On MAY 26, 2022 Genmab A/S (Nasdaq: GMAB) reported that multiple abstracts evaluating several investigational medicines in the company’s pipeline, or created using Genmab’s innovative drug development platforms, will be presented at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, being held at McCormick Place, in Chicago, IL, and virtually, June 3-7 (Press release, Genmab, MAY 26, 2022, View Source [SID1234615085]). The presentations will include data from multiple arms of the phase 1b/2 EPCORE NHL-2 clinical trial, evaluating the safety and preliminary efficacy of epcoritamab (DuoBody-CD3xCD20), an investigational subcutaneous bispecific antibody, in combination with standard-of-care therapies for the treatment of various types of B-cell non-Hodgkin lymphoma (NHL), including first-line, high-risk diffuse large B-cell lymphoma (DLBCL), relapsed or refractory DLBCL, and relapsed or refractory follicular lymphoma (FL). Epcoritamab is being co-developed by Genmab and AbbVie (NYSE: ABBV).

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In addition, several abstracts evaluating tisotumab vedotin (TIVDAK) in various tumor types will be presented, including an oral presentation of the innovaTV 205 study evaluating tisotumab vedotin in combination with carboplatin or pembrolizumab in first-line patients with recurrent or metastatic cervical cancer (r/mCC). Tisotumab vedotin is being co-developed by Genmab and Seagen (Nasdaq: SGEN), under an agreement in which the companies share costs and profits for the product on a 50:50 basis.

Results from several clinical trials evaluating Janssen Biotech, Inc. (Janssen’s) subcutaneous formulation of daratumumab, and Janssen’s bispecific programs leveraging Genmab’s DuoBody technology platform, will be presented. Daratumumab is being developed by Janssen under an exclusive worldwide license to develop, manufacture and commercialize daratumumab from Genmab, and the companies have a research and license agreement to create and develop bispecific antibodies using Genmab’s DuoBody technology platform.

All abstracts accepted for presentation have been published on the ASCO (Free ASCO Whitepaper) website.

"This year’s ASCO (Free ASCO Whitepaper) provides a great opportunity for Genmab to share data evaluating epcoritamab, our first-in-class approved medicine tisotumab vedotin, and our innovative technologies, which reinforce our commitment to delivering new therapeutic options to patients in need," said Dr. Judith Klimovsky, Executive Vice President and Chief Development Officer of Genmab. "Through our own research and development, and through industry partnerships, Genmab is developing differentiated therapies with the goal of transforming the future of cancer treatment."

Abstracts accepted for presentation at ASCO (Free ASCO Whitepaper) include:

Epcoritamab (DuoBody-CD3xCD20):

Abstract #: 7523. First-line treatment with subcutaneous (SC) epcoritamab (epco) + R-CHOP in patients (pts) with high-risk diffuse large B-cell lymphoma (DLBCL): phase 1/2 data update; Falchi et al. Saturday, June 4, 2022, 8:00-11:00 a.m. CDT/9:00 p.m.-12:00 p.m. EDT.
Abstract #: 7524. Subcutaneous epcoritamab with rituximab + lenalidomide (R2) in patients (pts) with relapsed or refractory (R/R) follicular lymphoma (FL): update from phase 1/2 trial; Falchi et al. Saturday, June 4, 2022, 8:00-11:00 a.m. CDT/9:00 p.m.-12:00 p.m. EDT.
Abstract #: 7528. Subcutaneous epcoritamab + R-DHAX/C in patients (pts) with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) eligible for autologous stem cell transplant (ASCT): preliminary phase 1/2 results; Abrisqueta et al. Saturday, June 4, 2022, 8:00-11:00 a.m. CDT/9:00 p.m.-12:00 p.m. EDT.
Abstract #: 7527. Epcoritamab (epco) with gemcitabine + oxaliplatin (GemOx) in patients (pts) with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) ineligible for autologous stem cell transplant (ASCT) induces high response rate even in pts failing CAR T therapy; Brody et al. Saturday, June 4, 2022, 8:00-11:00 a.m. CDT/9:00 p.m.-12:00 p.m. EDT.
Abstract #: 7576. DLBCL Cell of Origin Typing and Whole Transcriptome Analysis using Single Slides with HTG EdgeSeq; Loya, et al. Saturday, June 4, 2022, 8:00-11:00 a.m. CDT/9:00 p.m.-12:00 p.m. EDT.
Tisotumab Vedotin:

Abstract #: 5507. Tisotumab vedotin (TV) + pembrolizumab (pembro) in first-line (1L) recurrent or metastatic cervical cancer (r/mCC): Interim results of ENGOT Cx8/GOG 3024/innovaTV 205; D. Lorusso et al. Monday, June 6, 2022, 8:00-11:00 a.m. CDT/9:00 a.m.-12:00 p.m. EDT.
Abstract#: TPS5603. Trial in progress update on ENGOT-cx8/GOG-3024/innovaTV 205: Addition of a new cohort of tisotumab vedotin (TV) + pembrolizumab (pembro) + carboplatin (carbo) ± bevacizumab (bev) in first line (1L) recurrent/metastatic cervical cancer (r/mCC); I. Vergote et al. Saturday, June 4, 2022, 1:15-4:15 p.m. CDT/2:15-5:15 p.m. EDT.
Abstract #: TPS6100. innovaTV 207: New combination dosing cohorts in the open label phase 2 study of tisotumab vedotin in solid tumors; X. Le et al. Monday, June 6, 2022, 1:15-4:15 p.m. CDT/2:15 p.m.-5:15 p.m. EDT.
Abstract #: 5532. Factors Associated with Receipt of Second-Line Recurrent or Metastatic Cervical Cancer Treatment in the US: A Retrospective Administrative Claims Analysis; K. Sonawane et al. Saturday, June 4, 2022, 1:15-4:15 p.m. CDT/2:15-5:15 p.m. EDT.
Abstract #: 5523. Cervical Cancer Geographical Burden Analyzer: An Interactive, Open-Access Tool For Understanding Geographical Disease Burden in Recurrent or Metastatic Cervical Cancer Patients; T. Castellano et al. Saturday, June 4, 2022, 1:15-4:15 p.m. CDT/2:15-5:15 p.m. EDT
Abstract #: E17520. Productivity losses under various second-line recurrent or metastatic cervical cancer treatment scenarios in the US; T. Ayer et al.
Abstract #: E17525. Patterns of Care in Medicaid-Enrollees with recurrent or metastatic Cervical Cancer; C. A. Leath et al.
Daratumumab:

