Hand-foot Skin Reaction Research Articles

Lenvatinib as second-line treatment in patients with unresectable hepatocellular carcinoma: A retrospective analysis.

The purpose of this study is to determine the efficacy and safety of lenvatinib as second-line therapy in Chinese patients with unresectable hepatocellular carcinoma (HCC). We performed a retrospective analysis of Chinese patients with unresectable HCC who received second-line treatment of lenvatinib at three institutions from November 2018 to February 2022. Demographic and clinicopathologic characteristics, data on the treatment regimens were obtained from medical records. Tumor response was evaluated every 4-6 weeks by modified Response Evaluation Criteria in Solid Tumors (mRECIST). In total, 50 patients with unresectable HCC who received second-line treatment of lenvatinib were enrolled in this study. The objective response rate (ORR) was 18.0% and the disease control rate (DCR) was 74.0%, respectively. The duration of response (DoR) was 6.0 months. The median progression-free survival (PFS) and overall survival (OS) were 5.0 and 8.5 months, respectively. Patients who received ICIs combined with anti-angiogenic inhibitors as first-line therapy, achieving CR/PR at first-line therapy, with PFS≥6months at first-line therapy had a higher DCR. Univariate and multivariate analysis showed that AFP (ng/ml)<400, absence of extrahepatic metastasis, Child-Pugh A, tumor number<3, ICIs combined with anti-angiogenic inhibitors as first-line therapy, CR/PR to first-line therapy, and PFS≥6months at first-line therapy were independent factors of favorable PFS. Univariate analysis showed that absence of extrahepatic metastasis, tumor number<3, ICIs combined with anti-angiogenic inhibitors as first-line therapy, and PFS≥6months at first-line therapy were significantly associated with longer OS. Multivariate analysis showed that absence of extrahepatic metastasis, Child-Pugh A, tumor number<3, CR/PR to first-line therapy and PFS≥6months at first-line therapy were independent prognostic factors of OS. The majority of AEs were grade 1-2, and were reversible. Grade 3/4 AEs occurred in 12 patients (24.0%) and were mostly connected with hand-foot skin reactions (10.0%), and 10 patients had lenvatinib dose reductions. Two toxicity-related treatment interruptions were attributed to grade 3 hand-foot skin reaction, and grade 4 proteinuria, respectively. This study confirms the efficacy and safety of lenvatinib as second-line therapy after progression on sorafenib or ICIs combined with anti-angiogenic inhibitors.

Establishing the feasibility of a patient-engagement tool to improve outpatient symptom management and dosing of patients on regorafenib.

417 Background: Regorafenib (rego), an oral multikinase inhibitor, improves overall survival in patients (pts) with metastatic colorectal cancer (mCRC). However, its toxicity profile including, but not limited to, hand-foot skin reactions, fatigue, and hypertension significantly limits its use and often requires dose interruptions (40% rate) or modifications (20-25% rate). Inadequate symptom management can lead to frequent clinic visits, reduced quality of life, therapy non-adherence, and poor clinical outcomes. We aimed to establish the feasibility and usability of a CarePrompter smartphone application (app), a digital pt engagement tool with a pt and provider interface, to monitor and triage pt symptoms when starting rego. Methods: mCRC pts starting rego for the first time and with access to an iOS or Android smartphone with a data plan were recruited at MGUH. Pts were enrolled for the duration of their rego treatment. Once consented, recruiters downloaded and registered pts on the mobile app. Pts were provided a blood pressure (BP) cuff and trained on how to record their BP and answer a customized set of up to 17 questions daily on the app. The questions included documenting the status of the daily dose taken, completion of weekly labs, BP, whether pts needed advice, and severity of various side-effects if present on a 1-10 scale. Oncologists and nurses trained to use a CarePrompter triage tool were alerted when pts indicated missed doses, missed labs, high blood-pressure, high side-effect scores (8-10), and request for advice. Results: A total of 11 pts enrolled in the study. The study duration ranged from 1 to 5 months per pt. Pts, on average, completed the app questionnaire 10 out of 30 days, with the lowest rate of completion being 2 out of 30 days and the highest rate being 20 out of 30 days. BP recordings were logged an average of 10 times per pt in a 30-day period. An average of 2 provider alerts were triggered per pt. The alerts were primarily from pts documenting not performing labs or omitting rego doses. All alerts were acknowledged and resolved by a provider through the CarePrompter-triage tool. Providers found the tool usable based on qualitative interviews. There was an average dose increase of 1.25 rego pills from pt’s start to end dose. While 62.5% of pts were treated with the highest dose (160 mg) at one point in their treatment, by the end of the study 25%, 50%, and 25% remained on 160 mg, 120 mg, and 80 mg doses, respectively. Conclusions: The CarePrompter mobile app was technically feasible and usable by cancer patients and providers in monitoring symptoms and addressing real-time ambulatory issues during rego dosing. Additional studies are warranted to determine if routine utilization of this app in clinic translates to enhanced patient experiences, toxicity management, daily dosing, therapeutic compliance, and survival.

PD-1 inhibitors plus lenvatinib versus PD-1 inhibitors plus regorafenib in patients with advanced hepatocellular carcinoma after failure of sorafenib.

