BRAF V600E-mutant colorectal cancer with CNS metastases treated successfully with encorafenib, binimetinib and cetuximab.

This report describes a case of BRAF V600E-mutated colorectal cancer with CNS metastases in which treatment with encorafenib, binimetinib and cetuximab was effective. There is limited information on the ability of encorafenib, binimetinib and cetuximab to enter the CNS.The patient was a 53-year-old man was diagnosed with ascending colon cancer (cT3N3M1c stage IVc). BRAF V600E mutation was confirmed. FOLFOX was started, but CNS metastases soon appeared. Encorafenib, binimetinib and cetuximab were administered and had a favorable effect on the CNS lesions. The patient initially responded well, but his disease progressed 2 months later. Further research is needed to improve management strategies for BRAF V600E-mutated colorectal cancer with CNS metastases.

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Feasibility, safety, efficacy and potential scaling-up of sofosbuvir-based HCV treatment in Central and West Africa: (TAC ANRS 12311 trial).

Access to Hepatis C treatment in Sub-Saharan Africa is a clinical, public health and ethical concern. The multi-country open-label trial TAC ANRS 12311 allowed assessing the feasibility, safety, efficacy of a specific care model of HCV treatment and retreatment in patients with hepatitis C in Sub Saharan Africa. Between November 2015 and March 2017, with follow-up until mid 2019, treatment-naïve patients with HCV without decompensated cirrhosis or liver cancer were recruited to receive 12 week-treatment with either sofosbuvir + ribavirin (HCV genotype 2) or sofosbuvir + ledipasvir (genotype 1 or 4) and retreatment with sofosbuvir + velpatasvir + voxilaprevir in case of virological failure. The primary outcome was sustained virological response at 12 weeks after end of treatment (SVR12). Secondary outcomes included treatment adherence, safety and SVR12 in patients who were retreated due to non-response to first-line treatment. The model of care relied on both viral load assessment and educational sessions to increase patient awareness, adherence and health literacy. The study recruited 120 participants, 36 HIV-co-infected, and 14 cirrhotic. Only one patient discontinued treatment because of return to home country. Neither death nor severe adverse event occurred. SVR12 was reached in 107 patients (89%): (90%) in genotype 1 or 2, and 88% in GT-4. All retreated patients (n = 13) reached SVR12. HCV treatment is highly acceptable, safe and effective under this model of care. Implementation research is now needed to scale up point-of-care HCV testing and SVR assessment, along with community involvement in patient education, to achieve HCV elimination in Sub-Saharan Africa.

Efficacy-effectiveness analysis on survival in a population-based real-world study of BRAF-mutated metastatic colorectal cancer patients treated with encorafenib-cetuximab.

BACKGROUND: Encorafenib-cetuximab has been approved for pretreated BRAFV600E-mutated metastatic colorectal cancer (mCRC) patients based on efficacy demonstrated in the randomized phase III BEACON trial. The aim of this real-world effectiveness study is to improve knowledge on the generalizability of trial results. METHODS: This population-based real-world study includes all mCRC patients in the Netherlands treated with encorafenib-cetuximab since approval. Individual patient data and pathology reports were collected. Overall survival (OS) was compared to BEACON and subgroup analyses were conducted for patients who would have been eligible and ineligible for BEACON. RESULTS: 166 patients were included with a median follow-up time of 14.5 months. Median OS was 6.7 months (95% CI:6.0-8.3) and differed from BEACON (9.3 months; 95% CI:8.0-11.3, p-value 0.002). Thirty-six percent of real-world patients would have been ineligible for the BEACON trial. Trial ineligible subgroups with symptomatic brain metastases and WHO performance status ≥2 had the poorest median OS of 5.0 months (95% CI:4.0-NR) and 3.9 months (95% CI:2.4-NR). CONCLUSION: This real-world cohort of mCRC patients treated with encorafenib-cetuximab showed a clinically relevant efficacy-effectiveness gap for OS. The chance of survival benefit from encorafenib-cetuximab in patients with brain metastases and/or WHO performance status ≥2 is negligible as neither efficacy nor effectiveness has been demonstrated.