Subcutaneous daratumumab (DARA SC) versus active monitoring in patients (pts) with high-risk smoldering multiple myeloma (SMM): randomized, open-label, phase 3 AQUILA study; Dimopoulos et al.
Time to response, duration of response, and patient-reported outcomes (PROs) with daratumumab (DARA) plus lenalidomide and dexamethasone (D-Rd) vs lenalidomide and dexamethasone (Rd) alone in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM): subgroup analysis of the phase 3 MAIA study; Facon et al.
Efficacy and safety of daratumumab (DARA) in pediatric and young adult patients (pts) with relapsed/refractory T-cell acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL): results from the phase 2 DELPHINUS study; Hogan et al.
Daratumumab (DARA) + lenalidomide, bortezomib, and dexamethasone (RVd) in Black patients (pts) with transplant-eligible newly diagnosed multiple myeloma (NDMM): an updated subgroup analysis of GRIFFIN; Nooka et al.
Daratumumab (DARA) + lenalidomide, bortezomib, and dexamethasone (RVd) in transplant-eligible newly diagnosed multiple myeloma (NDMM): a post hoc analysis of sustained minimal residual disease (MRD) negativity from GRIFFIN; Rodriguez et al.
Daratumumab (DARA) in combination with bortezomib plus dexamethasone (D-Vd) or lenalidomide plus dexamethasone (D-Rd) in relapsed or refractory multiple myeloma (RRMM): subgroup analysis of the phase 3 CASTOR and POLLUX studies in patients (pts) with early or late relapse after initial therapy; Spencer et al.
About Epcoritamab
Epcoritamab is an investigational IgG1-bispecific antibody created using Genmab’s proprietary DuoBody technology. Genmab’s DuoBody-CD3 technology is designed to direct cytotoxic T cells selectively to elicit an immune response towards target cell types. Epcoritamab is designed to simultaneously bind to CD3 on T cells and CD20 on B-cells and induces T cell mediated killing of CD20+ cells.i Epcoritamab was developed with selective, silencing mutations that may limit systemic, non-specific activity.ii CD20 is expressed on B-cells and a clinically validated therapeutic target in many B-cell malignancies, including diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma and chronic lymphocytic leukemia.iii,iv Epcoritamab is being co-developed by Genmab and AbbVie as part of the companies’ broad oncology collaboration.

About Tisotumab Vedotin
Tisotumab vedotin-tftv (TIVDAK) is an antibody-drug conjugate (ADC) composed of Genmab’s human monoclonal antibody directed to tissue factor (TF) and Seagen’s ADC technology that utilizes a protease-cleavable linker that covalently attaches the microtubule-disrupting agent monomethyl auristatin E (MMAE) to the antibody. Nonclinical data suggests that the anticancer activity of tisotumab vedotin is due to the binding of the ADC to TF expressing cancer cells, followed by internalization of the ADC-TF complex, and release of MMAE via proteolytic cleavage. MMAE disrupts the microtubule network of actively dividing cells, leading to cell cycle arrest and apoptotic cell death. In vitro, tisotumab vedotin also mediates antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity.

In September 2021, the U.S. Food and Drug Administration granted accelerated approval for tisotumab vedotin-tftv (TIVDAK) in adult patients with previously treated recurrent or metastatic cervical cancer with disease progression on or after chemotherapy, making it the first and only approved ADC for these patients. The ongoing clinical trial InnovaTV 301, an open label, randomized, global trial, is intended as the confirmatory trial for use in verifying and describing the clinical benefit and as support for US and global regulatory applications.

TIVDAK (tisotumab vedotin-tftv) U.S Indication & Important Safety Information
TIVDAK is indicated for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Important Safety Information

BOXED WARNING: OCULAR TOXICITY
TIVDAK caused changes in the corneal epithelium and conjunctiva resulting in changes in vision, including severe vision loss, and corneal ulceration. Conduct an ophthalmic exam at baseline, prior to each dose, and as clinically indicated. Adhere to premedication and required eye care before, during, and after infusion. Withhold TIVDAK until improvement and resume, reduce the dose, or permanently discontinue, based on severity.

Warnings and Precautions
Ocular Adverse Reactions occurred in 60% of patients with cervical cancer treated with TIVDAK across clinical trials. The most common were conjunctival adverse reactions (40%), dry eye (29%), corneal adverse reactions (21%), and blepharitis (8%). Grade 3 ocular adverse reactions occurred in 3.8 % of patients, including severe ulcerative keratitis in 3.2% of patients. One patient experienced ulcerative keratitis with perforation requiring corneal transplantation. Cases of symblepharon were reported in patients with other tumor types treated with TIVDAK at the recommended dose. In innovaTV 204, 4% of patients experienced visual acuity changes to 20/50 or worse including 1% of patients who experienced a visual acuity change to 20/200. Of the patients who experienced decreased visual acuity to 20/50 or worse, 75% resolved, including the patient who experienced decreased visual acuity to 20/200.

