Wolin, Edward M.

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 .

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 .

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 Patients with neuroendocrine tumors (NETs) and carcinoid syndrome experience diarrhea that can have a debilitating effect on quality of life. Diarrhea also may develop in response to other hormonal syndromes associated with NETs, surgical complications, medical comorbidities, medications, or food sensitivities. Limited guidance on the practical approach to the differential diagnosis of diarrhea in these patients can lead to delays in appropriate treatment. This clinical review and commentary underscore the complexity in identifying the etiology of diarrhea in patients with NETs. Based on our collective experience and expertise, we offer a practical algorithm to guide medical oncologists and other care providers to expedite effective management of diarrhea and related symptoms in patients with NETs.

4111 Background: The primary statistical analysis for the NETTER-1 trial showed a clinically and statistically significant PFS benefit with 177Lu-DOTATATE vs. high-dose octreotide. 177Lu-DOTATATE treatment was also correlated with a significant delay in time to deterioration in HRQoL. In addition to HRQoL questionnaires, patients were asked to record presence or absence of a range of symptoms in a daily diary. Methods: A Mixed Model Repeated Measures (MMRM) was used to analyze the change, compared to baseline, of the occurrence of abdominal Pain, diarrhea and cutaneous flushing as these symptoms were regarded as the most relevant to judge the overall disease status. For each visit (week = 0, 4, 8, etc.) the number of days with symptoms during the previous period was calculated. At baseline, the number of days with symptoms was counted over the previous 6 weeks, whereas the time frame between visits lasted 4 weeks. Results: The estimated number of days with symptoms declined significantly more in the 177Lu-dotatate arm compared to the octreotide arm. The difference in change and the confidence intervals for the symptoms abdominal pain, diarrhea and flushing of skin are, respectively: -3.11 [-4.88; -1.34], -3.11 [-5.04; -1.18] and -1.98 [-3.88; -0.08]. Conclusions: Analysis of symptom diaries confirms that 177Lu-Dotatate can palliate clinically relevant symptoms when compared to high-dose octreotide.