On July 11, 2022 Greenwich LifeSciences, Inc. (Nasdaq: GLSI) (the "Company"), a clinical-stage biopharmaceutical company focused on the development of GLSI-100, reported that its Board of Directors has suspended the Company’s previously announced share repurchase program (Press release, Greenwich LifeSciences, JUL 11, 2022, View Source [SID1234616584]).

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Under the now suspended share repurchase program, the Company repurchased approximately 520,000 shares of common stock for an aggregate purchase price of approximately $7.5 million. Following these repurchases, the Company had approximately 12.8 million shares of common stock outstanding.

On July 11, 2022 Biomica Ltd., an emerging biopharmaceutical company developing innovative microbiome-based therapeutics and a subsidiary of Evogene Ltd. (NASDAQ: EVGN) (TASE: EVGN), reported the successful enrollment of the first patient in its first Proof-of-Concept (POC) Phase I clinical trial (Press release, Evogene, JUL 11, 2022, View Source [SID1234616583]).

The trial is designed primarily to evaluate the safety and tolerability of Biomica’s microbiome-based immuno-oncology drug candidate, BMC128, in combination with immune checkpoint inhibitor (ICI) immunotherapy (an anti PD-1 agent), in patients with either non-small cell lung cancer, melanoma or renal cell carcinoma. Bristol Myers Squibb’s Opdivo is the immune checkpoint inhibitor in the trial.

It has been previously reported that treatment with Biomica’s BMC128 in combination with ICI immunotherapy significantly enhanced anti-tumor activity in various preclinical models. Response to BMC128 was correlated with a desired anti-tumor immunological profile and led to a stimulation of the immune system shifting cold-tumors into hot-tumors.

BMC128 is a rationally designed consortium of microbes, which was identified and selected through a detailed functional microbiome analysis using PRISM, a high-resolution microbiome analysis platform powered by Evogene’s ‘MicroBoost AI’ tech engine and Big-Data platform.

Dr. Elran Haber, CEO of Biomica, stated: "We are very excited with our first patient in, under our first in-human, proof-of-concept trial. ICIs are a revolutionary treatment and have demonstrated their efficacy in prolonged survival rates of cancer patients. However, many patients are resistant to ICI, and it has been shown that the gut microbiome plays an important role in this resistance. Based on the compelling pre-clinical results that Biomica has achieved to-date, we are excited to evaluate BMC128 in a clinical setting for the first time. Our goal is to provide patients with a meaningful recovery, improved outcome and long-term response to treatment. We are thrilled in reaching this milestone and we look forward to embarking on the next phase of our clinical development process."

About BMC128:

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BMC128 is a rationally designed microbial consortium identified and selected through a detailed functional microbiome analysis using PRISM, a proprietary high-resolution microbiome analysis platform powered by Evogene’s ‘MicroBoost AI’ platform.

Developed as a Live Bacterial Product (LBP), BMC128 is an LBP consortium comprised of four unique bacterial strains, natural inhabitants of the human intestinal tract, that harbor specific functional capabilities with the potential to enhance immunological therapeutic responses and facilitate anti-tumor immune activity through multiple biological processes.

Rationally-designed consortia are multi-strain products designed to restore diversity and specific functionality to a host’s microbial community with individually selected, cultured bacteria.

On July 11, 2022 Sanofi reported the launch of its new investment fund, dubbed Impact, to support the distribution of 30 Sanofi medicines in 40 lower-income countries (Press release, EVERSANA, JUL 11, 2022, View Source [SID1234616582]). Launched under an entirely new brand, the fund will see standard of care medicines produced by Sanofi for disease areas such as diabetes, cardiovascular disease, tuberculosis, malaria and cancer, dedicated for nonprofit distribution to at-risk populations in the world’s most impoverished countries . At the same time, the French pharma giant also announced the beginning of a fund, also under the brand of Impact, that will support startup companies and other innovators that can deliver "scalable solutions for sustainable healthcare in underserved regions," including business financing and technical assistance.