Refer patients to an eye care provider for an ophthalmic exam including visual acuity and slit lamp exam at baseline, prior to each dose, and as clinically indicated. Adhere to premedication and required eye care to reduce the risk of ocular adverse reactions. Promptly refer patients to an eye care provider for any new or worsening ocular signs and symptoms. Withhold dose, reduce the dose, or permanently discontinue TIVDAK based on the severity of the adverse reaction.

Peripheral Neuropathy (PN) occurred in 42% of cervical cancer patients treated with TIVDAK across clinical trials; 8% of patients experienced Grade 3 PN. PN adverse reactions included peripheral neuropathy (20%), peripheral sensory neuropathy (11%), peripheral sensorimotor neuropathy (5%), motor neuropathy (3%), muscular weakness (3%), and demyelinating peripheral polyneuropathy (1%). One patient with another tumor type treated with TIVDAK at the recommended dose developed Guillain- Barre syndrome. Monitor patients for signs and symptoms of neuropathy. For new or worsening PN, withhold, dose reduce, or permanently discontinue TIVDAK based on the severity of PN.

Hemorrhage occurred in 62% of cervical cancer patients treated with TIVDAK across clinical trials. The most common all grade hemorrhage adverse reactions were epistaxis (44%), hematuria (10%), and vaginal hemorrhage (10%). Grade 3 hemorrhage occurred in 5% of patients. Monitor patients for signs and symptoms of hemorrhage. For patients experiencing pulmonary or CNS hemorrhage, permanently discontinue TIVDAK. For Grade ≥2 hemorrhage in any other location, withhold until bleeding has resolved, blood hemoglobin is stable, there is no bleeding diathesis that could increase the risk of continuing therapy, and there is no anatomical or pathologic condition that can increase the risk of hemorrhage recurrence. After resolution, either resume treatment or permanently discontinue TIVDAK.

Pneumonitis: Severe, life-threatening, or fatal pneumonitis can occur in patients treated with antibody-drug conjugates containing vedotin, including TIVDAK. Among patients with cervical cancer treated with TIVDAK across clinical trials, 2 patients (1.3%) experienced pneumonitis, including 1 patient who had a fatal outcome.

Monitor patients for pulmonary symptoms of pneumonitis. Infectious, neoplastic, and other causes for symptoms should be excluded through appropriate investigations.

Withhold TIVDAK for patients who develop persistent or recurrent Grade 2 pneumonitis and consider dose reduction. Permanently discontinue TIVDAK in all patients with Grade 3 or 4 pneumonitis.

Embryo-Fetal Toxicity: TIVDAK can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TIVDAK and for 2 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TIVDAK and for 4 months after the last dose.

Adverse Reactions
In the innovaTV 204 clinical trial (n=101), serious adverse reactions occurred in 43% of patients; the most common (≥3%) were ileus (6%), hemorrhage (5%), pneumonia (4%), PN, sepsis, constipation, and pyrexia (each 3%). Fatal adverse reactions occurred in 4% of patients who received TIVDAK, including septic shock, pneumonitis, sudden death, and multisystem organ failure (each 1%).

Adverse reactions leading to permanent discontinuation occurred in 13% of patients receiving TIVDAK; the most common (≥3%) were PN (5%) and corneal adverse reactions (4%). Adverse reactions leading to dose interruption occurred in 47% of patients; the most common (≥3%) were PN (8%), conjunctival adverse reactions (4%), and hemorrhage (4%). Adverse reactions leading to dose reduction occurred in 23% of patients; the most common (≥3%) were conjunctival adverse reactions (9%) and corneal adverse reactions (8%).

The most common (≥25%) adverse reactions, including laboratory abnormalities, were hemoglobin decreased (52%), fatigue (50%), lymphocytes decreased (42%), nausea (41%), PN (39%), alopecia (39%), epistaxis (39%), conjunctival adverse reactions (37%), hemorrhage (32%), leukocytes decreased (30%), creatinine increased (29%), dry eye (29%), prothrombin international normalized ratio increased (26%), activated partial thromboplastin time prolonged (26%), diarrhea (25%), and rash (25%).

Drug interactions

Strong CYP3A4 Inhibitors: Concomitant use with strong CYP3A4 inhibitors may increase unconjugated monomethyl auristatin E (MMAE) exposure, which may increase the risk of TIVDAK adverse reactions. Closely monitor patients for TIVDAK adverse reactions.

Use in Specific Populations

Moderate or Severe Hepatic Impairment: MMAE exposure and adverse reactions are increased. Avoid use.

Lactation: Advise lactating women not to breastfeed during TIVDAK treatment and for at least 3 weeks after the last dose.

Please see full prescribing information, including BOXED WARNING for TIVDAK here.

About DARZALEX(daratumumab)
DARZALEX (daratumumab) is the first monoclonal antibody (mAb) to receive U.S. Food and Drug Administration approval to treat certain multiple myeloma indications. Daratumumab is being developed by Janssen Biotech, Inc. under an exclusive worldwide license to develop, manufacture and commercialize daratumumab from Genmab. The subcutaneous formulation of daratumumab (daratumumab and hyaluronidase-fihj) is the first subcutaneous CD38 antibody approved for the treatment of certain multiple myeloma indications and the first and only approved treatment for certain patients with light-chain (AL) amyloidosis.v,vi,vii

Please see local country prescribing information for all labeled indication and safety information.

