Palmar-plantar Erythrodysesthesia Syndrome Research Articles

Plain language summary: an analysis of the safety of futibatinib treatment in people with different types of cancer.

Researchers combined information from three separate phase 1 and 2 clinical trials, including over 400 people who had one of 33 different cancer types and who all received futibatinib in their clinical trial. This type of study is called a pooled analysis. Futibatinib is taken orally (by mouth) as a tablet and works by reducing the activity of a group of proteins called fibroblast growth factor receptors (FGFRs). FGFRs drive the growth of some cancers, especially cancer cells with changes in FGFR genes that make the proteins more active. Researchers wanted to look at how common some side effects were in people treated with futibatinib, how soon the side effects happened after taking futibatinib, and how they could be managed. Researchers also wanted to provide recommendations to other health care professionals on how to manage these side effects in people with cancer. In this analysis, the researchers focused on side effects that they had seen in previously completed trials of futibatinib. Overall, futibatinib was safe and tolerable. Most people (82%) had a high phosphate level in their blood (hyperphosphatemia), 27% had nail disorders, 27% had liver side effects (changes in liver-related laboratory tests), 19% had a sore mouth (stomatitis), 13% had hand-foot syndrome (palmar-plantar erythrodysesthesia syndrome), 9% had a rash, 8% developed changes in the back of the eye (retinal disorders), and 4% of people developed cataracts. Most side effects were mild/moderate and reversible. The median time it took from starting treatment to experiencing a severe side effect ranged from 9days (hyperphosphatemia) to 125days (cataracts). Some side effects tended to occur early, while others developed later. Only 2% of people stopped taking futibatinib due to treatment-related side effects, and futibatinib caused no deaths. The side effects from taking futibatinib were manageable and similar in people with different types of cancer. To fully understand the safety of futibatinib, researchers will need to look at what side effects are reported in people taking futibatinib over a longer time in the real-world setting (outside of clinical trials).

Tasurgratinib in patients with cholangiocarcinoma or gastric cancer: Expansion part of the first-in-human phase I study.

Fibroblast growth factor receptors (FGFRs) are a highly conserved family of transmembrane receptor tyrosine kinases with multiple roles in the regulation of key cellular processes. Specific FGFR mutations have been observed in several types of cancers, including gastric carcinoma and cholangiocarcinoma. Dose escalation data of 24 Japanese patients with solid tumors treated with Tasurgratinib (previously known as E7090), a potent, selective FGFR1-3 inhibitor, was reported in a phase I, first-in-human, single-center study. Based on the safety, pharmacokinetic, and pharmacodynamic profiles observed in this study, the recommended dose of 140 mg once daily was selected for the expansion part (Part 2), a multicenter expansion of the dose-finding study restricted to patients with tumors harboring FGFR gene alterations. Safety and preliminary efficacy were assessed in Part 2. Pharmacodynamic pharmacogenomic markers (serum phosphate, FGF23, and 1,25-(OH)2-vitamin D, circulating tumor DNA) and pharmacokinetic profiles were also evaluated. A total of 16 patients were enrolled in Part 2, six with cholangiocarcinoma and 10 with gastric cancer. The most common treatment-emergent adverse events were hyperphosphatemia, palmar-plantar erythrodysesthesia syndrome, and paronychia. Five partial responses (83.3%) in cholangiocarcinoma patients and one partial response (11.1%) in gastric cancer patients were observed; median progression-free survival was 8.26 months (95% confidence interval [CI] 3.84, not evaluable [NE]) and 3.25 months (95% CI 0.95, 4.86), and overall survival was 22.49 months (95% CI 6.37, NE) and 4.27 months (95% CI 2.23, 7.95), respectively, in the two groups. In conclusion, Tasurgratinib 140 mg has a tolerable safety profile with good clinical efficacy in patients with cholangiocarcinoma harboring FGFR2 gene rearrangements.

Transcatheter arterial chemoembolization plus Sorafenib versus transcatheter arterial chemoembolization plus Lenvatinib for intermediate hepatocellular carcinoma

Background: Recent studies have highlighted that TACE in conjunction with Lenvatinib (TACE-L) offers a promising adjunct therapy for advanced HCC patients, outperforming TACE plus Sorafenib (TACE-S). However, there has been a lack of research comparing these two regimens for intermediate HCC. Aims: This study aims to address the research gap by evaluating the efficacy of TACE-L versus TACE-S in intermediate HCC patients. Methods: A retrospective analysis was conducted on a cohort of consecutive intermediate HCC patients who received either TACE-L or TACE-S from November 2018 to December 2022. Portal vein width was assessed using abdominal NMRI or Doppler ultrasonography, and inflammatory markers were derived from routine blood counts. The primary outcomes of interest were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse drug reactions (ADRs). Results: The study included 117 patients, with 56 in the TACE-S group and 61 in the TACE-L group. The TACE-S group demonstrated superior OS (HR = 1.704, 95% CI: 1.012–2.870, p = 0.045) compared to the TACE-L group. No significant difference was observed in PFS (HR:1.512, 95% CI: 0.988–2.313, p = 0.057) between the two groups. Subgroup analyses revealed that male patients, those with cirrhosis, and those with more than four tumors had better OS and PFS in the TACE-S group than in the TACE-L group. Inflammatory markers were comparable between the groups. The TACE-S group experienced a higher incidence of palmar-plantar erythrodysesthesia syndrome (PPE) (14/56 [25%] vs. 5/61 [8.1%], p = 0.014) but a lower incidence of hypertension (3/56 [5.3%] vs. 11/61 [18%], p = 0.035) compared to the TACE-L group. Conclusions: In patients with intermediate HCC, TACE-S was found to be more effective in terms of OS than TACE-L. No significant disparity was noted in PFS between the two treatment groups.

