Efficacy of aluminum chloride in severe regorafenib-associated hand-foot skin reactions: a single-arm trial.

BACKGROUND: Regorafenib, a multikinase inhibitor, causes a high frequency of hand-foot skin reactions (HFSRs). The present study evaluated the efficacy of topical aluminum chloride, a perspiration suppressant, in reducing the severity of hand-foot skin reactions (HFSRs) caused by regorafenib. METHODS: The present single-arm study included patients with metastatic colorectal cancer receiving regorafenib. Aluminum chloride ointment was applied topically one week prior to the start of regorafenib treatment, and the observation period was 12 weeks. The primary endpoint was the incidence of regorafenib-related grade 3 HFSR. Secondary endpoints were the incidence of all grades of HFSR, time to any grade of HFSR, time to improvement from grade 2 or higher to grade 1 or lower, treatment discontinuation rate, treatment interruption rate or dosage reduction due to HFSR, and incidence of adverse effects of aluminum chloride. RESULTS: In total 28 patients were enrolled, and 27 patients were analyzed. The incidence of grade 3 HFSR was 7.4%, meeting the primary endpoint. The incidence of all grades of HFSR was 66.7%, and the median time to the occurrence of any grade of HFSR was 15 days. No patients discontinued or reduced the regorafenib dosage because of HFSR. The most common reason for the interruption of regorafenib therapy was liver dysfunction in nine patients (33%) and HFSR in three patients (11%). No serious adverse events related to aluminum chloride were observed. CONCLUSIONS: Aluminum chloride ointment, a drug commonly used in routine practice to treat hyperhidrosis, is safe to use, has no serious side effects, and may be effective in reducing the occurrence of severe, regorafenib-related HFSR. TRAIL REGISTRATION: ClinicalTrials.gov. identifier: jRCTs031180096, Registered on 25/01/2019.

A phase I trial of riluzole and sorafenib in patients with advanced solid tumors: CTEP #8850.

BACKGROUND: Overexpression of metabotropic glutamate receptor 1 (GRM1) has been implicated in the pathogenesis of multiple cancers. Riluzole, an inhibitor of glutamate release, showed synergistic antitumor activity in combination with the multi-kinase inhibitor sorafenib in preclinical models. This phase I trial identified the toxicity profile, dose-limiting toxicities, maximum tolerated dose (MTD), and pharmacokinetic and pharmacodynamic properties of riluzole combined with sorafenib in patients with advanced cancers. PATIENTS AND METHODS: Patients with refractory solid tumors were enrolled utilizing a 3+3 dose-escalation design. Riluzole was given at 100 mg PO BID in combination with sorafenib, beginning at 200 mg PO daily and escalating in 200 mg increments per level in 28-day cycles. Restaging evaluations were performed every 2 cycles. RESULTS: 35 patients were enrolled over 4 dose levels. The MTD was declared at dose level 3 (riluzole: 100 mg PO BID; sorafenib: 400 mg AM/200 mg PM). Pharmacokinetic analyses did not reveal definitive evidence of drug-drug interactions. Consistent decreases in phospho-forms of ERK and AKT in tumor tissue analyses with accompanying decrease in GRM1 expression and increase in pro-apoptotic BIM suggest target engagement by the combination. Best responses included a partial response in 1 (2.9%) patient with pancreatic acinar cell carcinoma with a KANK4-RAF1 fusion, and stable disease in 11 (36%) patients. CONCLUSION: Combination therapy with riluzole and sorafenib was safe and tolerable in patients with advanced solid tumors. The partial response in a patient with a RAF1 fusion suggests that further exploration in a genomically selected cohort may be warranted.

