Performance Status Research Articles

Frailty assessed by a 10-item index from comprehensive geriatric assessment (FI-CGA-10) versus oncologist-assessed performance status (PS) in older adults with gastrointestinal (GI) cancer.

821 Background: A FI-CGA-10 is a recently developed measure of frailty in the geriatric oncology setting [Oncologist, 26, e1751 (2021)]. Our objective was to compare the multidimensional frailty assessment by FI-CGA-10 with PS assessed by a primary oncologist in older adults with cancer. Methods: This study included 790 older adults with GI cancer who underwent a CGA before cancer treatment decisions at a geriatric oncology service between September 2018 and May 2024, and whose PS was documented in the electronic medical record by a primary oncologist. Fitness and frailty level were evaluated using the FI-CGA-10, which assesses 10 domains: cognition, mood, communication, mobility, balance, nutrition, basic and instrumental activities of daily living, social support, and comorbidity. Deficits in each domain were scored as 0 (no problem), 0.5 (minor problem), and 1.0 (major problem). FI-CGA-10 scores (range 0-1) were calculated by dividing the sum of the scores for each domain by 10 and then categorized as fit (<0.2), pre-frail (0.2–0.35), and frail (>0.35). The strength of the ordinal association between the frailty category and each CGA domain score was assessed using Spearman’s non-parametric correlation coefficient (rho). Results: The median age was 79 years; 60% were male, 62% had GI tract cancer (esophageal, gastric, colorectal), 20% had hepatobiliary cancer, 15% had pancreatic cancer, and 46% had stage 4 disease. Overall (n=790), 25% of patients were fit, 40% were pre-frail, and 35% were frail (Table). Among patients with PS 0-1 (n=633), 30% were classified as fit, 48% as pre-frail, and 22% as frail. Among PS 0-1 patients, Spearman's rho was greater than 0.5 for the association between the frailty category (fit, pre-frail and frail) and cognition, IADL, and mobility domains. In this subcohort (PS 0-1), the proportion of patients with a cognition domain score of 0.5 (mild cognitive impairment) or 1.0 (dementia) was 7%, 30%, and 78% in the fit, pre-frail, and frail groups, respectively; the proportion of those with an IADL domain score of 0.5 (OARS IADL = 12-13) or 1.0 (OARS IADL ≤ 11) was 5%, 46%, and 92%, respectively; the proportion of those with a mobility domain score of 0.5 (0.8 m/s ≤ gait speed < 1.0 m/s) or 1.0 (gait speed < 0.8 m/s) was 45%, 85%, and 98%, respectively. Conclusions: In this study, 70% of older adults with GI cancer whose PS was scored as 0-1 by a primary oncologist were classified as pre-frail or frail when assessed using FI-CGA-10. Among patients with PS 0-1, there were strong correlations between the frailty levels and impairment levels in the cognition, IADL, and mobility domains, indicating that these domains are major contributors to the frailty classification (fit, pre-frail, and frail). All patients (n=790) Fit Pre-frail Frail PS 0 (n=351), n (%) 145 (41) 163 (46) 43 (12) PS 1 (n=282), n (%) 45 (16) 141 (50) 96 (34) PS 2-3 (n=157), n (%) 4 (3) 18 (11) 135 (86)

Nivolumab and hypofractionated radiotherapy in patients with advanced melanoma: A phase 2 trial.

Radiotherapy is thought to enhance anti-tumor immunity, particularly when delivered in a hypofractionated and multisite manner. Therefore, we investigated the effects of combining radiotherapy with nivolumab in patients with advanced melanoma. This was a multicenter, non-randomized, phase 2 trial that enrolled patients with treatment-naïve metastatic melanoma. They received nivolumab (240 mg / 2 weeks) plus radiotherapy (day 15, 6 Gy × 3). When feasible, one target from each organ was irradiated (no irradiation of all targets). The primary endpoint was 1-year overall survival (OS). This trial included 64 patients between March 2017 and July 2019. The median follow-up was 23.5 (2.3-43.8) months. The median age was 68 (35-95) years, patients were mostly male (67 %) with an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) score of 0 (72 %), stage IV-M1c disease (47 %), and were BRAF-wild-type (67 %). The 2-year OS and 1-year PFS rates were 65.2 % and 56 %, respectively (P = 0.22 and P = 0.03, vs. 58 % and 43 %, respectively, in the Checkmate 066 study). Thirty-seven (58 %) and twenty-seven (42 %) patients were irradiated at one and multiple targets, respectively. The ECOG-PS (1 vs. 0; HR = 3.5; P = 0.005) was an independent prognostic factor for OS. Irradiating more than one site and irradiating a smaller cumulative tumor volume tended to correlate with better outcome. Grade 3-4 treatment-related adverse events occurred in 21.9 % of the patients (no grade 5). Combined immunotherapy and hypofractionated radiotherapy did not improve survival compared to historical cohorts. The radiotherapy schedule needs to be optimized in order to improve these results.

Real-world clinical outcomes of trifluridine-tipiracil monotherapy (FTD-TPI) and FTD-TPI + bevacizumab combination therapy (FTD-TPI+bev) in 639 black patients (pts) with metastatic colorectal cancer (mCRC).

