Preemptive TIPS Promising for Fundal Variceal Bleeding

TOPLINE:
In patients with cirrhosis and acute fundal variceal bleeding, the use of preemptive transjugular intrahepatic portosystemic shunt (p-TIPS) with a covered stent within 72 hours of initial bleeding resulted in superior outcomes, with a higher probability of patients being free of death or rebleeding at 1 year than those using standard treatment.
METHODOLOGY:
Researchers conducted a randomised trial across 17 tertiary centres in France to compare two strategies for preventing rebleeding of non-type 1 gastro-oesophageal varices.
They included 101 patients with cirrhosis and acute fundal variceal bleeding (mean age, 58.2 years; 80% men) from January 3, 2019, to February 25, 2023, who achieved initial haemostasis with endoscopic glue injection for at least 12 hours.
Patients were randomly assigned to either receive p-TIPS within 72 hours of the initial endoscopic glue injection (n = 47) or continue with on-demand glue obliteration combined with non-selective beta blockers (n = 54).
The primary composite endpoint was all-cause mortality or clinically significant rebleeding, defined as recurrent melena or haematemesis requiring hospitalisation or blood transfusion or causing a 3 g/dL drop in haemoglobin, within 1 year from the initial haemostasis. Analyses were conducted in the modified intention-to-treat population.
TAKEAWAY:
The 1-year probability of being free from death or rebleeding was higher in the p-TIPS group than in the glue obliteration and non-selective beta-blocker group (77% vs 37%; hazard ratio, 0.25; P < .0001).
The overall survival did not differ significantly between the two groups; however, 37% of patients in the glue obliteration and non-selective beta-blocker group required TIPS after a median of 25 days. The cumulative incidence of hepatic encephalopathy at 1 year was 35% in the p-TIPS group and 32% in the glue obliteration and non-selective beta-blocker group.
Complications related to glue injection occurred in 22 procedures, including 13 bleeding episodes, eight glue migrations (three in the p-TIPS group and five in the glue obliteration group), and one case of cardiac decompensation in the p-TIPS group.
The number of patients who experienced any adverse or serious adverse event did not differ significantly between the groups, and no deaths were considered related to the treatment.
IN PRACTICE:
"The results of the present study strongly support the use of p-TIPS in the management of acute gastric variceal bleeding and add an additional argument in favour of TIPS, which improves prognosis by effectively treating the haemodynamic disorders associated with cirrhosis," the authors of the study wrote. "In patients with cirrhosis and bleeding from fundal varices, p-TIPS with a covered stent is associated with markedly decreased death or rebleeding and should therefore be considered as a first-line therapy," they added.
SOURCE:
This study was led by Jean-Paul Cervoni, MD, Service d'Hépatologie et de Soins Intensifs, CHU Besançon, Besançon, France. It was published online on June 12, 2025, in The Lancet Gastroenterology & Hepatology.
LIMITATIONS:
A small sample size precluded definitive subgroup analyses (eg, variceal type). An overrepresentation of alcohol-related cirrhosis may have limited the applicability of the findings to other aetiologies. Eight patients in the p-TIPS group were treated beyond the 72-hour window.
DISCLOSURES:
This study was funded by the French Ministry of Health. Two authors reported receiving payment for lectures and one author reported receiving consulting fees from Gore.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

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Do Tattoos Pose a Cancer Risk?