On May 26, 2022 Galera Therapeutics, Inc. (Nasdaq: GRTX), a clinical-stage biopharmaceutical company focused on developing and commercializing a pipeline of novel, proprietary therapeutics that have the potential to transform radiotherapy in cancer, reported data from its Phase 3 ROMAN trial of avasopasem for severe oral mucositis will be highlighted in an oral presentation at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting on Friday, June 3, 2022 from 2:45 p.m. – 5:45 p.m. CDT during the Head and Neck Cancer session (Press release, Galera Therapeutics, MAY 26, 2022, View Source [SID1234615084]). Topline data was announced in December 2021. Abstracts are currently available in the ASCO (Free ASCO Whitepaper) digital program.

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"We are pleased that our Phase 3 trial of avasopasem was selected for an oral presentation at ASCO (Free ASCO Whitepaper), where details of the clinically meaningful and statistically significant results will be shared," said Mel Sorensen, M.D., Galera’s President and CEO. "Our research shows that radiation oncologists and patients cite SOM as the most burdensome radiotherapy toxicity in head and neck cancer treatment, and there are currently no FDA-approved drugs to reduce the incidence or duration of SOM in solid tumors. Avasopasem has been granted Breakthrough Therapy and Fast Track Designations by the U.S. FDA for the reduction of SOM induced by radiotherapy, and we look forward to submitting a New Drug Application to the FDA by year end in order to bring this potential treatment to patients as quickly as possible."

Results from the 455-patient Phase 3 trial demonstrated a meaningful reduction in patients’ SOM burden across multiple endpoints, with statistically significant reductions on the primary endpoint of incidence of SOM and the secondary endpoint of number of days of SOM, more than halving the median number of days a patient suffered SOM. Exploratory analyses, such as time to SOM onset and SOM incidence at various landmarks of radiotherapy delivered, also demonstrated clinical benefit of avasopasem in reducing the burden of SOM. Avasopasem also appeared to be generally well tolerated compared to placebo. These results are consistent with those from the positive 223-patient Phase 2b trial (Anderson, J Clin Oncol, 2019) that was the basis for Breakthrough Therapy Designation.

Additionally, Galera’s Phase 2 GRECO-2 study of rucosopasem (GC4711) in combination with stereotactic body radiation therapy in pancreatic cancer will be presented at the ASCO (Free ASCO Whitepaper) Annual Meeting in a Trials in Progress poster session on Saturday, June 4, 2022, from 8:00 a.m. – 11:00 a.m. CDT. The primary endpoint of this trial is overall survival.

About Severe Oral Mucositis (SOM)
Approximately 42,000 patients with head and neck cancer undergo standard-of-care radiotherapy every year in the U.S. and are at risk of experiencing SOM. In patients with head and neck cancer, radiotherapy is a mainstay of treatment. Approximately 70 percent of patients receiving radiotherapy for head and neck cancer develop SOM, defined by the inability to eat solid food or drink liquids. The impact on patients who develop SOM is substantial, particularly when hospitalization and/or surgical placement of PEG tubes to maintain nutrition and hydration are required. SOM can adversely affect cancer treatment outcomes by causing interruptions in radiotherapy, which may compromise the otherwise good prognosis for tumor control in many of these patients. There is currently no drug approved to prevent or treat SOM for these patients.

About Avasopasem
Avasopasem manganese (avasopasem, or GC4419) is a selective small molecule dismutase mimetic in development for the reduction of radiation-induced severe oral mucositis (SOM) in patients with locally advanced head and neck cancer (HNC) and for the reduction of radiation-induced esophagitis in patients with lung cancer. The FDA has granted Fast Track and Breakthrough Therapy designations to avasopasem for the reduction of SOM induced by radiotherapy, with or without systemic therapy.

On May 26, 2022 Forma Therapeutics Holdings, Inc. (Nasdaq: FMTX), a clinical-stage biopharmaceutical company focused on sickle cell disease (SCD), prostate cancer and other rare hematologic diseases and cancers, reported that it will hold a virtual R&D Day today to provide a comprehensive update on its pipeline and strategic vision (Press release, Forma Therapeutics, MAY 26, 2022, View Source [SID1234615083]).

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The R&D event is taking place today at 8:00 a.m. ET. A live webcast will be available in the "News & Investors" section of Forma’s website.

"We are pleased to share insights into Forma’s unique commitment to patients and expansion of etavopivat development into transfusion-dependent populations that have tremendous unmet need across sickle cell disease, thalassemia and MDS," said Frank Lee, president and chief executive officer of Forma.

"In our early stage research pipeline, we are excited to introduce a USP1 program that targets a novel DNA damage repair pathway relevant to a broad range of tumor types." said David Cook, chief scientific officer of Forma. "We are also capitalizing on our knowledge of the emerging science of red blood cell health by exploring areas beyond hematologic disease."

Etavopivat (oral PKR activator) Program in SCD, thalassemia and MDS:

In addition to ongoing enrollment in the Phase II/III Hibiscus Study in SCD, Forma will outline ongoing and anticipated future development plans:

A Phase II trial is enrolling patients in three cohorts: SCD with chronic transfusion, and both transfusion-dependent and non-transfusion-dependent thalassemia. Etavopivat has the potential to address RBC health, hemolytic anemia and/or ineffective erythropoiesis in these populations, leading to reduction of transfusion burden and associated iron overload and improvement of anemia.

A Phase II trial in lower risk MDS is planned to commence in the second half of 2022. Dr. Michael Savona of Vanderbilt University will review the significant unmet need in lower-risk MDS and the potential for etavopivat to provide a well-tolerated oral treatment that may be able to improve the ability of bone marrow to produce healthier RBCs.

Analyses from the completed Phase I trial in SCD show benefit in both pain events reported in the trial and vaso-occlusive crises (VOC’s) occurring on treatment.

Enrollment in the Phase II/III Hibiscus Study in SCD is on track for the first interim analysis (IA1) in late 2022.