81 Background: In the phase 3 SUNLIGHT trial, FTD-TPI+bev improved overall survival (OS) as compared to FTD-TPI in treatment-refractory mCRC. Out of 492 pts in the study, only 7 (1.4%) pts self-identified as Black; therefore, the potential benefit of FTD-TPI+bev in this pt population was not well-examined. We present the largest analysis to date of real-world clinical outcomes of FTD-TPI and FTD-TPI+bev in Black pts with mCRC. Methods: We retrospectively identified Black adult pts with a documented exposure to FTD-TPI and diagnosis of mCRC at or prior to the initiation of FTD-TPI using United States-based electronic medical records and claims in the ConcertAI RWD360 dataset. Pts were categorized as having received FTD-TPI or FTD-TPI+bev. Kaplan-Meier analyses were used to compare the real-world overall survival (rwOS) and time to discontinuation (rwTTD) from the date of first exposure to FTD-TPI (index). Multivariate Cox regression analyses were used to control for pt characteristics including demographics, ECOG performance status (PS), comorbidities, metastatic sites, time from mCRC diagnosis to index, lab results, and prior receipt of regorafenib. Results: Out of 639 Black pts included in our study, 551 received FTD-TPI and 88 received FTD-TPI+bev. Index years were 2021-2023 for 26% and 92% pts receiving FTD-TPI and FTD-TPI+bev, respectively. Pts receiving FTD-TPI had median age 61 years; male 51.2%; any comorbidities 43.9%; ECOG PS 0-1 36.7%; median time from mCRC diagnosis to index 632 days. Pts receiving FTD-TPI+bev had median age 59 years; male 50.0%; any comorbidities 42.0%; ECOG PS 0-1 60.3 %; median time from mCRC diagnosis to index 579.5 days. The rwOS was significantly improved with FTD-TPI+bev as compared with FTD-TPI (10.8 vs 6.2 months, respectively; p=0.0001), similar to the SUNLIGHT study (Table). In the adjusted model, pts who received FTD-TPI+bev had a significantly lower risk of death as compared to pts who received FTD-TPI (hazard ratio [HR]=0.45; p<0.0001). The rwTTD was also significantly prolonged with FTD-TPI+bev as compared with FTD-TPI (3.8 vs 2.4 months, respectively; p<0.0001). In the adjusted model, pts who received FTD-TPI+bev had about half the risk of discontinuation as compared with pts who received FTD-TPI (HR=0.51; p<0.0001). Conclusions: This is the first study to compare the clinical outcomes with FTD-TPI vs. FTD-TPI+bev in Black pts with mCRC in the real-world setting. Our study confirmed OS improvement with FTD-TPI+bev as compared to FTD-TPI in Black pts with mCRC, as seen in the overall population of the SUNLIGHT trial. Current Study SUNLIGHT Black n rwOS months (95% CI) Black n OS months (95% CI) FTD-TPI 551 6.2 (5.7-6.9) 3 7.5 (6.3-8.6) FTD-TPI+bev 88 10.8 (7.8-16.0) 4 10.8 (9.4-11.8) HR 0.45 (95% CI 0.33-0.63; p<0.0001) HR 0.61 (95% CI 0.49-0.77; p<0.001)

Real-world clinical outcomes of patients (Pts) with metastatic colorectal cancer (mCRC) who received trifluridine-tipiracil (FTD-TPI) monotherapy or FTD-TPI + bevacizumab (FTD-TPI+bev) combination therapy.

79 Background: FTD-TPI+bev has shown survival benefit when compared to FTD-TPI alone in pts with mCRC and was approved in the U.S. in 2023. However, there is a lack of real-world data on outcomes for pts who received FTD-TPI+bev as compared to pts who received FTD-TPI. Methods: This retrospective study used data abstracted from electronic medical records and claims in the ConcertAI RWD360 dataset. Adult pts with a diagnosis of mCRC and exposure to FTD-TPI were included. Pts were categorized as having received FTD-TPI or FTD-TPI+bev based on first exposure to FTD-TPI (index date). Kaplan-Meier analyses were used to describe the overall survival (rwOS), real-world time to discontinuation (rwTTD), and time to next treatment or death (rwTTNTD) from the index date. Multivariate Cox regression analyses were used to control for patient characteristics, including demographics, ECOG performance status (PS), comorbidities, sites of metastatic disease, time from mCRC to index date, lab results, and receipt of prior regorafenib. Results: This study included 3,680 pts. The FTD-TPI cohort included 3,151 pts (median age 62 years; male 56.3%; White 63.3%; any comorbidities 40.6%; ECOG PS 0-1 34.8%; 2+ metastatic sites 25.4%; median time from mCRC diagnosis to index date 699 days). The FTD-TPI+bev cohort included 529 pts (median age 60 years; male 53.9%; White 68.1%; any comorbidities 34.4%; ECOG PS 0-1 51.4%; 2+ metastatic sites 25.1%; median time from mCRC diagnosis to index date 609 days). Prior to index date, 18.5% and 6.9% of pts had been exposed to regorafenib in the FTD-TPI and FTD-TPI+bev cohorts, respectively. FTD-TPI+bev significantly increased rwOS (median 9.4 [95% CI 8.0-10.1] vs 6.4 [95% CI 6.1-6.6] months; p<0.0001) and significantly decreased the risk of death (HR=0.68; p<0.0001) in the adjusted model. Other significant factors for rwOS included 2+ metastatic sites (vs.1 site, HR=1.16; p=0.002) and no receipt of regorafenib prior to index date of FTD-TPI (HR=0.80; p<0.0001). FTD-TPI+bev also significantly prolonged rwTTD as compared to FTD-TPI (median 3.5 [95% CI: 3.3-3.8] vs 2.4 [95% CI: 2.3-2.6] months; p<0.0001) and decreased risk of discontinuation (HR=0.65; p<0.0001) after adjusting for patient demographic and clinical characteristics. Additionally, the FTD-TPI+bev cohort had a significantly longer rwTTNTD as compared to the FTD-TPI cohort (median 5.0 [95% CI: 4.6-5.5] vs 3.9 [95%CI: 3.8-4.1] months; p<0.0001) in the adjusted model (HR=0.73; p<0.0001). Conclusions: This is the largest study to compare the clinical outcomes of pts receiving FTD-TPI and FTD-TPI+bev in the real-world setting. FTD-TPI+bev improved clinical outcomes including rwOS, rwTTD, and rwTTNTD, as compared to FTD-TPI in pts with mCRC. These findings align with the results of the SUNLIGHT trial.

Single-cycle neoadjuvant pembrolizumab in patients with stage I-III MMR-deficient colon cancer: Final analysis of the RESET-C study.

19 Background: Neoadjuvant treatment with immune checkpoint inhibitors has shown remarkable responses in patients with deficient mismatch repair (dMMR) colorectal cancer. However, the optimal choice and duration of treatment have yet to be established. Methods: RESET-C (NCT05662527) was an investigator-initiated, phase II, single-arm, multicenter study investigating the efficacy and safety of single-cycle neoadjuvant pembrolizumab in 85 patients with resectable stage I-III dMMR colon cancer. Additional inclusion criteria were ≥ 18 years of age, no indication for neoadjuvant therapy, and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. After inclusion, patients received one cycle of pembrolizumab 4mg/kg (maximum 400mg) and underwent surgery within three to five weeks. A tumor-response evaluation was done before surgery, including blood samples, a computed tomography scan of the chest and abdomen, and a colonoscopy. The primary endpoint was the pathological complete response (pCR) rate according to Mandard tumor regression grading (Clopper-Pearson method). Secondary endpoints included surgical complications, safety of pembrolizumab, major pathological response (Mandard tumor regression grade 1 or 2), and disease-free survival. Results: Between February 2023 and March 2024, 85 patients were included. The median age was 74 years (IQR, 68-79), 72% were women, and 60% had clinical stage III disease. All patients received pembrolizumab, and 84 patients proceeded to surgery. One patient with stage I disease decided not to undergo surgery. A pCR rate of 44% (37/84; 95% CI, 33-55) and a major pathological response rate of 57% (48/84; 95% CI, 46-68) were found. A significantly higher pCR rate was seen in patients with stage I-II (20/33) versus stage III (17/51) disease (61% vs 33%; p=0.02). A total of 41 surgical complications were seen in 31 patients (37%; 95% CI, 27-48). Of these, eight complications were Clavien-Dindo grade 3a or above, including three patients with anastomotic leakages and two deaths within 30 days. The patients who died were aged 80 and 81, had ECOG performance status 1, and clinical stage IIIB and IIIC disease, respectively. Seven out of 85 patients (8%; 95% CI, 3-16) experienced grade 3 adverse events, three of which were treatment-related. No grade 4 or 5 adverse events were registered. Finally, data on the association between endoscopically evaluated clinical complete response and pCR, along with the 1-year disease-free survival rate expected in January 2025, will be reported. Conclusions: A single cycle of neoadjuvant pembrolizumab was efficacious and safe in patients with localized dMMR colon cancer. For most patients with clinical stage I-II disease, a single cycle sufficed to achieve pCR. Clinical trial information: NCT05662527 .