Association of adverse events and quality of life in patients with unresectable hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the third-leading cause of cancer-related deaths globally. Patients are often diagnosed with advanced disease, in which systemic and locoregional therapies are commonly used as first-line treatment. Such treatments can cause adverse events (AEs) that negatively affect quality of life (QoL), which is particularly undesirable where prognosis is poor. The aim of the present study was to evaluate the impact of common AEs on QoL in patients with HCC. Data from the SARAH randomized controlled trial (RCT) were analyzed. Given the large number of distinct AEs that occurred in the trial, AEs were grouped as in the SARAH trial and prioritized using principal component analysis (PCA). Linear mixed-effects models were then applied with age, ECOG status, and AEs as predictors of the QoL change as measured with the EORTC Core Quality of Life Questionnaire (QLQ-C30). The PCA resulted in the selection of 28 AEs for inclusion in the linear mixed-effects models. Of the 28 AEs, diarrhea, decreased appetite, abdominal pain, and palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome) were significant drivers of reductions in QoL as measured using the QLQ-C30 global health status scale. Diarrhea, abdominal pain, and hand-foot syndrome were also significant drivers of reduced QoL outcomes. The present analysis showed that diarrhea, decreased appetite, abdominal pain, and palmar-plantar erythrodysesthesia were significantly associated with reduced QoL in patients with unresectable HCC. Reducing the incidence and/or severity of these AEs should therefore be a key focus when selecting the optimal treatments for these patients.

Efficacy and safety of Anlotinib based neoadjuvant chemotherapy for locally advanced triple negative breast cancer (TNBC)

BackgroundAnlotinib, an oral multitarget tyrosine kinase inhibitor, has shown the ability to inhibit tumor angiogenesis. This study aimed to assess the effectiveness and safety of anlotinib plus docetaxel, epirubicin, and cyclophosphamide (TEC) as a neoadjuvant chemotherapy regimen for locally advanced TNBC.MethodsLocally advanced TNBC patients who had received no prior systemic treatment were eligible for this study. The enrolled patients were scheduled to undergo six cycles of anlotinib (12 mg, d1-14, q3w) plus docetaxel (75 mg/m2, d1, q3w), epirubicin (75 mg/m2, d1, q3w) and cyclophosphamide (600 mg/m2, d1, q3w) prior to surgery, unless there was disease progression or severe toxicity. The primary objective of this study was the safety of this therapeutic regimen, and the secondary objective was the tumor response. The safety of this regimen was assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and the efficacy of this treatment was measured using the Response Evaluation Criteria in Solid Tumors version 1.1.ResultsA total of 18 patients were included in this study. Participants completed an average of 5.56 neoadjuvant treatment cycles. The objective response rate (ORR) was 83.33%, and the disease control rate was 100%, respectively. The pCR was 55.6%. No patients discontinued therapy because of Adverse effects (AEs). Grade 3 or 4 AEs were observed in 5 cases (27.8%), with neutropenia and palmar-plantar erythrodysesthesia syndrome being the most common.ConclusionsAnlotinib combined with TEC as neoadjuvant therapy demonstrated manageable toxicity and promising antitumor activity for locally advanced TNBC. Further investigation of this combination regimen is warranted.

International, open-label phase 2 study of regorafenib plus pembrolizumab in patients with advanced hepatocellular carcinoma (HCC) previously treated with immune checkpoint inhibitors (ICI).

4007 Background: The optimal second-line treatment for HCC after ICI is not established. Regorafenib is approved for treatment of advanced HCC after sorafenib. The primary aim of this study was to evaluate the activity of regorafenib plus pembrolizumab in patients with advanced HCC who progressed on only one prior ICI regimen. Methods: Patients aged ≥18 years, CP Class A, BCLC stage B or C, and ECOG PS of 0 or 1 received oral regorafenib 90 mg once daily 3 weeks (wk) on/1 wk off plus i.v. pembrolizumab 400 mg every 6 wk. The daily regorafenib dose could be escalated to 120 mg after the first 4-wk cycle of regorafenib if tolerated. Pembrolizumab dose reductions were not allowed. Cohorts were defined by prior treatment: Cohort 1 = atezolizumab + bevacizumab; Cohort 2 = any other ICI regimen (alone or combination). Primary endpoint was overall response rate (ORR) by independent central review (RECIST 1.1). Results: 95 patients were treated in 8 countries; Cohort 2 appeared to have more favorable disease characteristics (Table). Most common prior ICIs in Cohort 2 were durvalumab (30%), nivolumab (30%), ipilimumab (22%), and pembrolizumab (19%). Overall, median follow up was 7.1 months (mo). Median duration of regorafenib/pembrolizumab treatment (including interruptions, delays) was shorter in Cohort 1 vs Cohort 2 (11.0/9.4 wk vs 21.4/24.1 wk). ORR was 5.9% in Cohort 1 and 11.1% in Cohort 2; stable disease rates were 48.5% and 63.0%, respectively. Median PFS was 2.8 mo in Cohort 1 and 4.2 mo in Cohort 2. Overall, treatment-emergent adverse events (TEAE) were grade 3 in 56% of patients and grade 4 in 5%; drug-related grade 3 and 4 TEAE occurred in 37% and 3%, respectively. One patient (Cohort 1) had a grade 5 drug-related TEAE (cardiac arrest). Most common drug-related TEAE were palmar-plantar erythrodysesthesia syndrome (39%), asthenia (33%), decreased appetite (32%), diarrhea (28%), and hypertension (20%). Biomarkers assessed in paired biopsies (baseline and wk 6/day 1) showed on-treatment reductions in macrophages and angiogenesis RNA signatures. Conclusions: To our knowledge, this is the first prospective evaluation of a kinase inhibitor plus an ICI following first-line ICI therapy for HCC. Regorafenib plus pembrolizumab had modest activity in second line after first-line ICI regimens. The safety profile of the combination was consistent with those of either drug. Optimal treatment for patients with advanced HCC who progress after an ICI regimen remains an unmet need. Biomarker findings will be detailed in presentation. Clinical trial information: NCT04696055 . [Table: see text]

Role of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte-ratio (PLR) in unresectable hepatocellular carcinoma (uHCC): Subgroup analysis of patients treated with camrelizumab (cam) + rivoceranib (rivo) in the CARES-310 trial.