Over recent decades, tattoos have rapidly gained in popularity, with a Narrative Research survey in 2024 showing that 31% of the adult Canadian population has tattoos. Moreover, women are much more inclined to get a tattoo, including permanent makeup, than men (38% vs 28%). In Canada, the US, and Europe, a patient must be about 18 to start accumulating tattoos. Stephen A. Hoption Cann, PhD As tattoos grow in popularity, patients increasingly seek advice from general practitioners and dermatologists about potential health risks. While adverse effects such as infections and allergic reactions are well-documented, the longer-term health implications of tattoos, particularly cancer risks, have only recently begun to receive more attention. Although this commentary centers on Canada, its implications extend globally. Let's explore the key concerns tattoos present in terms of cancer risks and how clinicians should approach them. A patient may wonder whether injecting all manner of inks into the dermal layers of their skin poses any long-term risks. One might assume, wrongly, that since tattoos have been around for a very long time that cancer risks would have been exhaustively investigated. While there have been many case reports noting the occurrence of various types of cancerous lesions within tattoos, they do not tell us whether this association is causal or coincidental. Epidemiological studies exploring this question are few. On the surface, it seems like an easy question to explore: Just compare cancer risk in those with tattoos to those without. However, one must remember that there are hundreds of brands and thousands of colors of ink on the market — and individual tattoos often contain many colors. Then there is the question of tattoo size. Moreover, if people stopped at one tattoo, that would make it much easier for epidemiologists; however, individuals who were happy with their first tattoo may go on to get many more over subsequent years, adding complexity to the calculation of an individual's overall exposure risk. Then there are the many confounding factors such as smoking, alcohol, socioeconomic status, etc, which must be accounted for. Before we get into the epidemiological studies, we might want to know how tattoo inks are regulated. Health Canada has created a list of restricted or prohibited ingredients of tattoo inks. This list includes substances that are considered mutagenic, carcinogenic, toxic to reproduction, skin sensitizers, and irritants. The regulator also samples and tests tattoo inks to check for microbial contamination, heavy metals, and labeling accuracy. The European Union has taken a similar approach, but the FDA does not approve tattoo inks. Its regulation is mostly passive (eg, investigating safety concerns when adverse reactions are reported). So, what can be found in these tattoo inks? Nonorganic inks can contain a virtual smorgasbord of metals, including barium, cadmium, chromium, cobalt, iron, nickel, lead, titanium, and mercury, though the latter largely has been phased out due to toxicity concerns. Some nonorganic inks contain acrylics or synthetic pigments. All these substances aid in long-term color retention. In contrast, organic inks are often made from plant-based or carbon-based pigments but tend to fade faster as they lack the metallic or synthetic stabilizers found in nonorganic inks. While the FDA requires accurate labeling of these products, a recent US study found that 83% of tattoo inks tested (45 of 54) had major label discrepancies — not that clients getting a tattoo would even read the label. Many of the metals used are known carcinogens (eg, cadmium, chromium, lead, mercury, and nickel) or possible carcinogens (eg, cobalt and titanium), depending on the chemical species. Additionally, some of the pigments used, such as azo dyes, can decompose into carcinogenic aromatic amines. Other harmful substances in inks include polycyclic aromatic hydrocarbons, which have been proven to be carcinogenic to animals and humans. What about cancer risks? Most studies to date have examined lymphomas, as it has been demonstrated in animal and human studies that most of the pigment from tattoos will be transported to regional lymph nodes. In this mostly final resting place, it could cause chronic inflammation and carcinogenic processes over time. A couple of case-control studies have found a significant increase in lymphoma risk in tattooed subjects relative to comparison groups (see Table). A well-designed twin study noted a higher risk, particularly for large tattoos (ie, bigger than the palm of the hand, which may not seem so large today). While another study from Sweden noted an elevated risk for lymphoma and lymphoma subtypes, no finding was significant. In contrast, a Canadian study found no trend for non-Hodgkin lymphoma, although tattoos were uncommon (around 5%) in the population studied. Several studies have