Lenvatinib Plus Pembrolizumab in Previously Treated Advanced Endometrial Cancer: Updated Efficacy and Safety From the Randomized Phase III Study 309/KEYNOTE-775.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We report the final prespecified analysis for overall survival (OS), along with updated progression-free survival (PFS) and objective response rate (ORR), and safety from the open-label, randomized, phase III Study 309/KEYNOTE-775. In total, 827 patients with advanced, recurrent, or metastatic endometrial cancer (EC) were randomly assigned to receive lenvatinib 20 mg orally once daily plus pembrolizumab 200 mg intravenously once every 3 weeks (n = 411) or chemotherapy of the treating physician's choice (doxorubicin 60 mg/m2 intravenously once every 3 weeks or paclitaxel 80 mg/m2 intravenously once weekly [3 weeks on; 1 week off] [n = 416]). Efficacy was reported for patients with mismatch repair proficient (pMMR) tumors and all-comers, and by subgroups (histology, prior therapy, MMR status). Updated safety was also reported.Lenvatinib plus pembrolizumab showed benefits in OS (pMMR HR, 0.70; 95% CI, 0.58 to 0.83; all-comer HR, 0.65; 95% CI, 0.55 to 0.77), PFS (pMMR HR, 0.60; 95% CI, 0.50 to 0.72; all-comer HR, 0.56; 95% CI, 0.48 to 0.66), and ORR (pMMR patients, 32.4% v 15.1%; all-comers, 33.8% v 14.7%) versus chemotherapy. OS, PFS, and ORR favored lenvatinib plus pembrolizumab in all subgroups of interest. No new safety signals were observed. Lenvatinib plus pembrolizumab continued to show improved efficacy versus chemotherapy and manageable safety in patients with previously treated advanced EC.

Efficacy and tolerability of sorafenib in desmoid-type fibromatosis: A need to review dose.

BACKGROUND: Sorafenib is currently one of the recommended treatments for symptomatic patients with desmoid-type fibromatosis (DTF). In this study, we aim to assess the clinical efficacy and tolerability of sorafenib in DTF patients. METHODOLOGY: Patients aged>18 years with a histological diagnosis of DTF and who have received sorafenib were enroled in this prospective observational study. Demographic data, clinical profile, the initial dose of sorafenib, treatment-related toxicities, dose modifications, and responses were recorded. The primary objective was to assess the objective response rate (ORR). The secondary objectives were to evaluate progression-free survival (PFS), tolerability, and adverse effects of sorafenib. Response assessment was based on response evaluation criteria in solid tumours 1.1 criteria. Adverse effects were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 criteria. Time to event was calculated by Kaplan-Meier analysis, and survival was compared by log-rank test. Univariate and multivariable cox regression analysis were used to find independent predictors of relapse. RESULTS: A total of 104 patients were enroled in the study. The median age of the study population was 32 (range, 18-81) years, and 66.35% of patients were females. On response assessment, ORR was 46.1% and stable disease was observed in 31.7% patients. ORR was higher in the appendicular site (51.7%) compared to the abdominal site (27.2%). PFS at 1 and 2 years was 86.6% (79.6-92.7%) and 73.7% (62.4-82.8%), respectively. Two-thirds (66.6%) of patients had already received some form of treatment. At the time of analysis, 70 (67.3%) patients were continuing sorafenib. Only 4.8% stopped sorafenib due to progression, 10.5% due to intolerable adverse effects, and 17.3% due to other reasons. The common treatment-related toxicities were hand-foot skin reaction (HFSR) (89.4%), fatigue (79.8%), alopecia (70.1%), and diarrhoea (48.0%). In the patients with a starting dose of ≥400 mg (48.0% of patients), discontinuation was necessitated in 12% of patients, and further dose reduction was required in 58%, while only about 13% required dose reduction or discontinuation at a starting dose of 200 mg (51.9% of patients). Responses were not compromised due to lower starting doses. CONCLUSIONS: Sorafenib has good activity in DTF, but it is associated with significant toxicity. The adverse effect profile is distinct in Indian patients with higher HFSR and alopecia. Due to the high rate of dose reduction/discontinuation with a starting dose of 400 mg, a starting dose of 200 mg may be recommended in Indian patients.

Progressive erythrocytosis under lenvatinib treatment in patients with advanced hepatocellular carcinoma.

