587 Background: Vascular endothelial growth factor overexpression, increased angiogenesis, and activation of the c-MET pathway have biologic importance in GCT. Cabozantinib is an oral tyrosine-kinase inhibitor targeting c-MET, VEGF, RET, and AXL. We report results from a phase II trial of cabozantinib in refractory GCT. Methods: This single arm phase II trial used a Simon two-stage design investigating cabozantinib 60mg in pts with incurable relapsed/refractory GCT. Pts age≥18 with progressive metastatic GCT after first line cisplatin-based chemo and at least 1 salvage regimen were eligible. Primary endpoint was clinical benefit rate (CBR) [proportion of complete response (CR), partial response (PR), and stable disease (SD) for ≥3 mos using RECIST 1.1, modified to include AFP and hCG]. Simon’s 2-stage required clinical benefit in ≥ 2/18 pts to proceed to stage 2 and then enrolled up to 50 pts. Results: Simon stage I was met and expanded to stage 2. 44 pts were evaluable. 2 pts were female. Median age was 34.2 (21.4-63.2). 42 pts (95.5%) had nonseminomatous GCT. Primary site was testis for 79.5%, mediastinal 13.6%, ovary 4.6%, and retroperitoneal 2.3%. IGCCCG risk at initial diagnosis was good for 22.7%, intermediate 25%, poor 47.8%, and unknown 4.5%. 18 pts had late relapse disease. Median prior chemo regimens was 4. 63.6% of pts previously received high-dose chemotherapy with peripheral blood stem-cell transplant. Median AFP was 210.3 (1.1-120,693); hCG was 0.95 (0.6-72,759). CBR was 43.2%, with 2 pts (4.5%) achieving a PR and 17 (38.6%) achieving SD for ≥3 months. No CRs were seen. Median duration of treatment was 74 days (27-848). For those with SD as best response, median duration of SD was 3.7 mos (2.0-18.5). Stable radiographic disease was seen in 50% of pts, with median duration of 4.1 mos (2.01-27.9). Any measurable disease decrease was seen in 18 pts (46.2%). 95.5% of pts had AFP or hCG reduction, with 65.9% achieving at least 50% AFP or hCG reduction and 27.3% achieving at least 80% AFP or hCG reduction. The most common adverse event (AE) was diarrhea, occurring in 59.1% of pts, with 96.2% being G1/G2. Most common grade ≥3 AE was increased AST, occurring in 6.8% of pts. Table 1 lists AEs occurring in >25% of pts. 11 pts required dose reduction. 2 remain on treatment. Conclusions: Cabozantinib is the first non-cytotoxic chemotherapeutic agent with clinical benefit in refractory GCT. While no CRs were seen, clinical benefit was achieved in > 40% of pts, with half with stable radiographic response for a median of 4.1 mos. The AE profile has little overlapping toxicities with cytotoxic GCT chemo, presenting a unique opportunity to have less cumulative toxicity of further platinum chemo. Clinical trial information: NCT03375320 . AEs occurring in >25% of pts. Any Grade (%) Grade ≥3 (%) Diarrhea 26 (59.1) 1 (2.3) AST increased 24 (54.5) 3 (6.8) ALT increased 24 (54.5) 1 (2.3) Hypothyroid 22 (50) - Fatigue 20 (45.5) - Palmar-plantar erythrodysesthesia syndrome 19 (43.2) - Oral mucositis 13 (29.6) -