examined risks for various types of skin cancer. A study on cosmetic tattoos showed a nonsignificant elevated risk for basal cell carcinoma. Clemmensen et al, who conducted a case-control and a cohort study, showed significantly elevated risk for skin cancer associated with large tattoos in the former study and elevated risks for skin cancer and basal cell carcinoma in the latter study. In contrast, a recent study by Liljedahl et al found no evidence of risk for cutaneous squamous cell carcinoma. Aside from lymphomas, a few other hematologic cancers have been studied, but nothing significant has been found. Table: Research into tattoos and cancer risk. Download Table as PDF Ultimately, many uncertainties about cancer risks remain, and thus it is not surprising that some larger cohort studies have been established to answer these questions. A couple of examples include Tattoo inK, a cohort study of about 18,000 tattooed individuals and 160,000 untattooed controls within the German National Cohort, and Cancer Risk Attributable to the Body Art of Tattooing, a cohort study of about 13,000 tattooed individuals and 100,000 untattooed controls, which is integrated into the French Consultants des Centres d'Examens de Santé (Constances) cohort. While these are ample cohorts, one may have to wait one or more decades for findings to accrue. A patient who smokes or drinks can quit to reduce his or her cancer risk. But what about a patient with a tattoo? The most common removal technique is laser therapy, which uses high-intensity light pulses to break down tattoo ink particles. Can this process remove the potentially hazardous particles? Well, not exactly, as these fragments end up being funneled into the draining lymph nodes. Sending more pigment into this region could increase risk, but we don't know for sure. Dermabrasion, chemical peels, or surgical removal can remove the ink but can also produce significantly more scarring and thus are usually reserved for smaller tattoos. So, you have a patient with a new tattoo who is eager to hit the beach to show it off. What do you tell them? First, they should be warned that sun exposure will accelerate fading. And those degraded pigments don't just disappear, they release potentially harmful substances into the body. There is also a possible increased risk for skin cancer, so they're better off displaying their tattoos indoors or using sun-protective clothing or sunscreen. 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CHMP recommends third indication for darolutamide for patients with advanced prostate cancer

ORION CORPORATION PRESS RELEASE 20 JUNE 2025 at 13.30 EEST CHMP recommends third indication for darolutamide for patients with advanced prostate cancer CHMP adopts positive opinion for the marketing authorisation of darolutamide in combination with androgen deprivation therapy (ADT) for patients with metastatic hormone-sensitive prostate cancer (mHSPC) in the European Union. Positive opinion is based on results from the pivotal Phase III ARANOTE trial. Pending approval, this broadened indication would give doctors the option to use darolutamide plus ADT, with or without chemotherapy (docetaxel), offering greater flexibility to tailor treatment plans to meet mHSPC patients' needs. Orion's collaboration partner Bayer announced today that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency has recommended darolutamide, an oral androgen receptor inhibitor (ARi), plus androgen deprivation therapy (ADT) for marketing authorisation in the European Union (EU) for the treatment of patients with metastatic hormone-sensitive prostate cancer (mHSPC). The CHMP recommendation is based on positive results from the pivotal Phase III ARANOTE trial which showed that darolutamide plus ADT significantly reduced the risk of radiological progression or death by 46% compared to placebo plus ADT (HR 0.54; 95% CI 0.41–0.71; P<0.0001) in patients with mHSPC. A final decision on marketing authorisation from the European Commission is anticipated in the coming months. The U.S. Food and Drug Administration (FDA) recently approved darolutamide in combination with ADT for mHSPC in June 2025, making it the first and only in the US and FDA-approved ARi for the treatment of patients with mHSPC, in combination with ADT, with or without chemotherapy. Darolutamide, under the brand name Nubeqa®, is approved in over 85 countries for use with ADT and docetaxel in mHSPC, and with ADT alone in non-metastatic castration-resistant prostate cancer (nmCRPC) in patients who are at high risk of developing metastatic disease. Darolutamide is developed jointly by Orion and Bayer. Prostate cancer is the second most common cancer and the fifth most common cause of cancer death in men worldwide. In 2022, an estimated 1.5 million men were diagnosed with prostate cancer, and about 397,000 died from the disease worldwide.1 In Europe, there were almost 474,000 estimated new cases of prostate cancer in 2022 with approximately 115,000 deaths. 