PURPOSE: This manuscript reports on the occurrence of early and frequent erythrocytosis in advanced hepatocellular carcinoma (HCC) patients treated with lenvatinib. METHODS: A cohort of 23 patients with advanced HCC, treated with this antiangiogenic drug for at least one month, was retrospectively analyzed. RESULTS: These patients (82.7% men, median age 58.3, cirrhosis in 60.8%) were treated between October 2019 and September 2020 with lenvatinib, as first-line systemic therapy for 82.6% of them. For 20 patients (87%), an early and significant increase in hemoglobin (Hb) level, up to 1.41 g/dL (p < 0.001) was reported and remained elevated. Ten patients (43.5%), all men, reached erythrocytosis (Hb > 16.5 g/dL), 7 were treated with low-dose aspirin for primary thromboprophylaxis and 2 needed phlebotomy. None underwent thromboembolic complications. A significant Hb decrease was observed after treatment discontinuation (p < 0.05). Erythropoietin (EPO) serum levels also increased, which was attributed to HCC after immunostaining for EPO in liver biopsies. The Naranjo adverse drug reaction probability scale documented the relationship between erythrocytosis and lenvatinib and regression at treatment discontinuation. Erythrocytosis was hypothesized to be a class effect of anti-VEGF therapies, the magnitude of which might depend on the IC50 value of each molecule. CONCLUSION: This report documents the frequent occurrence of erythrocytosis during lenvatinib treatment for advanced HCC, likely secondary to EPO secretion by tumor cells through the antiangiogenic activity levatinib. An early and close monitoring of hematologic parameters is, thus, recommended, together with thromboprophylaxis by low-dose aspirin and phlebotomy in case of symptomatic erythrocytosis.

An Investigation of Popping During Radiofrequency Ablation After Lenvatinib Administration for Hepatocellular Carcinoma.

BACKGROUND/AIM: Lenvatinib is available as a molecular target agent for hepatocellular carcinoma (HCC). In this study, we investigated the popping phenomena in patients with HCC who underwent radiofrequency ablation (RFA) after taking lenvatinib. PATIENTS AND METHODS: Fifty-nine patients with HCC between 21-30 mm in diameter and no history of systemic treatment were enrolled in the study. The patients underwent RFA using a VIVA RFA SYSTEM with an ablation tip of 30 mm in length. For the initial lenvatinib administration, 16 patients had an adequate course of treatment and were treated with RFA as add-on therapy (combination group). The other 43 patients were treated by RFA monotherapy (monotherapy group). The popping frequency during RFA was recorded and compared. RESULTS: Popping frequency in the combination group (RFA combined with lenvatinib) was significantly higher than that in the monotherapy group. There was no significant difference between the combination group and the monotherapy group in ablation time, maximum output level, tumour temperature after ablation, or initial resistance value. CONCLUSION: Popping frequency was significantly higher in the combination group. It is possible that the intra-tumour temperature increased rapidly during RFA in the combination group due to the inhibitory effect of lenvatinib on tumour angiogenesis, leading to the occurrence of popping. Further studies are needed to investigate popping after RFA, and precise protocols need to be developed.

Phase II dose titration study of regorafenib in progressive unresectable metastatic colorectal cancer.

Regorafenib has shown significant survival benefit as a salvage therapy for colorectal cancer; however, its starting dose has been controversial in recent studies. Therefore, we conducted a prospective study on the efficacy and safety of the dose reduction of regorafenib to 120 mg. Patients received 120 mg regorafenib once per day for 3 weeks, followed by a 1-week off-treatment period. The primary endpoint was the investigator-assessed disease control rate (DCR). Sixty patients were registered, and the DCR was 38.3% with a median progression-free survival of 2.5 months (95% confidence interval [CI] 1.9-3.7) and median overall survival of 10.0 months (95% CI 6.9-15.2). Common grade 3-4 adverse events were hand-foot skin reaction and hypertension (20.0% each). The results of administration of 120 mg regorafenib as the starting dose are consistent with reports from prior phase III trials, which used starting doses of 160 mg. This lower initiating dose of regorafenib may be beneficial to certain patient populations. This clinical trial was registered in the UMIN Clinical Trials Registry (UMIN-CTR number UMIN000018968, registration date: 10/09/2015).

Regorafenib is suitable for advanced colorectal cancer patients who have previously received trifluridine/tipiracil plus bevacizumab.