e16197 Background: CARES-310 (NCT03764293) evaluated the combination of the PD-1 inhibitor, cam, and the VEGFR-2 tyrosine kinase inhibitor, rivo, compared to sorafenib (sor) for the treatment of 543 patients (pts) with uHCC. Cam + rivo significantly improved mOS (22.1 months [mo] [95% CI 19.1-27.2] vs 15.2 mo [13.0-18.5] HR 0.62 [95% CI 0.49-0.80]; one-sided p < 0.0001) and mPFS (5.6 mo [95% CI 5.5-6.3] vs 3.7 mo [2.8-3.7]; HR 0.54 [95% CI 0.44-0.67]; one-sided p < 0.0001) compared to sor. The most common (≥20%) grade ≥3 treatment-related adverse events (TRAEs) for cam + rivo were hypertension (37.5%) and increased AST (16.5%) vs palmar-plantar erythrodysesthesia syndrome (15.2%) for sor. An elevated level of inflammation, including NLR and PLR, have been associated with poor survival outcomes in pts with HCC (Lin S, et al. Trans Cancer Res. 2021). Here, we present a subgroup analysis of the CARES-310 trial evaluating the impact of baseline (BL) NLR and PLR status on pt outcomes. Methods: The subgroup of pts treated with cam+rivo and BL NLR < 5 or ≥5 and PLR < 300 or ≥300 were evaluated for mOS, mPFS, overall response rate (ORR), disease control rate (DCR), and safety. Results: Of 272 pts treated with cam+rivo, 64.3% of pts had extrahepatic spread, median AFP was 84.1 ng/mL, 86.8% were Child-Pugh (CP) class A5, 13.2% were CP class A6, 73.5% were ALBI grade 1, 26.5% were ALBI grade 2. Additionally, 249 pts had NLR < 5, 10 pts had NLR ≥5, 252 pts had PLR < 300, and 7 pts had PLR ≥300. Pts with BL NLR < 5 and PLR < 300 demonstrated improved outcomes in mOS, mPFS, ORR, and DCR vs pts with BL NLR ≥5 and PLR ≥300 (Table). Rates of any grade TRAEs and grade ≥ 3 TRAEs were comparable between pts with BL NLR < 5 and ≥5 and PLR < 300 and ≥300 (Table). Conclusions: These results suggest that NLR and PLR may serve as a prognostic marker in patients with uHCC, but larger studies are needed to validate these findings. Clinical trial information: NCT03764293 . [Table: see text]

Adjuvant therapy with donafenib plus anti–PD-1 antibody for patients (pts) with hepatocellular carcinoma (HCC) at high risk of recurrence after resection (PATH study).

e16228 Background: There is no universally accepted standard treatment option or strategy for post-surgery adjuvant therapy for HCC. Among BCLC A/B patients with MVI, adjuvant TACE provided a 1-year recurrence-free survival rate (RFSR) of around 60-70%. We conducted a pilot study to explore the utility of donafenib combined with anti-PD-1 antibody as adjuvant therapy for pts with high risks of recurrence. Methods: It was planned to enroll 30 HCC pts who had undergone radical surgery and with at least one of the following risk factors: a) Presence of microvascular invasion (MVI); b) Presence of satellite nodule(s); c) > 3 tumor nodules; d) Portal vein tumor thrombus. Pts with invasion of main portal venous were excluded. Donafenib plus anti-PD-1 antibody was initiated at 4 to 8 weeks after resection and continued for up to six months. No other adjuvant therapies were allowed before enrollment and during the study, except for anti-virus treatment. The primary endpoint was the cumulative 1-year RFSR. The secondary endpoints included recurrence-free survival (RFS), overall survival, and safety. Results: From June 2020 to November 2023, a total of 30 pts were recruited. 27 pts were included in efficacy analysis. The mean and median follow-up time was 347.9 days and 179.5 days. The mean and median time from surgery to enrollment was 42.5 days and 42.0 days. MVI was the most common risk factor (Table). Majority of the pts had only one risk factor. Relapse occurred in two pts (7.4%) and RFS was very immature. The RFSR at one year was 89.7% (90% CI, 70.6%-96.7%) in all the evaluable pts, and slightly higher in pts with M1 or only one risk factor (92.9% [90% CI, 68.1%-98.6%] and 93.3% [90% CI, 69.9%-98.7%], respectively). No deaths were observed. In 30 pts who had received at least one dose, the incidence of grade 3 treatment-related adverse events (TRAEs) was 40.0% (12/30). No grade 4 or 5 TRAEs were reported. The grade 3 TRAEs occurred in ≥2 pts were palmar-plantar erythrodysesthesia syndrome (13.3%), rash (13.3%), alanine aminotransferase increased (10.0%), and aspartate aminotransferase increased (6.7%). Conclusions: These results showed that a regimen of 6 months of adjuvant therapy with donafenib plus anti-PD-1 antibody may be efficient to reduce recurrence for BCLC A/B pts at high risk of recurrence, particularly those with ≤2 risk factors. No new safety issues were noticed. Clinical trial information: NCT04418401 . [Table: see text]

Camrelizumab plus famitinib in previously chemo-immunotherapy treated patients with advanced NSCLC: results from an open-label multicenter phase 2 basket study

BackgroundThe combination of immune checkpoint inhibitors and antiangiogenic agents has been effective in treating multiple cancers. This was further explored in an open-label, multicenter phase 2 basket study (NCT04346381), which evaluated the antitumor activity and safety of camrelizumab (an anti-PD-1 antibody) plus famitinib (a receptor tyrosine kinase inhibitor) in patients with advanced solid tumors. We herein report the findings from the cohort of advanced NSCLC patients who progressed after treatment with platinum-doublet chemotherapy and immunotherapy.MethodsEligible patients were enrolled and treated with camrelizumab (200 mg once every 3 weeks via intravenous infusion) and oral famitinib (20 mg once daily). The primary endpoint was the objective response rate (ORR). Secondary endpoints included the disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety.ResultsForty patients were enrolled in this cohort, with a median follow-up duration of 11.5 months. Three patients (7.5%) achieved a partial response, and 29 patients (72.5%) achieved stable disease. The ORR and DCR with this combination regimen were 7.5% (95% CI, 1.6–20.4) and 80.0% (95% CI, 64.4–90.9), respectively. The median DoR was 12.1 months (95% CI, 10.3-not reached). The median PFS was 5.4 months (95% CI, 4.1–7.5), and the median OS was 12.1 months (95% CI, 9.1–16.7). The estimated 12-month OS rate was 51.5% (95% CI, 34.9–65.9). The most frequent grade 3 or higher treatment-related adverse events occurring in more than 5% of patients included hypertension (27.5%), palmar-plantar erythrodysesthesia syndrome (10%), decreased neutrophil count (10%), and proteinuria (7.5%).ConclusionCamrelizumab plus famitinib demonstrated favorable benefits in PFS and OS, along with manageable safety profiles, in patients with advanced NSCLC who progressed after platinum-doublet chemotherapy and immunotherapy. This finding warrants further exploration.