A Practical Review of Encorafenib and Binimetinib Therapy Management in Patients with BRAF V600E-Mutant Metastatic Non-Small Cell Lung Cancer.

According to current guidelines, targeted therapy with a combination of BRAF plus MEK inhibitors is the preferred first-line treatment for patients with BRAF V600E-mutant metastatic non-small cell lung cancer (NSCLC). In the open-label, single-arm, phase 2 PHAROS trial (NCT03915951), the combination of encorafenib, a potent BRAF inhibitor, and binimetinib, a potent MEK inhibitor, demonstrated durable antitumor activity with a manageable safety profile in this patient population. On the basis of the results of this study, the combination of encorafenib plus binimetinib was approved by the US Food and Drug Administration on October 11, 2023, for patients with BRAF V600E-mutant metastatic NSCLC. In this review, we summarize the efficacy and safety of encorafenib plus binimetinib from the PHAROS study. In addition, we discuss strategies to manage adverse reactions with this combination therapy with the intent of minimizing unnecessary treatment discontinuations in these patients.

Treatment of patients with BRAFV600E-mutated metastatic colorectal cancer after progression to encorafenib and cetuximab: data from a real-world nationwide dataset.

BACKGROUND: Targeted therapy (TT) with encorafenib and cetuximab is the current standard for patients with BRAFV600E-mutated metastatic colorectal cancer (mCRC) who received one or more prior systemic treatments. However, the median progression-free survival (mPFS) is ∼4 months, and little is known about the possibility of administering subsequent therapies, their efficacy, and clinicopathological determinants of outcome. METHODS: A real-world dataset including patients with BRAFV600E-mutated mCRC treated with TT at 21 Italian centers was retrospectively interrogated. We assessed treatments after progression, attrition rates, and outcomes. RESULTS: Of the 179 patients included, 85 (47%), 32 (18%), and 7 (4%) received one, two, or three lines of treatment after TT, respectively. Those receiving TT in the second line were more likely to receive at least one subsequent therapy (53%), as compared with those treated with TT in the third line or beyond (30%; P < 0.0001), and achieved longer postprogression survival (PPS), also in a multivariate model (P = 0.0001). Among 62 patients with proficient mismatch repair/microsatellite stable (pMMR/MSS) tumors receiving one or more lines of treatment after second-line TT, combinatory chemotherapy ± anti-vascular endothelial growth factor (anti-VEGF) was associated with longer PFS and PPS as compared with trifluridine-tipiracil or regorafenib (mPFS: 2.6 versus 2.0 months, P = 0.07; PPS: 6.5 versus 4.4 months, P = 0.04). CONCLUSIONS: Our real-world data suggest that TT should be initiated as soon as possible after the failure of first-line treatment in BRAFV600E-mutated mCRC. Among patients with pMMR/MSS tumors, combinatory chemotherapy ± anti-VEGF appears the preferred treatment choice after TT failure.

Response Rate and Molecular Correlates to Encorafenib and Binimetinib in BRAF-V600E Mutant High-Grade Glioma.

PURPOSE: Although fewer than 5% of high-grade gliomas (HGG) are BRAF-V600E mutated, these tumors are notable as BRAF-targeted therapy shows efficacy for some populations. The purpose of this study was to evaluate response to the combination of encorafenib with binimetinib in adults with recurrent BRAF-V600-mutated HGG. PATIENTS AND METHODS: In this phase 2, open-label, Adult Brain Tumor Consortium (ABTC) trial (NCT03973918), encorafenib and binimetinib were administered at their FDA-approved doses continuously in 28-day cycles. Eligible patients were required to have HGG or glioblastoma with a BRAF-V600E alteration that was recurrent following at least one line of therapy, including radiotherapy. RESULTS: Five patients enrolled between January 2020 and administrative termination in November 2021 (due to closure of the ABTC). Enrolled patients received treatment for 2 to 40 months; currently one patient remains on treatment. Centrally determined radiographic response rate was 60%, with one complete response and two partial responses. Methylation profiling revealed that all tumors cluster most closely with anaplastic pleomorphic xanthoastrocytoma (PXA). Transcriptional profile for MAPK-response signature was similar across all tumors at baseline and did not correlate with response in this small population. Circulating tumor DNA measured in plasma samples before treatment, during response, and upon progression showed feasibility of detection for the BRAF-V600E alteration. No new safety signal was detected. CONCLUSIONS: Encorafenib and binimetinib exhibit positive tumor responses in patients with recurrent BRAF-V600E mutant HGG in this small series, warranting therapeutic consideration. Although toxicity remains a concern for BRAF-targeted therapies, no new safety signal was observed in these patients.