Regorafenib is a standard salvage line therapy used for advanced colorectal cancer (CRC). Recently, trifluridine/tipiracil (TFTD) plus bevacizumab also showed promising efficacy as a salvage line therapy for advanced CRC. However, the efficacy and safety of regorafenib for patients with advanced CRC who have previously received TFTD plus bevacizumab is unclear. We retrospectively collected clinicopathologic data from patients with advanced CRC who received regorafenib after TFTD plus bevacizumab in multiple institutions between April 2017 and June 2020.Thirty-four advanced CRC patients who received regorafenib were analyzed. The median age was 66.5 (range 43-81 years), 11 patients were male, and all had an ECOG performance status(PS) of 0 or 1. Twenty-two patients had left-sided tumors, 18 patients had RAS mutants, and 1 patient had a BRAF V600E mutation. The response rate was 0%, and the disease control rate was 31%. The median progression-free survival was 70 days (95% CI: 56-91), and the overall survival was 233 days (95% CI: 188-324). Treatment was discontinued in 32 patients, and 28 (82%) discontinued treatment due to progressive disease. The major grade 3 and4 toxicities were proteinurea (29%), hypertension (26%), hand-foot syndrome(15%), and platelet decrease (6%). Regorafenib after TFTD plus bevacizumab showed efficacy similar to that of the previous study, and no new adverse events were observed.

ALBI Grade Is a Predictive Factor of Lenvatinib Treatment Discontinuation due to Adverse Events in Hepatocellular Carcinoma.

BACKGROUND/AIM: Lenvatinib is a multiple-tyrosine kinase inhibitor used to treat hepatocellular carcinoma (HCC), and its systematic concentration varies according to liver function. The albumin-bilirubin (ALBI) grade is a novel indicator for predicting liver function in patients with hepatic disease. This study aimed to investigate the relationship between ALBI grade and HCC patients' lenvatinib treatment duration. PATIENTS AND METHODS: This is a retrospective cohort study of patients with HCC and Child-Pugh A treated with lenvatinib between April 2018 and December 2019. The baseline liver function was determined using the ALBI grade. The primary outcome was discontinuation owing to adverse events. The risk factors for discontinuation owing to adverse effects were analyzed using logistic regression. RESULTS: This investigation included 48 HCC patients. Patients with ALBI grade 2 had a significantly shorter time of discontinuation due to adverse events than those with grade 1 (p=0.036). However, the time of treatment failure did not differ between the groups. Multiple logistic regression analysis showed that ALBI grade 2 and non-use of antihypertensive drugs were independent factors for discontinuation due to adverse events [odds ratio (OR)=14.1, 95% confidence interval (CI)=1.46-135, p=0.022 and OR=5.48, 95% CI=1.13-23.9, p=0.024, respectively]. CONCLUSION: The ALBI grades may be useful in predicting adverse events caused by lenvatinib in patients with HCC and Child-Pugh A.

Outcomes of the Sequential Treatment of Unresectable Hepatocellular Carcinoma Using Lenvatinib.

BACKGROUND/AIM: The chemotherapeutic landscape for hepatocellular carcinomas (HCCs) has changed dramatically with the availability of several treatment options. This study aimed to assess the long-term outcomes of lenvatinib treatment and analyze its feasibility in the sequential treatment of HCCs. PATIENTS AND METHODS: Eighty-five consecutive patients who received lenvatinib for unresectable HCCs were investigated retrospectively. Survival was assessed based on when the patients were first radiologically diagnosed with progressive disease. Among those with radiologically diagnosed stable or progressive disease at 3 months after lenvatinib administration, the cutoff α-fetoprotein (AFP) ratio (ratio of the AFP level after lenvatinib treatment to the pretreatment AFP level) that was predictive of survival was determined using receiver operating characteristic analysis. RESULTS: The median survival time (MST) was significantly worse among patients diagnosed with progressive disease at 1 month after treatment than among those diagnosed at 2-3 or 3-4 months after treatment [MSTs at 1, 2-3, and 3-4 months: 2.2, 10.2, and 17.3 months, respectively (p<0.001)]. An AFP ratio of 1.36 (computed using the AFP level at 3 months after lenvatinib treatment) was significantly predictive of survival in patients with stable or progressive disease (26.3 vs. 11.3 months, p=0.0024). CONCLUSION: The prognosis of patients on lenvatinib who develop early progressive disease is dismal. Thus, their treatment should be ceased or switched. The 3-month AFP ratio of 1.36 may be a potentially useful cutoff for considering a switch to other treatments in patients radiologically diagnosed with stable or progressive disease.