Regorafenib combined with immunotherapy and prognosis of unresectable hepatocellular carcinoma.

541 Background: To investigate the prognosis and influencing factors of patients with unresectable hepatocellular carcinoma (uHCC) receiving regorafenib in different treatment modes. Methods: A total of 227 patients with uHCC who received at least 2 cycles of regorafenib treatment in the Affiliated Hospital of Qingdao University between June 2018 and August 2022 were retrospectively collected through the Hospital Information System (HIS). 204 patients were finally enrolled by inclusion and exclusion criteria after screening. Results: The median follow-up was 25.9 (4.5-69.7) months. The median overall survival (OS) of 204 patients with uHCC was 27.7 (95%CI 21.98-33.42) months. The 1, 2, 3 and 5-year OS were 80.9%, 55.9%, 41.4% and 26.7%, respectively. Univariate analysis showed that combination with immune checkpoint inhibitor (ICI) and metabolic-associated complications were independent factors for survival benefit of regorafenib, while the Eastern Cooperative Oncology Group Performance Status (ECOG‐PS) scale = 2, undecreased Alpha-fetoprotein (AFP), macrovascular invasion and extrahepatic metastasis were independent risk factors for poor prognosis (P<0.05). Compared with 60 patients receiving regorafenib alone, 144 patients receiving regorafenib combined with ICI had a significant survival benefit (median OS, 16.9 vs. 31.5 months, respectively, P=0.006). The median OS of 153 patients receiving second-line therapy with regorafenib was 30.3 months. Among 51 patients receiving third or more lines of therapy with regorafenib, compared with 4 patients receiving regorafenib alone, 47 patients receiving regorafenib combined with ICI had a significant survival benefit (median OS, 9.4 vs. 24.1 months, respectively, P=0.000). Among 148 patients receiving local treatment, the median OS of patients with regorafenib combined with ICI (n=115) or without ICI (n=33) was 33.2 and 16.5 months, respectively (P=0.005). Conclusions: Regorafenib has a good prognosis in second-line treatment of uHCC. The OS of patients with regorafenib combined with ICI were significantly better than that of patients without ICI. The OS benefit of regorafenib combined with ICI was also equivalent in patients with third or more lines. The benefit of regorafenib combined with ICI was better for patients receiving local treatment.

Hydronephrosis and survival in cervical cancer patients: The role of urinary diversion.

We aimed to assess the impact of urinary diversion on survival in patients with advanced cervical cancer (CC) and hydronephrosis. Additionally, we examined the influence of other patient factors and urinary diversion type on survival. A retrospective study analyzed survival in cervical cancer (CC) patients with hydronephrosis treated at two Mexican hospitals from 2011 to 2023. Patient data, including demographics, clinical, and pathological characteristics, were collected. Urinary diversion details and complications were recorded. Survival analysis was performed using Kaplan-Meier method and Cox regression model to identify predictors of survival. A total of 228 cervical cancer patients presenting with hydronephrosis were analyzed. Median follow-up was 9months. The majority of patients were in stage IVA (44.3%), with 66.7% exhibiting bilateral renal involvement. Urinary diversion was performed in 192 patients (84.2%). Median overall survival (OS) was 15.5months. Multivariate analysis identified stage, disease course, oncologic treatment, laterality, performance status, and urinary diversion as independent prognostic factors for survival. In patients undergoing urinary diversion, bilateral renal involvement (HR 2.0) and deteriorated performance status (HR 3.6) were risk factors for mortality. Neither the laterality (unilateral or bilateral) nor the type of diversion significantly affected overall survival. Survival in CC patients with hydronephrosis is influenced by factors such as: bilateral involvement, performance status, clinical stage, course and treatment of the underlying malignancy and urinary diversion. Urinary diversion improves survival, regardless of the specific diversion type or whether the diversion is unilateral or bilateral.

Randomized phase II trial of olaparib + pembrolizumab vs olaparib alone as maintenance therapy in patients with metastatic pancreatic cancer with germline BRCA1 or BRCA2 mutations: SWOG S2001 NCT04548752.

TPS793 Background: Olaparib was approved in 2019 as maintenance therapy for gBRCA1/2+ metastatic pancreatic cancer (mPDA) patients (pts). The POLO trial showed an improvement in median progression-free survival (mPFS) with olaparib compared to placebo (7.4 vs 3.8 months) for platinum sensitive gBRCA1/2+ mPDA pts. Preclinical studies have demonstrated that PARP inhibitors modulate the immune microenvironment by increasing genomic instability, PD-L1 expression and activating the immune inflammatory stimulator of interferon genes (STING) pathway. Results of the phase 2 pembrolizumab and olaparib (POLAR) maintenance trial in patients with germline or somatic BRCA1/2 or PALB2 mutations responding to platinum-based chemotherapy for at least 4 months was presented at ESMO 2024. In 33 patients, a 35% overall response rate with 90% disease control rate at 6 months was observed. S2001 is an important randomized study to better define the impact of the combination. Methods: S2001 was developed in collaboration with the Alliance and was activated in SWOG in October 2020. Key eligibility criteria include: mPDA pts with gBRCA1/2 mutations identified with standard of care germline genetic testing and progression-free after receiving at least 4 months of platinum-based chemotherapy (FOLFIRINOX, FOLFOX or gemcitabine/cisplatin +/- nab-paclitaxel). One cycle of gemcitabine and nab-paclitaxel is allowed while waiting for germline testing. Zubrod performance status (PS) 0 or 1 pts are eligible. Pts are stratified according to first line chemotherapy, PS 0 vs 1, and disease status after 1st line treatment. The primary objective of this study is to evaluate the PFS of mPDA pts treated with olaparib + pembrolizumab compared to olaparib alone as maintenance therapy. Based upon the POLO trial, we expect a mPFS of 7 months in the control arm. Targeting a mPFS of 11.7 months in the experimental arm (hazard ratio 0.6) and assuming 15 months follow-up, 80% power and a 1-sided alpha = 0.10, this design requires 78 evaluable pts with a total sample size of 88 pts. Prospective serial blood samples will be collected to bank DNA and RNA for future correlative studies. Support: NIH/NCI grants U10CA180888 and U10CA180819, U10CA180821 and U10CA180868. Clinical trial information: NCT04548752 .