Abstract Background: Fatty Acid Synthase (FASN) is a key lipogenic enzyme co-regulated with HER2 and highly expressed in ER+ and HER2+ BC. Its targeting downregulates HER2 expression. Our preclinical studies revealed that FASN inhibition can sensitize or restore sensitivity to trastuzumab, paclitaxel and ET in HER2+ BC models. Denifanstat (deni, formerly TVB-2640) is a novel FASN inhibitor that demonstrated promising clinical activity and safety in a prior phase I trial as either monotherapy or in combination with paclitaxel. The primary objective of this study was to evaluate the objective tumor response rate (ORR) of deni plus trastuzumab (H) in combination with paclitaxel (T) or ET. Methods: Two independent, phase II clinical trials were initiated to assess the efficacy and safety of deni plus H in combination with T (Cohort A) or ET (Cohort B). Key inclusion criteria included HER2+ MBC resistant to HER2-directed therapy, measurable disease, unlimited ET, ≤6 prior chemotherapy or antibody drug conjugate regimens, and confirmation of HER2+ MBC on a pre-registration biopsy. Deni was administered 100 mg/m2 orally once daily. HP or H plus ET (fulvestrant or aromatase inhibitor) was administered at standard dose and schedule. Blood was collected on Cycle 1 Day 1 (C1D1), C1D8 and C2D1 for serum FASN analysis. An additional MBC tumor biopsy was collected on C2D1 for correlative studies. A 2-stage Simon design with a safety-run in was used to test the null hypothesis that the true ORR is at most 5% against the alternative it is at least 20%. With a sample size of 32 patients (pts) per cohort, if ≥4 responses are seen, this design has a 90% chance of rejecting the true ORR is <5% when the true ORR is ≥20% at a 0.10 level of significance. The decision to close both trials to enrollment early was multifactorial. Results: From August 2017 - February 2024, 33 pts with HER2+ MBC pre-registered, among which 17 were eligible and 16 were evaluable (15 pts in Cohort A and 1 pt in Cohort B). The most common reason for ineligibility was HER2-negative status on central review of the pre-registration biopsy. Median age was 57 years (range 35-80). All pts were non-Hispanic and 13 (81.3%) were White. Median prior lines of therapy was 5 (range 0 - 11). In Cohort A, there were 5 partial responses; thus, the primary endpoint was met with the ORR estimated to be 33.3% (90% CI: 14.2-57.7%). The median PFS time was 7.0 months (95 %CI: 3.7 - 11.3), and median OS was 25.7 months (95%CI: 10.2 - NE). No dose limiting toxicities were observed during the C1 safety run-in (6 pts). In Cohort A, 7 (46.7%) developed a grade 3 or 4 adverse event (AE) attributed to combination therapy. Grade ≥2 AEs regardless of attribution occurring in ≥20% of all pts included anemia, fatigue, neutropenia, palmar plantar erythrodysesthesia (PPE), and peripheral neuropathy. Treatment was discontinued due to progression (12; 80%) or AE (3; 20% - pneumonitis; neuropathy; PPE). In Cohort B, the pt maintained stable disease through 8 cycles with grade 3 ALT increase, and she remained alive 31.2 months post-registration. Median C1D1 FASN level was 32.7 ng/mL (IQR: 18.7 - 49.6 ng/mL). There was minimal association between C1D8 and C2D1 FASN levels and time to disease progression (C1D8 n=9, Spearman rank correlation coefficient (r s) = 0.040; C2D1 n=13, r s = -0.019). Analyses of changes in MBC tumor expression of FASN, phospho-AKT, and phospho-S6 are in progress. Conclusion: Deni combined with HP provided clinical antitumor activity in pts with HER2+ MBC resistant to trastuzumab. Expected paclitaxel-associated AEs were observed. Nearly half of pts experienced a grade 3 or 4 AE attributed to the combination therapy, and 20% stopped treatment due to AE. Further study of deni, H plus ET is necessary to draw safety and efficacy conclusions. Citation Format: T. C. Haddad, V. J. Suman, R. R. Roa, B. J. Ernst, R. Lupu, T. Vander Steen, M. H. Solanki, M. Keeney, D. W. Northfelt, K. S. Anderson, T. J. Hobday, S. Chumsri, J. E. Hoppenworth, J. L. Carroll, K. V. Giridhar, C. C. O’Sullivan, R. A. Leon-Ferre, M. P. Goetz. Phase II Trial of the FASN Inhibitor, Denifanstat (TVB-2640), Plus Trastuzumab in Combination with Paclitaxel or Endocrine Therapy (ET) in Patients with HER2+ Metastatic Breast Cancer (MBC) Resistant to Trastuzumab [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-01-16.

Abstract Objective: To evaluate the efficacy and safety of topical La Roche-Posay New B5 Multi-Effect Soothing and Repairing Cream in the treatment of skin adverse reactions related to EGFR inhibitors and capecitabine. Methods: A randomized, double-blind, controlled clinical study was conducted. From October 2024 to June 2025, 40 patients with skin adverse reactions (such as rash, hand-foot syndrome, pruritus, dryness, discoloration, and skin chapping) during anti-tumor therapy (EGFR inhibitors and capecitabine) were recruited from the First Affiliated Hospital of Nanjing Medical University. They were divided into two groups with 20 cases each. The experimental group was treated with topical La Roche-Posay New B5 Multi-Effect Soothing and Repairing Cream, while the control group was treated with topical silicone oil cream, twice daily for 8 weeks. Follow-ups were conducted before treatment and at 2, 4, 6, and 8 weeks after treatment. Efficacy was evaluated based on the improvement rate of rash grade, the improvement time of rash grade, the improvement rate of hand-foot syndrome grade, the improvement time of hand-foot syndrome grade, Visual Analogue Scale (VAS), and Dermatology Life Quality Index (DLQI). Adverse events were recorded. Repeated measures analysis of variance and chi-square test were mainly used to compare efficacy and safety. Results: A total of 40 patients participated in this clinical study, including 22 males and 18 females, with age of (54.21 ± 14.47) years. Before treatment, there were no statistically significant differences between the two groups in gender, age, rash grade, hand-foot syndrome grade, VAS score, or DLQI score (all p > 0.05). After 2 weeks of treatment, the improvement rates of rash grade and hand-foot syndrome grade in the experimental group were 20.00% (2/10) and 20.00% (2/10), respectively, while those in the control group were 10.00% (1/10) and 20.00% (2/10), respectively. There were no statistically significant differences between the two groups (p > 0.05). After 4 weeks of treatment, the effective rate (rash grade improvement rate + hand-foot syndrome grade improvement rate) in the experimental group was 65.00% (13/20), which was significantly higher than that in the control group (40.00%, 8/20, p < 0.05). After 8 weeks of treatment, the effective rate in the experimental group was 70.00% (14/20), which was significantly higher than that in the control group (45.00%, 9/20, p < 0.05). After 4, 6, and 8 weeks of treatment, the VAS and DLQI scores in the experimental group were significantly lower than those in the control group (all p < 0.05). Conclusion: La Roche-Posay New B5 Multi-Effect Soothing and Repairing Cream is safe and effective in the treatment of skin adverse reactions related to EGFR inhibitors and capecitabine. It can significantly improve rash and hand-foot syndrome after 4 weeks of use and can be applied clinically. Citation Format: X. Yan, Y. Liang, X. Huang, Y. Yin. A Randomized Double-Blind Controlled Study on La Roche-Posay New B5 Multi-Effect Soothing and Repairing Cream in the Treatment of Skin Adverse Reactions Related to EGFR Inhibitors and Capecitabine [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-03-15.