Abstract RF01-07: The efficacy and safety of tinengotinib in patients with advanced or metastatic HR+/HER2- breast cancer or TNBC

Abstract Background: Tinengotinib is a novel multiple kinase inhibitor that strongly inhibits Aurora A/B, FGFR1/2/3, VEGFRs, JAK1/2, and CSF1R. Here we present the preliminary safety, pharmacokinetic and efficacy data of tinengotinib in patients (pts) with hormone receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer (BC) and triple-negative BC (TNBC) from Phase I TT420X2101 (NCT03654547) and Phase Ib/II TT420X1103 (NCT04742959) trials. Methods: Eligible pts with HR+/HER2- BC or TNBC who have no available standard therapeutic treatment options were enrolled to the TT420X2101 and TT420X1103 trials. Tinengotinib was given as monotherapy at different dose levels (5 mg QD, 10 mg QD and 12 mg QD); different dosing schedule (6 mg BID); and as combination (tinengotinib 8 mg QD and Abraxane 100 mg/m2). Recruitment spanned from January 2019 to March 2023. Results: As of June 2023, 36 pts with metastatic BC were treated: 30 with tinengotinib monotherapy at dose levels of 5 mg QD (n=1), 8 mg QD (n=4), 10 mg QD (n=5), 12 mg QD (n=18), 6 mg BID (n=2) and 6 with tinengotinib 8 mg QD in combination with nab-paclitaxel 100 mg/m2. Median age 51 years (range 24-75), ECOG PS 1 in 83.3% of pts, median lines of prior therapy were 5, and 77.8% of pts had prior taxanes. Of 30 pts receiving tinengotinib monotherapy, treatment related adverse events (TRAEs) were reported in 26 (86.7%) pts. 43.4% were Grade (G) 1-2, 43.3% were G3. No G4 or G5 TRAEs were reported. Common TRAEs (≥20%) of tinengotinib monotherapy were hypertension (60.0%), stomatitis (50.0%), palmar-plantar erythrodysesthesia syndrome (46.7%) and diarrhea (20.0%). All six (100%) pts receiving tinengotinib in combination with nab-paclitaxel experienced TRAEs, 16.7% were G1, 66.7% were G3, no G4 TRAEs, and one pt had G5 (pulmonary hemorrhage). Common TRAEs (≥20%) of tinengotinib in combination with nab-paclitaxel were neutrophil count decreased/neutropenia (50.0%), stomatitis (50.0%), hypertension (33.3%), hyponatremia (33.3%), hypokalemia (33.3%), and nausea (33.3%). Twenty-eight pts receiving tinengotinib monotherapy were efficacy evaluable. 11 pts with HR+/HER2- BC achieved objective response rate (ORR) of 45.5%, clinical benefit rate (CBR, CR+PR+SD ≥ 24 weeks) of 54.5% and median progression-free survival (mPFS) of 5.55 (95% CI 1.97-6.18) months. Partial responses were seen in 3 pts with HER2-zero (n=5) and 2 pts with HER2 low (1+/2+) pts (n=6), respectively. 17 pts with TNBC had ORR of 23.5%, CBR of 29.4% and mPFS of 2.73 (95% CI 1.68-6.41) months. In 6 pts treated with tinengotinib in combination with nab-paclitaxel, one out of 2 pts with HR+/HER2- BC achieved PR for 13 weeks as of data cutoff; two out of 4 pts with TNBC had SD. No significant difference in exposure was observed between tinengotinib monotherapy and tinengotinib in combination with nab-paclitaxel. Conclusions: Tinengotinib for the treatment of HR+HER2- BC or TNBC, whether as monotherapy or in combination with nab-paclitaxel, had manageable side effects. Tinengotinib has shown promising clinical benefit in heavily pre-treated pts with refractory HR+HER2- BC or TNBC. Clinical benefit was similar across the subgroups of pts with HR+ HER2-zero and HR+ HER2 low disease. Citation Format: Piha-Paul Sarina, Binghe Xu, Ying Fan, Yuan Yuan, Sayeh Lavasani, Joanne Mortimer, Sanjay Goel, Apostolia Tsimberidou, Nuhad Ibrahim, Sausan Abouharb, Carlos Barcenas, Adaeze lheme, Daniel Karp, Jordi Rodon Ahnert, Ecaterina Dumbrava, Jean Fan, Peng Peng, Caixia Sun, Hui Wang, Katie Hennessy, Ximei Fu, Ruolan Xu, Shumao Ni, Frank Wu, Funda Meric-Bernstam. The efficacy and safety of tinengotinib in patients with advanced or metastatic HR+/HER2- breast cancer or TNBC [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr RF01-07.

A phase IV study to evaluate the safety of fruquintinib in Chinese patients in real-world clinical practice.

Fruquintinib is approved in China for patients with metastatic colorectal cancer (CRC) who progressed after 2 lines of chemotherapy. This postmarketing study was conducted to evaluate the safety of fruquintinib in the Chinese population, including previously treated patients with advanced CRC and other solid tumors. Patients in the first cycle of fruquintinib or expected to start fruquintinib within a week were enrolled. Fruquintinib was administrated according to the label or per physicians' discretion. Patient characteristics and safety information were collected at baseline, 1 month, and 6 months after consent (or 30 days after the last dose). Overall, 3005 patients enrolled between April 24, 2019 and September 27, 2022. All enrolled patients received at least one dose of fruquintinib. Most patients had metastases at baseline. The median age was 60 years. More than half (64.0%) of the patients started fruquintinib at 5 mg, and the median treatment exposure was 2.7 months. Nearly one-third (32.5%) of patients with CRC received fruquintinib with concomitant antineoplastic agents. Treatment-emergent adverse events (TEAEs) leading to dose modification were reported in 626 (20.8%) patients, and 469 (15.6%) patients experienced TEAEs leading to treatment discontinuation. The most common grade ≥ 3 TEAEs were hypertension (6.6%), palmar-plantar erythrodysesthesia syndrome (2.2%), and platelet count decreased (1.0%). Combination therapy did not lead to excessive toxicities. The safety profile of fruquintinib in the real world was generally consistent with that in clinical studies, and the incidence of TEAEs was numerically lower than known VEGF/VEGFR inhibitor-related AEs. Fruquintinib exhibited manageable safety and tolerability in Chinese patients in the real-world setting.