Efficacy and safety of anlotinib as a later-line treatment for advanced colorectal cancer.

194 Background: Colorectal cancer (CRC) is increasingly prevalent in China, with rising incidence and mortality rates. Often, early-stage CRC presents with no symptoms, leading to most patients being diagnosed at an advanced stage, where prognosis is poor. First- and second-line treatments for advanced CRC typically include chemotherapy combined with cetuximab or bevacizumab. However, third-line therapies such as regorafenib, furosemide, and TAS102 have shown limited efficacy. Anlotinib, a multi-targeted tyrosine kinase inhibitor (TKI), has demonstrated improved progression-free survival (PFS) in refractory metastatic CRC (mCRC) in a phase III trial (NCT02332499), showing both efficacy and manageable toxicity. This report provides updated results from extended follow-up. Methods: This study enrolled 73 patients with advanced colorectal cancer who had undergone at least two prior standard treatments and were treated with oral anlotinib hydrochloride (8-12 mg daily, days 1-14 of a 21-day cycle) between November 2021 and March 2024 at Tangdu Hospital. Patients were treated until disease progression or intolerable adverse events. Efficacy was assessed using RECIST version 1.1, and adverse reactions were evaluated using CTCAE version 5.0. The primary endpoints were PFS, disease control rate (DCR), and adverse events (AEs), while secondary endpoints included overall survival (OS). Results: Of the 73 patients included, 38 had an ECOG performance status (PS) of 0-1, and 35 had a PS of 2. Clinical staging identified 18 patients with stage IIIB/IIIC and 55 with stage IV disease. Patients received anlotinib doses of 8 mg (n=11), 10 mg (n=44), or 12 mg (n=18), with 48 patients also receiving chemotherapy and 25 receiving anlotinib alone. The median PFS was 4.0 months (95% CI: 3.4-4.6), and the median OS was 7.0 months (95% CI: 5.7-8.3). Subgroup analysis indicated that patients under 60 years of age, those without liver metastases, and those with ECOG PS 0-1 derived greater benefit from anlotinib. The most common treatment-related adverse event was hypertension (19.2%). Other notable adverse events included elevated AST (11.0%), proteinuria (6.8%), and jaundice (6.8%). Most adverse reactions were grade 1-2, although 1 patient experienced grade ≥3 gastrointestinal bleeding. Conclusions: Anlotinib showed promising efficacy and a favorable safety profile as a later-line treatment for advanced colorectal cancer. These findings suggest that anlotinib may be a viable clinical option for advanced CRC, though larger-scale clinical trials are necessary to confirm these results and further define its role in treatment.

Correlation between immune-related adverse events and clinical outcomes in patients treated with first-line nivolumab plus chemotherapy for advanced gastric or gastroesophageal junction cancer: A multi-center retrospective study in Japan.

439 Background: The CheckMate 649 trial and ATTRACTION-4 trial showed the efficacy of first-line nivolumab plus chemotherapy (Nivo-CT) for advanced gastric or gastroesophageal junction (GEJ) cancer. Recent studies have shown that immune-related adverse events (irAEs) caused by immune checkpoint inhibitors were associated with survival benefit in patients with solid tumors. However, there were few data on correlation between irAEs and efficacy of first-line Nivo-CT for advanced gastric or GEJ cancer. Methods: This multi-center retrospective study included patients with histologically confirmed advanced gastric or GEJ adenocarcinoma who were started on first-line Nivo-CT between December 2021 and December 2023. We divided the patients into two groups according to occurrence of irAEs; those with irAEs (irAE group) or those without (non-irAE group) and assessed the efficacy in both groups. Efficacy was evaluated by overall survival (OS), progression-free survival (PFS) and objective response rate (ORR). Landmark analysis at 2 months after initiating Nivo-CT was performed to adjust effects of early progression or death, in which patients who had events up to 2 months were excluded. Results: A total of 271 patients were included (median age, 70 [range 18–85] years; male/female, 64/36%; performance status (PS) 0/1/2, 47/49/4%; primary tumor site gastric/GEJ, 90/10%; status unresectable/recurrent, 81/19%; histology intestinal/diffuse, 30/70%; PD-L1 CPS <1/1~5/>5, 15/33/53%). Median follow-up time was 11.3 (range 1-30) months, and 80 (30%) patients developed irAE. In the landmark analysis, the median PFS was 11.1 months in the irAE group and 7.2 months in non-irAE group (HR 0.70 [95%CI 0.50-0.97], p = 0.034), and the median OS was 22.5 months in the irAE group and 17.9 months in non-irAE group (HR 0.77 [95%CI, 0.50-1.17], p = 0.219). The ORR were 67.4% in the irAE group and 66.7% in non-irAE group (p = 0.934). Multivariate analysis indicated that PS ≥1 (HR 1.66 [95%CI, 1.20-2.30], p = 0.02), elevated ALP (HR 1.61 [95%CI, 1.13-2.27], p = 0.008), and absence of irAEs (HR 1.55 [95%CI, 1.08-2.22], p = 0.018) were associated with poor prognosis. The most frequent irAEs were pneumonitis (n = 16), and grade ≥3 irAEs were observed in 26 (9.6%) patients: pneumonitis (n = 6), hepatitis/hypophysitis (n = 5). Conclusions: Development of irAEs was associated with improved outcomes in advanced gastric or GEJ cancer patients receiving first-line Nivo-CT.

TROP2 expression in small bowel adenocarcinoma: A potential target for novel therapeutic strategies.