Safety and Efficacy of Encorafenib, Binimetinib, and Cetuximab for BRAFV600E-Mutant Metastatic Colorectal Cancer: Results of the Japanese Expanded Access Program.

BACKGROUND: The phase 3 BEACON CRC study demonstrated the survival benefits of encorafenib and cetuximab, with or without binimetinib (the BEACON triplet or doublet regimen), for BRAFV600E-mutant metastatic colorectal cancer (mCRC). This expanded access program (EAP) and subsequent follow-up study assessed the efficacy and safety of the BEACON triplet regimen in Japanese patients with BRAFV600E-mutant mCRC. MATERIALS AND METHODS: The EAP was an open-label, single-arm study including Japanese patients with BRAFV600E-mutant mCRC whose disease progressed after 1 to 2 prior regimens. The patients received the BEACON triplet regimen with 28-day cycles. The subsequent follow-up study assessed the survival outcomes following EAP completion. Safety was assessed only during the EAP. RESULTS: Among the 86 enrolled patients, 81 received the BEACON triplet regimen. The objective response rate and median progression-free survival were 27.6% (95% confidence interval [CI], 18.0%-39.1%) and 5.26 (95% CI, 4.14-5.52) months, respectively. Grade 3 to 4 adverse events and treatment-related adverse events occurred in 43.2% and 28.4% of patients, respectively. No new safety signals were observed during the EAP. Among 58 patients with confirmed survival at EAP completion, 57 were included in the follow-up study. With a median observation period of 9.17 months through the EAP and follow-up study, the median overall survival was 10.38 (95% CI, 9.00-16.16) months. CONCLUSION: The efficacy and safety of the BEACON triplet regimen in Japanese patients with BRAFV600E-mutant mCRC were consistent with those reported in the BEACON CRC trial, supporting its use as a standard treatment for pretreated patients with BRAFV600E-mutant mCRC.

Hepatitis C Virus-Related One-Year Hepatocellular Carcinoma Recurrence After Directly Acting Antivirals: A Randomized Controlled Trial.

PURPOSE: Available data on hepatocellular carcinoma (HCC) recurrence after direct-acting antivirals (DAAs) treatment for hepatitis C virus (HCV) are conflicting. No randomized trials were done. This study aims to compare the 1-year HCC recurrence rates in patients who received DAAs after tumor ablation versus those who postponed HCV treatment for 1 year. METHODS: Included patients were randomized after complete HCC ablation into two groups: a postponed DAAs group for whom DAAs initiation was postponed for 12 months and a DAAs group who were given sofosbuvir/velpatasvir. Patients were followed for 1 year. RESULTS: Eighty-four HCV patients with a mean age of 56.35 ± 8.12 years were included; 78.57% of them were males. The number of lesions per patient ranged from 1 to 3 lesions, and the size of the largest lesion ranged from 1.5 to 5 cm. There were no statistically significant differences between both groups regarding baseline characteristics. In the DAAs group (43 patients), 11 patients had HCC recurrence, while 25 patients in the postponed DAAs group (41 patients) had HCC recurrence. Using Kaplan-Meier analysis, the 1-year recurrence-free survival (RFS) was significantly higher in the DAAs group (72.2% vs. 38%, P = 0.001). On multivariate analysis, both higher albumin levels (HR 0.147, 95% CI 0.066-0.329) and receiving DAAs (HR 0.358, 95% CI 0.176-0.730) 1 year after ablation were associated with significantly lower recurrence. CONCLUSION: Direct-acting antiviral usage after complete hepatocellular carcinoma ablation significantly decreases the 1-year HCC recurrence rates, but the risk of recurrence is still not eliminated. The study registration number on clinicaltrials.gov : NCT04653818 (initial release on 28/11/2020).