BackgroundLenvatinib, regorafenib and anti-programmed cell death protein-1 (PD-1) immunotherapy have shown promising clinical outcomes in patients with advanced hepatocellular carcinoma (HCC) after sorafenib failure, respectively. However, the combination of the two treatments has not been reported. We compared the efficacy of PD-1 inhibitors with lenvatinib (PL) and PD-1 inhibitors plus regorafenib (PR) in patients with advanced HCC in this study.MethodsWe conducted a retrospective study of advanced HCC patients who undergone PD-1 inhibitors combined with lenvatinib or regorafenib after failure of sorafenib at Second Affiliated Hospital of Nanchang University from July 2018 and December 2020. The overall survival (OS), progression-free survival (PFS), effective rates and treatment-related adverse events (TRAEs) were investigated.ResultsIn total, 61 patients met the criteria and were included in the present study, and they were divided into the PL group (n = 32) and PR group (n = 29). The overall response rate (ORR) (12.5%vs. 10.3%, respectively; p = 0.557) and disease control rate (DCR) (71.9%vs. 58.6%, respectively; p < 0.207) were higher in the PL group than in the PR group, but there was no statistical difference.Furthermore, median PFS and OS were not significantly different between the two groups in Kaplan-Meier survival analysis (PFS: 5.3 months vs 4.0 months, p = 0.512; OS: 14.1 months vs 13.7 months, p = 0.764 for the PL group vs PR group). The most common treatment-related adverse events (TRAEs) were hand -foot skin reaction (24/61,39.3%), hypertension (20/61,32.8%) and hypothyroidism (13/61,21.3%). The frequent TRAEs (≥Grade 3) during PD-1 inhibitors plus lenvatinib or regorafenib treatment were hand-foot skin reaction (5/29,12.4%), thrombocytopenia (2/29 6.90%) and proteinuria (n =2/32,6.25%).ConclusionsCombination of lenvatinib/regorafenib and PD-1 inhibitors is a promising therapy for HCC patients after sorafenib failure.

Transarterial chemoembolization (TACE) plus apatinib vs. TACE alone for hepatocellular carcinoma

ObjectiveTransarterial chemoembolization (TACE) is a common therapy for hepatocellular carcinoma (HCC), while TACE-induced tumor angiogenesis would increase progression and metastasis risk. Besides, apatinib possesses the capability of inhibiting tumor angiogenesis. Thus, this study aimed to explore the efficacy and safety of TACE plus apatinib compared to TACE alone in HCC patients. MethodsNinety-six intermediate-advanced HCC patients were retrospectively enrolled and classified into TACE plus apatinib group (N = 45) and TACE group (N = 51) based on the treatment. ResultsObjective response rate (68.9% vs. 47.1%) was increased in TACE plus apatinib group than in TACE group (P = 0.031). However, no difference was found in disease-control rate between groups (95.6% vs. 86.3%) (P = 0.167). Progression-free survival (PFS) (median PFS (95% confidence interval (CI)): 20.0 (13.2–26.8) vs. 14.0 (8.3–19.7) months) was enhanced in TACE plus apatinib group compared with TACE group (P = 0.030), while no difference was found in overall survival between groups (P = 0.060). Additionally, multivariate Cox's analysis presented that TACE plus apatinib (vs. TACE alone) independently associated with prolonged PFS (P = 0.043, hazard ratio = 0.617). Regarding safety profile, no difference in liver function indexes (albumin, total bilirubin, alanine aminotransferase and aspartate aminotransferase) was found after treatment between two groups; meanwhile, only the incidence of hand-foot skin reaction (24.4% vs. 7.8%) was higher in TACE plus apatinib group compared to TACE group (P = 0.025), while no difference was found in other adverse events between two groups (all P > 0.05). ConclusionTACE plus apatinib illustrates a superior efficacy with tolerable safety than TACE alone in intermediate-advanced HCC patients.

1579P Prophylactic strategies for hand-foot syndrome/skin reaction associated with systemic cancer treatment: A meta-analysis of randomized controlled trials

Hand-foot syndrome (HFS) and Hand Foot Skin Reaction (HFSR) are common toxicities of several systemic cancer treatments. Multikinase inhibitor- induced HFSR is distinguished from chemotherapy-induced HFS in terms of pathogenesis, symptomatology, and treatment. Multiple trials have investigated the efficacy of preventive strategies such as COX-inhibitors, pyridoxine and urea cream, however, no consensus has been made. This meta-analysis evaluated data from high quality trials to provide strong evidence in forming recommendations to prevent systemic cancer therapy-induced HFS/HFSR.

Abstract IA11: Molecular targeted therapies for advanced HCC

Abstract Hepatocellular carcinoma (HCC) remains one of the most prevalent and deadliest cancers. Current major advancements have impacted the management of patients with advanced HCC substantially improving their life expectancy. Several systemic therapies have resulted in positive III investigations (atezolizumab plus bevacizumab, durvalumab plus tremelimumab, sorafenib, lenvatinib, regorafenib, cabozantinib and ramucirumab) and two additional therapies obtained accelerated FDA approval owing to evidence of efficacy (pembrolizumab and nivolumab plus ipilimumab). Specifically, among TKIs, sorafenib and lenvatininb remain as first line option therapies in patients with contraindications or upon progression to immunotherapies. In second-line, regorafenib, cabozantinib and ramucirumab are the accepted choices. Few studies suggest that biomarkers or treatment related-AEs are associated with better outcome, as it is the case with hand-foot skin reaction with sorafenib, or AFP&amp;gt; 400 ng/ml or hypertension for ramucirumab. The fact that most HCC do not have a dominant actionable target has prevented precision oncology. Nonetheless, current studies are exploring abrogating main drivers previously unactionable, such as wnt signaling. The fact that TKI and VEGF-based MAb have also immunomodulatory activities has boosted their combination with immune therapies which nowadays are dominant in the landscape of management of HCC and ongoing phase III trials. Citation Format: Josep M. Llovet. Molecular targeted therapies for advanced HCC [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA11.

