On July 24, 2025 Candel Therapeutics, Inc. (Candel or the Company) (Nasdaq: CADL), a clinical-stage biopharmaceutical company focused on developing multimodal biological immunotherapies to help patients fight cancer, reported that the European Medicines Agency (EMA) has granted Orphan Designation for CAN-2409 (aglatimagene besadenovec) for the treatment of pancreatic cancer (Press release, Candel Therapeutics, JUL 24, 2025, View Source [SID1234654505]). This designation complements CAN-2409’s existing U.S. Food and Drug Administration (FDA) Orphan Drug Designation and FDA Fast Track Designation for the treatment of pancreatic ductal adenocarcinoma (PDAC) awarded to CAN-2409 in April 2024 and December 2023, respectively, and underscores the significant unmet medical need in this disease beyond the U.S.

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CAN-2409 is an investigational, off-the-shelf, replication-defective adenovirus engineered to deliver the herpes simplex virus thymidine kinase (HSV-tk) gene to tumor cells. When administered with a prodrug (valacyclovir or acyclovir), the HSV-tk enzyme converts the prodrug into DNA-incorporating nucleotide analogs, causing immunogenic cell death and the release of tumor (neo)antigens within the tumor microenvironment (TME). This mechanism has the potential to induce an individualized, systemic immune response against multiple therapy-resistant solid tumors, including prostate cancer, non-small cell lung cancer (NSCLC), and PDAC.

The Company previously reported positive overall survival (OS) data from its randomized controlled phase 2a clinical trial of CAN-2409 plus valacyclovir in borderline resectable PDAC, demonstrating remarkable survival benefits with estimated median OS of 31.4 months in the CAN-2409 plus standard of care arm versus 12.5 months in the standard of care control arm, supported by immunological biomarker data. Notably, three of seven patients treated with CAN-2409 were still alive at the time of data cut-off (February 20, 2025) with survival of 66.0, 63.6 and 35.8 months after enrollment, respectively, suggesting a long tail of survival.

"Pancreatic cancer remains one of the most challenging malignancies to treat, particularly in patients whose disease is unresectable," said Garrett Nichols, MD, MS, Chief Medical Officer at Candel. "We observed that CAN-2409 profoundly remodels the tumor microenvironment, transforming it from ‘cold’ (non-inflamed and immunosuppressive) to ‘hot’ (inflamed with active immune infiltration) and extends survival."

The EMA grants Orphan Designation to drugs and biologics intended for the treatment, diagnosis or prevention of rare, life-threatening or chronically debilitating diseases or conditions that affect fewer than five in 10,000 people in the European Union. Orphan Designation allows pharmaceutical companies certain benefits, including reduced regulatory fees, clinical protocol assistance, research grants and up to 10 years of market exclusivity in the European Union, if approved.

"Receiving EMA Orphan Designation for CAN-2409 represents a significant regulatory milestone for CAN-2409 in this disease," said Paul Peter Tak, MD, PhD, FMedSci, President and Chief Executive Officer of Candel. "This designation, alongside our existing FDA Orphan Drug and Fast Track Designations for CAN-2409 in PDAC, underscores the promise of our novel multimodal immunotherapy approach. The notable benefits we’ve observed with CAN-2409, including evidence of a long tail of survival, highlight the transformative potential of this immunotherapy. As we advance our regulatory strategy across global markets, we remain committed to bringing CAN-2409 to patients who face limited therapeutic options. We look forward to continuing our development efforts and working with regulatory authorities across the world to make this innovative therapy available to patients in need."

CAN-2409 has received regulatory designations recognizing its potential across multiple solid tumor indications. In addition to the EMA Orphan Designation announced today and the FDA Orphan Drug Designation and FDA Fast Track Designation for PDAC mentioned above, CAN-2409 has also received FDA Fast Track Designation for NSCLC and localized prostate cancer, as well as FDA Regenerative Medicine Advanced Therapy designation (RMAT) for intermediate-to-high risk, localized prostate cancer.