2 Prostate cancer diagnoses are projected to increase to 2.9 million by 2040.3 About the ARANOTE trial The ARANOTE trial is a randomized, double-blind, placebo-controlled Phase III study designed to assess the efficacy and safety of darolutamide plus ADT in patients with mHSPC. 669 patients were randomized 2:1 to receive 600mg of darolutamide twice daily or matching placebo in addition to ADT. The primary endpoint of this study is rPFS, measured as time from randomization to date of first documented radiological progressive disease or death due to any cause, whichever occurs first. Secondary endpoints include overall survival (time to death from any cause), time to first castration resistant event, time to initiation of subsequent anti-cancer therapy, time to prostate-specific antigen (PSA) progression, PSA undetectable rates, time to pain progression, and safety assessments. Results from the Phase III ARANOTE trial presented at ESMO 2024 and published in The Journal of Clinical Oncology showed that darolutamide plus ADT significantly reduced the risk of radiological progression or death by 46% compared to placebo plus ADT (HR 0.54; 95% CI 0.41–0.71; P<0.0001), in patients with mHSPC. Consistent benefits in radiological progression-free survival (rPFS) were observed across prespecified subgroups, including patients with high-volume (HR 0.60, 95% CI: 0.44-0.80) and low-volume (HR 0.30, 95% CI: 0.15-0.60) mHSPC. The incidence of adverse events in the treatment group with darolutamide plus ADT in the ARANOTE study was comparable to placebo plus ADT. Darolutamide plus ADT was generally well tolerated and showed lower discontinuation rates due to adverse events compared to placebo plus ADT. About darolutamide Darolutamide is an oral ARi with a unique chemical structure that binds with high affinity to the androgen receptor and exhibits a strong antagonistic effect against the androgen receptor inhibiting the receptor function and the growth of prostate cancer cells. Additionally, preclinical models and neuroimaging data in healthy humans, support darolutamide's low potential for blood-brain barrier penetration. Darolutamide (plus ADT or plus ADT and docetaxel) demonstrated a side effect profile, in both mHSPC registrational studies where the incidences of adverse events were roughly similar to the respective comparator arm. Darolutamide is a treatment option for doctors and patients, considering its tolerability and low risk of drug interaction. A robust clinical development program is underway investigating darolutamide across various stages of prostate cancer. The program includes the Phase III ARASTEP trial evaluating darolutamide plus ADT compared to ADT alone in hormone-sensitive high-risk biochemical recurrence (BCR) prostate cancer, who have no evidence of metastatic disease by conventional imaging and a positive PSMA PET/CT at baseline. Furthermore, darolutamide is also being investigated by Bayer in the collaborative Phase III DASL-HiCaP (ANZUP1801) trial led by the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP). The study evaluates darolutamide as a treatment for localized prostate cancer in combination with radiotherapy. About metastatic hormone-sensitive prostate cancer At the time of diagnosis, most men have localized prostate cancer, meaning their cancer is confined to the prostate gland and can be treated with curative surgery or radiotherapy. mHSPC is a stage in the disease where the cancer has spread outside of the prostate to other parts of the body. Up to 10% of men will present with mHSPC when first diagnosed.4,5,6 For patients with mHSPC, ADT is the cornerstone of treatment, in combination with chemotherapy docetaxel and/or an androgen receptor inhibitor (ARi). Despite treatment, most men with mHSPC will eventually progress to castration-resistant prostate cancer (CRPC), a condition with limited survival. References Bray F et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Accessed: June 2025. Ferlay J et al. 2024. Global Cancer Observatory: Cancer Today. Lyon, France: International Agency for Research on Cancer. Available at: Accessed June 2025.. James ND et al. Lancet 2024; 403: 1683–722. Piombino C et al. Cancers (Basel). 2023 Oct 11;15(20):4945. Helgstrand JT et al. Cancer. 2018;124(14):2931-2938. Buzzoni C et al. Eur. Urol. 2015;68:885–890. Publisher:Orion CorporationCommunicationsOrionintie 1A, FI-02200 Espoo, Orion is a globally operating Nordic pharmaceutical company – a builder of well-being for over a hundred years. We develop, manufacture and market human and veterinary pharmaceuticals and active pharmaceutical ingredients. Orion has an extensive portfolio of proprietary and generic medicines and consumer health products. The core therapy areas of our pharmaceutical R&D are oncology and pain. Proprietary products developed by Orion are used to treat cancer, neurological diseases and respiratory diseases, among others. In 2024 Orion's net sales amounted to EUR 1,542 million and the company employed about 3,700 professionals worldwide, dedicated to building well-being. 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Exelixis' Partner Ipsen Receives Positive CHMP Opinion for CABOMETYX® (cabozantinib) for Patients with Previously Treated Advanced Neuroendocrine Tumors