Efficacy and safety of apatinib in advanced refractory soft tissue sarcoma and association with histologic subtypes: a multicenter retrospective study.

BackgroundAntiangiogenic therapy is a potential strategy against advanced refractory soft tissue sarcoma (STS). This retrospective study aimed to assess the efficacy and safety of apatinib in patients with advanced refractory STS and explore its clinical effect on the different histologic subtypes.MethodsPatients with pathologically diagnosed and metastatic STS who had failed at least standard chemotherapy and were naive to angiogenesis inhibitors were enrolled in this multicenter respective study. Apatinib was administered orally at a dosage of 250 to 850 mg/day. The primary endpoints were objective response rate (ORR) and disease control rate (DCR). The secondary endpoints were progression free survival (PFS) and overall survival (OS). Tumor assessment was done after the first 4 weeks and every 8 weeks thereafter.ResultsTwenty-six patients were enrolled from seven centers between December 2015 and December 2020, consisting of 9 leiomyosarcomas (LMS), 4 rhabdomyosarcomas (RMS), 3 undifferentiated pleomorphic cell sarcomas (UPS), 3 fibrosarcomas (FS), 3 alveolar soft part sarcomas (ASPS), 2 angiosarcomas (AS) and 2 synovial sarcomas (SS). The median age was 49.0 [26–77] years, 15 females and 11 males. The ORR was 34.62% [9/26, 95% confidence interval (CI): 19.42–53.78%] and DCR was as high as 84.62% (22/26, 95% CI: 66.47–93.85%). The median progression-free survival and overall survival were 6.0 months (95% CI: 2.42–9.58) and 19.3 months (95% CI: 7.31–31.29) respectively. Furthermore, 181 patients from seven studies as well as this trial were included for pooled analysis of apatinib efficacy dependency on histology. In terms of ORR, RMS (41.7%), ASPS (78.6%), and Ewing sarcoma (40.7%) seemed to benefit more than the other histologic subtypes. Common adverse events (AEs) included hand-foot skin reaction (n=13, 50.0%), hypertension (n=12, 46.15%), proteinuria (n=10, 38.46%). Seven patients (7/26, 26.92%) had grade 3 AEs and no grade 4 AEs occurred. 2 patients (2/26, 7.69%) and 15 patients (15/26, 57.69%) experienced dose withdrawal and dose reduction respectively.ConclusionsApatinib showed promising efficacy and a manageable safety profile in patients with advanced refractory STS. In addition, the response to apatinib in STS seemed to be dependent on histology.

Hepatic arterial infusion chemotherapy plus regorafenib in advanced colorectal cancer: a real-world retrospective study

BackgroundHepatic arterial infusion chemotherapy delivers the drug directly to the liver. We aim to explore the benefits and tolerability of Hepatic arterial infusion chemotherapy plus regorafenib in advanced colorectal liver metastasis refractory to standard systemic chemotherapy.MethodsThis study analyzed 47 patients treated with hepatic arterial infusion chemotherapy plus regorafenib after standard systemic oxaliplatin and/or irinotecan in combination with bevacizumab or cetuximab between Jan 2017 and Jun 2020. Regorafenib was given for only 3 weeks in a 4-week cycle.ResultsAmong 47 patients, 32 (68%) were males. The median age was 61 (29–75). With a median follow-up of 22.2 months (3.7–50.7 months). Before Hepatic arterial infusion chemotherapy administration in combination with regorafenib, 34 (72.3%) patients previously received ≥ 2 prior lines of systemic therapy and 37 (78.7%)patients previously received targeted biological treatment (anti-VEGF or anti-EGFR, or both). The initial doses of regorafenib were 40 mg/d (n = 1, 2.13%), 80 mg/d (n = 11, 23.43%), 120 mg/d (n = 2, 4.26%), and 160 mg/d (n = 23, 48.94%), while for 24.6% (n = 14) dose was unknown. Median Overall Survival was 22.2 months. Median Progression-Free Survival was 10.8 (95% CI: 9.0–13.7) months. Common Adverse Events were hand-foot skin reaction (12.77%), fatigue (6.38%), vomiting (6.38%), and decreased appetite (6.38%). Only 2 patients discontinued regorafenib due to Adverse Events.ConclusionsRegorafenib combined with Hepatic arterial infusion was effective and tolerable in patients with liver predominant metastasis of colorectal cancer. Hence, this therapy can be considered as an alternative for second- or subsequent lines of therapy in patients refractory to standard systemic chemotherapy.