FT-7051 (oral CBP/p300 inhibitor) in prostate cancer:

Forma’s Phase I trial continues to enroll men with metastatic castration-resistant prostate cancer (mCRPC).

As of May 12, 2022, 25 patients have enrolled in the Phase I dose escalation trial, assessing the predicted efficacious exposure range supported by target engagement.

The trial population is heavily pre-treated, with a high AR-v7 positivity rate and mutation burden.

Future trial enrollment to include less heavily pre-treated patients and alternative dosing schedule to address adverse events, with updated results expected in the first half of 2023.

Research Pipeline/RBC Health:

Forma’s ongoing research efforts are focused on novel mechanisms of action in oncology and expansion in red blood cell health and hematologic diseases:

Forma’s research pipeline is led by the USP1 program (FT-3171), targeting a novel DNA damage repair pathway with potential to address multiple tumor types in both poly ADP ribose polymerase inhibitor (PARPi)-sensitive and resistant settings.

FT-3171 IND filing is expected in the first half of 2023.

Ongoing pre-clinical research is targeting areas of expansion for RBC health, novel mechanisms that may be complementary to etavopivat in rare hematology, and targeted oncology.

On May 26, 2022 Exelixis, Inc. (Nasdaq: EXEL) reported detailed results from multiple cohorts of the phase 1b COSMIC-021 trial of cabozantinib (CABOMETYX) as a monotherapy and in combination with atezolizumab in patients with locally advanced or metastatic solid tumors (Press release, Exelixis, MAY 26, 2022, View Source [SID1234615081]). Data from urothelial carcinoma (UC) cohorts 3, 4 and 5 and from non-small cell lung cancer (NSCLC) cohorts 7 and 20 will be presented during oral abstract sessions at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, which is being held June 3-7.

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UC Cohorts 3, 4 and 5 (abstract 4504):

UC results will be presented by Sumanta Pal, M.D., Clinical Professor, City of Hope, and the principal investigator for the COSMIC-021 study beginning at 2:45 p.m. CT on Friday, June 3 during the Oral Abstract Session: Genitourinary Cancer – Kidney and Bladder. In these cohorts, enrolled patients had inoperable locally advanced or metastatic UC with transitional cell histology and Eastern Cooperative Oncology Group Performance Status of 0-1. Cohort 3 had not received prior systemic therapy for advanced/metastatic disease and was ineligible for cisplatin-based chemotherapy, cohort 4 had not received prior systemic therapy for advanced/metastatic disease and was eligible for cisplatin-based chemotherapy and cohort 5 had received one prior immune checkpoint inhibitor (ICI) and no prior vascular endothelial growth factor receptor (VEGFR)-tyrosine kinase inhibitor (TKI) therapy. Patients in all three cohorts received cabozantinib in combination with atezolizumab.

At a median follow-up of 27.9 months for cohort 3, 19.1 months for cohort 4 and 32.9 months for cohort 5, the primary endpoint of objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by investigator was 20%, 30% and 10%, respectively. Cabozantinib in combination with atezolizumab demonstrated encouraging clinical activity for other endpoints and a manageable safety profile across all three cohorts. See other efficacy outcomes, the most common treatment-related adverse events (AEs) and discontinuation rates in Table 1 below.

"People with advanced bladder cancer face a poor prognosis, meaning new treatment options are needed, both in the first-line setting and after disease progression," said Dr. Pal. "Building on previous positive results in bladder cancer from cohort 2 of COSMIC-021, the findings that the combination of cabozantinib and atezolizumab benefited multiple bladder cancer populations are encouraging for these patients and their physicians. These results, together with the newest findings from multiple COSMIC-021 lung cohorts also being presented at ASCO (Free ASCO Whitepaper), underscore the broad potential of this combination regimen for patients with advanced cancers who require additional treatment options."

NSCLC Cohorts 7 and 20 (abstract 9005):

Results for cohorts 7 and 20 will be presented by Joel Neal, M.D., Ph.D., Associate Professor of Medicine (Oncology), Stanford School of Medicine, beginning at 1:00 p.m. CT on Friday, June 3 during the Oral Abstract Session: Lung Cancer – Non-Small Cell Metastatic. Eligible patients had stage IV non-squamous NSCLC and had progressed on one prior ICI, with no more than two lines of prior systemic anticancer therapy, but not VEGFR-TKI therapy. Patients received either cabozantinib in combination with atezolizumab (cohort 7) or cabozantinib alone (cohort 20).

At a median follow-up of 24.7 months for cohort 7 and 21.5 months for cohort 20, the primary endpoint of ORR per RECIST version 1.1 by investigator was 19% and 6%, respectively. A manageable safety profile was seen in both cohorts. Other efficacy outcomes, the most common treatment-emergent AEs and discontinuation rates are shown in Table 2 below. In cohort 7, clinical activity was observed with cabozantinib in combination with atezolizumab irrespective of PD-L1 expression.

"We are pleased to present these promising findings of cabozantinib in combination with atezolizumab at ASCO (Free ASCO Whitepaper) 2022, reinforcing our longstanding commitment to advancing therapies that improve outcomes for those with advanced solid tumors," said Vicki L. Goodman, M.D., Executive Vice President, Product Development & Medical Affairs, and Chief Medical Officer, Exelixis. "We look forward to continuing research for these cancers, including through our ongoing phase 3 CONTACT-01 pivotal trial of cabozantinib in combination with atezolizumab in non-small cell lung cancer. Beyond cabozantinib, we launched the phase 1b STELLAR-001 and STELLAR-002 trials of our next-generation TKI, XL092, in combination with immunotherapies in genitourinary cancers, and we are also studying our next-generation tissue factor-targeting antibody-drug conjugate, XB002, in advanced solid tumors, including lung and bladder cancers."