Lenvatinib Versus Sorafenib in Advanced Hepatic Cell Carcinoma: A Double Center Retrospective Analysis.

BACKGROUND/AIM: We conducted a retrospective analysis in our center (Umberto I Polyclinic) in collaboration with Campus Biomedico Polyclinic to assess the results of the REFLECT study, which was the first study that demonstrated the non-inferiority of Lenvatinib to Sorafenib. PATIENTS AND METHODS: We identified 21 patients affected by advanced hepatocellular carcinoma during the last 3 years who were treated in our centers. They were subdivided according to the treatment administered (Lenvatinib or Sorafenib). Progression-free survival (PFS) and overall survival (OS) were calculated, and subgroups were compared using the log-rank test. Specific predictive and prognostic factors were identified. The safety profile of the two drugs and the collateral effects were evaluated. RESULTS: The OS in patients in the Lenvatinib arm was 19 (months and 12.5 months in the Sorafenib arm. PFS in patients in the Lenvatinib arm was 6 months and 2.5 months in the Sorafenib arm. OS and PFS in patients treated with Lenvatinib were higher in any subcategory analyzed whereas no positive predictors of response to Sorafenib were found. Based on data from literature, the albumin bilirubin index (ALBI) grade was found to be a key prognostic factor. Patients treated with Sorafenib had more adverse events than those treated with Lenvatinib (100% versus 81.8%, respectively). Patients treated with Sorafenib had more frequently hand-foot syndromes, diarrhea, and nausea whereas patients treated with Lenvatinib commonly had hypertension, proteinuria, and weight loss. CONCLUSION: Lenvatinib was found to be better than Sorafenib in terms of both survival and toxicity, in advanced hepatic cell carcinoma patients.

A Phase Ib/II Study of Lenvatinib and Pembrolizumab in Advanced Endometrial Carcinoma (Study 111/KEYNOTE-146): Long-Term Efficacy and Safety Update.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The open-label phase Ib/II Study 111/KEYNOTE-146 of daily lenvatinib 20 mg plus pembrolizumab 200 mg once every 3 weeks showed promising efficacy and tolerable safety in patients with previously treated advanced endometrial carcinoma (EC; primary data cutoff date: January 10, 2019). This updated analysis reports long-term follow-up efficacy and safety data from 108 patients with previously treated EC included in the primary analysis. End points included objective response rate, duration of response, progression-free survival, overall survival, and safety. Investigators performed tumor assessments per immune-related RECIST. At the updated data cutoff date (August 18, 2020), the median study follow-up duration was 34.7 months (95% CI, 30.9 to 41.2), the objective response rate was 39.8% (95% CI, 30.5 to 49.7), and the median duration of response was 22.9 months (95% CI, 10.2 to not estimable). The median progression-free survival and overall survival were 7.4 months (95% CI, 5.2 to 8.7) and 17.7 months (95% CI, 15.5 to 25.8), respectively. Treatment-related treatment-emergent adverse events of any grade occurred in 104 (96.3%) patients. The most common grade ≥ 3 treatment-related treatment-emergent adverse events were hypertension (33.3%), elevated lipase (9.3%), fatigue (8.3%), and diarrhea (7.4%). The results demonstrate extended efficacy and tolerability of lenvatinib plus pembrolizumab in this cohort of patients with previously treated advanced EC.

Tivozanib in Patients with Advanced Renal Cell Carcinoma Previously Treated With Axitinib: Subgroup Analysis from TIVO-3.