Real-World Single-Center Clinical Data on Sorafenib in Patients with Unresectable Hepatocellular Carcinoma

"Introduction. Hepatocellular carcinoma (HCC) is a malignant tumor that frequently develops in conjunction with chronic liver disease and cirrhosis, and is often identified late in its course, with a median survival of around 6 to 20 months following diagnosis. Although surgical excision is the gold standard of treatment, most patients are ineligible due to tumor size or underlying liver dis-ease. The hepatic reserve of the patient, as determined by the Child-Turcotte-Pugh classification, frequently influences treatment options. Method. Between January 2016 and June 2018, 42 patients admitted to Fundeni Clinical Institute's Department of Medical Oncology who had previously been treated with Sorafenib for more than two months were recruited in this retrospective analysis. We evaluated the etiology and stage of illness (BCLC), residual liver function (CHILD), performance status (ECOG), treatment response and side effects, progression-free survival, and overall survival. Results. The study group had good short and long-term outcomes: median progression-free survival was 7.7 months and median overall survival was 11.6 months. The most frequently reported adverse effects were skin rashes, diarrhea, hypertension, and hand-foot skin reaction. Conclusion. This retrospective, single-center study confirmed the benefit of sorafenib in the treatment of advanced HCC, particularly in patients with good liver function and performance status. Method. Between January 2016 and June 2018, 42 patients admitted to Fundeni Clinical Insti-tute's Department of Medical Oncology who had previously been treated with Sorafenib for more than two months were recruited in this retrospective analysis. We evaluated the etiology and stage of illness (BCLC), residual liver function (CHILD), performance status (ECOG), treatment response and side effects, progression-free survival, and overall survival. Results. The study group had good short and long-term outcomes: median progression-free survival was 7.7 months and median overall survival was 11.6 months. The most frequently-re-ported adverse effects were skin rashes, diarrhea, hypertension, and hand-foot skin reaction. Conclusion. This retrospective, single-center study confirmed the benefit of sorafenib in the treatment of advanced HCC, particularly in patients with good liver function and performance sta-tus"

Prophylactic strategies for hand-foot syndrome/skin reaction associated with systemic cancer treatment: a meta-analysis of randomized controlled trials.

Hand-foot syndrome (HFS) and hand-foot skin reaction (HFSR) are common toxicities of several systemic cancer treatments. Multikinase inhibitor-induced HFSR is distinguished from chemotherapy-induced HFS in terms of pathogenesis, symptomatology, and treatment. Multiple trials have investigated the efficacy of preventive strategies such as COX-inhibitors, pyridoxine, and urea cream; however, no consensus has been made. This meta-analysis evaluated data from high-quality trials to provide strong evidence in forming recommendations to prevent systemic cancer therapy-induced HFS/HFSR. A systematic search of PubMed, Embase, Cochrane, clinical trials databases, and hand searching were utilized to identify randomized trials (RCTs) investigating prophylactic strategies for HFS/HFSR in cancer patients receiving systemic treatment. Trials published until August 2021 were included. Using the random effects model, pooled odds ratios were calculated for rates of all-grade and severe HFS/HFSR. Subgroup analysis based on type of cancer treatment given was done. Sixteen RCTs were included (N=2814). For all-grade HFS/HFSR, celecoxib (OR 0.52, 95% CI 0.32-0.85, p=0.009) and urea cream (OR 0.48, 95% CI 0.39-0.60, p<0.00001) both showed statistically significant risk reduction. Celecoxib was effective in preventing HFS in patients who received capecitabine (50.5% vs 65%, p=0.05), while urea cream was effective in both capecitabine HFS (22.3% vs 39.5%, p=0.02) and sorafenib-induced HFSR (54.9% vs 71.4%, p<0.00001). Pyridoxine at higher doses showed a trend towards benefit in preventing all grade HFS (69.6% vs 74.1%, p=0.23). Urea cream and celecoxib are both effective in preventing HFS/HFSR in patients receiving systemic cancer treatment. Particularly, celecoxib is more effective in preventing all-grade capecitabine-induced HFS, while urea cream shows more benefit in preventing moderate to severe sorafenib-induced HFSR. Studies investigating optimal dosing for celecoxib and urea cream are recommended. There is inadequate evidence to make recommendations regarding pyridoxine.

Development of hand-food skin reaction correlates with prognosis of patients with HCC who were treated with sorafenib.

e16171 Background: Sorafenib is one of the effective systemic therapy in patient with advanced hepatocellular carcinoma (HCC). However, there are few prospective studies that have examined prognostic factors of sorafenib response. In this study, we analyzed prognostic factors of HCC patients who were treated with sorafenib. Methods: Between May 2016 and May 2018, 288 advanced HCC patients treated with sorafenib were enrolled at 13 hospitals. We analyzed possible prognostic factors of sorafenib response (overall survival and progression free survival) using Univariate and Multivariate analyses with Cox proportional hazards regression model. Results: Among the 288 patients, chronic hepatitis B (68.4%) was main cause in development of HCC. 85.4% of patients were in the advanced stage of Barcelona Clinic Liver Cancer. Hand-foot skin reactions (HFSR) were observed in 142 patients (49.2%). The univariate analysis identified presence of ascites, serum albumin level and creatinine level, presence of HFSR as potential prognostic factors for overall survival (OS). In multivariate analysis for OS, presence of HFSR (HR 0.144; 95% CI: 0.063-0.330, p 0.002), albumin level (HR ratio 0.283; 95% CI: 0.148-0.544, p &lt; 0.001), creatinine level (HR 1.395; 95% CI 1.133-1.717, p 0.002) were significant factors of OS. In univariate and multivariate analysis, presence of HFSR (HR 0.212; 95% CI: 0.091-0.495, p &lt; 0.001), and serum albumin level (HR 0.30, 95% CI: 0.158-0.568, p &lt; 0.001) were show significant correlation with progression free survival. Conclusions: Developing HFSR from sorafenib therapy and high serum albumin level were associated with improved OS and PFS. Developing HFSR have been suggested as possible predictor of good sorafenib response. Clinical trial information: NCT03212625.