Includes 8 patients who initiated therapy with cabozantinib plus atezolizumab after experiencing disease progression.

About COSMIC-021

COSMIC-021 is a multicenter, phase 1b, open-label study that enrolled a total of 914 patients. The trial was divided into two parts: a dose-escalation phase and an expansion cohort phase. The dose-escalation phase was designed to enroll patients either with advanced renal cell carcinoma (RCC) with or without prior systemic therapy or with inoperable, locally advanced, metastatic or recurrent UC (including renal, pelvis, ureter, urinary bladder and urethra), after prior platinum-based therapy. Ultimately, all 12 patients who enrolled in this stage of the trial had advanced RCC. The dose-escalation phase of the study determined the recommended dose of cabozantinib to be 40 mg daily when given in combination with atezolizumab (1200 mg infusion once every three weeks).

In the expansion phase, the trial enrolled a total of 902 patients across 23 cohorts in 12 tumor types: RCC, UC, NSCLC, metastatic castration-resistant prostate cancer (CRPC), hepatocellular carcinoma (HCC), triple-negative breast cancer, epithelial ovarian cancer, endometrial cancer, gastric or gastroesophageal junction adenocarcinoma, colorectal adenocarcinoma, head and neck cancer and differentiated thyroid cancer (DTC).

Four of the cohorts were exploratory single-agent cohorts: two in advanced UC or NSCLC, one in advanced CRPC evaluating cabozantinib as a single-agent, and one in advanced CRPC evaluating single-agent atezolizumab.

Exelixis is the study sponsor of COSMIC-021. Both Ipsen Pharma SAS (Ipsen) and Takeda Pharmaceutical Company Limited (Takeda) have opted in to participate in the trial and are contributing to the funding for this study under the terms of the companies’ respective collaboration agreements with Exelixis. Roche is providing atezolizumab for the trial.

More information about COSMIC-021 is available at ClinicalTrials.gov.

About UC

UC is the most common type of bladder cancer, accounting for 90% of all cases.1 Bladder cancer is the sixth most common cancer in the U.S., with more than 81,000 new cases expected to be diagnosed in 2022.2 Bladder cancer occurs mainly in older people and is more common in men.3 Over half of cases are found at early stages, when the five-year survival rate is 96%. The five-year survival rate is only 7.7%, however, for metastatic disease.4

About NSCLC

Lung cancer is the second most common type of cancer in the U.S., with more than 236,000 new cases expected to be diagnosed in 2022. The disease is the leading cause of cancer-related mortality in both men and women, causing 25% of all cancer-related deaths. The majority (84%) of lung cancer cases are NSCLC, which mainly comprise adenocarcinoma, squamous cell carcinoma and large cell carcinoma.5,6 The five-year survival rate for patients with NSCLC is 26%, but that rate falls to just 7% for those with advanced or metastatic disease.7 More than half of lung cancer cases are diagnosed at an advanced stage, and more options are needed for these patients.8

About CABOMETYX (cabozantinib)

In the U.S., CABOMETYX tablets are approved for the treatment of patients with advanced RCC; for the treatment of patients with HCC who have been previously treated with sorafenib; for patients with advanced RCC as a first-line treatment in combination with nivolumab; and for adult and pediatric patients 12 years of age and older with locally advanced or metastatic DTC that has progressed following prior VEGFR-targeted therapy and who are radioactive iodine-refractory or ineligible. CABOMETYX tablets have also received regulatory approvals in the European Union and additional countries and regions worldwide. In 2016, Exelixis granted Ipsen 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 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.

CABOMETYX is not indicated as a treatment for metastatic UC or NSCLC.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Severe and fatal hemorrhages occurred with CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX patients in RCC, HCC, and DTC studies. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage and prior to surgery as recommended. Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.

Perforations and Fistulas: Fistulas, including fatal cases, occurred in 1% of CABOMETYX patients. Gastrointestinal (GI) perforations, including fatal cases, occurred in 1% of CABOMETYX patients. Monitor patients for signs and symptoms of fistulas and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a Grade 4 fistula or a GI perforation.

Thrombotic Events: CABOMETYX increased the risk of thrombotic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic events occurred in CABOMETYX patients. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events that require medical intervention.

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. 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 with medical management; when controlled, resume at a reduced dose. Permanently discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis.

Diarrhea: Diarrhea occurred in 62% of CABOMETYX patients. Grade 3 diarrhea occurred in 10% of CABOMETYX 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): PPE occurred in 45% of CABOMETYX patients. Grade 3 PPE occurred in 13% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.

Hepatotoxicity: CABOMETYX in combination with nivolumab can cause hepatic toxicity with higher frequencies of Grades 3 and 4 ALT and AST elevations compared to CABOMETYX alone. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes than when the drugs are administered as single agents. For elevated liver enzymes, interrupt CABOMETYX and nivolumab and consider administering corticosteroids.

With the combination of CABOMETYX and nivolumab, Grades 3 and 4 increased ALT or AST were seen in 11% of patients. ALT or AST >3 times ULN (Grade ≥2) was reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST resolved to Grades 0-1 in 74 (89%). Among the 44 patients with Grade ≥2 increased ALT or AST who were rechallenged with either CABOMETYX (n=9) or nivolumab (n=11) as a single agent or with both (n=24), recurrence of Grade ≥2 increased ALT or AST was observed in 2 patients receiving CABOMETYX, 2 patients receiving nivolumab, and 7 patients receiving both CABOMETYX and nivolumab. Withhold and resume at a reduced dose based on severity.

Adrenal Insufficiency: CABOMETYX in combination with nivolumab can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold CABOMETYX and/or nivolumab and resume CABOMETYX at a reduced dose depending on severity.