Reductions in concomitant antiseizure medication drug load during adjunctive cenobamate therapy: Post-hoc analysis of a subset of patients from a phase 3, multicenter, open-label study.

OBJECTIVE: Many patients with epilepsy require polytherapy, which increases their antiseizure medication (ASM) drug load, a measure that considers the doses of all ASMs a patient is taking. Changes in concomitant ASM drug load after adding cenobamate were evaluated post-hoc in a subset of the open-label, phase 3 study. METHODS: Patients 18-70 years old with uncontrolled focal seizures taking 1-3 ASMs were enrolled. Total concomitant ASM drug load (not including cenobamate) was calculated by dividing the patient's prescribed dose for each ASM by its defined daily dose, per the World Health Organization, then summing the ratios. Changes in concomitant ASM drug load were measured from baseline in 3-month intervals up to 24 months by both total and class-specific ASM drug load. Subgroups of interest included: older adults (65-70 years), prior epilepsy-related surgery vs none, and baseline seizure frequency < 3 vs ≥ 3 seizures/28 days. RESULTS: Data from 240 patients were available (mean age 41.8 years, mean baseline drug load 3.57). Following cenobamate initiation, the mean concomitant ASM drug load was reduced by 29.4 % at Month 12 % and 31.8 % at Month 24. Reductions occurred in all assessed ASM drug classes, with the largest reduction in benzodiazepines (55.2 % at Month 24). Each assessed subgroup exceeded a 30 % reduction in concomitant ASM drug load at Month 24. Over 24 months, maintenance of ≥ 50 % response occurred in 89.3 %, 86.4 %, and 90.6 % of patients with low (-0.25 to <0), moderate (-0.59 to -0.25), or high (-3.3 to -0.59) numerical reductions in concomitant ASM drug load from baseline, respectively, compared with 86.0 % in patients with no change in drug load; maintenance of 100 % response occurred in 80.7 %, 84.3 %, and 70.0 % of patients with low, moderate, or high numerical reductions in concomitant ASM drug load, compared with 82.0 % in patients with no change. CONCLUSIONS: Adding cenobamate led to reduced mean concomitant ASM drug loads during 1 and 2 years of treatment. Reductions occurred regardless of ASM drug class, patient age, or epilepsy disease characteristics and did not impact maintenance of response rates.

A plain language summary of the PHAROS study: the combination of encorafenib and binimetinib for people with BRAF V600E-mutant metastatic non-small-cell lung cancer.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of the results of a study called PHAROS. This study looked at combination treatment with encorafenib (BRAFTOVI®) and binimetinib (MEKTOVI®). This combination of medicines was studied in people with metastatic non-small-cell lung cancer (NSCLC). NSCLC is the most common type of lung cancer. Metastatic means that the cancer has spread to other parts of the body. All people in this study had a type of NSCLC that has a change in a gene called BRAF termed a BRAF V600E mutation. A gene is a part of the DNA that has instructions for making things that your body needs to work, and the BRAF V600E mutation contributes to the growth of the lung cancer. WHAT WERE THE RESULTS?: In this study, 98 people with BRAF V600E-mutant metastatic NSCLC were treated with the combination of encorafenib and binimetinib (called encorafenib plus binimetinib in this summary). Before starting the study, 59 people had not received any treatment for their metastatic NSCLC, and 39 people had received previous anticancer treatment. At the time of this analysis, 44 (75%) out of 59 people who did not receive any treatment before taking encorafenib plus binimetinib had their tumors shrink or disappear. Eighteen (46%) out of 39 people who had received treatment before starting encorafenib plus binimetinib also had their tumors shrink or disappear. The most common side effects of encorafenib plus binimetinib were nausea, diarrhea, fatigue, and vomiting. WHAT DO THE RESULTS MEAN?: These results support the use of encorafenib plus binimetinib combination treatment as a new treatment option in people with BRAF V600E-mutant metastatic NSCLC. The side effects of encorafenib plus binimetinib in this study were similar to the side effects seen with encorafenib plus binimetinib in people with a type of skin cancer called metastatic melanoma.

Cenobamate in refractory epilepsy: Overview of treatment options and practical considerations.