799 Background: Small bowel adenocarcinoma (SBA) is a rare cancer with limited chemotherapy options. To explore TROP2 as a potential therapeutic target for SBA and develop new treatment strategies, we examined TROP2 protein expression in SBA and analyzed associated clinicopathological features and prognosis, including PD-L1 expression levels in the same tumor samples from our previous studies. Methods: We retrospectively reviewed patients diagnosed with SBA who underwent adjuvant or palliative chemotherapy between July 2010 and July 2023 at our hospital. Immunohistochemistry staining of TROP2 (clone: SP295) was performed for pathological samples. The intensity of TROP2 membranous staining in tumor cells was classified as 0 (absent), 1 (weak to moderate), or 2 (strong). TROP2 positivity was defined as intensity 1 with ≥ 50% expression or intensity 2 with ≥ 10% expression. We also assessed overall survival (OS) in patients receiving palliative chemotherapy to examine the association between prognosis and TROP2, excluding microsatellite instability-high (MSI-H) patients treated with immunotherapy. Results: Pathological samples and clinical data were available for 51 patients. The median age was 63 years (range: 23–82), and 76% were male. Most patients (94%) had a performance status (PS) of 0–1. The primary lesion was in the duodenum in 49% of patients and in the jejunum or ileum in 51%. Surgery and adjuvant chemotherapy resulted in no recurrence in 12% of patients, while 88% received oxaliplatin-based palliative chemotherapy for unresectable SBA. Among those with unresectable SBA, 8% (4/51) had MSI-H and were treated with immunotherapy. TROP2 positivity was 84.3% (43/51). There were no differences in age, sex, or primary lesion between the TROP2-positive and TROP2-negative groups. In this cohort, the median CPS was 3 (range, 0–60). CPS was lower in TROP2-positive samples compared to negative samples (median CPS 7.9% vs. 23.4%, p = 0.030). However, all MSI-H cases were found to be TROP2-positive. Among patients receiving palliative chemotherapy, excluding those with MSI-H treated with immunotherapy, OS did not differ significantly between TROP2-positive and TROP2-negative patients (17.0 months vs. 9.2 months, HR 0.70, p = 0.480). Even after adjusting for age and PS, TROP2 expression was not identified as a prognostic factor. Conclusions: Our study highlighted that TROP2 is frequently expressed in SBA, suggesting it could be an effective therapeutic target for new treatment strategies. Further investigation is needed to confirm its potential.

Nivolumab plus ipilimumab (N+I) in patients (pts) with pancreatic cancer (PC) with BRCA1/2 mutation (mut): Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study.

715 Background: TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results from a cohort of pts with PC with BRCA1/2 mut treated with N+I are reported. Methods: Eligible pts had measurable disease, ECOG performance status (PS) 0-2, adequate organ function, and no standard treatment (tx) options or prior immune checkpoint inhibitor tx. PD-L1 expression testing was not required. Genomic testing was performed in CLIA-certified, CAP-accredited site-selected labs. Most genomic tests did not distinguish between germline or somatic mut. Pts received I at 3 mg/kg every 3 weeks (wks) for 4 doses with N at 1 mg/kg IV every 3 wks for 4 doses. N alone was then continued at 240 mg every 2 wks or 480 mg every 4 wks until disease progression. Primary endpoint was disease control (DC) per investigator defined as complete (CR) or partial (PR) response per RECIST v. 1.1, or stable disease of at least 16 wks duration (SD16+). CR is based on radiographic assessment. CA 19-9 levels were not collected. Simon 2-stage design tested null DC rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 have DC, 18 more pts are enrolled; otherwise, the cohort is closed. If ≥7 of 28 pts have DC, the null DC rate is rejected. Secondary endpoints were objective response (OR), progression-free survival (PFS), overall survival (OS), duration of response (DOR) and SD, and safety. DOR is defined as time from pt’s first documented OR to progressive disease. Results: 32 pts with PC with BRCA1 (n=8), BRCA2 (n=22) or both BRCA1/2 (n=2) were enrolled between October 2017 and March 2023. 4 pts were not evaluable for efficacy. Pts had adenocarcinoma (n=29), acinar cell carcinoma (n=2), and poorly differentiated carcinoma (n=1). Table shows demographics and outcomes. 1 CR, 3 PR and 4 SD16+ were observed for a DC rate of 31% (90% CI, 18 to 100) and OR rate of 14% (95% CI, 4 to 33). The pt with CR had a BRCA1 mut, the pts with PR had BRCA1 (n=1) and BRCA2 (n=2) muts, and the pts with SD16+ had BRCA1 (n=2) and BRCA2 (n=2) muts. The null DC rate was rejected (p=0.04). The pt with CR remains on tx with a DOR of 311 wks as of May 2024. 15 pts received prior tx with olaparib and 1 of those pts had SD16+ on this study. 17 pts had ≥1 drug-related grade 3-4 adverse event (AE) or serious AE. All were consistent with N+I labels except generalized muscle weakness and lymphopenia. Conclusions: N+I shows antitumor activity in pts with PC with BRCA1/2 mut and warrants further study. Clinical trial information: NCT02693535 . Demographics (N=32) and efficacy outcomes (n=28). Median (Med) age, years (range) 66 (37-80) ECOG PS, % 0-12 31 (97)1 (3) Prior systemic regimens, % 0-2≥3 10 (31)22 (69) DC rate, % (OR and SD16+) (90% CI) 31 (18, 100) OR rate, % (95% CI) 14 (4, 33) Med PFS, wks (95% CI) 9 (7, 16) Med OS, wks (95% CI) 34 (14, 46)

A multi-institutional retrospective study evaluating clinical outcomes and prognostic factors in patients with metastatic appendiceal adenocarcinoma.

69 Background: Appendiceal adenocarcinoma (AA), a rare cancer, has been reported to have high incidences of mucinous type histology, peritoneal metastasis, and relatively good prognosis. However, its chemotherapeutic efficacy and prognostic factors is not well known. Methods: We collected patients with metastatic AA treated with chemotherapy between February 2005 and March 2023 in two high volume cancer centers in Japan. We retrospectively analyzed the clinical outcomes of the chemotherapy of patients with metastatic AA and the clinical factors associated with treatment efficacy and prognosis by multivariate analysis. Results: A total of 66 patients with a median age of 54 years, were enrolled. 40 patients (60.6%) received an oxaliplatin-based regimen in combination with bevacizumab. The response rate was 22.0% and the disease control rate was 87.8%. With median follow-up period was 15.5 months [1.9-103.1], median progression-free survival (PFS) was 10.9 months [95% CI: 7.2-15.2] and median overall survival (OS) was 23.0 months [95% CI: 19.6-35.8]. 77.4% of patients received subsequent chemotherapy. In multivariate analysis, pretreatment carcinoembryonic antigen (CEA) and/or carbohydrate antigen 19-9 (CA19-9) were associated with significantly shorter PFS (HR: 2.93, P = 0.0049). Presence of primary tumor (HR:2.50, P = 0.015), ECOG performance status (PS) ≥1 (HR: 2.67, P = 0.0091), moderate to massive ascites (HR: 3.06, P = 0.0043) and high tumor marker levels (HR: 2.46, P = 0.026) were associated with significantly shorter OS. Classifying the patients by number of these prognostic factors for OS into three groups (0, 1-2, and 3-4), the group with prognostic factors (1-2 or 3-4) had a significantly shorter prognosis compared to the group without any these factors (0 vs 1-2: HR: 4.70, P = 0.038, 0 vs 3-4: HR: 17.6, P < 0.01). In addition, the group with 3-4 prognostic factors had relatively lower rate of subsequent chemotherapy ratio than the group without these factors (66.7% vs 100%, P = 0.25). Conclusions: We confirmed our treatment outcomes were consistent with previous studies and elevation of tumor markers presence of primary tumor, ECOG PS ≥1, moderate to massive ascites were significantly associated with survival in patients with metastatic AA.