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. Adrenal insufficiency led to permanent discontinuation of CABOMETYX and nivolumab in 0.9% and withholding of CABOMETYX and nivolumab in 2.8% of patients with RCC.

Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15 patients. Of the 9 patients in whom CABOMETYX with nivolumab was withheld for adrenal insufficiency, 6 reinstated treatment after symptom improvement; of these, all (n=6) received hormone replacement therapy and 2 had recurrence of adrenal insufficiency.

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): ONJ occurred in <1% of CABOMETYX patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain, or slow healing of the mouth or jaw after dental surgery. 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, if possible. Withhold CABOMETYX for development of ONJ until complete resolution, resume at a reduced dose.

Impaired Wound Healing: Wound complications occurred with CABOMETYX. Withhold CABOMETYX for at least 3 weeks prior to elective surgery. Do not administer CABOMETYX 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): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic findings on MRI, can occur with CABOMETYX. Evaluate for RPLS in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.

Thyroid Dysfunction: Thyroid dysfunction, primarily hypothyroidism, has been observed with CABOMETYX. Based on the safety population, thyroid dysfunction occurred in 19% of patients treated with CABOMETYX, including Grade 3 in 0.4% of patients.

Patients should be assessed for signs of thyroid dysfunction prior to the initiation of CABOMETYX and monitored for signs and symptoms of thyroid dysfunction during CABOMETYX treatment. Thyroid function testing and management of dysfunction should be performed as clinically indicated.

Hypocalcemia: CABOMETYX can cause hypocalcemia. Based on the safety population, hypocalcemia occurred in 13% of patients treated with CABOMETYX, including Grade 3 in 2% and Grade 4 in 1% of patients. Laboratory abnormality data were not collected in CABOSUN.

In COSMIC-311, hypocalcemia occurred in 36% of patients treated with CABOMETYX, including Grade 3 in 6% and Grade 4 in 3% of patients.

Monitor blood calcium levels and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue CABOMETYX depending on severity.

Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Verify the pregnancy status of females of reproductive potential prior to initiating CABOMETYX and advise them to use effective contraception during treatment 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, 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 CYP3A4 Inducers: If coadministration with strong 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.

On May 26, 2022 Exelixis, Inc. (Nasdaq: EXEL) reported results from a phase 2, investigator-sponsored trial of cabozantinib (CABOMETYX) in combination with pembrolizumab in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) (Press release, Exelixis, MAY 26, 2022, View Source [SID1234615080]). The data will be presented at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting during Oral Abstract Session: Head and Neck Cancer on Friday, June 3 beginning at 2:45 p.m. CT.

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The trial met its primary endpoint of objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 at 54%. The overall clinical benefit rate was 91%. At a median follow-up of 10.6 months, the one-year progression-free survival rate was 54.0% (95% confidence interval [CI]: 31.5-72.0%), and median progression-free survival was 14.6 months. The one-year overall survival (OS) rate was 68.4% (95% CI: 45.1-83.5%; median OS: 22.3 months). For the 17 patients with a PD-L1 combined positive score (CPS) under 20, the one-year OS rate was 54.9% (95% CI: 24.5-77.5%; median OS: 14.6 months). For the 17 patients with a CPS score of 20 or more, the one-year OS rate was 83.6% (95% CI: 48.0-95.7%; median OS: 32.9 months).

"Metastatic head and neck cancer is a challenging disease to treat, particularly following disease progression after definitive therapy, meaning patients need additional options beyond radiation and chemotherapy," said Nabil F. Saba, M.D., Professor and Vice Chair, Hematology and Medical Oncology, The Lynne and Howard Halpern Chair in Head and Neck Cancer Research, Co-Director of Head and Neck Cancer Multidisciplinary Program, Winship Cancer Institute, Emory University, and primary investigator of the investigator-sponsored trial. "These results showing promising clinical activity of cabozantinib in combination with pembrolizumab are encouraging to these patients who face poor outcomes."

In this phase 2 trial, eligible patients had recurrent or metastatic HNSCC that was deemed inoperable, with measurable disease per RECIST version 1.1, a life expectancy of at least 3 months and an Eastern Cooperative Group Performance Status of 0 or 1. Of the 36 evaluable patients, 61% had cancer in the oropharynx, 16% in the nasopharynx, 11% in the larynx, 6% in the hypopharynx and 6% in the oral cavity. Eighty-nine percent of patients had received prior radiation therapy and all had received prior chemotherapy.

The most frequent adverse events (AEs) were fatigue (44.4%), diarrhea (33.3%), hypothyroidism (33.3%), constipation (30.6%), dry mouth (27.8%), anorexia (25.0%), headache (25.0%), hypertension (25.0%), hyponatremia (25.0%) and oral mucositis (25.0%). Grade 3/4 treatment-related AEs were aspartate aminotransferase (AST) increase (8.3%), hyponatremia (8.3%), gamma-glutamyl transferase increase (5.6%), lipase increase (5.6%), oral mucositis (5.6%), alanine transaminase/AST increase (2.8%), bilirubin increase (2.8%) and hypertension (2.8%). Dose reductions occurred in 47.2% of patients, and AEs leading to discontinuation occurred in 25.0% of patients.

"Treatment options for patients with metastatic head and neck squamous cell carcinoma are limited, leaving a critical unmet need for this community," said Vicki L. Goodman, M.D., Executive Vice President, Product Development & Medical Affairs, and Chief Medical Officer, Exelixis. "These data support the further development of a combination regimen of cabozantinib and an immune checkpoint inhibitor in patients with metastatic head and neck carcinoma and we are pleased to share these data at ASCO (Free ASCO Whitepaper). Through our research, including our investigator-sponsored trials program, we continue to advance toward our goal of bringing new treatment options to people with difficult-to-treat cancers."