Management of drug resistant epilepsy (DRE) represents a challenge to the treating clinician. This manuscript addresses DRE and provides an overview of treatment options, medical, surgical, and dietary. It addresses treatment strategies in polytherapy, then focuses on the role cenobamate (CNB) may play in reducing the burden of DRE while providing practical advice for its introduction. CNB is a recently approved, third generation, anti-seizure medication (ASM), a tetrazole-derived carbamate, thought to have a dual mechanism of action, through its effect on sodium channels as well as on GABAA receptors at a non-benzodiazepine site. CNB, having a long half-life, is an effective add-on ASM in refractory focal epilepsy with a higher response rate and a higher seizure-freedom rate than is usually seen in regulatory clinical trials. Experience post-licensing, though still limited, supports the findings of clinical trials and is encouraging. Its spectrum of action in relation to generalized epilepsies and seizures remains to be established, and there are no data on its efficacy in monotherapy. At the time of writing, CNB has been prescribed for some 50 000 individuals with DRE and focal epilepsy. A larger number is needed to fully establish its safety profile. It should at all times be introduced slowly to minimize the risk of serious allergic drug reactions. It has clinically meaningful interactions which must be anticipated and managed to maximize tolerability and likelihood of successful treatment. Despite the above, it may well prove to be of major benefit in the treatment of many patients with drug resistant epilepsy.

A Real-World Study to Compare the Safety and Efficacy of Paritaprevir/Ombitasvir/Ritonavir and Dasabuvir, with or without Ribavirin, in 587 Patients with Chronic Hepatitis C at the Fundeni Clinical Institute, Bucharest, Romania.

BACKGROUND In the European Union, a tablet with fixed doses of ombitasvir, paritaprevir, and ritonavir combined with dasabuvir is an authorized treatment for patients with chronic hepatitis C virus (HCV) infection. Ribavirin is a broad-spectrum antiviral used in several treatment regimens for patients with HCV infection. This real-world study aimed to compare the safety and efficacy of ombitasvir, paritaprevir, and ritonavir combined with dasabuvir, with or without ribavirin, in 587 patients with chronic hepatitis C attending the Fundeni Clinical Institute, Bucharest, Romania. MATERIAL AND METHODS This is an observational prospective study including 315 patients with F4 degree of fibrosis and compensated cirrhosis, 185 patients with F3 fibrosis, and 83 patients with F2 fibrosis. Liver fibrosis was evaluated by liver biopsy or Fibromax. Efficacy was defined as undetectable HCV-RNA at 12 weeks after the end of treatment. In terms of safety, we monitored the development of adverse reactions, liver cytolysis, cholestasis, and hematologic disorders. RESULTS Of the 587 patients, 2 patients with B-cell lymphoma died during therapy. In total, 3/585 patients (0.51%) did not achieve sustained virologic response. Common adverse effects were nausea and asthenia (especially in patients with other medical treatments; P=0.03 and P=0.04, respectively) and anemia in patients who received ribavirin (P<0.01). None of the patients discontinued antiviral treatment. Patients with kidney transplant or end-stage kidney disease did not receive or discontinued ribavirin. CONCLUSIONS Ombitasvir, paritaprevir, and ritonavir combined with dasabuvir, with or without ribavirin had an efficacy rate of over 99% in HCV genotype 1b infection. We report no serious adverse reactions.

Encorafenib plus cetuximab treatment in BRAF V600E-mutated metastatic colorectal cancer patients pre-treated with an anti-EGFR: An AGEO-GONO case series.