Abstract Background: Capecitabine is a valid monotherapy option in multiple metastatic breast cancer (mBC) subtypes. While case reports of capecitabine-related hepatic steatosis have been published, its prevalence remains unknown. Traditional monitoring relies primarily on biochemical tests, which may not fully capture hepatic changes. Our aim was to evaluate the prevalence of capecitabine-related hepatic steatosis and determine whether routinely performed [18F]FDG PET/CT could quantify hepatic changes during capecitabine treatment, including in patients without visually evident steatosis. Methods: We conducted a retrospective analysis of patients with mBC treated with capecitabine between 2014 and 2021 at Gustave Roussy. Clinico-biological variables (age, BMI, metastatic sites, therapy line, dihydropyrimidine dehydrogenase (DPD) testing, biochemical liver tests) at baseline were collected. Baseline PET/CT, first evaluation (<180 days), and last PET/CT scans under capecitabine treatment were analyzed to assess hepatic steatosis prevalence. Hepatic steatosis was defined by visual assessment as a decreased liver attenuation relative to spleen and/or increased hepatic vessel visualization on unenhanced CT. Finally, hepatic changes were quantified using standardized uptake values (SUV) on PET images and Hounsfield units (HU) on CT images. Results: The study cohort included 183 patients with mBC. The median age at capecitabine initiation was 66.3 years (range 51-96), and median BMI was 24.2 (range 14.7-39.1). The most frequent metastatic sites were bone (67%), liver (40%) and lymph nodes (33%), with a median of 2 metastatic sites per patient. 86% of patients received capecitabine as monotherapy. Capecitabine was administered across multiple treatment lines: 1st line (14%), 2nd line (32%), 3rd line (31%) and >= 4th line (23%). When available, DPD testing revealed partial deficit in 16/138 patients (12%). Median treatment duration was 298 days (range 80-2162). Sequential imaging analysis was available for 122 patients with both baseline and first evaluation PET/CT scans, and 77 patients at capecitabine discontinuation. No patients showed hepatic steatosis at baseline. At first evaluation, hepatic steatosis was observed in 3/122 patients (2.5%). All 3 patients with steatosis underwent dose reduction due to other capecitabine toxicities (hand-foot syndrome in 2 patients, general condition deterioration requiring weight-based dose adjustment in 1 patient), resulting in resolution of CT steatosis in 2 patients. At final PET/CT, steatosis was present in 4/77 patients (5.2%) and resolved in 3 patients on follow-up imaging after changing treatment line. All patients who developed visible steatosis received capecitabine monotherapy. Quantitative analysis revealed small magnitude hepatic changes during capecitabine treatment: mean HU liver decreased by -2.3 units (95%CI -4.0 to -0.6, p=0.007) and SUVmean liver increased by +0.2 units (95% CI +0.1 to +0.2, p<0.001). These quantitative changes occurred independently of baseline liver metastases presence (p=0.470 for HU, p=0.881 for SUVmean). Among clinico-biological variables, only baseline bilirubin showed significant correlation with HU changes (p=0.044), while other liver function tests, BMI, and DPD status showed no significant association. Conclusions: This study provides a first estimate of capecitabine-induced hepatic steatosis prevalence, and initial evidence supporting the feasibility of using follow-up [18F]FDG PET/CT to assess its occurrence and reversibility after dose reduction or discontinuation. Further studies are needed to evaluate the potential impact of systematic steatosis evaluation on imaging follow-up, including shorter follow-up intervals and preemptive dose adjustments. Citation Format: A. Daverio, T. Ben Ahmed, J. M Ribeiro, C. Bousrih, E. Rassy, M. Mokdad-Adi, S. Morbelli, B. Pistilli, D. Deandreis, A. Viansone, T. Henry. A retrospective analysis of capecitabine-induced imaging hepatic steatosis in metastatic breast cancer: prevalence and resolution [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-06-17.

Abstract Background: HER2-positive early breast cancer patients achieving a pathological complete response (pCR) during neoadjuvant therapy demonstrate a more favorable prognosis. The KATHERINE study indicated that for HER2-positive early breast cancer patients who did not achieve pCR (the presence of residual tumor lesions) after neoadjuvant therapy, the administration of TDM-1 during postoperative adjuvant therapy significantly reduces the risk of disease recurrence compared to trastuzumab. This study aims to evaluate the efficacy and safety of trastuzumab in combination with pyrotinib and capecitabine in HER2-positive early breast cancer patients who did not achieve pCR following neoadjuvant therapy. Methods: This single-arm, open-label, multicenter study enrolled patients with HER2-positive early breast cancer who did not achieve pCR (defined as residual invasive tumor >1 cm or lymph node metastasis) following neoadjuvant therapy. Eligible patients received trastuzumab (initial loading dose of 8 mg/kg followed by 6 mg/kg every three weeks for one year, encompassing both neoadjuvant and adjuvant settings), pyrotinib (400 mg/day for one year post-surgery), and capecitabine (1000 mg/m2 twice daily for six 3-week cycles, with continuation at the investigator's discretion beyond six cycles). Primary prophylaxis with loperamide was administered to mitigate pyrotinib-induced diarrhea. The primary endpoint was 3-year invasive disease-free survival (iDFS), with secondary endpoints including distant disease-free survival (DDFS), overall survival, and safety. This study is registered with ClinicalTrials.gov (identifier NCT05292742). Results: From July 2021 to November 2023, a total of 102 patients were enrolled, all of whom did not achieve pCR following neoadjuvant therapy. As of June 30, 2025, with a median follow-up of 25 months, 2-year iDFS rate was 91.3% (95%CI, 83.3-95.6), and 2-year DDFS rate was 96.8% (95%CI, 90.5-99.0). Regarding safety, 22 patients (21.6%) experienced grade ≥3 adverse events, with the most common being diarrhea (13.7%), white blood cell count decreased (2.0%), and hand-foot syndrome (1.0%). Adverse events led to the treatment interruption of any agent in 66 patients (64.7%), discontinuation of any agent in 8 patients (7.8%), and dose reduction of any agent in 37 patients (36.3%). Conclusions: For patients with HER2-positive early breast cancer who did not achieve pCR (residual invasive tumor >1 cm or lymph node metastasis) following neoadjuvant therapy, the combination of pyrotinib, trastuzumab and capecitabine as postoperative adjuvant therapy appears to improve prognosis. The overall safety profile of the regimen was acceptable, with no new safety signals identified. Primary prophylaxis with loperamide effectively reduced the incidence of grade ≥3 diarrhea during adjuvant therapy with pyrotinib. Citation Format: C. Wang, F. Fu, J. Zhang, S. Lin, Z. Song, Z. Ouyang, X. Chen, M. Lin, G. Cui, G. Han, W. Guo, X. Chen, L. Jia, C. Song, S. Yang, R. Luo, Y. Yan, Y. Zeng, D. Chen, J. Lin, F. Yang, R. Huang, Y. Wang, Z. Zeng, Z. Zhang. Trastuzumab Combined with Pyrotinib and Capecitabine as Postoperative Adjuvant Therapy in Non-Pathological Complete Response HER2-Positive Early Breast Cancer Following Neoadjuvant Therapy: A Multicenter Phase II Study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-11-05.