Adjuvant gemcitabine plus cisplatin (GemCis) versus capecitabine (CAP) in patients (pts) with resected lymph node (LN)-positive extrahepatic cholangiocarcinoma (CCA): A multicenter, open-label, randomized, phase 2 study (STAMP).

4019 Background: Adjuvant CAP is the standard of care for resected CCA according to the BILCAP trial. However, the prognosis of patients with resected CCA is still poor. As GemCis is the standard first-line therapy for unresectable/metastatic BTC, we investigated the role of adjuvant GemCis in resected BTC. Because BTC is heterogeneous disease according to the primary tumor site, this study included only pts with resected LN+ extrahepatic CCA. Methods: STAMP is a multicenter, open-label, randomized phase 2 study. Pts with ≥ 19 years, ECOG PS 0/1, adenocarcinoma of perihilar or distal bile duct, at least one regional LN metastasis (N1 or greater), complete macroscopic (R0 or R1) resection within 12 weeks before randomization were eligible. Distant metastasis or R2 disease, previous chemotherapy or radiotherapy, or a serum CA 19-9 level ≥ 100 U/mL were ineligible. Pts were randomized 1:1 to GemCis (Gem 1,000 mg/m2 IV, and Cis 25 mg/m2 IV on day 1 and 8, every 3 weeks) or CAP (1,250 mg/m2 orally twice daily on days 1-14, every 3 weeks) for 8 cycles. Tumor response was performed every 12 weeks for the first 2 years, followed by every 24 weeks for the next 3 years. Primary endpoint was disease-free survival (DFS). Secondary endpoints were overall survival (OS) and safety. This study was designed to improved 2-year DFS rates from 22% (CAP) to 40% (GemCis). Considering follow-up loss rates of 10% with a 1-sided type I error of 0.1 and a type II error of 0.2, a total of 100 patients (50 in each arm) were required. Results: Between JUL 2017 and NOV 2020, a total of 101 pts (50 for GemCis group and 51 for CAP group) were included in the ITT population. Perihilar and distal bile duct were primary tumor sites in 45 pts (44.6%) and 56 pts (55.4%), respectively and 32 pts (31.7%) had R1 resection. Pts characteristics were well balanced between two arms. With median follow-up duration of 28.7 mo (IQR 17.2-39.4), the 2-year DFS rates were 38.5% (1-sided 90% CI, 29.5-47.4%) in GemCis group and 25.1% (17.4-33.5%) in CAP group. The median DFS were 14.3 mo (10.7-16.5 mo) in GemCis group and 11.1 mo (8.4-12.7 mo) in CAP group (HR=0.96 [0.71-1.30], p=0.86). The median OS were 35.7 mo (29.5 mo-not estimated [NE]) in GemCis group and 35.7 mo (30.9 mo-NE) in CAP group (HR=1.08 [0.72-1.64], p=0.81). Grade 3-4 adverse events (AEs) occurred in 42 pts (84.0%) and 8 (16.0%) in GemCis and CAP groups, respectively. The most common AE of grade 3-4 was neutropenia (n = 36, 72.0%) in GemCis group and hand-foot skin reaction (n = 4, 8.0%) in CAP group. Conclusions: In this study including prognostically homogeneous pts population, GemCis was feasible as adjuvant therapy, but failed to improve survival outcomes compared to CAP. CAP should remain standard adjuvant therapy for resected BTC. Clinical trial information: NCT03079427.

Lenvatinib plus hepatic arterial infusion of modified FOLFOX regime(FOHAIC) in patients with BCLC stage C hepatocellular carcinoma.

e16000 Background: Lenvatinib is the first-line TKI treatment for BCLC stage C hepatocellular carcinoma (HCC) with better objective response rate (ORR) and longer progression free survival (PFS) than sorafenib, but the prognosis is still unsatisfactory. Hepatic arterial infusion chemotherapy of modified FOLFOX regime (FOHAIC) has shown promising results for patients with advanced HCC. This study aimed to update the result of efficacy and safety for lenvatinib plus FOHAIC in patients with BCLC stage C hepatocellular carcinoma. Methods: This was a retrospective study including 46 patients from Nov 2018 to April 2021 Patients with BCLC stage C hepatocellular carcinoma. Patients were treated with 8 mg(≤60kg) or 12mg(&gt; 60kg) lenvatinib once daily initially and FOHAIC (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, fluorouracil bolus 400 mg/m2 on day 1, and fluorouracil infusion 2400 mg/m2 for 46 hours, every 3 weeks). Best response according to the RECIST 1.1 and mRECIST criteria. PFS, overall survival (OS) and treatment-related adverse events(TRAE) were also evaluated. Results: 46 patients(median age: 54.9 years) underwent a total of 223 cycles of HAIC therapy (mean: 4.8 cycles). 43 (93.5%) patients with HBV infection.35(76.1%). Patients were diagnosed with vascular invasion. 45 (97.8%) patients were classified as Child-pugh A class and 1 (2.2%) patients were Child-pugh B class. The ORR were 58.7% (RECIST 1.1, 27 of 46) and 76.1% (mRECIST, 35 of 46), the disease control rate (DCR) was 93.5% (RECIST 1.1/mRECIST). With a median follow-up period of 14.9 months, the median PFS and median OS were 15.9 months and 27.9 months, respectively.TRAE occurred in 36 of 46 patients (78.3%), most common TRAE were hypertension (41.3%), diarrhea (34.8%), fatigue(34.8%), abdominal pain(32.6%), hand-foot skin reaction(23.9%),and weight loss(19.6%). The grade 3/4 TRAE were more frequent in abdominal pain(8.7%), hypertension (6.5%) and diarrhea(6.5%). Conclusions: This study demonstrated that lenvatinib plus FOHAIC had acceptable toxic effects and shown promising ORR, PFS and OS in BCLC stage C hepatocellular carcinoma. Warrants its further investigation in a large-scale trial.[Table: see text]