– A regulatory decision by the European Medicines Agency is anticipated in 2025 – – In March 2025, the U.S. Food and Drug Administration approved CABOMETYX in this setting – ALAMEDA, Calif., June 20, 2025--(BUSINESS WIRE)--Exelixis, Inc. (Nasdaq: EXEL) today announced that its partner Ipsen received a positive opinion from the European Medicine Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) for CABOMETYX® (cabozantinib) for adult patients with unresectable or metastatic, well-differentiated extra-pancreatic (epNET) and pancreatic (pNET) neuroendocrine tumors who have progressed following at least one prior systemic therapy other than somatostatin analogues. The European Commission (EC), which has the authority to approve medicines for the European Union (EU), will now review the CHMP recommendation, and a final decision on the application is expected in the coming months. "Neuroendocrine tumors are difficult to treat given their indolent nature and lack of robust responses to traditional oncology agents. This often results in people living with this type of cancer for long periods of time and running out of effective options, underscoring the critical need for new treatments following disease progression," said Amy Peterson, M.D., Executive Vice President, Product Development and Medical Affairs, and Chief Medical Officer. "The CHMP's recommendation is a pivotal milestone for our partner Ipsen as they work to bring CABOMETYX to patients in Europe, and we look forward to hearing the European Commission's decision in the coming months." The CHMP recommendation is based on results from the phase 3 CABINET pivotal trial, which is evaluating CABOMETYX compared with placebo in two cohorts of patients with previously treated NET: advanced pNET and advanced epNET. CABINET was the basis for the U.S. Food and Drug Administration (FDA) approval of CABOMETYX in March 2025 for the treatment of 1) adult and pediatric patients 12 years of age and older with previously treated, unresectable, locally advanced or metastatic, well-differentiated pNET; and 2) adult and pediatric patients 12 years of age and older with previously treated, unresectable, locally advanced or metastatic, well-differentiated epNET. Final progression-free survival (PFS) results were presented at the 2024 European Society for Medical Oncology Congress and published in The New England Journal of Medicine. About CABINET (Alliance A021602)CABINET (Randomized, Double-Blinded, Phase III Study of CABozantinib versus Placebo In Patients with Advanced NEuroendocrine Tumors After Progression on Prior Therapy) is sponsored by the National Cancer Institute (NCI), part of the National Institutes of Health, and is being led and conducted by the NCI-funded Alliance for Clinical Trials in Oncology with participation from the NCI-funded National Clinical Trials Network, as part of Exelixis' collaboration through a Cooperative Research and Development Agreement with the NCI's Cancer Therapy Evaluation Program. CABINET is a multicenter, randomized, double-blinded, placebo-controlled phase 3 pivotal trial that enrolled a total of 298 patients in two separate cohorts (pNET and epNET) in the U.S. at the time of the final analysis. Patients were randomized 2:1 to cabozantinib (60 mg) or placebo; each cohort was randomized separately and had its own statistical analysis plan. The trial was stopped early after an interim analysis showed superior efficacy associated with cabozantinib as compared to placebo in each of the two cohorts. Patients with epNET had primary tumors arising in the gastrointestinal (GI) tract, lung, unknown primary sites and other organs. Patients must have had measurable disease per RECIST 1.1 criteria and must have experienced disease progression or intolerance after at least one U.S. FDA-approved line of prior systemic therapy other than somatostatin analogs. The primary endpoint in each cohort was PFS per RECIST 1.1 by blinded independent central review. Secondary endpoints included overall survival, objective response rate and safety. More information about this trial is available at About NETNET are cancers that begin in the specialized cells of the body's neuroendocrine system.1 These cells have traits of both hormone-producing endocrine cells and nerve cells.1 It is estimated that 161,000 to 192,000 people in the U.S. are living with unresectable, locally advanced or metastatic NET.2 The number of people diagnosed with NET has been increasing in