Abstract Background: Although the KEYNOTE-522 trial demonstrated a significant pCR following neoadjuvant chemoimmunotherapy, 35.2% of patients had evidence of residual disease following surgery, a population who may be recommended to receive adjuvant capecitabine per the CREATE-X trial. However, there is a paucity of real-world data evaluating the tolerability of adjuvant pembrolizumab, per KEYNOTE-522, when combined with adjuvant capecitabine, per CREATE-X. Our study examines the tolerability of the adjuvant combination in a real-world, diverse, urban population at a large tertiary referral center. Methods: We performed a retrospective chart review of patients (pts) with stage II-III TNBC who received the KEYNOTE-522 regimen within our institution’s health system from August 2021 to February 2025. Pts who received >/= 1 cycle of adjuvant pembrolizumab were included in our analysis. Pts were stratified based on receipt of adjuvant pembrolizumab alone versus combination of pembrolizumab and capecitabine. Demographics, adjuvant toxicity data including rates of treatment delays, dose holds, and treatment discontinuations were extracted from the medical record. Descriptive statistics were used to describe patient data, and non-parametric tests were utilized in the stratified analyses. Due to the exploratory nature of our analysis, p-values are reported unadjusted. Results: 83 pts received adjuvant pembrolizumab and were included in this analysis. Overall, 64% (N=53) were on adjuvant pembrolizumab alone and 36% (N=30) on the combination of adjuvant pembrolizumab and capecitabine. Overall, 83% had Stage II disease and 45% with lymph node involvement. 28% of pts (N=23) identified as White, 28% (N=23) Black, 16% (N=13) Asian, 19% (N=16) Hispanic, and 9% (N=8) as Other. The early discontinuation rates (prior to 9 cycles) of adjuvant pembrolizumab in the pembrolizumab cohort and combination cohort were 17% (N=9) and 13% (N=4), respectively (p=0.761). Pembrolizumab was discontinued most frequently due to irAEs including thyroiditis, colitis, pneumonitis and myocarditis. In the combination cohort of 30 pts, 47% (N=14) required a capecitabine dose reduction, 27% (N=8) required a dose hold, and 30% (N=9) discontinued capecitabine prior to 6 cycles (Table 1). Capecitabine was dose reduced or held most frequently for non-hematologic reasons including hand-foot syndrome, GI toxicity, and mucositis. Conclusion: The adjuvant combination of capecitabine and pembrolizumab appeared to be well tolerated. Treatment was held, dose reduced or discontinued more commonly from known side effects of capecitabine or pembrolizumab, but not as the result of worsening toxicity from combination therapy. Overall, the combination of capecitabine and pembrolizumab warrants further study for pts with residual disease after neoadjuvant KEYNOTE-522. Citation Format: J. Anderson, E. Baldwin, J. Dejesus, G. Van Hyfte, P. Pandu, N. Krishnamurthy, M. Rattu, R. Farley, R. Patel, A. Tiersten. Evaluating the tolerability of the combination of adjuvant pembrolizumab and capecitabine in a diverse real-world cohort of patients with early-stage TNBC [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-07-29.