Potential Antitumor Activity of Combined Lycopene and Sorafenib against Solid Ehrlich Carcinoma via Targeting Autophagy and Apoptosis and Suppressing Proliferation.

An FDA-approved kinase inhibitor called sorafenib (SOR) is used to treat primary kidney and liver cancer as well as to stop the spread of advanced breast cancer. Side effects from SOR, such as palmar-plantar erythrodysesthesia syndrome, can negatively impact an individual's quality of life. There are a lot of data supporting the importance of lycopene (LYC) in preventing cancer. The antitumor properties of the combination of sorafenib and lycopene were examined in this study. A viability test against MDA-MB-231 was used to assess the anticancer efficacy of sorafenib, lycopene, and their combination in vitro. Moreover, a cell cycle analysis and Annexin-V/PI double staining were performed by using flow cytometry. In addition, the protein level of JNK-1, ERK-1, Beclin-1, P38, and P53 of the MDA-MB-231 cell line was estimated using ELISA kits. In addition, mice with SEC were divided into four equal groups at random (n = 10) to investigate the possible processes underlying the in vivo antitumor effect. Group IV (SEC-SOR-LYC) received SOR (30 mg/kg/day, p.o.) and LYC (20 mg/kg/day, p.o.); Group I received the SEC control; Group II received SEC-SOR (30 mg/kg/day, p.o.); and Group III received SEC-LYC (20 mg/kg/day, p.o.). The findings demonstrated that the combination of sorafenib and lycopene was superior to sorafenib and lycopene alone in causing early cell cycle arrest, suppressing the viability of cancer cells, and increasing cell apoptosis and autophagy. Likewise, the combination of sorafenib and lycopene demonstrated inhibition of the levels of Bcl-2, Ki-67, VEGF, IL-1β, and TNF-α protein. Otherwise, the quantities of the proteins BAX, P53, and caspase 3 were amplified. Furthermore, the combined treatment led to a substantial increase in TNF-α, caspase 3, and VEGF gene expression compared to the equivalent dosages of monotherapy. The combination of sorafenib and lycopene enhanced apoptosis and reduced inflammation, as seen by the tumor's decreased weight and volume, hence demonstrating its potential anticancer effect.

Abstract CT059: Phase 1b trial Mipasetamab Uzoptirine (ADCT-601-102) dose escalation in patients with advanced bone and soft tissue sarcomas

Abstract Background: AXL is a cell surface receptor tyrosine kinase widely expressed in solid tumors (ST), including sarcomas. ADCT-601 (Mipasetamab uzoptirine; Mipa) is an antibody-drug conjugate comprising a humanized anti-AXL antibody conjugated via a cleavable linker to SG3199 (pyrrolobenzodiazepine dimer cytotoxin). Mipa demonstrated antitumor activity in pre-clinical mice models of sarcoma, adrenocortical carcinoma and pancreatic cancer, and clinical activity in ST patients (pts) in its first-in-human trial. Here, we report initial clinical data in pts with advanced bone and soft tissue sarcomas treated in dose escalation with Mipa. Objective: To characterize the safety and tolerability of Mipa in pts with sarcoma indications who exhausted standard of care therapy. Method: This is a phase 1b, open-label, dose-escalation, dose expansion study of Mipa (NCT05389462; EudraCT: 2021-00566-18). Pts received Mipa every 3 weeks (Q3W) at escalating dose levels, in a 3+3 dose escalation design. Results: As of 04 December 2023, 18 sarcoma patients (15 [83%], soft tissue sarcoma [STS] and 3 [17%] bone sarcoma), unselected for AXL expression, with a median number of 3 prior lines of therapy (1-10), were enrolled in 4 different dose cohorts: 7.5mg, 11mg, 13mg and 15mg. Reasons for treatment discontinuation were disease progression (10 pts [55.6%]), adverse events (3 pts [16.7%]) and consent withdrawal (2 pts [11.1%]). Treatment emergent adverse events (TEAE) were seen in 17 pts (94.4%). Most common TEAE (all grades and relationship [≥20%]) were palmar-plantar erythrodysesthesia syndrome (7 pts [38.9%]); anemia (6 pts [33.3%]); rash maculopapular (5 pts [27.8%]); cheilitis and constipation (4 pts each [22.2%]). TEAE≥grade 3 were seen in 9 pts (50%). Most common TEAE≥grade 3 (≥10%) were GGT increase (2 pts [11.1%]). Two dose limiting toxicities were seen: cheilitis grade 2 and grade 3 at 15mg and 13mg respectively. Cutaneous reactions, all grades, are more prominent in higher doses. Maximum tolerated dose (MTD) has not been established. In 17 sarcoma pts evaluable per RECISTv1.1, best overall response was partial response (PR) (2 pts [11.8%]), including a confirmed PR; stable disease (SD) (8 pts [47.1%]); progressive disease (7 pts [41.2%]). Tumor reductions was observed at 7.5mg, 11mg and 13mg. By week 12, 6/17 pts (35.3%) did not demonstrate PD . Initial IHC staining showed AXL expression in all sarcoma baseline biopsies tested so far. Initial pharmacokinetic (PK) data indicate exposures with moderate to marked interpatient variability; rapid clearance with no accumulation by Cycle 2. Updated biomarkers and PK data will be presented. Conclusion: The MTD was not established. Due to the incidence of TEAE judged related to Mipa and the preliminary activity observed, 15mg was selected as the highest dose to be tested in a fixed dose Q3W regimen. The study continues to enroll to further optimize Mipa dosing regimen and in dose escalation with gemcitabine. Citation Format: Brian Andrew Van Tine, Christopher T. Chen, Victor Moreno, Elizabeth J. Davis, Maria J. de Miguel, Antoine Italiano, Esma Saada-Bouzid, Mohammed Milhem, Claudia Valverde, Sant P. Chawla, Abdul Rafeh Naqash, Louise Carter, Robin Jones, Ilaria Conti, Joe Boni, Karin Havenith, Yvan LeBruchec, Serafino Pantano, Jean-Yves Blay. Phase 1b trial Mipasetamab Uzoptirine (ADCT-601-102) dose escalation in patients with advanced bone and soft tissue sarcomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT059.