About CAN-2409

CAN-2409 (aglatimagene besadenovec), Candel’s most advanced multimodal biological immunotherapy candidate, is an investigational, off-the-shelf, replication-defective adenovirus designed to deliver the herpes simplex virus thymidine kinase (HSV-tk) gene to a patient’s tumor. After intratumoral administration, HSV-tk enzyme activity results in conversion of prodrug (valacyclovir) into deoxyribonucleic acid (DNA)-incorporating nucleotide analogs, leading to immunogenic cell death in cells exhibiting DNA damage and proliferating cells, with subsequent release of a variety of tumor (neo)antigens in the tumor microenvironment. At the same time, the adenoviral serotype 5 capsid protein promotes inflammation through the induction of expression of pro-inflammatory cytokines, chemokines, and adhesion molecules. Together, this regimen is designed to induce an individualized and specific CD8+ T cell-mediated response against the injected tumor and uninjected distant metastases for broad anti-tumor activity, based on in situ immunization against a variety of tumor antigens. CAN-2409 has the potential to treat a broad range of solid tumors. Encouraging monotherapy activity as well as combination activity with standard of care radiotherapy, surgery, chemotherapy, and immune checkpoint inhibitors have previously been shown in several preclinical and clinical settings. More than 1,000 patients have been dosed with CAN-2409 with a favorable tolerability profile to date, supporting the potential for combination with standard of care, when indicated.

On July 24, 2025 Revolution Medicines, Inc. (Nasdaq: RVMD), a late-stage clinical oncology company developing targeted therapies for patients with RAS-addicted cancers, reported the publication of a peer-reviewed research paper in Science (Press release, Revolution Medicines, JUL 24, 2025, View Source [SID1234654504]). The scientific paper details the discovery and development of zoldonrasib (RMC-9805), a RAS(ON) G12D-selective covalent inhibitor.

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Oncogenic RAS mutations are observed in approximately 92% of pancreatic ductal adenocarcinoma (PDAC), 50% of colorectal cancer, and 30% of non-small cell lung cancer (NSCLC) cases. RAS G12D, an oncogenic variant of RAS that contains an aspartic acid in place of glycine at amino acid 12, is one of the most common RAS mutations in human solid tumors. Historically, it has been particularly challenging to target aspartic acid residues with covalent inhibitors. ​This publication details the novel mechanism of zoldonrasib, a member of the differentiated class of targeted protein binders called tri-complex inhibitors. This natural product-like compound successfully overcomes the challenge of engaging aspartic acid residues by leveraging a neomorphic protein-protein interface between the cellular chaperone cyclophilin A and activated RAS, or RAS(ON), to selectively catalyze covalent bond formation with RAS(ON) G12D proteins. Data reported in this paper demonstrate that this activity drives deep and durable tumor regressions in preclinical models of multiple tumor types with KRAS G12D mutations.

"The tri-complex inhibitor modality has proven to be a productive approach to solving the challenge of developing mutant-selective inhibitors for RAS variants beyond the G12C substitution, as demonstrated by zoldonrasib that targets the G12D variant," said Jan Smith, Ph.D., chief scientific officer of Revolution Medicines. "This report demonstrates the novel features of zoldonrasib that enable it to bind to the active or RAS(ON) state, including a highly novel covalent bond formed selectively with the substituted aspartic acid in this oncogenic variant. The preclinical profile combined with recent clinical data presentations provide an encouraging picture of the therapeutic potential for zoldonrasib in cancers caused by RAS G12D and further validate the broad utility of this drug discovery approach."

The full manuscript, titled "A neomorphic protein interface catalyzes covalent inhibition of RAS G12D aspartic acid in tumors," is available online at Science.

Zoldonrasib is currently undergoing evaluation in several clinical trials, including RMC-9805-001 (NCT06040541), a multicenter, open-label, dose escalation and dose-expansion Phase 1 study designed to evaluate zoldonrasib in patients with advanced solid tumors harboring a KRAS G12D mutation. NSCLC results from this study were presented in April 2025 at the American Academy for Cancer Research annual meeting and PDAC results from this study were presented in October 2024 at the EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics.

On July 24, 2025 Labcorp (NYSE: LH), a global leader of innovative and comprehensive laboratory services, reported results for the second quarter ended June 30, 2025 and raised full-year guidance (Press release, LabCorp, JUL 24, 2025, View Source [SID1234654503]).