Pembrolizumab plus chemotherapy versus placebo plus chemotherapy in patients with advanced HER2-negative gastric or gastroesophageal junction (G/GEJ) adenocarcinoma enrolled in the Republic of Korea: KEYNOTE-859.

428 Background: After a median follow-up of 41.6 mo, data from the global phase 3 KEYNOTE-859 study (NCT03675737; N = 1579) continued to show that use of pembrolizumab (pembro) plus chemotherapy (chemo) provided a significant and clinically meaningful improvement in overall survival (OS), with manageable safety, versus placebo (pbo) plus chemo for patients (pts) with locally advanced or metastatic HER2-negative G/GEJ adenocarcinoma. This post hoc analysis evaluated the safety and efficacy of pembro plus chemo in pts enrolled in KEYNOTE-859 in the Republic of Korea. Methods: Eligible pts aged ≥18 years with locally advanced unresectable or metastatic HER2-negative G/GEJ adenocarcinoma, measurable disease per RECIST v1.1, and an ECOG performance status (PS) of 0 or 1 were randomly assigned 1:1 to receive pembro 200 mg or pbo IV Q3W for ≤35 cycles. All pts received investigator’s choice of chemo (FP or CAPOX). The primary end point was OS. Secondary end points included progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR) per RECIST v1.1 by blinded independent central review, and safety. Efficacy end points were evaluated in all randomly assigned pts (intention to treat). Results: A total of 150 pts (66, pembro plus chemo; 84, pbo plus chemo) from the Republic of Korea were enrolled. The median time from randomization to database cutoff (August 22, 2023) was 48.1 mo (range, 32.7-56.8). Baseline characteristics were generally well balanced between treatment groups. Most pts were male (71.3%) with an ECOG PS of 1 (66.7%); 43.3% of pts had ≥3 metastases. The median OS was 19.5 mo (95% CI, 14.2-26.2) for pembro plus chemo versus 15.2 mo (95% CI, 11.7-19.8) for pbo plus chemo (HR, 0.80; 95% CI, 0.55-1.15). Additional efficacy data are reported in the Table. Treatment-related adverse events occurred in 63 pts (95.5%) in the pembro plus chemo group and 78 pts (92.9%) in the pbo plus chemo group; 39 (59.1%) and 31 (36.9%) pts, respectively, were grade 3 or 4. No treatment-related deaths occurred. Conclusions: Consistent with the global results, clinical outcomes favored pembro plus chemo versus pbo plus chemo with manageable safety in pts from the Republic of Korea with HER2-negative G/GEJ adenocarcinoma enrolled in KEYNOTE-859. Clinical trial information: NCT03675737 . Pembro + chemon = 66 Pbo + chemon = 84 Median PFS (95% CI), mo a 11.0 (6.9-17.6) 7.2 (5.6-8.9) PFS HR (95% CI) b 0.74 (0.48-1.13) ORR, % (95% CI) c 53.0 (40.3-65.4) 46.4 (35.5-57.6) Median DOR (range), mo 15.0 (1.4+ to 50.8+) 6.9 (1.4+ to 44.3+) Responses lasting ≥24 mo, a % 42.6 23.6 a Based on Kaplan-Meier estimates. b Based on the unstratified Cox regression model with the Efron method of tie handling with treatment as a covariate. c Based on the stratified Miettinen and Nurminen method with strata weighting by sample size.

Real-world safety of trastuzumab deruxtecan with gastric cancer: All-patient post-marketing surveillance study in Japan.

399 Background: Interstitial lung disease and pneumonitis (ILD/p) is an important identified risk in the Japanese risk management plan of trastuzumab deruxtecan (T-DXd). In Japan, an all-patient post-marketing surveillance (PMS) study was conducted to investigate the incidence of ILD/p and factors associated with its development among patients with gastric cancer treated with T-DXd in the real-world setting. Methods: This is an observational, multicenter, PMS study (jRCT2001200001) with an observation period of 12 months that enrolled all patients who initiated T-DXd treatment for HER2-positive unresectable advanced or recurrent gastric cancer between Sep 2020 and Dec 2021. All suspected ILD/p events reported by physicians were adjudicated by an independent ILD adjudication committee; events adjudicated as drug-related ILD/p were summarized. The factors associated with the development of adjudicated drug-related ILD/p were investigated using a Cox proportional hazards model. Effectiveness endpoints included best overall response rate according to the RECIST 1.1 and overall survival, which was estimated using the Kaplan–Meier method. Results: The safety analysis set included 1070 patients (77.4% male, 89.9% ECOG performance status ≤1) with median age of 70 years (range: 23-100). Median initial dose and treatment duration of T-DXd were 6.4 mg/kg (range: 3.1-6.4) and 3.9 months (range: 0.7-12.0), respectively.The incidence of any grade, grade ≥3, and grade 5 adjudicated drug-related ILD/p were 9.6% (n=103), 2.8% (n=30) and 1.2% (n=13), respectively. Within 24 weeks from onset, 73.8% of adjudicated drug-related ILD/p had resolved, were resolving, or resolved with sequelae.A multivariate analysis identified that medical history and/or comorbidity of ILD/p [hazard ratio (HR) = 3.372, 95% confidence interval (95% CI): 1.431, 7.840], radiation pneumonitis (HR = 8.523, 95% CI: 2.006, 36.215), COPD or emphysema (HR = 1.962, 95% CI: 1.032, 3.731) and age ≥75 years (HR = 1.648, 95% CI: 1.058, 2.567) were factors of interest associated with the development of ILD/p in patients with gastric cancer. The overall response rate at 12 months post-treatment initiation of T-DXd was 34.2%. Overall survival after 364 days post-treatment initiation of T-DXd was 43.8% (median survival time: 303.0 days). Conclusions: The results suggest that the risk of ILD/p in this PMS study does not differ from that in the Destiny Gastric-01 study, and no new safety concerns were identified. Medical history and/or comorbidity of ILD/p, radiation pneumonitis, COPD or emphysema and age ≥75 years were identified as factors of interest associated with the development of ILD/p in patients with gastric cancer. Further investigation into the identified factors of interest may offer insights into the development of ILD/p among T-DXd treated gastric cancer patients in Japan. Clinical trial information: jRCT2001200001.