Abstract Introduction Triple-negative breast cancer (TNBC) is an aggressive subtype lacking estrogen (ER), progesterone (PR), and HER2 expression. It accounts for ∼15% of breast cancers and is more common in Black women, younger patients, and those with BRCA1 mutations. TNBC carries a poor prognosis with 5-year survival rates of 92% (localized), 66.8% (regional), and 14.3% (metastatic). Patients with high-risk of recurrence can be treated with different adjuvant therapies based on results of 3 trials (capecitabine, pembrolizumab, olaparib), but data on adverse events (AE) on their combination is limited.High-risk, stage II-III TNBC is treated with curative intent using neoadjuvant chemotherapy with pembrolizumab, followed by surgery and radiation. Pembrolizumab, an anti-PD-1 checkpoint inhibitor, was FDA-approved in 2021 based on KEYNOTE-522. This phase III trial showed that pembrolizumab plus chemotherapy significantly improved pathologic complete response (pCR) and event-free survival (EFS). 3-year EFS was 84.5% vs. 76.8% with placebo (HR 0.63); 5-year follow-up confirmed sustained benefit, with OS of 86.6%. Patients achieving pCR had better outcomes, while those with residual disease remained at high risk for recurrence, justifying further adjuvant therapy.In KEYNOTE-522, grade ≥3 treatment-related (AEs occurred in 77.1% receiving pembrolizumab-chemotherapy vs. 73.3% with placebo-chemotherapy. Pembrolizumab was linked to more serious AEs (34.1% vs. 20.1%) and higher discontinuation rates (23.3% vs. 12.3%). Before pembrolizumab, capecitabine was standard of care for TNBC with residual disease, based on the CREATE-X trial (HR 0.52 for OS benefit). Common AEs included hand-foot syndrome, fatigue, and liver enzyme elevation. Notably, KEYNOTE-522 excluded adjuvant capecitabine, and CREATE-X predated the use of pembrolizumab. Olaparib, a PARP inhibitor, was FDA-approved in 2022 for high-risk early TNBC with germline BRCA mutations, based on OlympiA. It improved invasive disease-free and OS. Grade ≥3 AEs included anemia, neutropenia, and fatigue. OlympiA did not include pembrolizumab or capecitabine, limiting insight into optimal sequencing or combination. Currently, no trials compare pembrolizumab, capecitabine, or olaparib directly, nor do they guide how to sequence or combine these therapies. Despite NCCN guidelines allowing combined/sequential use in high-risk patients, real-world safety and outcome data are lacking. This study aims to evaluate and compare the safety and effectiveness of capecitabine, olaparib, pembrolizumab, and their combinations. We will describe AE rates, onset, discontinuation, and dose modifications to inform clinical management and help reduce early termination of effective therapies. Methods We conducted a retrospective observational study across all Mayo Clinic sites. Eligible patients were ≥18 years with early-stage TNBC who initiated adjuvant therapy with capecitabine, pembrolizumab, olaparib, or combinations (capecitabine + pembrolizumab or olaparib + pembrolizumab) from October 2018 to September 2024. Patients with metastatic disease, other active malignancies, or receiving concurrent investigational therapy were excluded. The primary outcomes were incidence and timing of treatment-related AEs. Secondary outcomes included time to AE resolution, immune-related AEs, treatment interruptions/modifications, early discontinuation, and EFS. Time-to-event data will be analyzed using Kaplan-Meier and Cox proportional hazards models. Subgroup analyses by age, DPYD status, regimen, and dosing will be conducted. Data was abstracted from electronic health records and managed using REDCap. Results Data collection is completed. Final analyses are being conducted, and results will be presented at SABCS 2025. Citation Format: R. Garza-Morales, F. Raheem, D. Alton, S. Sharma, B. Murad, W. Harris, E. Terwilliger, F. Batalini. Analysis of Adverse Events and Outcomes of Adjuvant Therapies in TNBC as Monotherapy and Combination: Pembrolizumab, Capecitabine, and Olaparib [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-10-06.

Hepatocellular carcinoma (HCC) develops on background chronic liver disease where uncontrolled inflammation drives hepatocarcinogenesis. First-line therapies have limited response. There are no agents that specifically target the underlying liver inflammation. We investigated the safety and efficacy of itacitinib, a highly selective JAK1 inhibitor, as a potential second- or third-line therapy. Biomarkers of response were investigated. Participants with advanced stage HCC, Child Pugh ≤B7 who had progressed through at least one previous line of therapy received 400 mg of itacitinib QID every 28 days. Treatment-related adverse events (trAEs) were assessed weekly during cycle 1 then every 28 days (CTC-AE version 4.03). Response was assessed 8-weekly using RECIST 1.1. Progression-free (PFS) and overall survival (OS) were reported as secondary endpoints. Tumour samples were analysed for targeted transcriptomics. Sequential serum samples were assessed for metabonomic determinants of toxicity and response. 19 patients were enrolled. The most common trAEs were thrombocytopenia (31%), fatigue (26%) and palmar-plantar erythrodysesthesia syndrome (26%); four episodes of dose-limiting thrombocytopaenia were observed. Over a median follow-up of 3.5 months, the best overall response was stable disease (47%). Median PFS and OS were 3.5 (95% CI: 2.6 - 4.5 months) and 7.4 months (95% CI: 4.3-10.5 months), respectively. Subgroup analysis illustrated a significantly increased risk of progression for patients that had received combination immunotherapy prior to itacitinib (HR 4.7, 95%CI 1.3-16.6, p = 0.016). Untargeted tumour and serum transcriptomics identified a signature predictive of response. Itacitinib either as second- or third-line therapy showed promising activity. We identified a transcriptomic signature predictive of response.

Oral mucosal melanoma (OMM) is a rare subtype of melanoma but exhibits highly invasive biological behavior. Programmed cell death protein 1 (PD-1) monotherapy showed lower response in OMM than other subtypes of melanoma. We retrospectively analyzed the efficacy and safety of pembrolizumab with anlotinib in patients with advanced OMM between August 2018 and September 2024. The primary endpoint was objective response rate (ORR); the secondary endpoints included disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs). Forty-one patients were enrolled in our study. Seventeen patients (41.4%) achieved an objective response. The median PFS was 6.4 months (95% confidence interval [CI], 4.5-8.3 months), and the median OS was 10.0 months (95% CI, 8.3-11.7 months). Thirty-three patients (80.5%) experienced at least one TRAE. The most common TRAEs were hypertension (29.3%), hand-foot syndrome (19.5%), and anemia (19.5%). Grade 3 or higher TRAEs occurred in two patients (4.8%), and no grade 5 TRAEs were observed. Our study suggested that pembrolizumab with anlotinib in patients with advanced OMM showed potential efficacy and manageable adverse effects. Further studies are needed to confirm the efficacy of this combination strategy.

Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide, with increasing incidence in the US. Improvements in disease management and the increasing incidence of patients with metastatic CRC (mCRC) at younger ages has resulted in more patients being treated in the third-line setting. Treatment has evolved beyond chemotherapy with the approval of newer agents, but there is no consensus on the optimized choice or sequencing post second-line treatment. Identification of the drivers of treatment decisions may provide evidence to guide decision-making, ensuring that patients receive optimal care. The objective of this study was to evaluate treatment preferences and prescribing patterns for third-line mCRC among community-based physicians. This study surveyed community-based physicians in the US who were actively treating patients with mCRC. Overall survival (OS) and impacts to patient quality of life (QoL) were primary considerations for any third-line treatment for mCRC. Physicians considered OS and progression-free survival (PFS) as extremely important factors when making third-line treatment decisions. Most physicians selected trifluridine-tipiracil (FTD-TPI) combined with bevacizumab as their first treatment choice for third-line mCRC (60%), compared to regorafenib (12%), FTD-TPI monotherapy (8%), capecitabine (8%), and fruquintinib (6%). Physicians identified fatigue, neutropenia, and hand-foot syndrome as the most challenging adverse events (AEs) to manage, while hand-foot syndrome and allergic reactions were AEs that would most likely lead physicians to discontinue treatment. These findings highlight the third-line treatment preferences and prescribing patterns of community-based physicians who are actively treating patients with mCRC.

Adjuvant camrelizumab combined with capecitabine in patients with intrahepatic cholangiocarcinoma after surgical resection in China (ACC): a single-arm, single-centre, open-label, phase 2 trial.

Tinengotinib for adults with advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 trial.

Kawasaki disease (KD) and multisystem inflammatory syndrome in children (MIS-C) are pediatric inflammatory conditions with overlapping mucocutaneous features that may complicate early diagnosis. We performed a narrative review of the literature to characterize and compare cutaneous manifestations reported in children with KD and MIS-C and to assess their diagnostic relevance. Published studies describing dermatologic findings in patients aged 0-18 years were reviewed. The analysis revealed a broad heterogeneity of skin manifestations in both conditions, ranging from classic polymorphous rash and acral erythema to atypical presentations, including annular, psoriasiform, vesiculobullous, urticarial, and erythema nodosum-like lesions. Reactivation at Bacillus Calmette-Guérin vaccination sites and associated mucocutaneous findings, such as conjunctivitis and oral changes, emerged as supportive diagnostic clues, particularly for incomplete KD. Considerable overlap in cutaneous phenotypes between KD and MIS-C was observed, especially in patients with persistent fever and systemic inflammation, highlighting the risk of diagnostic delay. These findings underscore the importance of recognizing atypical dermatologic patterns as part of an integrated diagnostic approach, as delayed identification may increase the risk of cardiovascular complications. Early recognition of cutaneous clues can support timely initiation of immunomodulatory therapy and improve clinical outcomes.

Hand-foot syndrome (HFS) is a common adverse event associated with capecitabine. While the fibroblast growth factor receptor (FGFR) signaling pathway is involved in skin wound healing, its essential role in capecitabine-induced HFS remains unclear. We examined the association between polymorphisms in FGFR signaling pathway-related genes and capecitabine-induced HFS in patients with colorectal cancer (CRC). This retrospective study included patients with CRC who received capecitabine and oxaliplatin. HFS was evaluated using CTCAE v5.0, up to 2 cycles. Polymorphisms were identified using whole-exome sequencing and confirmed using direct sequencing. The association between HFS and polymorphisms was analyzed using Fisher's exact test. The Bonferroni correction for multiple testing was performed to calculate the corrected p-value (Pc). Overall, 937 polymorphisms were identified in 71 genes. Intronic FGFR2 rs2981460 C/C, and rs2981461 T/T genotypes, and haplotype II/II comprising the C and T alleles were associated with a lower HFS incidence (p=0.0161, Pc=0.113; p=0.0163, Pc=0.114; and p=0.0161, Pc=0.113, respectively). Synonymous FGFBP2 rs2286459 A/A was associated with a lower HFS frequency (p=0.0469, Pc=0.328). 3'-Untranslated region and nonsynonymous variants SPRY2 rs11911 T/G or G/G and rs504122 G/A or A/A, and homozygotes or heterozygotes of haplotype 2 comprising respective G and A alleles, were significantly associated with higher HFS incidence (p=0.0000803, Pc=0.000562; p=0.0000803, Pc=0.000562; and p=0.0000803, Pc=0.000562, respectively). A significantly higher HFS incidence was observed in patients with a combined risk genotype and diplotypes of FGFR2 any/II or any/any, FGFBP2 rs2286459 G/G or G/A, and SPRY2 2/2 or any/2 (p=0.0000314). Variants in FGFR signaling pathway-related factors were significantly associated with capecitabine-induced HFS.