BACKGROUND: Encorafenib plus cetuximab is efficient in anti-EGFR-naïve patients with BRAFV600E mutated (BRAFm) metastatic colorectal cancer (mCRC). No data are available concerning the efficacy of BRAF inhibitors associated with anti-EGFRs (B + E) in patients previously treated with an anti-EGFR agent. METHODS: We retrospectively collected a series of patients with BRAFm mCRC treated with B + E after previous anti-EGFR treatment, in 14 centers. Progression-free survival (PFS) and overall survival (OS) were calculated from the start of treatment, and we reported objective response and disease control rates (ORR, DCR; RECIST V1.1). RESULTS: Twenty-five BRAFm mCRC patients were enrolled. Prior to B + E treatment, 4/10/11 patients were treated with 1/2/> 2 previous treatment lines. Ten patients received previous panitumumab, 14 cetuximab, 1 both. Immediate progression with previous anti-EGFR was reported for 7 patients. Anti-BRAF was encorafenib for 21 patients, dabrafenib for 4 patients, with cetuximab for 24 patients and panitumumab for 1 patient. ORR was 40% (10 patients) and DCR was 80% (20 patients). Median PFS and OS were 4.8 months (95% CI, 4.01-7.95) and 10.1 months (95% CI, 7.75-NR). DCR amongst patients with previous primary resistance to anti-EGFR (N = 7) was 100%. Two patients discontinued B + E due to drug-related adverse event. CONCLUSIONS: Though in a limited retrospective series of patients, these results show the efficacy of the combination of anti-BRAF and anti-EGFRs in BRAFm mCRC patients previously treated with an anti-EGFR. The use of this combination should thus not be ruled out in this population with limited therapeutic options.

Benzimidazole-carbamate anthelmintics: Perspective candidates for the anticancer drug development.

Cellular oncogenesis involves a complex interplay between the several synchronized, interdependent pathways that collectively determine the pathogenesis and pathophysiology of cancer. Limited therapeutic success with the existing anticancer drugs drew huge interest in the design and development of new pharmacophores with improved clinical efficacy, however despite huge investments in anticancer RD; the average number of Food and Drug Administration-approved anticancer drugs declined since the 1990s. The contemporary anticancer medications possess high attrition rates, bear substantial costs, and experience low efficacy owing to the drug resistance expressed by the aggressive tumors. Mainly, the translation of novel candidate anticancer drugs into clinical practice, their commercialization, and transformation from the bench to bedside require a long timeframe of 10-15 years and capital worth millions of dollars. The repurposing strategy substantially accelerated the anticancer drug development regime as the approved drugs with tested safety and efficacy ensure a minimal risk of failure, and nominal R&D expenses as anticipated for the newly identified candidate drugs yet to enter the clinical trials. In addition, the repurposed drugs ensure a rapid clinical translation due to a validated clinical profile and their ability to target the identified hallmarks and hitherto unknown vulnerabilities of cancer. The flagship project "Repurposing Drugs in Oncology" (ReDO) identified 268 "hard repurposing" noncancer medications as candidate drugs with a promising anticancer profile (https://www.anticancerfund.org/en/redo-db). However, the generic profile of 84% of repurposed drugs in ReDO data set discourages the commercial sponsors from funding the repurposing trials, especially the Phase III efficacy trials that require significant capital.

Bilateral Serous Retinal Detachment Associated with a Mitogen-activated Protein KinaseKinase Inhibitor in a Patient with BRAF-mutant Colorectal Cancer.

We herein report a 73-year-old woman with BRAF V600E-mutated colon cancer treated with encorafenib plus cetuximab with binimetinib as standard salvage therapy for patients with advanced colorectal cancer. She developed bilateral serous retinal detachment the next day, and the regimen was discontinued, resulting in complete resolution by the third day. Doublet therapy without binimetinib was initiated along with a weekly ophthalmologic examination for 10 weeks without recurrence of retinal detachment. Thus, binimetinib was presumed to have been the cause of the retinal detachment. This clinical course suggests the need for close monitoring of patients for vision impairment and close collaboration with ophthalmologists.

Drug-induced colitis on BRAF and MEK inhibitors for BRAF V600E-mutated non-small cell lung cancer: a case report.