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The German Ministry of Health has published an updated draft version of the "Financial Stabilisation of the Statutory Health Insurance System" (GKV-Finanzstabilisierungsgesetz) bill. The current draft, which replaces the premature release in March that caused uproar across the pharma industry, became public at the beginning of this week but has not been made available on the Ministry’s website. The new draft has been slightly amended from its previous incarnation but still contains some of the "most problematic provisions," suggested Alexander Natz, General Secretary of EUCOPE in a statement emailed to EVERSANA. In Natz’s eyes, the new draft also contains "further measures which negatively affect the pharmaceutical industry."

With a newly released revised proposal, Democrats are hoping to finally unleash a dormant economic package this summer, at the earliest, to lower the prices of drugs for seniors. The revisions come after Senate Majority Leader Charles E. Schumer (D-New York) spent weeks speaking privately with Senator Joe Manchin (D-West Virginia) who had reservations about a past bill called the Build Back Better Act. Manchin resisted the $2 trillion Build Back Better Act over concerns that it would add too much federal debt and further drive inflation. The proposal aims to give the federal government the authority to negotiate prices of certain drugs covered by Medicare, limit drug costs for Medicare beneficiaries to $2,000 per annum and penalize companies that pad drug prices at a faster rate than inflation.

THE DETAILS

COVID-19

The European Medicines Agency (EMA) has stated that regulators worldwide have agreed on fundamental principles for adapting vaccines to tackle COVID-19 variants. According to EMA, International Coalition of Medicines Regulatory Authorities (ICMRA) members and the World Health Organization (WHO) agreed that authorized COVID-19 vaccines continue to offer protection against severe disease, hospitalization, and death and encouraged their use, where available, both as primary series and as booster doses.

Novavax is expecting to provide a COVID-19 vaccine targeting Omicron in Q4 2022 as it accelerates the development of shots to protect against the BA.4 and BA.5 subvariants. The company said it is already "well underway" in its variant program and will focus on Omicron BA.4/5, as recommended by the U.S. Food and Drug Administration’s (FDA) independent experts on the Vaccines and Related Biological Products Advisory Committee in their guidance on June 30.

The U.S. Food and Drug Administration has revised the Emergency Use Authorization (EUA) for Pfizer’s Paxlovid (nirmatrelvir and ritonavir) to enable state-licensed pharmacists to prescribe the pill. "Since Paxlovid must be taken within five days after symptoms begin, authorizing state-licensed pharmacists to prescribe Paxlovid could expand access to timely treatment for some patients who are eligible to receive this drug for the treatment of COVID-19," said Patrizia Cavazzoni, M.D., director for the FDA’s Center for Drug Evaluation and Research.

The Africa Centres for Disease Control and Prevention (CDC) announced it inked a memorandum of understanding with Pfizer for the supply of Paxlovid (nirmatrelvir and ritonavir), an antiviral pill for the treatment of COVID-19. The Memorandum of Understanding (MOU) will enable members of the African Union to access Paxlovid at cost, according to Ahmed Ogwell Ouma, acting director of the CDC.

POLICY

With a newly released revised proposal, Democrats are hoping to finally unleash a dormant economic package this summer, at the earliest, to lower the prices of drugs for seniors. The revisions come after Senate Majority Leader Charles E. Schumer (D-New York) spent weeks speaking privately with Senator Joe Manchin (D-West Virginia) who had reservations about a past bill called the Build Back Better Act. Manchin resisted the $2 trillion Build Back Better Act over concerns that it would add too much federal debt and further drive inflation. The proposal aims to give the federal government the authority to negotiate prices of certain drugs covered by Medicare, limit drug costs for Medicare beneficiaries to $2,000 per annum and penalize companies that pad drug prices at a faster rate than inflation.

The German Ministry of Health has published an updated draft version of the "Financial Stabilisation of the Statutory Health Insurance System" (GKV-Finanzstabilisierungsgesetz) bill. The current draft, which replaces the premature release in March that caused uproar across the pharma industry, became public at the beginning of this week but has not been made available on the Ministry’s website. The new draft has been slightly amended from its previous incarnation but still contains some of the "most problematic provisions," suggested Alexander Natz, General Secretary of EUCOPE in a statement emailed to EVERSANA. In Natz’ eyes, the new draft also contains "further measures which negatively affect the pharmaceutical industry."