Anlotinib in radioactive iodine-refractory differentiated thyroid cancer and the usefulness of SUVmax as an prognostic indicator.

e18077 Background: Radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC) is characterized by poor therapeutic effect on radioactive iodine with poor prognosis. Therefore, a variety of molecularly targeted drugs are used in the treatment of RAIR-DTC. However, sorafenib and lenvatinib are not “broad-spectrum” anti-cancer drugs for RAIR-DTC. The efficacy and safety of Anlotinib in the treatment of RAIR-DTC need to be studied. Methods: From September 2020 to September 2021, 9 patients with RAIR-DTC were included. Follow-up continued until disease progression or intolerable adverse events occurred. Efficacy was evaluated by serum triglycerides (Tg) and imaging (RECIST1.1). Adverse events were also recorded. Gender, age, maximum standard unit value (SUVmax), tumor metabolic volume (MTV), total glycolysis (TLG), pathological type and tumor stage were included in the univariate analysis. Results: 8 patients reached the standard of “partial biochemical remission”. The average Tg level of these 8 patients decreased by 74.8% after Anlotinib treatment. 15 target lesions (TLs) were found in 6 patients. The average reduction ratio of TLs in these 6 patients was 28.7%. Furthermore, we observed three (50%) PR, three (50%) SD, with an ORR of 50% and a DCR of 100% in these 6 patients. The severity of AEs in all 9 patients did not exceed Grade 2. The most common AEs were hand-foot skin reactions, diarrhea, and hypertension, which accounted for 5/9, 3/9, and 3/9, respectively. Serious drug-related AEs did not occur. The average decrease in Tg after 3 courses was significantly greater in the high metabolism group (TL SUVmax 27.9) compared with the average decrease in the low metabolism group (TL SUVmax &lt; 7.9), with 83.25% and 16.11% respectively (p = 0.027). There was no correlation between age, gender, pathological type, staging, other metabolic indexes of PET/CT and the ratio of patients' Tg reduction. Conclusions: Anlotinib can be used for the treatment of RAIR-DTC. This study confirmed the efficacy of Anlotinib with a high disease control rate. SUVmax can be used as an indicator to predict the therapeutic effect of Anlotinib in RAIR-DTC patients.

Efficacy and safety of sequential therapy with sorafenib and regorafenib for advanced hepatocellular carcinoma: a two-center study in China.

Regorafenib is a standard 2nd-line treatment for patients with advanced hepatocellular carcinoma (HCC), but the efficacy and safety of sequential therapy with sorafenib and regorafenib among advanced HCC patients in China is not clear. This was a retrospective, two-center, cohort study of advanced HCC patients who received sequential therapy of sorafenib and regorafenib from October 2018 to April 2020 at 2 Chinese institutions. The patients were converted directly to regorafenib after failing to respond to sorafenib monotherapy. The patients underwent evaluations every 4-6 weeks to determine the efficacy and safety of the treatment according to physiological, laboratory, and radiological results. A radiological evaluation using computed tomography or magnetic resonance imaging scans was conducted. The outcomes included overall survival (OS) and progression-free survival (PFS). A total of 43 patients received regorafenib as a 2nd-line treatment after sorafenib progression. Of these patients, 26 (60.5%) and 17 (39.5%) were diagnosed with Barcelona Clinic Liver Cancer (BCLC) stages B and C, respectively. The median PFS was 11.0 [95% confidence interval (CI): 5.8-16.2] months, and the median OS was 17.0 (95% CI: 12.8-21.2) months. Conversely, the most common toxicities were hand-foot skin reaction (48.8%), diarrhea (32.6%), and hypertension (14%). The most common grade 3-4 toxicities were hypoalbuminemia (4.7%), anemia (4.7%), and thrombocytopenia (4.7%). Alpha-fetoprotein (AFP) ≥400, alanine transaminase (ALT) ≥60 IU/L, and aspartate aminotransferase (AST) ≥60 IU/L before 2nd-line treatment were associated with PFS in the univariable analyses. The Cox proportional-hazards regression analysis showed that AFP [hazard ratio (HR) =0.225; 95% CI: 0.073-0.688; P=0.009], ALT (HR =0.195; 95% CI: 0.051-0.741; P=0.016), AST (HR =0.209; 95% CI: 0.063-0.697; P=0.011), and presence of extrahepatic metastasis (HR =0.074; 95% CI: 0.009-0.608; P=0.015) before 2nd-line treatment were independently associated with PFS. The sequential therapy of sorafenib and regorafenib is well-tolerated and effective in advanced HCC patients after sorafenib progression based on our two-center real-world data. Patients with good liver function reserve and a high level of AFP before 2nd-line treatment may benefit from sequential treatment. These results still need further validation.

The efficacy and safety of apatinib in patients with recurrent or metastatic nasopharyngeal carcinoma: a systematic review and meta-analysis.