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"Labcorp had a very strong second quarter, delivering double-digit topline growth, while expanding margins across both segments," said Adam Schechter, chairman and CEO of Labcorp. "We brought innovative tests to market, and applied our leadership in science and technology to drive growth, enhance the customer experience and improve our operations.  We remain committed to delivering sustained value to our customers, employees and shareholders as we execute on our long-term strategy. Based upon our performance in the first half and our momentum going into the second half of the year, we’re raising our guidance."

In the second quarter, Labcorp advanced its position as a partner of choice for hospitals, health systems and regional/local laboratories:

Announced an agreement to acquire select assets of Incyte Diagnostics’ clinical and anatomic pathology testing businesses in the Pacific Northwest.
Continued to progress the acquisition of select oncology and clinical testing assets from BioReference Health.
Subsequent to quarter end, Labcorp announced an agreement to acquire select assets of the outreach business from Community Health Systems across 13 states.
Labcorp also continued to incorporate the power of science, innovation and technology across the organization during or subsequent to the quarter:

Expanded its oncology portfolio with key launches including Labcorp Plasma Detect, a liquid biopsy test that assesses colon cancer recurrence risk and PGDx elio plasma focus Dx, the first-and-only FDA-authorized pan-solid tumor liquid biopsy test for targeted treatment guidance.
Continued to advance its leading position in Alzheimer’s disease, and plans in the coming weeks to offer Fujirebio FDA-cleared biomarker test that aids in diagnosing the disease.
Expanded its consumer offerings by launching several consumer-initiated tests through Labcorp OnDemand, including tests that measure an individual’s cortisol and leptin levels, and introducing a new and improved Ovia app, providing women with a single platform to support their health journey.
Introduced Labcorp Whole Health Solutions for functional medicine, integrative medicine and primary care practices. The solution offers specialized test panels and a test menu of more than 1,000 scientifically backed biomarkers.
Added digital pathology capabilities in Central Labs, including advanced image scanning to preserve critical sample data and AI-powered solutions to provide analysis on large datasets instantly.
On July 10, 2025, the company announced a quarterly cash dividend of $0.72 per share of common stock, payable on September 11, 2025, to stockholders of record at the close of business on August 28, 2025. In the quarter, Labcorp repurchased $200 million of common stock.

Additionally, Labcorp raised 2025 guidance for enterprise revenue, adjusted EPS and free cash flow primarily driven by currency, as well as the underlying strength of its businesses.

On July 24, 2025 GSK plc (LSE/NYSE: GSK) reported the approval of Blenrep in the European Union (EU) for the treatment of adults with relapsed or refractory multiple myeloma in combination with bortezomib plus dexamethasone (BVd) in patients who have received at least one prior therapy, and in combination with pomalidomide plus dexamethasone (BPd) in patients who have received at least one prior therapy including lenalidomide (Press release, GlaxoSmithKline, JUL 24, 2025, View Source [SID1234654502]).

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The approval is based on superior efficacy results demonstrated by Blenrep combinations in the pivotal DREAMM-7 and DREAMM-8 phase III trials in relapsed or refractory multiple myeloma. These include statistically significant and clinically meaningful progression-free survival (PFS) for Blenrep combinations versus triplet standard of care combinations in both trials and overall survival (OS) versus a daratumumab-based triplet in DREAMM-7.2,3,4 The safety and tolerability profiles of the Blenrep combinations were broadly consistent with the known profiles of the individual agents.2,3

Hesham Abdullah, Senior Vice President, Global Head Oncology, R&D, GSK, said: "Today’s approval of Blenrep combinations is a redefining moment for patients with relapsed or refractory multiple myeloma in the EU. Blenrep has the potential to extend remission and survival, with superior efficacy versus standards of care in our DREAMM clinical trial programme and the option to administer in both academic and community-based settings."

More than 50,000 cases of multiple myeloma are diagnosed in Europe each year, accounting for more than a quarter of global incidence.5 Blenrep is the only anti-BCMA (B-cell maturation antigen) antibody-drug conjugate (ADC) approved in multiple myeloma, providing patients with a differentiated mechanism of action to potentially help slow disease progression and extend survival.1 Blenrep combinations can be administered to a range of patient types across oncology treatment settings, enabling broad accessibility of an anti-BCMA therapy.