Medicines for Europe has suggested a number of policy reforms to help strengthen European health systems’ use of off-patent medicines. Speaking at the Medicines for Europe annual conference, the group suggested that when revising the EU pharmaceutical legislation, the EU must encourage the use of generic, biosimilar and value-added medicines to increase patient access to medicines and ensure budgetary sustainability, among other initiatives.

The Netherlands’ House of Representatives has voted on seven motions submitted in response to a debate held on pharmaceuticals policy on June 9. The majority of the House voted in favor of a motion by the Den Haan faction, which calls on the cabinet to accelerate the authorization of medicines in the Netherlands.

HTA

EUnetHTA has issued a statement notifying that the public consultations for Applicability of Evidence; Validity of clinical studies and Guidance for JCA Submission Dossier Template are now open. The three deliverables, known as D4.5, D4.6 and D5.1 are now open until August 2, 2022 at midnight. In its release, EUnetHTA 21 specified that comments received from organizations outside EU/EEA countries are welcome but may not be considered by EUnetHTA 21 if the organization is not directly impacted by the regulation (HTAR). In addition, only one consolidated comment form per organization is accepted. If multiple are submitted, the first will be considered the intended submission.

The Italian Medicines Agency (AIFA) has confirmed Zolgensma’s (onasemnogene abeparvovec) requirement for therapeutic innovation following a re-evaluation after one year, for the treatment of spinal muscular atrophy (SMA) 5q in patients weighing up to 13.5 kg.

Economist Impact and Roche have released a report on the "Value of Real-World Evidence in Health Technology Assessment (HTA)," exploring the value that Real-World Evidence (RWE) can add for assessing relative treatment effects during the first HTA of innovative new medicines. The researchers also found that positive language was only used in two of the assessments – Evrysdi and Zolgensma – in one or more final HTA reports about the impact of RWE for decision making. More often than not, RWE was either not cited, considered but disregarded, or discussed "but in a neutral or ambiguous manner."

PRICING & REIMBURSEMENT

Sanofi has announced the launch of its new investment fund, dubbed Impact, to support the distribution of 30 Sanofi medicines in 40 lower-income countries. Launched under an entirely new brand, the fund will see standard of care medicines produced by Sanofi for disease areas such as diabetes, cardiovascular disease, tuberculosis, malaria and cancer, dedicated for nonprofit distribution to at-risk populations in the world’s most impoverished countries. At the same time, the French pharma giant also announced the beginning of a fund, also under the brand of Impact, that will support startup companies and other innovators that can deliver "scalable solutions for sustainable healthcare in underserved regions," including business financing and technical assistance.

The High Health Authority (HAS) of France has published a favorable opinion for reimbursing Amgen’s Lumykras (sotorasib) for the treatment of adult patients with advanced non-small cell lung cancer (NSCLC) with the KRAS G12C mutation, whose disease has progressed after at least one line of prior systemic treatment.

France’s High Authority for Health (HAS) has published a favorable opinion for maintaining reimbursement of Kymriah (tisagenlecleucel) to treat diffuse large B-cell lymphoma (DLBCL).

The National Institute for Health and Care Excellence (NICE) has recommended Janssen’s Tremfya (guselkumab), either alone or with methotrexate, for the treatment of active psoriatic arthritis in adults whose disease has not responded well enough to disease-modifying antirheumatic drugs (DMARDs) or who cannot tolerate them. The cost of a 100 mg prefilled disposable injection of Tremfya is £2,250.00, but Janssen has agreed to both a simple discount patient access scheme and a complex patient access scheme that make the therapy available to the NHS with a discount.

The Italian Medicines Agency (AIFA) has amended the Yescarta (axicabtagene ciloleucel) register to allow treatment of adult patients with diffuse large B-cell lymphoma (DLBCL) and refractory or relapsed primary mediastinal large B-cell lymphoma (PMBCL) after two or more lines of systemic therapy up to 75 years of age.