Abstract CT033: Avelumab combined with regorafenib in solid tumors with tertiary lymphoid structures: A phase 2 REGOMUNE trial cohort

Abstract Background: Mature tertiary lymphoid structures (mTLS) predict improved outcome in patients treated with immune checkpoint inhibitors (ICIs). However, a significant proportion of patients with TLS-positive tumors do not respond to ICI when used as a single agent and may therefore benefit from combination therapy. The multikinase inhibitor, regorafenib, deplete regulatory T cells, an immune population associated with resistance to ICI in TLS-positive tumors. We report the results of the PD-L1 inhibitor avelumab combined with regorafenib in patients with mTLS-positive advanced solid tumors. Methods: ‘Regomune’ is an open-label, multicenter phase II study assessing the combination of avelumab (10mg/kg IV every 14 days) with regorafenib (160 mg daily for 3 weeks in a 4-week cycle) in patients with advanced mTLS-positive solid tumors. The mTLS status was centrally assessed as previously described (Vanhersecke et al Nature Cancer 2021). All patients had confirmed progressive disease at inclusion, based on a central review of imaging. The primary efficacy endpoint was a 6-month non-progression rate using RECIST v1.1 based on blinded central review. 29 assessable patients were deemed necessary, and to meet the primary endpoint, at least 8 patients needed to be progression-free at 6 months. Results: Between January 2021 and July 2022, 132 patients (5 centers) underwent mTLS screening. Of these, 55 (41.7%) were identified as mTLS+, and 38 were included in the study. The top five histological subtypes were MSS colorectal cancer (15.8%), sarcoma (13.1%), oesogastric (10.5%), biliary tract (7.9%), and pancreatic cancer (7.9%). The most frequent grade 3/4 adverse events were palmar-plantar erythrodysesthesia syndrome (23.7%), maculo-papular rash (18.4%), fatigue, and oral mucositis (7.9% each). No treatment-related deaths were reported. Of the 34 patients assessed for efficacy, 16 (47%) showed tumor shrinkage, with 9 achieving a partial response (26.7%) and 7 having stable disease (20.6%). The median duration of response was 6 months. Twelve patients (comprising various tumor types including MSS colorectal cancer, small bowel carcinomas, biliary tract cancer, sarcomas, thyroid and gynecological tumors.) were progression-free at 6 months, marking the study’s primary endpoint achievement. The median progression-free survival and overall survival were 3.6 months and 8.6 months, respectively. Spatial transcriptomics, multiplex immunofluorescence (IF) of tumor tissues, and comprehensive plasma proteomics analysis have collectively uncovered critical biomarkers that significantly determine both sensitivity and resistance to treatment. Conclusions: This is the first histology-agnostic clinical trial employing mTLS as a biomarker for patient selection for treatment with an immune checkpoint inhibitor-based regimen. Durable responses were recorded, even in cases typically resistant to immunotherapy, confirming the predictive value of mTLS. Trial Registration NCT03475953 Citation Format: Antoine Italiano, Sophie Cousin, Carine Bellera, Jean-Philippe Guegan, Jean-Philippe Metges, Antoine Adenis, Rastilav Bahleda, Philippe Cassier, Coralie Cantarel, Michele Kind, Jean Palussiere, Lucile Vanhersecke, Alban Bessede. Avelumab combined with regorafenib in solid tumors with tertiary lymphoid structures: A phase 2 REGOMUNE trial cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT033.

Regorafenib plus nivolumab in unresectable hepatocellular carcinoma: the phase 2 RENOBATE trial

Regorafenib has anti-tumor activity in patients with unresectable hepatocellular carcinoma (uHCC) with potential immunomodulatory effects, suggesting that its combination with immune checkpoint inhibitor may have clinically meaningful benefits in patients with uHCC. The multicenter, single-arm, phase 2 RENOBATE trial tested regorafenib–nivolumab as front-line treatment for uHCC. Forty-two patients received nivolumab 480 mg every 4 weeks and regorafenib 80 mg daily (3-weeks-on/1-week-off schedule). The primary endpoint was the investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The secondary endpoints included safety, progression-free survival (PFS) and overall survival (OS). ORR per RECIST version 1.1 was 31.0%, meeting the primary endpoint. The most common adverse events were palmar-plantar erythrodysesthesia syndrome (38.1%), alopecia (26.2%) and skin rash (23.8%). Median PFS was 7.38 months. The 1-year OS rate was 80.5%, and the median OS was not reached. Exploratory single-cell RNA sequencing analyses of peripheral blood mononuclear cells showed that long-term responders exhibited T cell receptor repertoire diversification, enrichment of genes representing immunotherapy responsiveness in MKI67+ proliferating CD8+ T cells and a higher probability of M1-directed monocyte polarization. Our data support further clinical development of the regorafenib–nivolumab combination as front-line treatment for uHCC and provide preliminary insights on immune biomarkers of response. ClinicalTrials.gov identifier: NCT04310709.

Safety Profile and Adverse Event Management for Futibatinib, An Irreversible FGFR1-4 Inhibitor: Pooled Safety Analysis of 469 Patients.

Futibatinib, a covalently-binding inhibitor of fibroblast growth factor receptor (FGFR)1-4 gained approval for the treatment of refractory, advanced intrahepatic cholangiocarcinoma (iCCA) harboring an FGFR2 fusion/other rearrangement. An integrated analysis was performed to evaluate safety and provide guidance on the management of futibatinib-associated adverse events (AEs) in patients with unresectable/metastatic tumors, including iCCA. Data from three global phase I or II studies of futibatinib (NCT02052778; JapicCTI-142552) were pooled. AEs were graded per NCI CTCAE v4.03, where applicable. Safety was analyzed for patients receiving any futibatinib starting dose (overall population) and in those receiving the approved starting dose of 20 mg once every day. In total, 469 patients with one of 33 known tumor types were analyzed, including 318 patients who received futibatinib 20 mg every day. AEs of clinical interest (AECI; any grade/grade ≥3) in the overall population included hyperphosphatemia (82%/19%), nail disorders (27%/1%), hepatic AEs (27%/11%), stomatitis (19%/3%), palmar-plantar erythrodysesthesia syndrome (PPES; 13%/3%), rash (9%/0%), retinal disorders (8%/0%), and cataract (4%/1%). Median time to onset of grade ≥3 AECIs ranged from 9 days (hyperphosphatemia) to 125 days (cataract). Grade ≥3 hyperphosphatemia, hepatic AEs, PPES, and nail disorders resolved to grade ≤2 within a median of 7, 7, 8, and 28 days, respectively. Discontinuations due to treatment-related AEs were rare (2%), and no treatment-related deaths occurred. AE management included phosphate-lowering medication and dose adjustments. Futibatinib showed a consistent and manageable safety profile across patients with various tumor types. AECIs were mostly reversible with appropriate clinical management.