Clinicopathological factors related to survival in gastroenteropancreatic neuroendocrine tumors (GEP-NET): 20 years experience in the American British Cowdray Medical Center.

656 Background: Neuroendocrine neoplasms (NEN) are a diverse group of tumors originating from neuroendocrine cells found throughout the body. Their “rarity”, heterogeneity, and non-specific presentation contribute to limited reliable epidemiological data, especially in developing countries such as Mexico. This study aims to analyze the clinical and pathological features of gastroenteropancreatic neuroendocrine tumors (GEP-NET) and their association with survival in a third-level center in Mexico. Methods: A retrospective cohort study at the American British Cowdray Medical Center, in Mexico City, was conducted. We included all histopathological confirmed GEP-NET from 2004 to 2024. Clinical, biochemical, and radiological features at diagnosis were analyzed. Survival was estimated using Kaplan-Meier and Log-Rank test. Results: We identified 110 NENs, of which 89% were GEP-NET, 56.1% were female, and the median age was 57.7 (SD 13.8) years. The clinical stage was metastatic (50%), localized (37.7%), and locally advanced (6.1%). The primary sites were the pancreas (49%), small bowel (23.5%), gastric (10.2%), colon (7.1%), rectum (5.1%), appendix (3.1%), and unknown (2%). ECOG performance status were 0-1 in 96.9%. In the metastatic setting, liver involvement was 96.2%, mainly high hepatic burden (59.6%). Symptoms were abdominal pain (34.6%), diarrhea (16.3%), and bowel obstruction (6.1%). Functioning tumors were 26.8%, and carcinoid syndrome was found in 9.2%. Grades 1, 2, and 3 were 62.9%, 34%, and 3.1% respectively. The median of Ki-67 was 6.4%. At diagnosis, Ga-68 PET/CT scan, serum CgA, and urinary 5-HIIA were performed in 98.2%, 39.7%, and 16.3% of patients. Among metastatic patients, 87.1% received at least one line of systemic treatment, primarily with somatostatin analogs (62.9%). In all population, the median follow-up was 42.5 months and the median overall survival (OS) was 164.9 (SD 12.2) months. Univariate analyses showed that primary site (p=0.02), Ki-67 <5% (p=0.02), CgA <700 ng/ml (p=0.03), and low hepatic burden (p=0.01) were statistically significantly associated with OS. Conclusions: This study provides critical insights into GEP-NET characteristics in a Mexican population, highlighting clinical, biochemical, and radiological factors associated with better survival.

Real-world (RW) experience with atezolizumab + bevacizumab (A+B) for the treatment of unresectable HCC (uHCC): A multicenter study.

537 Background: A+B is the preferred first-line (1L) standard of care for uHCC, with emerging RW evidence supporting its use in a broad patient (pt) cohort. We evaluated pt characteristics, clinical and treatment outcomes in pts treated at five U.S. institutions: Mayo Clinic, Houston Methodist, Moffitt Cancer Center, Mays Cancer Center, and University of Arizona. Methods: This is a retrospective study of uHCC pts who initiated A+B after January 1, 2019. De-identified pt data were extracted by treating oncologists. Overall survival (OS) and real-world progression-free survival (rwPFS) were assessed using Kaplan-Meier methods for all pts and for a “trial-like” subgroup with characteristics similar to those in the IMbrave150 trial (ECOG performance status [PS] 0-1, Child-Pugh [CP] class A, albumin-bilirubin [ALBI] grade 1-2). HCC-related hospitalizations were evaluated within 1 year of A+B initiation. Results: A total of 300 eligible pts were treated with 1L A+B (median age 68 years, 79% male, 79% White, 82% BCLC C, 44% viral etiology,12% ECOG PS >1). Liver function was CP A in 73% (36% A5, 31% A6, 6% not reported), CP B in 26% pts (15% B7, 7% B8, 5% B9), and CP C in 2 (<1%) pts. Compared with CP A, more CP B pts had characteristics of compromised liver function (CP A vs B: cirrhosis: 61% vs 91%; ascites: 7% vs 46%; encephalopathy: 4% vs 17%; esophageal varices: 14% vs 32%), bile duct invasion (2% vs 11%), and ECOG PS>1 (8% vs 22%), all Ps<0.001. Over a median follow-up of 8.7 mos, 244 (81%) pts discontinued A+B, primarily due to disease progression. Toxicity-related treatment discontinuation and hospitalizations due to treatment-related adverse events (TRAE) were similar between the two groups (Table). Median OS (mOS) was 14.4 mos (95% CI: 12.3, 18.2) and median rwPFS was 6.8 mos (95% CI: 5.8, 8.4). In the trial-like subgroup (n=194), mOS was 19.5 mos (95%CI: 14.6, 24.7) and median rwPFS was 8.8 mos (95% CI: 7.6, 12.1). In the CP B subgroup, mOS was 5.6 mos (95% CI: 4.6, 11.3) and median rwPFS was 3.1 mos (95% CI: 2.4, 5.8). Conclusions: This study demonstrates the RW outcomes of 1L A+B in a diverse pt cohort. Results from the “trial-like” pts further confirm the reproducible efficacy of A+B in clinical practice. Although pts with CP-B had higher hospitalization rates due to disease progression or symptoms, consistent with their underlying liver complications, they had similar rates of toxicity-related treatment discontinuation and TRAE-related hospitalizations compared to CP-A. Further characterization of safety for A+B in CP B pts within a prospective, controlled trial is warranted. N (%) CP A (n=219) CP B (n=79) Treatment discontinuation* 167 (76) 75 (95) Atezolizumab-related toxicity 20 (12) 13 (17) Bevacizumab-related toxicity 26 (16) 16 (21) Hospitalization* 87 (40) 58 (73) Symptom-related 42 (48) 35 (60) Progression 8 (9) 11 (19) TRAE 7 (8) 6 (10) *P-value comparing CP A vs CP B <0.001.

MDM2 amplification in patients with biliary tract cancer in RETUD registry.