recent decades.3 Functional NET release peptide hormones that can cause debilitating symptoms, like diarrhea, hypertension and flushing, while symptoms of non-functional NET are related primarily to tumor growth.4,5,6,7,8 Most NET take years to develop and grow slowly, but eventually all patients with advanced or metastatic NET will develop refractory and progressing disease.9,10 NET can start in the pancreas (pNET), where they tend to be more aggressive, with a five-year survival rate of only 23% for advanced disease.1,11 NET can also develop in any part of the body, but most commonly start in the GI tract or in the lungs, where they have historically been referred to as carcinoid tumors and are more recently called epNET.1 The five-year survival rates for advanced GI and lung NET tumors are 68% and 55%, respectively.12,13 For advanced NET patients, treatment options include somatostatin analogs, chemotherapy, molecular targeted therapy and peptide-receptor radionuclide therapy.14 About CABOMETYX® (cabozantinib)In the U.S., CABOMETYX tablets are approved as monotherapy for the treatment of patients with advanced renal cell carcinoma (RCC) and in combination with nivolumab as a first-line treatment for patients with advanced RCC; for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib; for adult and pediatric patients 12 years of age and older with locally advanced or metastatic differentiated thyroid cancer (DTC) that has progressed following prior VEGFR-targeted therapy and who are radioactive iodine-refractory or ineligible; for the treatment of adult and pediatric patients 12 years of age and older with previously treated, unresectable, locally advanced or metastatic, well-differentiated pNET; and adult and pediatric patients 12 years of age and older with previously treated, unresectable, locally advanced or metastatic, well-differentiated epNET. CABOMETYX tablets have also received regulatory approvals in over 65 countries outside the U.S. and Japan, including the EU. In 2016, Exelixis granted Ipsen Pharma SAS exclusive rights for the commercialization and further clinical development of cabozantinib outside of the U.S. and Japan. In 2017, Exelixis granted exclusive rights to Takeda Pharmaceutical Company Limited for the commercialization and further clinical development of cabozantinib for all future indications in Japan. Exelixis holds the exclusive rights to develop and commercialize cabozantinib in the U.S. IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Hemorrhage: CABOMETYX can cause severe and fatal hemorrhages. The incidence of Grade 3-5 hemorrhagic events was 5% in CABOMETYX patients in RCC, HCC, and DTC studies. Discontinue CABOMETYX for Grade 3-4 hemorrhage and before surgery. Do not administer to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena. Perforations and Fistulas: Fistulas, including fatal cases, and gastrointestinal (GI) perforations, including fatal cases, each occurred in 1% of CABOMETYX patients. Monitor for signs and symptoms, and discontinue CABOMETYX in patients with Grade 4 fistulas or GI perforation. Thrombotic Events: CABOMETYX can cause arterial or venous thromboembolic event. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic events have occurred. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events. Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension was reported in 37% (16% Grade 3 and <1% Grade 4) of CABOMETYX patients. In CABINET (n=195), hypertension occurred in 65% (26% Grade 3) of CABOMETYX patients. Do not initiate CABOMETYX in patients with uncontrolled hypertension. Monitor blood pressure regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled; when controlled, resume at a reduced dose. Permanently discontinue CABOMETYX for severe hypertension that cannot be controlled with antihypertensive therapy or for hypertensive crisis. Diarrhea: CABOMETYX can cause diarrhea and it occurred in 62% (10% Grade 3) of treated patients. Monitor and manage patients using antidiarrheals as indicated. Withhold CABOMETYX until improvement to ≤ Grade 1; resume at a reduced dose. Palmar-Plantar Erythrodysesthesia (PPE): CABOMETYX can cause PPE and it occurred in 45% of treated patients (13% Grade 3). Withhold CABOMETYX until PPE resolves or decreases to Grade 1 and resume at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE. Hepatotoxicity: CABOMETYX in combination with nivolumab in RCC can cause hepatic toxicity with higher frequencies of Grades 3 and 4 ALT and AST elevations compared to CABOMETYX alone. With the combination of CABOMETYX and nivolumab, Grades 3 and 4 increased ALT or AST were seen in 11% of patients. Monitor liver enzymes before initiation of treatment and periodically. Consider more frequent monitoring as compared to when the drugs are administered as single agents. Consider withholding CABOMETYX and/or nivolumab, initiating corticosteroid therapy, and/or permanently discontinuing the combination for severe or life-threatening hepatotoxicity. Adrenal Insufficiency: CABOMETYX in combination with nivolumab can cause primary or secondary adrenal insufficiency. Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received CABOMETYX with nivolumab, including Grade 3 (2.2%), and Grade 2 (1.9%) adverse reactions. Withhold CABOMETYX and/or nivolumab and resume CABOMETYX at a reduced dose depending on severity. Proteinuria: Proteinuria was observed in 8% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. For Grade 2 or 3 proteinuria, withhold CABOMETYX until improvement to ≤ Grade 1 proteinuria; resume CABOMETYX at a reduced dose. Discontinue CABOMETYX in patients who develop nephrotic syndrome. Osteonecrosis of the Jaw (ONJ): CABOMETYX can cause ONJ and it occurred in <1% of treated patients. Perform an oral examination prior to CABOMETYX initiation and periodically during treatment. Advise patients regarding good oral hygiene practices. Withhold CABOMETYX for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures. Withhold CABOMETYX for development of ONJ until complete resolution; resume at a reduced dose. Impaired Wound Healing: CABOMETYX can cause impaired wound healing. Withhold CABOMETYX for at least 3 weeks prior to elective surgery. Do not administer for at least 2 weeks after major surgery and until adequate wound healing. The safety of resumption of CABOMETYX after resolution of wound healing complications has not been established. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): CABOMETYX can cause RPLS. Perform evaluation for RPLS and diagnose by characteristic finding on MRI any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS. Thyroid Dysfunction: CABOMETYX can cause thyroid dysfunction, primarily hypothyroidism, and it occurred in 19% of treated patients (0.4% Grade 3). Assess for signs of thyroid dysfunction prior to the initiation of CABOMETYX and monitor for signs and symptoms during treatment. Hypocalcemia: CABOMETYX can cause hypocalcemia, with the highest incidence in DTC patients. Based on the safety population, hypocalcemia occurred in 13% of CABOMETYX patients (2% Grade 3 and 1% Grade 4). Monitor blood calcium levels and replace calcium as necessary during treatment. Withhold and resume CABOMETYX at a reduced dose upon recovery or permanently discontinue CABOMETYX depending on severity. Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm. Advise pregnant women of the potential risk to a fetus and advise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for 4 months after the last dose. ADVERSE REACTIONS The most common (≥20%) adverse reactions are: CABOMETYX as a single agent: diarrhea, fatigue, PPE, decreased appetite, hypertension, nausea, vomiting, weight decreased, and constipation. CABOMETYX in combination with nivolumab: diarrhea, fatigue, hepatotoxicity, PPE, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection. DRUG INTERACTIONS Strong CYP3A4 Inhibitors: If coadministration with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage. Avoid grapefruit or grapefruit juice. Strong or Moderate CYP3A4 Inducers: If coadministration with strong or moderate CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage. Avoid St. John's wort. USE IN SPECIFIC POPULATIONS Lactation: Advise women not to breastfeed during CABOMETYX treatment and for 4 months after the final dose. Hepatic Impairment: In patients with moderate hepatic impairment, reduce the CABOMETYX dosage. Avoid CABOMETYX in patients with severe hepatic impairment. Pediatric Use: Physeal widening has been observed in children with open growth plates when treated with CABOMETYX. Physeal and longitudinal growth monitoring is recommended in children (12 years and older) with open growth plates. Consider interrupting or discontinuing CABOMETYX if abnormalities occur. The safety and effectiveness of CABOMETYX in pediatric patients less than 12 years of age have not been established. Please see accompanying full Prescribing Informationhttps:// You are encouraged to report negative side effects of prescription drugs to the FDA. Visit or call 1-800-FDA-1088. About ExelixisExelixis is a globally ambitious oncology company innovating next-generation medicines and regimens at the forefront of cancer care. Powered by drug discovery and development excellence, we are rapidly evolving our product portfolio to target an expanding range of tumor types and indications with our clinically differentiated pipeline of small molecules, antibody-drug conjugates and other biotherapeutics. This comprehensive approach harnesses decades of robust investment in our science and partnerships to advance our investigational programs and extend the impact of our flagship commercial product, CABOMETYX® (cabozantinib). Exelixis is driven by a bold scientific pursuit to create transformational treatments that give more patients hope for the future. For