Efficacy and safety results of FGFR1-3 inhibitor, tinengotinib, as monotherapy in patients with advanced, metastatic cholangiocarcinoma: Results from phase II clinical trial.

434 Background: Tinengotinib is a spectrum-selective multi-kinase inhibitor with unique binding properties to FGFR, potently inhibited FGFR2 fusion/rearrangement and acquired resistant mutations in pre-clinical models and in phase I trials that included cholangiocarcinoma (CCA) patients (pts). Here we present the efficacy and safety of tinengotinib in a phase II clinical trial. Methods: Eligible pts with advanced/metastatic CCA who had received ≥ 1 prior systemic chemotherapy therapy and ECOG PS 0 or 1 were treated with tinengotinib 10 mg QD. Four cohorts included: Cohort A1: FGFR2 fusion(s) with primary progression on previous FGFR inhibitor ( FGFRi), A2: FGFR2 fusion(s) with progression after prior response to FGFRi (acquired resistance); B: non-fusion FGFR alteration(s): C: FGFR wild-type ( FGFRwt). Primary endpoint was objective response rate (ORR) per RECIST v1.1. CTCAE V5.0 was used for safety assessments. Results: As of 7Aug2023, 48 pts with CCA were enrolled, 13 in Cohort A1, 10 in A2, 12 in B, 13 in C. Median age 61.5 [range 25-81] years old, 41.7% male, 58.3% had ≥ 3 lines of prior therapy. ECOG PS 0 in 47.9% pts. Among 35 pts with FGFR alterations, 80.0% had ≥ 1 prior FGFRi therapy, and 97.1% had prior chemotherapy. Forty (40) pts were efficacy evaluable. In A1, 1 out of 11 pts (9.1%) achieved PR with tumor reduction of 31.8%. In A2, 3 out of 8 pts (37.5%) achieved PR with tumor reduction of 40.7%, 47.0% and 54.6%. In B, 3 out of 9 pts (33.3%) achieved PR with tumor reduction of 36.5%, 48.6%, and 60.6%. No PR was observed in C. Overall DCR was 94.7% (18/19) in FGFR2 fusion/rearrangement pts (A1+A2), 88.9% (8/9) in other FGFR alterations pts (B), and 75% (9/12) in FGFRwt pts (C). Median progression-free survival (mPFS) was 5.26 months (95%CI, 2.86-9.10) in A1+A2, 5.98 months (95%CI, 1.87-NA) in B and 3.84 months (95% CI, 1.84-4.80) in C. Among 48 treated pts, treatment-related AEs (TRAEs) occurred in 45 (93.8%) pts, 14 (29.2%) in G1-2, 29 (60.4%) in G3 and 2 (4.2%) in G4. The most common G3 TRAEs were hypertension in 12 (25%), palmar-plantar erythrodysesthesia syndrome in 3 (6.3%), diarrhea in 3 (6.3%) and stomatitis in 3 (6.3%). One subject had G4 increased TSH and G4 increased lipase, and another subject had G4 posterior reversible encephalopathy syndrome. No G5 TRAE was observed. Conclusions: Tinengotinib has promising clinical benefit for FGFR2 fusion CCA after prior FGFRi and for non-fusion FGFR alterations. Tinengotinib-related toxicities were manageable. An ongoing randomized, controlled phase III study will evaluate the clinical efficacy, safety, and pharmacodynamic effect of Tinengotinib vs Physicians’ choice in subjects with FGFR2-altered refractory/relapsed CCA after prior chemotherapy and FGFRi therapy. Clinical trial information: NCT04919642 .

Tinengotinib (TT-00420) in combination with atezolizumab in Chinese patients (pts) with biliary tract carcinoma (BTC): Preliminary efficacy and safety results from a phase Ib/II study.

473 Background: Programmed Cell Death Ligand 1 (PD-L1) inhibitor durvalumab in combination with gemcitabine and cisplatin has been approved as first-line therapy for BTC. However, the efficacy of subsequent standard of care is limited. Tinengotinib is a spectrum-selective multi-kinase inhibitor that targets cell proliferation, angiogenesis, and immune-oncology pathways by inhibiting Aurora kinases A/B, Janus kinases and receptor tyrosine kinases (FGFRs and VEGFRs). Tinengotinib combined with PD-L1 has demonstrated promising antineoplastic activity in preclinical study. Here we present the preliminary data of tinengotinib in combination with atezolizumab (atezo) in pts with advanced BTC from a phase Ib/II trial in China. Methods: In combination therapy, eligible pts with advanced/metastatic BTC were enrolled and treated with tinengotinib plus atezo 1200 mg/20 mL in 21-day cycle. Dose escalation (Phase Ib) and dose expansion (Phase II) were designed. Dose escalation followed a standard 3+3 design. Primary objectives in phase Ib were safety, tolerability, and determination of the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Results: As of 17-Aug-2023, six pts (5 cholangiocarcinoma, 1 gallbladder carcinoma) were enrolled and treated with tinengotinib 8 mg QD plus atezo (n=3) or tinengotinib 10 mg QD plus atezo (n=3). Median age was 62.0 years (range 47-75), 83.3% had ECOG performance status of 1, 83.3% had stage IV disease, 50% had ≥ 3 lines of prior antineoplastic therapies, and 50% had prior immunotherapy. No DLT was observed in these two dose levels. Treatment-related adverse events (TRAEs) were reported in 6 (100%) pts, including Grade (Gr)1-2 for 6 pts, Gr 3 in 2 pts. No Gr 4-5 TRAE. The most common TRAEs (≥ 50%) included hypertension, palmar-plantar erythrodysesthesia syndrome, blood bilirubin increased, proteinuria, hypertriglyceridemia and platelet count decreased. Two pts achieved partial response (PR). One prior immunotherapy naïve pt had a tumor reduction of 48.0% lasting for more than 5 months (tinengotinib 8 mg QD plus atezo). Another pt with prior immunotherapy (sintilimab), target therapy (donafenib) and chemotherapy had a tumor reduction of 39.1% (tinengotinib 10 mg QD plus atezo). Three pts had stable disease (SD). Conclusions: Tinengotinib in combination with atezo was well-tolerated for the treatment of Chinese BTC pts. Preliminary encouraging efficacy of tinengotinib in combination with atezo was observed in pts with heavily pre-treated BTC. The ongoing study is to further evaluate the safety and efficacy of tinengotinib in combination with atezo in pts with BTC who had prior immunotherapy and/or chemotherapy. Clinical trial information: NCT05253053 .