María-Victoria Mateos, MD, PhD, Head of Myeloma and Clinical Trials Unit, Haematology Department and Professor of Medicine at the University of Salamanca, Spain, and DREAMM-7 principal investigator, said: "With the approval of Blenrep combinations in the EU, we now have additional tools in our efforts to keep patients in remission longer, maintain quality of life and extend survival. The robust efficacy supported by the DREAMM-7 and DREAMM-8 trials, together with manageable outpatient administration in academic and community settings, positions Blenrep combinations as a fundamentally differentiated treatment approach for multiple myeloma patients starting from first relapse."

Both DREAMM-7 and DREAMM-8 showed statistically significant and clinically meaningful PFS improvements for the Blenrep combinations compared to standard of care triplet combinations in the second line or later treatment of multiple myeloma.2,3 In DREAMM-7, the Blenrep combination (n=243) nearly tripled median PFS versus the daratumumab-based comparator (n=251) (36.6 months versus 13.4 months, respectively (hazard ratio [HR]: 0.41 [95% confidence interval (CI): 0.31-0.53], p-value<0.00001).2 DREAMM-7 also met the key secondary endpoint of OS, showing a statistically significant and clinically meaningful 42% reduction in the risk of death at a median follow-up of 39.4 months favouring the Blenrep combination versus the daratumumab-based comparator (HR: 0.58; 95% CI: 0.43-0.79; p=0.00023). The median OS was not reached in either arm of the study. The three-year OS rate was 74% in the Blenrep combination arm and 60% in the daratumumab combination arm.4 In DREAMM-8, at a median follow-up of 21.8 months, the median PFS was not yet reached (95% CI: 20.6-not yet reached [NR]) with the Blenrep combination compared to 12.7 months in the bortezomib combination (95% CI: 9.1-18.5) at the time of primary analysis.3

Blenrep combinations consistently benefited a broad range of patients, including those with poor prognostic features or outcomes, such as high-risk cytogenetics or those refractory to lenalidomide. Both trials also showed clinically meaningful improvements across all other secondary efficacy endpoints, including deeper and more durable responses versus the respective comparators.2,3

DREAMM-7 and DREAMM-8 showed that eye-related side effects associated with Blenrep can be managed and reversed with appropriate dose modifications and follow-up. This allowed patients to maintain benefit and resulted in low rates of discontinuation due to eye-related side effects (≤9%) in both trials.2,3 The most commonly reported non-ocular adverse events (>30% of participants) in the Blenrep combination arm were thrombocytopenia (87%) and diarrhoea (32%) in DREAMM-7, and neutropenia (63%), thrombocytopenia (55%) and COVID-19 (37%) in DREAMM-8.2,3

Blenrep combinations are also approved in relapsed or refractory multiple myeloma in the UK6 and Japan7 as well as other markets, including Canada and Switzerland (based on the results of DREAMM-8). Applications are currently under review in all major markets globally, including the US8 and China9 (based on the results of DREAMM-7, with Breakthrough Therapy Designation for the combination and priority review for the application).

About multiple myeloma
Multiple myeloma is the third most common blood cancer globally and is generally considered treatable but not curable.10,11 There are approximately more than 180,000 new cases of multiple myeloma diagnosed globally each year.5 Research into new therapies is needed as multiple myeloma commonly becomes refractory to available treatments.1 Many patients with multiple myeloma are treated in a community cancer setting, leaving an urgent need for new, effective therapies with manageable side effects that can be administered outside of an academic centre.12,13

About Blenrep
Blenrep is an ADC comprising a humanised BCMA monoclonal antibody conjugated to the cytotoxic agent auristatin F via a non-cleavable linker. The drug linker technology is licensed from Seagen Inc.; the monoclonal antibody is produced using POTELLIGENT Technology licensed from BioWa Inc., a member of the Kyowa Kirin Group.

Indication
In the EU, Blenrep is indicated in adults for the treatment of relapsed or refractory multiple myeloma:

in combination with bortezomib and dexamethasone in patients who have received at least one prior therapy; and
in combination with pomalidomide and dexamethasone in patients who have received at least one prior therapy including lenalidomide.
IMPORTANT SAFETY INFORMATION FOR BLENREP
Refer to the Blenrep EMA Reference Information14 which will soon be available for a full list of adverse events and the complete important safety information in the EU.