615 Background: Antagonism of Mouse double minute 2 homolog ( MDM2 ) can restore p53 activity and represents a novel therapeutic strategy in biliary tract cancer (BTC). We aimed to characterize the epidemiology of total population versus that harbouring MDM2 amplifications; potential associations of MDM2 to other genetic alterations and survival outcomes. Methods: We evaluated a large real-world cohort of patients (pt) diagnosed with BTC from 1st January 2017 to 31st December 2022 from the Spanish RETUD registry. Next generation sequencing (NGS) test was performed in all patients. Data collected included demographic and clinical characteristics, molecular profile, systemic oncologic treatment and effectiveness (best response and survival outcomes). Progression free survival (PFS) outcomes and best response were calculated for pts who received first line therapy. Descriptive statistic was used to analyse sociodemographic data, tumor characterization, molecular analysis, and best response. PFS and overall survival (OS) were estimated by the Kaplan-Meier method. Results: A total of 301 evaluable pt were included in 24 sites. MDM2 amplifications were reported in 19 pt (6.3%) and 2 pt (10.5%) had TP53 mutations. At primary diagnosis, in the MDM2 amplified population the tumour was mostly intrahepatic (63.2%); followed by gallbladder cancer (21.0%). Half of the pt had advanced disease at diagnosis (52.6%) and 21.0% resectable disease. No significant differences were observed in clinical characteristics (age, sex, tumor location, stage, ECOG performance status and metastasis location) and most common actionable genomic alterations (BRAF, HER2, IDH, FGFR2) in pt with MDM2 amplification compared to overall population. Median overall survival (95% Confidence Interval [CI]) in pt with MDM2 amplification was 18.4 months (12.3-19.9), and 17.8 months (95% CI, 12.3-19.9, p=0.247 in pt without amplification. Median PFS in first-line was 5.3 months (95% CI, 2.7-8.9) in MDM2 amplified group, as compared with 6.0 months in non- MDM2 amplified group (95% CI, 5.3-6.8; p=0.4233. The objective response rate in first-line was 21.4% in the MDM2 amplified group versus 29.6% in non-amplified group. The proportion of pt who received systemic therapy in first, second and third line was similar in both groups. The main first-line regimen in MDM2 amplified pt was cisplatin/gemcitabine (n=9, 47.4%), followed by clinical trial (n=3, 15.8%), GEMOX (n=2, 10.5%) and gemcitabine (n=2, 10.5%). The median OS and PFS of patients treated with cisplatin/gemcitabine in first line was similar in both groups. Conclusions: This analysis provides insights into the characterization of MDM2 amplified BTC pt. Similar incidence of MDM2 amplification was observed compared to other cohorts of BTC. No significant differences were observed in clinical characteristics, molecular profile and survival in MDM2 amplified pt compared to non-amplified pt.

Efficacy and safety of cabozantinib for advanced gastrointestinal (GI) neuroendocrine tumors (NET) after progression on prior therapy: Subgroup analysis of the phase 3 CABINET trial (Alliance A021602).

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 .

Nivolumab (NIVO) plus ipilimumab (IPI) vs lenvatinib (LEN) or sorafenib (SOR) as first-line (1L) therapy for unresectable hepatocellular carcinoma (uHCC): CheckMate 9DW expanded analyses.

520 Background: In the phase 3 CheckMate 9DW study (NCT04039607), 1L NIVO + IPI demonstrated significant overall survival (OS) benefit vs LEN/SOR, higher objective response rate (ORR) with durable responses, and manageable safety in uHCC. We present efficacy by best overall response (BOR) subgroups and baseline characteristics, and additional safety analyses from the preplanned interim analysis. Methods: Patients (pts) with previously untreated HCC not eligible for curative surgical or locoregional therapies, Child-Pugh score 5 or 6, and ECOG performance status 0 or 1 were randomized 1:1 to receive NIVO 1 mg/kg + IPI 3 mg/kg Q3W (up to 4 cycles), then NIVO 480 mg Q4W or LEN 8 mg or 12 mg QD or SOR 400 mg BID until disease progression or unacceptable toxicity. NIVO was given for a maximum of 2 years. The primary endpoint was OS; secondary endpoints included ORR and duration of response (DOR) per blinded independent central review (BICR) using RECIST v1.1. Results: A total of 668 pts were randomized to NIVO + IPI (n = 335) or LEN/SOR (n = 333). At a median follow-up of 35.2 (range 26.8–48.9) months (mo), median OS (95% CI) was 23.7 (18.8–29.4) mo with NIVO + IPI vs 20.6 (17.5–22.5) mo with LEN/SOR (HR 0.79 [95% CI 0.65–0.96]; P = 0.0180). ORR (95% CI) per BICR was significantly higher with NIVO + IPI vs LEN/SOR (36% [31–42] vs 13% [10–17]; P < 0.0001); median DOR (95% CI) was 30.4 (21.2–not estimable [NE]) mo vs 12.9 (10.2–31.2) mo. Survival benefit of NIVO + IPI vs LEN/SOR was observed across BOR subgroups at the 24-week landmark timepoint (Table). In subgroup analyses, ORR (95% CI) per BICR was higher with NIVO + IPI vs LEN/SOR across HCC etiologies (uninfected: 35% [26–44] vs 8% [4–15]; HBV infected: 25% [17–34] vs 17% [10–25]; HCV infected: 50% [39–61] vs 16% [9–25]) and in pts with Barcelona Clinic Liver Cancer stage ≤B (33% [23–43] vs 13% [6–21]) or stage C (37% [31–44] vs 14% [10–19]). Safety data are shown in the Table. Additional exploratory analyses will be presented. Conclusions: These additional analyses from CheckMate 9DW demonstrate the efficacy and manageable safety of 1L NIVO + IPI in uHCC and further support its use as a potential standard-of-care treatment option in this setting. Clinical trial information: NCT04039607 . OS by BOR at week 24 landmark NIVO + IPI LEN/SOR BOR CR + PR (n = 101) SD a (n = 105) PD (n = 47) CR + PR (n = 28) SD a (n = 212) PD (n = 31) Median OS (95% CI), mo NR (44.4–NE) 30.0(23.5–37.8) 16.0(12.0–18.7) 28.3(20.6–NE) 22.5(20.5–24.8) 13.5(8.7–25.3) All treated pts NIVO + IPI (n = 332) LEN/SOR (n = 325) Any-grade/grade 3–4 TRAEs, n (%) 278 (84)/137 (41) 297 (91)/138 (42) Hepatobiliary 44 (13)/35 (11) 15 (5)/10 (3) Cardiovascular 10 (3)/3 (< 1) 138 (42)/39 (12) Hemorrhagic 2 (< 1)/1 (< 1) 20 (6)/5 (2) a Includes non-CR/non-PD. CR, complete response; NR, not reached; PD, progressive disease; PR, partial response; SD, stable disease; TRAE, treatment-related adverse event.