Doxorubicin (DOX) is one of the most potent chemotherapeutic agents for cancer treatment. However, its cumulative and often irreversible, life-threatening cardiotoxicity significantly limits its clinical applications. While strategies like dose reduction, iron chelation, and liposome encapsulation have aided in mitigating cardiotoxicity to certain extent, they are associated with decreased therapeutic efficacy and potential cancer relapse, the risk of developing secondary malignancy, and the incidence of the Hand-foot syndrome. Exosomes (Exo) are naturally occurring nanoparticles that can be engineered to display targeting moieties on their surface, thereby enhancing drug delivery efficacy. We aimed to develop an exosomal DOX formulation targeting broad epidermal growth factor receptor (EGFR) variants to enhance its anti-tumor efficacy and minimize cardiotoxicity. The native 53-amino-acid EGF was decorated on the surface of exosomes by genetically engineering exosome-producing A549 cells. The EGF-Exo was effectively internalized by tumor cell lines in a manner dependent on EGFR expression levels, and exhibited enhanced accumulation in xenograft A549 tumors relative to the heart, with minimal cardiac accumulation. When loaded with DOX, these engineered exosomes were rapidly internalized, inducing higher apoptosis in A549 cells compared to liposomal-DOX. Upon systemic administration in an A549 xenograft mouse model, EGF-Exo-DOX exhibited enhanced accumulation in tumors relative to the heart, with minimal cardiac accumulation, significantly reducing tumor burden, mitigating DOX-induced cardiotoxicity, and exhibiting no tumorigenic effects. This favorable therapeutic profile is primarily attributed to DOX-induced apoptosis. Our findings demonstrate that tumor-derived exosomes engineered with EGF on their surface enable targeted drug delivery to tumors with high EGFR expression. Although the exosomes modestly increase cell proliferation in vitro, the EGF-Exo-DOX formulation exhibits enhanced tumor accumulation relative to the heart, minimal cardiac uptake, and shows no tumorigenic effects in vivo. Compared to Lipo-DOX, a widely used clinical formulation of liposomal DOX in China, EGF-Exo-DOX demonstrates superior cellular uptake, greater induction of tumor cell apoptosis, and improved anti-tumor efficacy. These results highlight the potential of engineered exosomes as a targeted drug delivery platform for patients with EGFR-overexpressing tumors.

Lenvatinib is a standard systemic therapy for radioiodine-refractory differentiated thyroid cancer (RAI-R DTC). Although pivotal trials such as SELECT demonstrated significant efficacy, real-world evidence remains limited, particularly regarding treatment timing and the role of planned drug holidays. We retrospectively analyzed 44 consecutive patients with RAI-R DTC treated with lenvatinib between 2015 and 2024. All patients initiated therapy at 24 mg/day, with dose reductions and treatment interruptions-including planned drug holidays-implemented according to toxicity. Efficacy outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and best tumor shrinkage. A subgroup analysis was conducted in patients with lung metastases. The median PFS was 36.0 months, and the median OS was 76.7 months. ORR was 52.3% and DCR was 95.5%. In the lung metastases-only subgroup (n = 25), outcomes were particularly favorable: PFS 58.1 months, unreached OS, ORR 64.0%, and DCR 100%. Univariate Cox analysis identified performance status, histological subtype, TV-DT, and tumor burden as significant prognostic factors. The most common adverse events were hypertension, proteinuria, fatigue, and palmar-plantar erythrodysesthesia; these were generally manageable with dose adjustments and individualized planned holidays. Clinically meaningful renal dysfunction was rare despite frequent proteinuria. Lenvatinib demonstrated durable efficacy and acceptable tolerability in real-world practice, especially in patients with lung metastases. Early treatment initiation and individualized toxicity management-including planned drug holidays-enabled sustained dose intensity and prolonged disease control. These findings support the clinical utility of personalized adverse event management strategies in routine care for RAI-R DTC.

The combination of hepatic arterial infusion chemotherapy (HAIC) with immune checkpoint inhibitors (ICIs) and anti-angiogenic agents represents a potential therapeutic strategy for advanced hepatocellular carcinoma (HCC). This study aimed to compare the efficacy and safety of triple therapies combining HAIC with ICIs and either bevacizumab or tyrosine kinase inhibitors (TKIs) in these patients. This retrospective single-center study enrolled 65 consecutive patients with advanced HCC who received HAIC combined with ICIs plus either bevacizumab (bevacizumab group, n = 31) or TKIs (TKIs group, n = 34) between June 2021 and June 2023. Primary endpoints included progression-free survival (PFS), objective response rate (ORR), duration of response (DOR), and safety profiles. The bevacizumab group demonstrated significantly prolonged median PFS (10.9 vs. 7.4 months, p = 0.001) and higher ORR (83.9% vs. 61.8%, p = 0.047) compared with the TKIs group. DOR was longer in the bevacizumab group (7.9 vs. 5.3 months, p = 0.008). Median overall survival (OS) was not reached in the bevacizumab group versus 22.6 months in the TKIs group. Grade 3-4 adverse events occurred in 67.7% of the bevacizumab group and 73.5% of the TKIs group, with distinct toxicity profiles. Gastrointestinal hemorrhage (45.2%) and gastric ulcer (22.6%) predominated in the bevacizumab group, whereas the TKIs group exhibited more hepatic enzyme elevations (aspartate aminotransferase, 67.6%; alanine aminotransferase, 61.8%), proteinuria (29.4%), diarrhea (26.5%), hand-foot syndrome (20.6%), and reactive cutaneous capillary endothelial proliferation (11.8%). Bevacizumab-containing triplet therapy was associated with improved tumor control and delayed progression compared to TKIs-based regimens in advanced HCC. The higher bleeding risk in the bevacizumab group highlights the necessity of standardized baseline evaluation and adequate preventive measures.