information about the company and its mission to help cancer patients recover stronger and live longer, visit follow @ExelixisInc on X (Twitter), like Exelixis, Inc. on Facebook and follow Exelixis on LinkedIn. Forward-Looking StatementsThis press release contains forward-looking statements, including, without limitation, statements related to: the therapeutic potential of CABOMETYX for patients with previously treated advanced neuroendocrine tumors; the regulatory review process in the EU, including the expected timing for a final decision from the EC; Exelixis' or its partner Ipsen's ability or plans to support these new indications for patients in Europe; and Exelixis' scientific pursuit to create transformational treatments that give more patients hope for the future. Any statements that refer to expectations, projections or other characterizations of future events or circumstances are forward-looking statements and are based upon Exelixis' current plans, assumptions, beliefs, expectations, estimates and projections. Forward-looking statements involve risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in the forward-looking statements as a result of these risks and uncertainties, which include, without limitation: complexities and the unpredictability of the regulatory review and approval processes in the EU and elsewhere, including the risk that the EC may not approve CABOMETYX for the treatment of adult patients with unresectable or metastatic, well-differentiated epNET and pNET who have progressed following at least one prior systemic therapy other than a somatostatin analogue in a timely fashion, if at all; unexpected concerns that may arise as a result of the occurrence of adverse safety events or additional data analyses of clinical trials evaluating cabozantinib; Exelixis' dependence on its relationships with its collaboration partners, including their pursuit of regulatory approvals for partnered compounds in new indications and their adherence to their obligations under relevant collaboration agreements; Exelixis' ability to protect its intellectual property rights; market competition, including the potential for competitors to obtain approval for generic versions of CABOMETYX; changes in economic and business conditions; and other factors affecting Exelixis and its partners to obtain regulatory approval for cabozantinib in new indications; and other factors detailed from time to time under the caption "Risk Factors" in Exelixis' most recent Annual Report on Form 10-K and subsequent Quarterly Reports on Form 10-Q, and in Exelixis' other future filings with the Securities and Exchange Commission. All forward-looking statements in this press release are based on information available to Exelixis as of the date of this press release, and Exelixis undertakes no obligation to update or revise any forward-looking statements contained herein, except as required by law. Exelixis, the Exelixis logo and CABOMETYX are registered U.S. trademarks of Exelixis. ____________________ 1 Neuroendocrine Tumors. Cleveland Clinic website. Available at: Accessed June 2025. 2 Population Estimate: Unresectable, Locally Advanced or Metastatic Extra-Pancreatic NET. June 2024 (internal data on file). 3 Pathak, S., Starr, J.S., Halfdanarson T., et al. Understanding the increasing incidence of neuroendocrine tumors. Expert Rev Endocrinol Metab. September 2023;18(5):377-385. 4 Pancreatic Neuroendocrine Tumors (Islet Cell Tumors) Treatment (PDQ®)–Patient Version. NCI website. Available at: Accessed June 2025. 5 What Is a Pancreatic Neuroendocrine Tumor? ACS website. Available at: Accessed June 2025. 6 Carcinoid Syndrome. Cleveland Clinic website. Available at: Accessed June 2025. 7 Signs and Symptoms of Gastrointestinal Carcinoid Tumors. ACS website. Available at: Accessed June 2025. 8 Signs and Symptoms of Lung Carcinoid Tumors. ACS website. Available at: Accessed June 2025. 9 McClellan, K., Chen. E.Y, Kardosh A., et al. Therapy Resistant Gastroenteropancreatic Neuroendocrine Tumors. Cancers. 2022;14(19):4769. 10 What is a Gastrointestinal Carcinoid Tumor? ACS website. Available at: Accessed June 2025. 11 Survival Rates for Pancreatic Neuroendocrine Tumor. ACS website. Available at: Accessed June 2025. 12 Survival Rates for Gastrointestinal Carcinoid Tumors. ACS website. Available at: Accessed June 2025. 13 Survival Rates for Lung Carcinoid Tumors. ACS website. Available at: Accessed June 2025. 14 Neuroendocrine Tumor (NET). NCI website. Available at: Accessed June 2025. View source version on Contacts Investors Contact:Susan HubbardEVP, Public Affairs and Investor RelationsExelixis, Inc.(650) 837-8194shubbard@ Media Contact:Claire McConnaugheySenior Director, Public AffairsExelixis, Inc.(650) 837-7052cmcconn@ Error in retrieving data Sign in to access your portfolio Error in retrieving data Error in retrieving data Error in retrieving data Error in retrieving data