DRUG APPROVAL

The European Commission has approved Sanofi’s Nexviadyme (avalglucosidase alfa) for the treatment of both late-onset and infantile-onset Pompe disease. The enzyme replacement therapy (ERT) is now the first approved medicine for the rare, progressive, and debilitating muscle disorder since 2006 – since Myozyme (alglucosidase alfa) was greenlit.

The U.S. Food and Drug Administration (FDA) has granted orphan drug designation to Phanes’ PT886 for the treatment of pancreatic cancer.

Health Canada has approved Pfizer’s Cibinqo (abrocitinib) for the treatment of patients 12 years and older with refractory moderate to severe atopic dermatitis, including the relief of pruritus, announced the company.

The U.S. Food and Drug Administration (FDA) has accepted Eiasai and Biogen’s Biologics License Application (BLA) under the accelerated approval pathway for lecanemab, the companies’ Alzheimer’s candidate.

The U.S. Food and Drug Administration (FDA) has accepted Roche and Genentech’s Biologics License Application (BLA) and granted Priority Review for mosunetuzumab for the treatment of adults with relapsed or refractory (R/R) follicular lymphoma (FL) who have received at least two prior systemic therapies.

GlaxoSmithKline (GSK) has announced that Health Canada has accepted its New Drug Submission (NDS) for daprodustat for the potential treatment of patients with anemia of chronic kidney disease (CKD).

On July 11, 2022 Researchers at the Case Western Reserve University School of Dental Medicine reported that it will use a $3.25 million grant from the National Institutes of Health (NIH) to better understand how HIV impacts the human body, from mouth lesions to oral cancer (Press release, Case Western Reserve University, JUL 11, 2022, View Source [SID1234616581]).

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HIV is a virus that attacks the body’s immune system and interferes with its ability to fight infections. More than a third of HIV patients will develop some form of oral side effects, like mouth ulcers from immune systems and can greatly impact quality-of-life.

The five-year research project will center on a type of white blood cell called regulatory T-cells, otherwise known as "Tregs." These cells help the immune system signal an appropriate response to fight off infection. But sometimes Treg cells can malfunction, resulting in too many or too few of them. That can trigger diseases, including mouth and throat issues and eventually lead to prolonged inflammation. The goal is to identify genetic, microbiome and metabolic biomarkers that cause these oral complications.

Pushpa Pandiyan, an associate professor of biological sciences at the School of Dental Medicine, is leading the research as principal investigator.

Pushpa Pandiyan
"We’re looking at the dysfunctionality of immune cells and how these cells are associated with inflammatory lesions in the mouths of HIV/AIDS patients," explained Pandiyan. "We also know that HIV patients also have a higher prevalence of oral cancer, and we want to see if the metabolic genes in these immune cells are associated with increased rates of cancer."

This grant will allow the researchers to build on a previous Case Western Reserve-led study published last fall in Nature Communications, which focused on individuals taking HIV antiretroviral drugs. The research looked at how to increase T-cell counts while reducing the number of cells that behave dysfunctionally and cause inflammation.

Pandiyan said the new NIH grant will support work designed to identify potential targets for therapeutics in HIV-positive patients and increase understanding of the gut microbiome’s role in oral manifestations of HIV.

"We’d like to eventually expand our current research to examine the role of bacteria found in the mouth and the gut microbiome," Pandiyan said. "Good bacteria can be helpful while fighting disease, but it can shift in a way that results in unwanted inflammation. These changes in the microbiome affect the cytokines (a type of protein produced by immune and non-immune cells) in HIV patients and warrant further study."

The research team will involve faculty from the Case Western Reserve School of Medicine, including: Adam Burgener, Mark Cameron, Mahmoud Ghannoum and Jeffrey Jacobson.