BackgroundApatinib is a small-molecule tyrosine kinase inhibitor targeting VEGFR-2, which was recently used in a phase II clinical trial for the treatment of recurrent or metastatic nasopharyngeal carcinoma (rmNPC). However, there is no consistent conclusion on its efficacy and safety on rmNPC. This study conducted a meta-analysis of clinical research on the efficacy and safety of apatinib in the treatment of rmNPC.MethodsIn April 2022, the PubMed, Web of Science, Scopus, Chinese National Knowledge Infrastructure (CNKI), CMB, and Wanfang databases were systematically searched, and relevant research literature were screened and analyzed. The clinical trial literatures using apatinib as the main single or combined treatment for rmNPC patients were selected and combined with objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and other efficacy and safety indicators.ResultsThe meta-analysis included 12 studies, including 408 patients with rmNPC. The methodological index for nonrandomized studies scale was used to evaluate the bias of the included literatures and found that the bias was low. A total of 408 rmNPC patients were included in the included literature, with 11 studies being a phase II single-arm trial and one being a phase II non-randomized controlled trial. The ORR of patients with rmNPC treated with apatinib was 41.5% (95% CI: 34.8%, 48.2%), and the DCR was 80.2% (95% CI: 70.9%, 89.6%). The median PFS was 6.4 months (95% CI: 5.3, 7.4), and the median OS was 14.8 months (95% CI: 10.7, 18.9). The incidence of hypertension, hand-foot skin reaction, and proteinuria was 31% (95% CI: 19–43%), 29% (95% CI: 20–39%), and 13% (95% CI: 6–20%), respectively.DiscussionThe efficacy of apatinib in the treatment of rmNPC patients is similar to that of the previous second-line chemotherapy drugs, but since most studies are phase II single-arm studies, the advantages and disadvantages of the existing second-line chemotherapy regimens cannot be determined.

Toxicities of anti-VEGF therapies used in metastatic renal cell carcinoma: A real-world experience.

e16533 Background: Tumor endothelial proliferation inhibition using vascular endothelial growth factor-tyrosine kinase inhibitors (VEGF-TKIs) have revolutionized metastatic renal cell carcinoma (mRCC) therapy. We retrospectively analyzed data on various anti-VEGF adverse events (AEs) utilizing the FDA Adverse Events Reports System (FAERS). Methods: We examined the FAERS public dashboard data on VEGF inhibitors’ reported AEs for the years 2019-2021. Data analyzed using descriptive statistics. Results: A total of 34,651 AEs were identified for anti-VEGF therapies, of which 29,328 (84.6%) were serious and 5,830 (16.82%) reported deaths (Table). Lenvatinib has most reported serious hemorrhagic events and thyroid impairment in 5.5% and 1.2%, respectively, and least (3.4%) reported dermatologic toxicity (including Hand-foot skin reaction, depigmentation, and rash. Cabozantinib has most (2.8%) reported gastrointestinal (GI) perforation and fistula. Pazopanib has most bone marrow suppression (BMS)—neutropenia, leukopenia, thrombocytopenia, and anemia (43.3%), dermatologic toxicity (25.8%), hepatotoxicity—jaundice, elevated transaminases, hyperbilirubinemia, hepatic encephalopathy, coagulopathy, ascites, and/or hepatorenal syndrome (23.9%), arterial thromboembolic events (ATE)—comprising cerebral infarction, ischemic stroke, transient ischemic attack, myocardial infarction, angina (19.8%), proteinuria and nephrotic syndrome (NS; 10.4%), pulmonary toxicity—interstitial lung disease, and pneumonitis (7.2%), posterior reversible encephalopathy syndrome (PRES; 4.9%), cardiotoxicity—cardiac failure (3.1%), and tumor lysis syndrome (TLS; 0.9%). Sunitinib has most reported osteonecrosis of the jaw AEs (ONJ; 37.3%), QT Prolongation and various arrhythmias (11.9%), severe hypertension (SHTN—including accelerated, urgency, and emergency; 10.0%), and aortic complications—including aortic aneurysm, dissection, and rupture (3.1%). Conclusions: Pazopanib has most while axitinib has least reported BMS, ATE, and pulmonary AEs. Cabozantinib has most reported GI AEs and sunitinib has most reported ONJ, SHTN, QT prolongation, arrhythmias, and aortic complications. With expanding treatment landscape for mRCC, this study helps shed light on the different anti-VEGF toxicity profiles and would therefore support treatment decision making.

P-44 Impact of regorafenib dose optimization on clinical outcomes compared to best supportive care and TAS-102 in the treatment of relapsed/refractory metastatic colorectal cancer