Capecitabine (CAP) side effect, a prodrug of 5-fluorouracil (5-FU), is hand-foot syndrome (HFS), a localized skin disorder of the hands and feet that is believed to induce a decrease in skin barrier function. Stratum corneum (SC) lipids play an important role in skin barrier function; therefore, this study compared the SC lipid structure and composition of healthy participants with those of patients with CAP-induced HFS. Forty patients receiving a combination regimen of CAP and oxaliplatin as adjuvant chemotherapy for colorectal cancer were enrolled. All patients received 1,000 mg/m2 twice daily on days 1-14. SC samples were obtained from 11 patients with CAP-induced HFS (CSC). The SC lipid structure was analyzed using synchrotron X-ray diffraction. SC lipid components, ceramides (CERs), free fatty acids (FFAs), CAP, and its metabolites in CSC samples were analyzed using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). In healthy SC (HSC), lipids formed two lamellar phases. Hexagonal and orthorhombic hydrocarbon chain packing was observed in lateral lipid organization. However, in CSC, these structures have almost disappeared. UPLC-MS/MS analysis revealed that the composition of CER and FFA differed between CSC and HSC, and that the carbon chain length of SC lipid components in CSCs was reduced compared to that in HSCs. 5-FU was detected in CSCs at 3.4 ± 1.4 ng/mg. CAP induces changes in SC lipid structure due to changes in SC lipid composition and a decrease in carbon chain length in CSCs. CAP-induced HFS is associated with 5-FU accumulation in SC.

Treatment options for recurrent osteosarcoma remain limited, and prognosis is poor. Pazopanib, a multi-targeted tyrosine kinase inhibitor, has shown activity in various sarcomas. This study evaluated the efficacy and safety of pazopanib combined with doxorubicin and cisplatin (Paz + AP regimen) in patients with recurrent osteosarcoma and analyzed its impact on survival. This single-center retrospective cohort study included recurrent osteosarcoma patients treated between February 2022 and February 2023. Propensity score matching was used to balance baseline characteristics. A total of 100 patients were analyzed: 50 received the Paz + AP regimen, and 50 received conventional chemotherapy (AP regimen). Treatment efficacy was assessed using response evaluation criteria in solid tumors (RECIST 1.1) criteria. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), objective response rate, disease control rate, safety, and treatment compliance. Baseline characteristics were well balanced between groups (P > .05). The Paz + AP group achieved a higher disease control rate than the control group (62.0% vs 42.0%, P = .046), whereas the difference in objective response rate was not significant (26.0% vs 14.0%, P = .13). Median PFS was significantly longer in the Paz + AP group than in controls (5.1 vs 2.2 months, P = .04). Although the median OS was slightly shorter in the Paz + AP group (8.0 vs 9.6 months), its survival curve declined more slowly after 12 months, showing a significant difference (P = .03). The incidence of adverse events was comparable (92.0% vs 88.0%), though hypertension (28.0% vs 10.0%, P = .03) and hand-foot syndrome (22.0% vs 4.0%, P = .01) were more frequent with pazopanib. No differences were observed in grade ≥3 or serious adverse events. Subgroup analysis indicated greater PFS benefits among patients with lung metastasis, recurrence interval ≥6 months, Eastern Cooperative Oncology Group (ECOG 0–1), and those receiving full-dose pazopanib. The Paz + AP regimen significantly prolonged PFS and improved disease control in recurrent osteosarcoma, with manageable toxicity and good compliance. Although OS improvement was limited, the regimen showed potential clinical value, particularly for patients with favorable performance status and longer recurrence intervals. Prospective studies are warranted to confirm these findings.

Introduction: Despite recent advances in treatment for unresectable hepatocellular carcinoma (uHCC), median overall survival (OS) in the first-line setting across immune-based combination therapies has plateaued at 16–24 months. Evaluation of potentially more potent therapies is warranted. We report results of the first prospective phase 1b study of lenvatinib (multi-kinase inhibitor) + nivolumab (anti-programmed death receptor1 antibody) for treating advanced uHCC. Methods: This open-label study was conducted in Japan among adults (≥20 years) with histologically/cytologically confirmed HCC. Patients received monotherapy-approved doses of either 8 mg (body weight <60 kg) or 12 mg (body weight ≥60 kg) oral lenvatinib once daily + 240 mg intravenous nivolumab every 2 weeks (days 1 and 15) in 4-week cycles. Part 1 planned to enroll 6 patients to evaluate the tolerability of lenvatinib+nivolumab. Part 2 evaluated safety and preliminary antitumor activity. Primary endpoints were dose-limiting toxicities (DLTs; part 1 only) and safety. Secondary endpoints were objective response rate (ORR) and pharmacokinetics of lenvatinib and nivolumab. Additional exploratory endpoints (including OS and progression-free survival [PFS]; part 2 only) were assessed. Results: No DLT was observed among patients (n = 6) in part 1. Treatment-related adverse events (TRAEs) were observed in all patients (n = 30) in part 1 and 2. The most common TRAEs were palmar-plantar erythrodysesthesia syndrome (60%), dysphonia (53.3%), and decreased appetite (50.0%). Distributions of lenvatinib AUC(0-t) were similar to those observed for lenvatinib in HCC previously and were within the distributions of AUC(0-τ) observed with lenvatinib monotherapy in the REFLECT trial. ORR by mRECIST per investigator review was 66.7% in part 1 and 79.2% in part 2. In part 2, median PFS was 9.07 months by mRECIST per investigator review, and median OS was 26.94 months. Conclusion: Lenvatinib+nivolumab was well tolerated and had encouraging antitumor activity in patients with advanced uHCC in this phase 1b study.