About HNSCC

HNSCC comprises head and neck cancers that begin in the squamous cells that line the mucosal surfaces of the head and neck.1 Accounting for about 90% of all head and neck cancers, HNSCC is classified by its location: it can occur in the oral cavity, oropharynx, nasal cavity and paranasal sinuses, nasopharynx, larynx or hypopharynx.1,2 Oral cavity and larynx cancers are generally associated with tobacco consumption, alcohol abuse or both, whereas pharynx cancers are increasingly attributed to infection with human papillomavirus (HPV), primarily HPV-16.3 About 50,000 new cases of HNSCC are diagnosed in the U.S. every year.1 HNSCC is more common among men and people over the age of 50.4 Depending on the site of the cancer and level of metastases, the five-year survival rate for metastatic HNSCC ranges from 4-35%.5

About CABOMETYX (cabozantinib)

In the U.S., CABOMETYX tablets are approved for the treatment of patients with advanced renal cell carcinoma (RCC); for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib; for patients with advanced RCC as a first-line treatment in combination with nivolumab; and 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 vascular endothelial growth factor receptor (VEGFR)-targeted therapy and who are radioactive iodine-refractory or ineligible. CABOMETYX tablets have also received regulatory approvals in the European Union and additional countries and regions worldwide. 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.

CABOMETYX is not indicated as a treatment for recurrent or metastatic HNSCC.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Severe and fatal hemorrhages occurred with CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX patients in RCC, HCC, and DTC studies. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage and prior to surgery as recommended. Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.

Perforations and Fistulas: Fistulas, including fatal cases, occurred in 1% of CABOMETYX patients. Gastrointestinal (GI) perforations, including fatal cases, occurred in 1% of CABOMETYX patients. Monitor patients for signs and symptoms of fistulas and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a Grade 4 fistula or a GI perforation.

Thrombotic Events: CABOMETYX increased the risk of thrombotic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic events occurred in CABOMETYX patients. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events that require medical intervention.

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. 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 with medical management; when controlled, resume at a reduced dose. Permanently discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis.

Diarrhea: Diarrhea occurred in 62% of CABOMETYX patients. Grade 3 diarrhea occurred in 10% of CABOMETYX 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): PPE occurred in 45% of CABOMETYX patients. Grade 3 PPE occurred in 13% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.

Hepatotoxicity: CABOMETYX in combination with nivolumab can cause hepatic toxicity with higher frequencies of Grades 3 and 4 ALT and AST elevations compared to CABOMETYX alone. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes than when the drugs are administered as single agents. For elevated liver enzymes, interrupt CABOMETYX and nivolumab and consider administering corticosteroids.

With the combination of CABOMETYX and nivolumab, Grades 3 and 4 increased ALT or AST were seen in 11% of patients. ALT or AST >3 times ULN (Grade ≥2) was reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST resolved to Grades 0-1 in 74 (89%). Among the 44 patients with Grade ≥2 increased ALT or AST who were rechallenged with either CABOMETYX (n=9) or nivolumab (n=11) as a single agent or with both (n=24), recurrence of Grade ≥2 increased ALT or AST was observed in 2 patients receiving CABOMETYX, 2 patients receiving nivolumab, and 7 patients receiving both CABOMETYX and nivolumab. Withhold and resume at a reduced dose based on severity.

Adrenal Insufficiency: CABOMETYX in combination with nivolumab can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold CABOMETYX and/or nivolumab and resume CABOMETYX at a reduced dose depending on severity.

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. Adrenal insufficiency led to permanent discontinuation of CABOMETYX and nivolumab in 0.9% and withholding of CABOMETYX and nivolumab in 2.8% of patients with RCC.

Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15 patients. Of the 9 patients in whom CABOMETYX with nivolumab was withheld for adrenal insufficiency, 6 reinstated treatment after symptom improvement; of these, all (n=6) received hormone replacement therapy and 2 had recurrence of adrenal insufficiency.

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): ONJ occurred in <1% of CABOMETYX patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain, or slow healing of the mouth or jaw after dental surgery. 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, if possible. Withhold CABOMETYX for development of ONJ until complete resolution, resume at a reduced dose.

Impaired Wound Healing: Wound complications occurred with CABOMETYX. Withhold CABOMETYX for at least 3 weeks prior to elective surgery. Do not administer CABOMETYX 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): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic findings on MRI, can occur with CABOMETYX. Evaluate for RPLS in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.

Thyroid Dysfunction: Thyroid dysfunction, primarily hypothyroidism, has been observed with CABOMETYX. Based on the safety population, thyroid dysfunction occurred in 19% of patients treated with CABOMETYX, including Grade 3 in 0.4% of patients.

Patients should be assessed for signs of thyroid dysfunction prior to the initiation of CABOMETYX and monitored for signs and symptoms of thyroid dysfunction during CABOMETYX treatment. Thyroid function testing and management of dysfunction should be performed as clinically indicated.

Hypocalcemia: CABOMETYX can cause hypocalcemia. Based on the safety population, hypocalcemia occurred in 13% of patients treated with CABOMETYX, including Grade 3 in 2% and Grade 4 in 1% of patients. Laboratory abnormality data were not collected in CABOSUN.

In COSMIC-311, hypocalcemia occurred in 36% of patients treated with CABOMETYX, including Grade 3 in 6% and Grade 4 in 3% of patients.

Monitor blood calcium levels and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue CABOMETYX depending on severity.

Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Verify the pregnancy status of females of reproductive potential prior to initiating CABOMETYX and advise them to use effective contraception during treatment 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, 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 CYP3A4 Inducers: If coadministration with strong 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.