In a randomized controlled trial (RCT) ReDOS of relapsed/refractory metastatic colorectal cancer (mCRC) patients, regorafenib dose optimization (rego 80+), starting at 80 mg/day with 40 mg weekly increments to the standard dose of 160 mg/day, was found to improve tolerability and clinical outcomes compared to regorafenib at standard dose (rego 160), 160 mg/day for 21 days of a 28-day cycle. This network meta-analysis (NMA) aims to further investigate the impact of rego 80+ on efficacy and safety compared to best supportive care (BSC) and trifluridine/tipiracil (TAS-102). RCTs included in the NMA were identified via a systematic literature review conducted in April 2021. A feasibility assessment was performed to ensure that the included trials did not differ significantly with respect to treatment effect modifiers. Bayesian fixed effect NMAs were performed to simultaneously synthesize hazard ratios (HRs) for overall survival (OS) and progression-free survival (PSF) and odds ratios for safety endpoints of interest, and their respective 95% credible intervals (Crl). The HRs from the NMA were applied to the rego 80+ OS and PFS Kaplan Meier Curves from the ReDOS trial to estimate predicted median OS and PFS for each treatment. Three global or US-only RCTs (ReDOS, CORRECT, RECOURSE) and three Asian-only RCTs (TERRA, Yoshino 2012, and CONCUR) were included in the NMA. When all trials were analyzed, rego 80+ was associated with statistically significant improvements in OS and PFS vs. BSC (HR [95% CrI]: 0.49 [0.33, 0.73] and 0.35 [0.24, 0.53], respectively) and numerically favorable improvements in OS and PFS vs. rego 160 (0.72 [0.49, 1.05] and 0.84 [0.56,1.25]), and TAS-102 (0.71 [0.47, 1.08] and 0.78 [0.52, 1.18]). Median OS (95% confidence interval [CI]) was estimated to be 9.8 (7.5, 11.9) months for rego 80+, 7.5 (4.6, 11.9) months for rego 160, 7.5 (4.4, 11.9) months for TAS-102, and 6.4 (2.5, 10.3) months for BSC. Median PFS (95% CI) was 2.80 (2.0, 2.5) months for rego 80+, 2.07 (1.89, 5.85) months for rego 160, 1.98 (1.8, 5.76) months for TAS-102, and 1.89 (1.17, 2.16) months for BSC. For grade 3+ adverse events (AEs), BSC was the most favorable, with the exception of increased aspartate transaminase (AST). Compared to rego 160, rego 80+ was numerically favorable in all AEs analyzed including hand-foot skin reactions (HSFR), diarrhea, fatigue, hypertension, and increased AST. Compared to TAS-102, rego 80+ had higher incidence of HSFR, comparable fatigue and hypertension, and numerically lower incidence of diarrhea, increased AST, neutropenia, febrile neutropenia, leukopenia, and anemia. All NMA findings were consistent when Asian-only trials were excluded from the analyses. Findings from this NMA indicate that rego 80+ provides additional survival benefits (over standard dose rego 160) when compared to BSC and TAS-102; with gains of median OS of 3.4 months (∼50% risk reduction), and 2.3 months (∼30% risk reduction), respectively. Results also suggest that rego 80+ delays disease progression in comparison. With its more favorable safety profile, rego 80+ should be considered a preferred option for optimizing clinical outcomes in patients with relapsed/refractory mCRC.

Prospective phase II study of sunitinib rechallenge in metastatic renal cell carcinoma: The “retry” study from the Italian Group of Onco-Nephrology (G.I.O.N.)

Background: Sunitinib is still a recommended treatment option for metastatic renal cell carcinoma (RCC) patients; lack of cross-resistance to sequential antiangiogenic drugs has been postulated. Objective: The possibility of a successful rechallenge with sunitinib was tested in this prospective phase II trial. Methods: Main inclusion criteria were: histologically proven RCC with clear cell component, previous first-line sunitinib with a Disease Control Rate lasting ⩾10 months, and second-line everolimus. The primary end-point was 6-months progression-free survival (PFS). A Simon’s 2-stage design was used; after testing sunitinib on 12 patients, the trial would have been terminated if ⩽5 had a PFS &lt;6 months. Otherwise, the trial would have proceeded enrolling a total of 38 patients. If the total number of patients free of progression at 6 months would have been ⩽18, sunitinib would have been rejected. Results: A total of 39 patients (30 males, 9 females) were enrolled. The study reached the second stage, and ultimately succeeded; indeed, 6-months PFS was 64.1%, median PFS being 14.9 months (95% confidence interval: 9.06–20.91). Treatment-related grade 3–4 adverse events observed in ⩾5% of the patients were: hand-foot skin reaction, fatigue, nausea, hypertriglyceridemia, hypophosphatemia, hypocalcemia, hyperglycemia, and neutropenia. One case each of myocardial infarction, atrial flutter, and spontaneous pneumothorax, were also reported. Conclusions: Despite an ineluctable time-lead-bias, median PFS on sunitinib rechallenge was high, clearly showing that many patients may become sensitive again to antiangiogenic treatment. In countries where treatment options are still limited, sunitinib rechallenge could represent an option. EudraCT number: 2012-000473-23.

Real-World Data: Fruquintinib in Treating Metastatic Colorectal Cancer.

Fruquintinib, also called HMPL-013, was first discovered by Hutchison Whampoa Pharmaceuticals Co. Ltd., Shanghai, China, and it is an oral vascular endothelial growth factor receptor (VEGFR) inhibitor. In clinical trials, fruquintinib has demonstrated a survival benefit in metastatic colorectal cancer (mCRC) patients. The purpose of this study was to retrospectively evaluate the efficacy and toxicity of fruquintinib in real-world patients. We collected data from patients with mCRC treated with oral fruquintinib from 2018 to 2020 in six different institutions. Patients with mCRC initially received 5 mg of oral fruquintinib daily for 3 weeks. Progression-free survival (PFS) was evaluated using the Kaplan–Meier method. The efficacy and safety of fruquintinib were also assessed. Seventy-five patients were involved in our study, and 29.3% of patients achieved stable disease (SD). Median PFS was 5.4 months (95% CI: 4.841–5.959). The treatment-emergent adverse events (TEAEs) with fruquintinib were acceptable with grade 3 TEAEs of 6%. The grade 3 TEAEs were hand–foot skin reaction (HFSR), fatigue, and stomatitis. The ECOG performance status was associated with PFS. In this real-world study, the clinical activity of fruquintinib was consistent with what has been reported in previous clinical trials. The level of safety was acceptable, and the side effects were manageable.