Patient-reported outcomes (PROs) <65 or ≥ 65 years old (yo) from CARES-310 camrelizumab + rivoceranib vs sorafenib as first-line treatment for patients with unresectable hepatocellular carcinoma (uHCC).

456 Background: CARES-310 (NCT03764293) evaluated the combination of the anti-PD-1 inhibitor, camrelizumab (cam), and the VEGFR-2 tyrosine kinase inhibitor, rivoceranib (rivo), compared to sorafenib (sor) for the treatment of uHCC. Cam + rivo significantly improved OS and PFS compared to sor (OS, 22.1 months [mo] [95% CI 19.1-27.2] vs 15.2 mo [13.0-18.5] HR 0.62 [95% CI 0.49-0.80]; one-sided p<0.0001); PFS, 5.6 mo [95% CI 5.5-6.3] vs 3.7 mo [2.8-3.7]; HR 0.52 [95% CI 0.41-0.65]; one-sided p<0.0001). The most common (≥20%) grade ≥3 treatment-related adverse events for cam + rivo were hypertension (37.5%) and increased AST (16.5%) vs palmar-plantar erythrodysesthesia syndrome (15.2%) for sor. This analysis evaluated PROs stratified by age: <65 yo (baseline, overall cam + rivo n=191, sor n=210) or ≥65 yo (baseline, overall cam + rivo n=81, sor n=61). Methods: Patients completed EORTC QLQ-C30 and EORTC QLQ-HCC18 at baseline, each visit, and post-last-dose follow-up periods. Endpoints included time to deterioration (TTD) with a ≥10-point decrease from baseline of patient reported QoL, physical functioning, role functioning, and patient-reported symptoms. Results: Mean completion rates across questionnaires were 98.56% and 96.78% for cam + rivo and 98.91% and 98.75% for sor in the <65 and ≥65 yo groups, respectively, from baseline through ≥121 weeks of treatment. In the <65 yo group, cam + rivo vs sor had improved TTD in fatigue measured by EROTC-QLQ-C30. In the ≥65 yo group, cam + rivo had significantly longer median TTD of pain measured by EROTC-QLQ-HCC18 and QLQ-C30, respectively. The median TTD of appetite loss in the ≥65 yo group favored cam + rivo. Median TTD for jaundice was significant for sor in both <65 yo and ≥65 yo group. Median GHS/HRQoL in the ≥65 yo group favored cam + rivo. Conclusions: Cam + rivo was associated with improvement in varied QoL aspects in both patient groups. These PRO results support the clinical benefit and use of cam + rivo in patients with uHCC who have not received prior systemic therapy. Clinical trial information: NCT03764293 . [Table: see text]

Results of the safety and tolerability of ivaltinostat plus capecitabine in the phase 1b portion of a phase 1b/2, dose-escalation, randomized, multi-center study in the maintenance (maint) setting in patients with metastatic pancreatic adenocarcinoma (mPDAC).

666 Background: The standard of care for patient (pts) with advanced or mPDAC typically consists of mFOLFIRINOX or gemcitabine/nab-paclitaxel used in the front-line setting until disease progression (prog) or toxicity. A tolerable maint therapy (tx) that can effectively delay disease prog while preserving quality of life with minimal cumulative toxicity is highly desirable. There is no standard main tx. Ivaltinostat (ival) is a pan-HDAC (histone deacetylation) inhibitor that increases histone acetylation (HA), suppresses PDAC cell proliferation, and promotes apoptosis in PDAC cell lines. Preclinical data demonstrated synergy with 5-FU/capecitabine in mouse models. The phase 1b study will determine an optimal combination of ival and cape followed by a randomized P2 trial of ival plus cape vs cape alone in the maint setting for pts with mPDAC who have not progressed on front-line mFOLFIRINOX. Methods: Key eligibility criteria for P1b include: locally advanced or mPDAC; at least 1 prior line of tx regardless disease prog; ECOG PS 0-1; and no known gBRCA1/2 mutation. Dose-limiting toxicities (DLT) in 3 dose levels of ival, (60, 125, and 250mg/m2 iv weekly on days 1 and 8) in combination with cape (1000mg/m2 po BID on days 1-14) of a 21-day cycle will be evaluated. The primary objective is to evaluate the safety, tolerability and determine the recommended phase 2 dose (RP2D) as well as pharmacokinetics (PK) of ival and cape. Results: As of the date of data-cut, 32 pts had been enrolled at the 60 (7 pts), 125 (14 pts) and 250 (11 pts) mg/m2 dose level, 8 were screen failures and 9 still ongoing with a goal of at least 6 DLT-evaluable pts per dose level. Average prior lines of tx was 3.6 (range 1-5). The median age was 68 (range 51-83) and 21(66%) were males. No DLTs were observed across the 3 dose levels. SAEs occurred in 2 pts that were not related to study drugs. Both ival and cape-related TEAEs were similar except palmar-plantar erythrodysesthesia syndrome (PPES) 9(28%) attributed to cape; fatigue, diarrhea and nausea were the only TEAEs occurred >15%. Two pts had ³grade 3 diarrhea, another pt had cape-related PPES. The TEAE profile was similar across the dose levels. At the time of data-cut there were 6 deaths among pts who discontinued study due to prog. Among 15 pts who had been evaluated for response since baseline, the best ORR were 11 SD(73.3%), 1(6.7%) no RECIST-measurable evidence of disease and 3 PD(20%). PK evaluations for ival indicated dose proportionate increases. The trend of PK observed in this study was similar to the PK trend observed in previous studies. Conclusions: Combination therapy of ival with cape has been well tolerated and the safety and PK/PD data support a RP2D of ival of 250 mg/m2. Clinical trial information: NCT05249101 .