INTRODUCTION: The combination of BRAF and MEK inhibitors has deeply changed the treatment of BRAF V600-mutant non-small cell lung cancer patients. These agents demonstrated high antitumor activity as well as safe and manageable toxicity profile. Hypertension, pyrexia and increased liver enzymes are the most common adverse events. Gastrointestinal toxicities are rare, and mainly consist of mild grade vomiting and diarrhea. CASE REPORT: We report the case of 70-year-old man affected by BRAF V600-mutant NSCLC with bilateral lung and bone metastases. First-line treatment with encorafenib (450 mg once daily) and binimetinib (45 mg twice daily) was administered within a clinical trial. At the first radiological assessment, computed tomography (CT) scan showed a partial response and signs of intestinal inflammation were reported. The investigational treatment was timely withheld. The subsequent colonoscopy demonstrated the presence of ulcerative lesions at the caecal tract, and the histological diagnosis suggested a drug-induced colitis. No specific treatment was given as the patient did not report abdominal disturbances. Forty-five days after treatment interruption a new CT scan showed the resolution of bowel inflammation and investigational treatment was resumed at the same doses. The patient is still alive and free of toxicity recurrence after 11 months from treatment initiation. Conclusion. Severe gastrointestinal toxicities are uncommon with BRAF and MEK inhibitors, although cases of colitis and intestinal perforation have already been reported in literature. The pathogenesis seems to be related to the MAPK pathway inhibition performed by MEK inhibitors. These adverse events should be accounted given the potential to evolve into life-threatening conditions.

Upfront progression under pembrolizumab followed by a complete response after encorafenib and cetuximab treatment in BRAF V600E-mutated and microsatellite unstable metastatic colorectal cancer patient: A case report.

Two new treatments have recently become standard care for patients with metastatic colorectal cancer (mCRC): encorafenib (BRAF inhibitor) associated with cetuximab (anti-EGFR) in the second or third line of chemotherapy for BRAF V600E tumors, and pembrolizumab (an anti PD-1 immune checkpoint inhibitor) for tumors harboring microsatellite instability (MSI)-high and/or deficient mismatch repair (dMMR). Furthermore, 30% of BRAF V600E mutated mCRC are MSI/dMMR through a sporadic hypermethylation of the promoter of hMLH1. We report here, for the first time, the case of a patient with BRAF V600E, PIK3CA, and SMAD4 mutated and dMMR/MSI mCRC, in whom we observed an atypical response pattern under the sequence of pembrolizumab followed by the doublet encorafenib and cetuximab treatment. The patient was progressive after a single cycle of pembrolizumab followed by a rapid complete response after only 2 months of treatment with encorafenib and cetuximab, discovered during R0 cytoreduction surgery for peritoneal carcinomatosis.

Direct Relationship between Interleukin-10 Gene Polymorphism and Hepatocellular Carcinoma Complicated by Direct Acting Antiviral Treatment of Hepatitis C Virus.

OBJECTIVE: This study aimed to assess the correlation between the genotyping of interleukin-10 (IL-10 polymorphism rs 1800871) and the incidence hepatocellular carcinoma (HCC) among patients with hepatitis C virus (HCV) treated with direct acting antivirals (DAAs). METHOD: For 200 patients with HCV infection who completed DAA treatment and followed up for 1 year, IL-10 polymorphism SNP(-819) rs 1800871 analysis was conducted via real time polymerase chain reaction. During the follow-up period, 100 patients who developed HCC were selected and compared with 100 patients who did not develop any complications. RESULTS: The studied patients were divided into two groups according to the incidence of complications after completion of DAA treatments. During the follow-up, 100 patients with HCV infection who developed HCC were selected and compared with 100 patients with HCV infection who did not develop any complications (positive control group). For the HCC group (n = 100), the mean age was 58.1 ± 6.4 years, with 92.7% being male and 7.3% being female; 91% had cirrhosis, 10% had lymphadenitis, 75% had splenomegaly, and 17% had ascites. In the positive control group (n = 100), mean age was 46.3 ± 9.4 years, with 68% being male and 32% being female; 20% had cirrhosis, 12% had splenomegaly, and 4.2% had ascites. The results demonstrated that sofosbuvir (SOF) + daclatasvir + ribavirin regimen was the most prevalent drug treatment for patients with HCC (72%), while SOF + Simeprevir was the most safe treatment for HCV infection among patients with HCC (2%). CT genotype was the most common genotype in the HCC group (56%), among different drug regimen (67.8%). T allele was the most prevalent in HCC group (61%), while the C allele was the least prevalent (39%). CONCLUSION: IL-10 genotyping may help in selecting the safest and most accurate drug regimen according to the safest genotype response relationship and follow-up of genotype resistance.