On July 11, 2022 Exelixis, Inc. (Nasdaq: EXEL) reported that COSMIC-313 met its primary endpoint, demonstrating significant improvement in progression-free survival (PFS) at the primary analysis. COSMIC-313 is an ongoing phase 3 pivotal trial evaluating the combination of cabozantinib (CABOMETYX), nivolumab and ipilimumab versus the combination of nivolumab and ipilimumab in patients with previously untreated advanced intermediate- or poor-risk renal cell carcinoma (RCC) (Press release, Exelixis, JUL 11, 2022, View Source [SID1234616580]). At a prespecified interim analysis for the secondary endpoint of overall survival (OS), the combination of cabozantinib, nivolumab and ipilimumab versus the combination of nivolumab and ipilimumab did not demonstrate a significant benefit. Therefore, the trial will continue to the next analysis of OS.

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"As the treatment landscape continues to evolve, resulting in more options for advanced kidney cancer, there is still a need for additional effective first-line treatment options for patients with intermediate- or poor-risk disease," said Toni Choueiri, M.D., Director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute and the Jerome and Nancy Kohlberg Professor of Medicine at Harvard Medical School. "These initial findings from COSMIC-313 suggest that the triplet combination of cabozantinib, nivolumab and ipilimumab may have potential to serve as an additional option for this patient population."

In the primary analysis of PFS per Response Evaluation Criteria in Solid Tumors version 1.1, as assessed by Blinded Independent Radiology Committee, cabozantinib in combination with nivolumab and ipilimumab significantly reduced the risk of disease progression or death compared with the combination of nivolumab and ipilimumab (hazard ratio: 0.73; 95% confidence interval: 0.57-0.94; P=0.01). The safety profile observed in the trial was reflective of the known safety profiles for each single agent, as well as the combination regimens used in this study. No new safety signals were identified.

Exelixis intends to discuss the results with the U.S. Food & Drug Administration (FDA) to determine next steps toward a potential regulatory submission for the combination regimen for patients with previously untreated advanced intermediate- or poor-risk RCC. Detailed findings will be submitted for presentation at a future medical meeting.

"COSMIC-313 is the first trial to show that a tyrosine kinase inhibitor added to dual checkpoint inhibition can improve progression-free survival in patients with advanced kidney cancer," said Vicki L. Goodman, M.D., Executive Vice President, Product Development & Medical Affairs, and Chief Medical Officer, Exelixis. "With these findings in hand, we look forward discussing the results with the FDA and presenting the data at a future medical meeting."

About COSMIC-313
COSMIC-313 is a multicenter, randomized, double-blinded, controlled phase 3 pivotal trial that enrolled 855 patients at 177 sites globally. Patients were randomized 1:1 into the experimental or control arms of the study. Patients in the experimental arm received cabozantinib (40 mg, once daily) in combination with nivolumab (3 mg/kg infusion, once every 3 weeks for 4 doses total) and ipilimumab (1 mg/kg infusion, once every 3 weeks for 4 doses total) followed by cabozantinib (40 mg, once daily) and nivolumab (480 mg/kg flat dose infusion, once every 4 weeks for up to 2 years). Patients in the control arm received cabozantinib-matched placebo in combination with nivolumab (3 mg/kg infusion, once every 3 weeks for 4 doses total) and ipilimumab (1 mg/kg infusion, once every 3 weeks for 4 doses total) followed by cabozantinib-matched placebo and nivolumab (480 mg/kg flat dose infusion, once every 4 weeks for up to 2 years). The primary endpoint is PFS; the secondary endpoint is OS. Exelixis is funding the trial, and Bristol Myers Squibb is providing nivolumab and ipilimumab for use in this trial. More information about this trial is available at ClinicalTrials.gov.

About RCC
The American Cancer Society’s (ACS) 2022 statistics cite kidney cancer as among the top ten most commonly diagnosed forms of cancer among both men and women in the U.S.1 Clear cell RCC is the most common type of kidney cancer in adults.2 If detected in its early stages, the five-year survival rate for RCC is high; for patients with advanced or late-stage metastatic RCC, however, the five-year survival rate is only 14%.1 Approximately 33,000 patients in the U.S. and over 71,000 worldwide will require systemic treatment for advanced kidney cancer in 2022, with over 15,000 patients in need of a first-line treatment in the U.S.3

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 hepatocellular carcinoma 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 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 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 in combination with nivolumab and ipilimumab is not indicated as a treatment for previously untreated advanced RCC.

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.