About DREAMM-7
DREAMM-7 is a multicentre, open-label, randomised phase III clinical trial evaluating the efficacy and safety of belantamab mafodotin combined with bortezomib plus dexamethasone (BVd) compared to daratumumab combined with bortezomib plus dexamethasone (DVd) in patients with relapsed or refractory multiple myeloma who previously were treated with at least one prior line of multiple myeloma therapy, with documented disease progression during or after their most recent therapy. The trial enrolled 494 participants who were randomised 1:1 to receive either BVd or DVd. Belantamab mafodotin was administered at a dose of 2.5mg/kg intravenously every three weeks in combination for the first eight cycles and then continued as a single agent. The primary endpoint was PFS as per an independent review committee, with secondary endpoints including OS, duration of response (DOR), and minimal residual disease (MRD) negativity rate as assessed by next-generation sequencing. Other secondary endpoints include overall response rate (ORR), safety, and patient reported and quality of life outcomes.

PFS results were presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Plenary Series in February 2024 and published in the New England Journal of Medicine. OS results were presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in December 2024.2,4

About DREAMM-8
DREAMM-8 is a multicentre, open-label, randomised phase III clinical trial evaluating the efficacy and safety of belantamab mafodotin in combination with pomalidomide plus dexamethasone (BPd) compared to bortezomib and pomalidomide plus dexamethasone (PVd) in patients with relapsed or refractory multiple myeloma previously treated with at least one prior line of multiple myeloma therapy, including a lenalidomide-containing regimen, and who have documented disease progression during or after their most recent therapy. The trial included 302 participants who were randomised 1:1 to receive either BPd or PVd. Compared to the patient population studied in the DREAMM-7 trial, patients in DREAMM-8 were more heavily pre-treated in that all had prior exposure to lenalidomide, 78% were refractory to lenalidomide, 25% had prior daratumumab exposure and of those most were daratumumab refractory. Belantamab mafodotin was administered at a dose of 2.5mg/kg intravenously for the first cycle and then 1.9mg/kg intravenously every four weeks. The primary endpoint was PFS as per an independent review committee, with key secondary endpoints including OS and MRD negativity rate as assessed by next-generation sequencing. Other secondary endpoints include ORR, DOR, safety, and patient reported and quality of life outcomes.

Results were first presented at the 2024 ASCO (Free ASCO Whitepaper) Annual Meeting and published in the New England Journal of Medicine.3 Updated PFS results were presented at the European Hematology Association (EHA) (Free EHA Whitepaper) Congress in June 2025.

On July 24, 2025 Exelixis, Inc. (Nasdaq: EXEL) reported that its partner Ipsen received approval from the European Commission (EC) for CABOMETYX (cabozantinib) for the treatment of adult patients with unresectable or metastatic, well-differentiated pancreatic (pNET) and extra-pancreatic (epNET) neuroendocrine tumors who have progressed following at least one prior systemic therapy other than somatostatin analogues (Press release, Exelixis, JUL 24, 2025, View Source [SID1234654501]). This approval follows the positive opinion received from the European Medicines Agency’s Committee for Medicinal Products for Human Use in June 2025 and allows for the marketing of CABOMETYX in this indication in all 27 member states of the European Union (EU), Norway, Liechtenstein and Iceland.

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"The availability of CABOMETYX in the European Union for patients with previously treated advanced neuroendocrine tumors is a significant milestone as there have been limited treatment advancements in the past decade, including very few options shown to improve outcomes across a heterogenous population," said Amy Peterson, M.D., Executive Vice President, Product Development and Medical Affairs, and Chief Medical Officer, Exelixis. "This approval builds on the global CABOMETYX franchise and extends its benefit to even more patients in need of new treatment options. We are proud to partner with Ipsen in our shared commitment to improving the standard of care for people living with advanced, difficult-to-treat cancers."

The EC approval is based on results from the phase 3 CABINET pivotal trial, which evaluated 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 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.

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 ClinicalTrials.gov.

About NET
NET 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.