with previously untreated mCRC, addition of high-dose vitamin D 3 , vs standard-dose vitamin D 3 , to standard chemotherapy plus bevacizumab did not improve PFS. Trial Registration ClinicalTrials.gov Identifier: NCT04094688

4178 Background: In the CABINET trial, CABO significantly prolonged progression-free survival (PFS) compared to placebo (PB) in patients (pts) with advanced, previously treated extrapancreatic NET (epNET) or pancreatic NET (pNET) (Chan et al., NEJM, 2025). Here we report outcomes according to functional status based on NET hormone secretion. Methods: Pts with locally advanced or metastatic epNET or pNET were randomized 2:1 in separate cohorts to receive CABO 60 mg daily vs PB. Eligibility included progression by RECIST within 12 months (mo) before registration, ≥ 1 prior systemic therapy not including somatostatin analogs (SSA). Pts with functional NET due to hormone secretion and non-functional NET were included. In this post hoc subgroup analysis, we analyzed PFS by blinded independent central review and adverse events for pts receiving CABO vs PB based on functional status. Cox regression models were used with stratification on primary tumor site (epNET vs pNET). Subset analyses to evaluate treatment arm differences were conducted in pts with functional and non-functional tumors. Due to small numbers, separate results for those with unknown functional status are not included. Results: Of the total 298 pts enrolled in both cohorts, 74 had a functional NET (CABO, n = 47; PB, n = 27); 179 had a non-functional NET (CABO, n = 123; PB, n = 56); 45 had unknown functional status (CABO, n = 28; PB, n = 17). For functional NET, primary tumor sites were GI tract (n = 50; 68%), pancreas (n = 15; 20%), unknown (n = 4; 5%), lung (n = 3; 4%), and thymus (n = 2; 3%). Secreted hormones that were reported included serotonin (55%), somatostatin (18%), gastrin (16%), glucagon (4%), insulin (4%), ACTH (1%), and vasoactive intestinal peptide (1%). For non-functional NET, primary tumor sites were pancreas (n = 75; 42%), GI tract (n = 42; 23%), lung (n = 30; 17%), unknown (n = 17; 9%), thymus (n = 8; 4%), and other (n = 7; 4%). Concurrent SSA was received by 91% and 53% of pts with functional and non-functional NET, respectively. In both subgroups, CABO was associated with improved PFS compared to PB (for functional NET: stratified hazard ratio [sHR], 0.40; 95% confidence interval [CI]: 0.20-0.82, P = 0.012; for non-functional NET: sHR, 0.26; 95% CI: 0.17-0.41, P < 0.001). The most frequent grade 3/4 adverse events (AEs) attributed to CABO vs PB in pts with functional NET included hypertension (21% vs 11%), diarrhea (9% vs 11%), and fatigue (2% vs 15%); in pts with non-functional NET, grade 3/4 AEs included hypertension (21% vs 4%) and fatigue (18% vs 4%). Conclusions: Subset analyses of the CABINET trial suggest that CABO is an effective treatment option for pts with functional and non-functional epNET or pNET. Efficacy and safety results for pts with functional or non-functional NET treated with CABO are consistent with results for the entire trial. Clinical trial information: NCT03375320 .

The prognosis of high-grade gastroenteropancreatic neuroendocrine tumors (GEP-NETs) is highly variable and reported median overall survival remains low. There is no established standard of care for patients with higher grade 2 (G2) (Ki-67 ≥ 10% and ≤ 20%) and grade 3 (G3) (Ki-67 ≥ 20% and ≤ 55%) GEP-NETs and most of the current treatment regimens, particularly for G3 NETs, are extrapolated from lower-grade GEP-NET treatments or based on data from small retrospective studies. Robust evidence to support treatment recommendations for high-grade NETs, especially in the first-line (1L) setting, is limited and the optimal treatment sequence has not been clearly defined. This review summarizes the latest literature on sequencing of therapies, identifies patient selection considerations for utilizing peptide receptor radionuclide therapy (PRRT), and offers data-driven expert opinions and clinical practice recommendations in high-grade GEP-NETs. As authors, we recommend that all patients with well-differentiated, higher G2 and G3 NETs are evaluated with [68Ga]Ga-DOTA-peptide positron emission tomography (PET) for baseline somatostatin receptor expression and if positive, a 1L treatment option of PRRT should be considered, especially in clinically stable patients. Somatostatin analog therapy may benefit patients with low-volume, indolent disease, and chemotherapy is usually a better fit for patients in visceral crisis, in need of urgent treatment, or with no access to [68Ga]Ga-DOTA-peptide PET. In complex cases, a robust discussion at a multidisciplinary NET tumor board can be beneficial.

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 .

ASCO Guidelines provide recommendations with comprehensive review and analyses of the relevant literature for each recommendation, following the guideline development process as outlined in the ASCO Guidelines Methodology Manual . ASCO Guidelines follow the ASCO Conflict of Interest Policy for Clinical Practice Guidelines . Clinical Practice Guidelines and other guidance (“Guidance”) provided by ASCO is not a comprehensive or definitive guide to treatment options. It is intended for voluntary use by clinicians and should be used in conjunction with independent professional judgment. Guidance may not be applicable to all patients, interventions, diseases or stages of diseases. Guidance is based on review and analysis of relevant literature and is not intended as a statement of the standard of care. ASCO does not endorse third-party drugs, devices, services, or therapies and assumes no responsibility for any harm arising from or related to the use of this information. See complete disclaimer in Appendix 1 and 2 (online only) for more. PURPOSE To develop a clinical practice guideline and recommendations for symptom management of patients with well-differentiated grade 1 to grade 3 metastatic gastroenteropancreatic neuroendocrine tumors. METHODS ASCO convened an Expert Panel to develop a clinical practice guideline by reviewing the literature for relevant guidelines, systematic reviews, randomized controlled trials (RCTs), and observational studies to develop recommendations for clinical practice. RESULTS The literature review identified eight guidelines, 19 systematic reviews, and three RCTs that informed the development of guideline recommendations. RECOMMENDATIONS Recommendations are included for carcinoid syndrome, carcinoid heart disease and carcinoid crisis, and functional pancreatic neuroendocrine tumor syndromes. Recommendations are provided for surgical management, liver-directed therapy, and systemic therapy options, as well as palliative care. Limited guidance is provided for sequencing of interventions. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines .

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 .

PURPOSE To develop recommendations for systemic therapy for well-differentiated grade 1 (G1) to grade 3 (G3) metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs). METHODS ASCO convened an Expert Panel to conduct a systematic review of relevant studies and develop recommendations for clinical practice. RESULTS Eight randomized controlled trials met the inclusion criteria for the systematic review. RECOMMENDATIONS Somatostatin analogs (SSAs) are recommended as first-line systemic therapy for most patients with G1-grade 2 (G2) metastatic well-differentiated GI-NETs. Observation is an option for patients with low-volume or slow-growing disease without symptoms. After progression on SSAs, peptide receptor radionuclide therapy (PRRT) is recommended as systematic therapy for patients with somatostatin receptor (SSTR)–positive tumors. Everolimus is an alternative second-line therapy, particularly in nonfunctioning NETs and patients with SSTR-negative tumors. SSAs are standard first-line therapy for SSTR-positive pancreatic (pan)NETs. Rarely, observation may be appropriate for asymptomatic patients until progression. Second-line systemic options for panNETs include PRRT (for SSTR-positive tumors), cytotoxic chemotherapy, everolimus, or sunitinib. For SSTR-negative tumors, first-line therapy options are chemotherapy, everolimus, or sunitinib. There are insufficient data to recommend particular sequencing of therapies. Patients with G1-G2 high-volume disease, relatively high Ki-67 index, and/or symptoms related to tumor growth may benefit from early cytotoxic chemotherapy. For G3 GEP-NETs, systemic options for G1-G2 may be considered, although cytotoxic chemotherapy is likely the most effective option for patients with tumor-related symptoms, and SSAs are relatively ineffective. Qualifying statements are provided to assist with treatment choice. Multidisciplinary team management is recommended, along with shared decision making with patients, incorporating their values and preferences, potential benefits and harms, and other characteristics and circumstances, such as comorbidities, performance status, geographic location, and access to care. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines .

High-grade neuroendocrine neoplasms are a rare disease entity and account for approximately 10% of all neuroendocrine neoplasms. Because of their rarity, there is an overall lack of prospectively collected data available to advise practitioners as to how best to manage these patients. As a result, best practices are largely based on expert opinion. Recently, a distinction was made between well-differentiated high-grade (G3) neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas, and with this, pathologic details, appropriate imaging practices and treatment have become more complex. In an effort to provide practitioners with the best guidance for the management of patients with high-grade neuroendocrine neoplasms of the gastrointestinal tract, pancreas, and gynecologic system, the North American Neuroendocrine Tumor Society convened a panel of experts to develop a set of recommendations and a treatment algorithm that may be used by practitioners for the care of these patients. Here, we provide consensus recommendations from the panel on pathology, imaging practices, management of localized disease, management of metastatic disease and surveillance and draw key distinctions as to the approach that should be utilized in patients with well-differentiated G3 neuroendocrine tumors vs poorly differentiated neuroendocrine carcinomas.

TPS514 Background: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs), which represent approximately 70% of NETs, frequently develop metastatic disease with limited treatment options. Current standard therapies for well-differentiated high grade 2 and grade 3 GEP-NETs include cytoreductive procedures, somatostatin analogues, molecular targeted therapies (everolimus or sunitinib), chemotherapy and peptide receptor radionuclide therapy (PRRT), with no specified sequence of use. PRRT may stabilize disease and induce objective tumor responses. This treatment uses radiolabeled somatostatin analogues to selectively target somatostatin receptor expressing (SSTR+) tumor cells. 177 Lu-edotreotide is an innovative radiolabeled somatostatin analogue with a favorable safety profile and promising efficacy. Retrospective data in metastatic GEP-NETs treated with two or more 177 Lu-edotreotide cycles demonstrated a progression free survival (PFS) of at least 30 months. The currently recruiting Phase III COMPETE trial compares the efficacy and safety of 177 Lu-edotreotide, versus everolimus, in grade 1 and grade 2 GEP-NETs. Methods: COMPOSE (NCT04919226) is a prospective, randomized, controlled, open-label, multi-center Phase III study, in patients with well-differentiated high grade 2 and grade 3 (Ki-67 index 15−55%), SSTR+, GEP-NETs. This trial is to evaluate the efficacy, safety and patient-reported outcomes of first- or second-line treatment with 177 Lu-edotreotide PRRT compared to best standard of care. It aims to randomize 202 patients 1:1 to a defined number of cycles of 177 Lu-edotreotide or an active comparator (either chemotherapy [CAPTEM or FOLFOX] or everolimus, according to investigator´s choice). The primary endpoint is PFS, assessed every 12 weeks until disease progression (RECIST v1.1), or death, whichever occurs earlier. Secondary outcomes include overall survival, assessed up to 2 years after disease progression. Study recruitment for COMPOSE commenced in September 2021. It is expected that COMPOSE will inform optimal treatment options for patients with well-differentiated high grade 2 and grade 3 SSTR+ GEP-NETs, including for first-line therapy. Clinical trial information: NCT04919226.