BACKGROUND: In phase III TIVO-3 trial, tivozanib improved progression-free survival (PFS) compared to sorafenib for patients with metastatic renal cell carcinoma (mRCC). However, the effectiveness of this drug after exposure to other selective VEGFR agents has not yet been defined. Herein, we characterize the clinical efficacy of tivozanib in patients with mRCC previously treated with axitinib. METHODS: We identified patients from the intention to treat (ITT) population, in the TIVO-3 trial, who received treatment with axitinib before enrolment in the study and evaluated PFS, response rate (RR), and safety. RESULTS: Out of 350 patients, 172 (83:89, tivozanib:sorafenib) had received prior treatment with axitinib in TIVO-3. In this subgroup, PFS was 5.5 months with tivozanib and 3.7 months with sorafenib (HR 0.68). RR was 13% and 8% favoring tivozanib. CONCLUSIONS: Tivozanib is active in the treatment of patients with mRCC who have progressed on prior therapies, including axitinib.

Sorafenib versus nivolumab after lenvatinib treatment failure in patients with advanced hepatocellular carcinoma.

BACKGROUND AND AIM: An optimal sequential anti-hepatocellular carcinoma (HCC) agent that can be used after failed lenvatinib treatment has not been established. Here, we compared the outcomes of sorafenib and nivolumab as second-line agents after failed lenvatinib treatment in patients with advanced HCC. METHODS: Patients with advanced HCC who had received sorafenib or nivolumab as second-line agents after failed lenvatinib treatment were recruited from two Korean tertiary institutions between November 2018 and June 2020. RESULTS: The median age of the 60 participants (52 treated with sorafenib and eight treated with nivolumab) at baseline was 56.8 years. The demographic, laboratory and tumor variables, as well as lenvatinib treatment duration, were similar between the two groups. The median durations of sorafenib and nivolumab treatment were 1.2 and 2.6 months, respectively ( P = 0.164). Twenty-four (40.0%) patients died during the follow-up period (median, 15.8 months). The median overall survival (OS) of the study population was 5.8 months. The median OS of patients treated with sorafenib was significantly longer than the median OS of patients treated with nivolumab (8.7 vs. 3.0 months; P = 0.046). Sorafenib treatment (vs. nivolumab) was independently associated with a lower risk of mortality (hazard ratio = 0.194; 95% confidence interval, 0.053-0.708; P = 0.013). Worse Eastern Cooperative Oncology Group performance status, larger maximal tumor size, lymph node metastases and higher total bilirubin levels were independently associated with increased mortality risk (all P < 0.05). CONCLUSIONS: Lenvatinib-sorafenib sequential treatment resulted in significantly better survival did than lenvatinib-nivolumab sequential treatment in patients with advanced HCC. Larger studies are needed to validate our results.

Lenvatinib-induced Interstitial Pneumonia in a Patient with Hepatocellular Carcinoma.

Lenvatinib is a multi-targeted tyrosine kinase inhibitor available for the treatment of unresectable hepatocellular carcinoma (HCC). We herein report an 84-year-old-man with interstitial pneumonia caused by lenvatinib. Four months after the start of lenvatinib administration for HCC, chest computed tomography revealed bilateral ground-glass opacity. However, he continued to take lenvatinib for four more months until he complained of dyspnea on exertion. This is a case of lenvatinib-induced interstitial pneumonia that progressed relatively slowly with a long asymptomatic period despite the appearance of pneumonia on image findings.

Efficacy of regorafenib combined with PD-1 inhibitors in elderly patients with advanced metastatic colorectal cancer.

OBJECTIVE: This is the first clinical study that wants to investigate the treatment patterns, clinical outcomes, and prognostic factors of regorafenib plus PD-1 inhibitors therapy in Chinese elderly patients with advanced colorectal cancer. METHODS: A cohort of metastatic colorectal cancer patients 60 years or older who received treatment with regorafenib combined with PD-1 inhibitors was included in our analysis. The endpoints included overall survival (OS), progression-free survival (PFS), and prognostic factors. RESULTS: In total, 24 patients were enrolled with the median age of 68 years, and 62.5% were female. The median OS and PFS were 15.03 months (95% CI 7.0-23.0) and 4.0 months (95% CI 1.8-6.2), respectively. The objective response rate was 8.3%, and the disease control rate was 70.8%. Patients previously treated with regorafenib had a longer median PFS than those without (6.3 versus 2.8 months). In terms of final daily doses, it showed a trend toward better PFS (median PFS was 10.0 months) in high-dose group (daily dose above 80 mg of regorafenib) compared to low-dose group (daily dose no more than 80 mg of regorafenib) (median PFS was 3.5 months). CONCLUSIONS: This real-world evidence confirms that Chinese elderly patients with advanced colorectal cancer may benefit from the treatment of regorafenib combined with PD-1 inhibitors, similarly with this combination therapy strategies in all age patients.

Regorafenib and trifluridine/tipiracil in real clinical practice.

Background: Colorectal cancer is the ninth leading cause of death in Spain. The latest therapeutic developments in the advanced stages of this disease are the oral drugs trifluridine/tipiracil and regorafenib. Objective: Results of clinical trials (CTs) are not in real conditions and therefore, we want to study the effectiveness and the safety profile in the usual clinical practice and compare it with the bibliography. Materials and Methods: A retrospective and unicentric study was carried out in a health area of 500,000 inhabitants. Patients who started treatment with regorafenib and/or trifluridine/tipiracil were included from the date of marketing until June 2019. Patient-related variables, pathology, effectiveness, and treatment toxicity were collected. The statistical analysis was carried out with the PSPP program. Results: Fifty-four patients were analyzed. Men accounted for 59.3% of patients. Regorafenib was the treatment for 22.2% of patients and 77.8% received trifluridine/tipiracil. The reason for the drug's suspension was the disease progression in 85.2% of patients. No patient had a full response and 3.2% achieved partial response. The median progression-free survival time in treatments with regorafenib was 2.5 months (95% confidence interval [CI]: 0.0-5.4) and the overall survival time was 3.1 months (95% CI: 0.0-6.7), while in treatments with trifluridine/tipiracil, these data were, respectively, 2.8 (95% CI: 2.5-3.2) and 5.7 months (95% CI: 3.8-7.6). Side effects occurred in 91.7% of patients treated with regorafenib and in 100% of treated with trifluridine/tipiracil. Hematological adverse reactions were, on average, 0.4 ± 0.5/patient with regorafenib and 1.5 ± 0.9 with trifluridine/tipiracil. General (77.8%) and gastrointestinal disorders (50%) were common with both drugs. Conclusions: The effectiveness results of standard clinical practice are lower than those described in CTs and in the literature. The toxicity profile does reproduce what is described in the bibliography.

Effectiveness, Toxicity, and Survival Predictors of Regorafenib in Metastatic Colorectal Cancer: A Multicenter Study of Routinely Collected Data.

OBJECTIVES: To assess the effectiveness and toxicity of regorafenib in patients with metastatic colorectal cancer (mCRC) in routine clinical practice, as well as predictive factors of effectiveness. METHODS: This was a retrospective multicenter study in patients with mCRC who received regorafenib from November 2013 to May 2020. Effectiveness was evaluated by overall survival (OS) and progression-free survival (PFS) using the Kaplan-Meier method. Cox regression was performed to determine survival predictors. RESULTS: Ninety patients were enrolled (median age, 64.3 years). Fifty-two patients (57.8%) were male, and 57 (63.3%) had an ECOG performance status (PS) of 0 to 1. Median follow-up was 2.80 months. Median OS was 8.03 months (95% CI, 5.90-10.17), and median PFS was 2.90 months (95% CI, 2.59-3.21). Eighty-eight patients (97.8%) experienced drug-related adverse events. The most frequent were fatigue in 66 patients (73.3%), followed by palmar-plantar erythrodysesthesia in 40 (44.4%). Low liver tumor burden score (LTBS) and good ECOG PS were independent OS predictive factors. CONCLUSIONS: Patients taking regorafenib had OS and PFS rates similar to those reported in previous randomized trials; the agent had a poor toxicity profile. We identified low LTBS and good ECOG PS as possible predictive factors of better OS, useful in selecting patients with mCRC who might benefit from regorafenib.