On August 21, 2023 Amgen (NASDAQ:AMGN) reported that the U.S. Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee (ODAC) will review data supporting the supplemental New Drug Application (sNDA) for the full approval of LUMAKRAS (sotorasib) for adults with previously treated locally advanced or metastatic KRAS G12C-mutated non-small cell lung cancer (NSCLC) at a meeting on Oct. 5, 2023 (Press release, Amgen, AUG 21, 2023, View Source [SID1234634594]).

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LUMAKRAS/LUMYKRAS is approved in several markets outside the United States including Europe, South America, Asia and the European Union. To date, over 6,500 patients around the world have received LUMAKRAS/LUMYKRAS through the clinical development program and commercial use.

Lumakras has demonstrated a favorable benefit/risk profile in multiple studies in non-small lung cancer and other tumor types such as colo-rectal cancer. Amgen is progressing the largest and broadest global KRASG12C inhibitor development program exploring multiple combination regimens, with clinical trial sites spanning five continents.

"We believe in the clinical value of LUMAKRAS for prescribers and patients navigating KRAS G12C-mutated NSCLC and we look forward to discussing the comprehensive data package for LUMAKRAS with members of the Committee," said David M. Reese, M.D., executive vice president of Research and Development at Amgen.

LUMAKRAS received accelerated approval from the FDA on May 28, 2021. The sNDA for full approval of LUMAKRAS was accepted by the FDA for standard review and a Prescription Drug User Fee Act (PDUFA) target action date of Dec. 24, 2023, has been set.

About LUMAKRAS/LUMYKRAS (sotorasib)

Amgen took on one of the toughest challenges of the last 40 years in cancer research by developing LUMAKRAS/LUMYKRAS, a KRASG12C inhibitor.1 LUMAKRAS/LUMYKRAS has demonstrated a positive benefit-risk profile with rapid, deep, and durable anticancer activity in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring the KRAS G12C mutation with a once daily oral formulation.2

In May 2021, LUMAKRAS was the first KRASG12C inhibitor to receive regulatory approval with its approval in the U.S., under accelerated approval. LUMAKRAS/LUMYKRAS is also approved in the European Union, Japan, United Arab Emirates, South Korea, Hong Kong, Switzerland, Taiwan, Turkey, Thailand, Qatar, Australia, Argentina, Brazil, Canada, Great Britain, Kuwait, Macao, Singapore, Mexico, Israel, Bulgaria, Hungary, Romania, and Russia. Additionally, Amgen has submitted MAAs in Colombia, Malaysia and Saudi Arabia.

LUMAKRAS/LUMYKRAS is also being studied in multiple other solid tumors.

About Non-Small Cell Lung Cancer and the KRAS G12C Mutation

Lung cancer is the leading cause of cancer-related deaths worldwide, and it accounts for more deaths worldwide than colon cancer, breast cancer and prostate cancer combined.3 Overall survival rates for NSCLC are improving but remain poor for patients with advanced disease, and 5-year survival is only 9% for those with metastatic disease.4

KRAS G12C is the most common KRAS mutation in NSCLC.5 About 13% of patients with NSCLC harbor the KRAS G12C mutation.6 The unmet medical need remains high and treatment options are limited for NSCLC patients with the KRAS G12C mutation whose first-line treatment has failed to work or has stopped working. The outcomes with other approved therapies are suboptimal, with a median progression-free survival of approximately four months following second-line treatment of KRAS G12C-mutated NSCLC.7

About CodeBreaK

The CodeBreaK clinical development program for Amgen’s drug sotorasib is designed to study patients with an advanced solid tumor with the KRAS G12C mutation and address the longstanding unmet medical need for these cancers.  

CodeBreaK 100, the Phase 1 and 2, first-in-human, open-label multicenter study, enrolled patients with KRAS G12C-mutant solid tumors.8 Eligible patients must have received a prior line of systemic anticancer therapy, consistent with their tumor type and stage of disease. The primary endpoint for the Phase 2 study was centrally assessed objective response rate. The Phase 2 trial in NSCLC enrolled 126 patients, 124 of whom had centrally evaluable lesions by RECIST at baseline.2 The Phase 2 trial in metastatic colorectal cancer (mCRC) enrolled 62 patients and results have been published.9

CodeBreaK 200, the global Phase 3 multicenter, randomized, open-label, active-controlled study compared the efficacy, safety, and tolerability of sotorasib to docetaxel in KRAS G12C-mutated NSCLC completed enrollment of 345 patients. Eligible patients had previously treated, locally advanced and unresectable or metastatic KRAS G12C-mutated NSCLC. The primary endpoint was progression-free survival and key secondary endpoints included overall survival, objective response rate, and patient-reported outcomes.10

CodeBreaK 300, the global Phase 3 randomized active-controlled study comparing sotorasib in combination with panitumumab to investigator’s choice (trifluridine and tipiracil, or regorafenib) in chemorefractory KRAS G12C-mutated mCRC, has completed enrollment of 160 patients. Eligible patients had KRAS G12C-mutated mCRC, received at least one prior line of therapy, and have received and progressed on or after fluoropyrimidine, irinotecan, and oxaliplatin. The primary endpoint is progression-free survival and key secondary endpoints include overall survival (OS) and objective response rate (ORR).11

Amgen also has several Phase 1b studies investigating sotorasib in combination with several other treatments across various advanced solid tumors (CodeBreaK 101) open for enrollment.12 A Phase 3 randomized controlled study will evaluate frontline sotorasib in combination with platinum doublet chemotherapy versus pembrolizumab platinum doublet combination in patients with PD-L1-negative, advanced KRAS G12C-mutated NSCLC (CodeBreaK 202).13

LUMAKRAS (sotorasib) U.S. Indication

LUMAKRAS is indicated for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test, who have received at least one prior systemic therapy.

This indication is approved under accelerated approval based on overall response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

LUMAKRAS (sotorasib) Important U.S. Safety Information

Hepatotoxicity

LUMAKRAS can cause hepatotoxicity, which may lead to drug-induced liver injury and hepatitis.
Among 357 patients who received LUMAKRAS in CodeBreaK 100, hepatotoxicity occurred in 1.7% (all grades) and 1.4% (Grade 3). A total of 18% of patients who received LUMAKRAS had increased alanine aminotransferase (ALT)/increased aspartate aminotransferase (AST); 6% were Grade 3 and 0.6% were Grade 4. In addition to dose interruption or reduction, 5% of patients received corticosteroids for the treatment of hepatotoxicity.
Monitor liver function tests (ALT, AST and total bilirubin) prior to the start of LUMAKRAS every 3 weeks for the first 3 months of treatment, then once a month or as clinically indicated, with more frequent testing in patients who develop transaminase and/or bilirubin elevations.
Withhold, dose reduce or permanently discontinue LUMAKRAS based on severity of adverse reaction.
Interstitial Lung Disease (ILD)/Pneumonitis

LUMAKRAS can cause ILD/pneumonitis that can be fatal. Among 357 patients who received LUMAKRAS in CodeBreaK 100, ILD/pneumonitis occurred in 0.8% of patients, all cases were Grade 3 or 4 at onset, and 1 case was fatal. LUMAKRAS was discontinued due to ILD/pneumonitis in 0.6% of patients.
Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold LUMAKRAS in patients with suspected ILD/pneumonitis and permanently discontinue LUMAKRAS if no other potential causes of ILD/pneumonitis are identified.
Most Common Adverse Reactions

The most common adverse reactions occurring in ≥ 20% were diarrhea, musculoskeletal pain, nausea, fatigue, hepatotoxicity and cough.
Drug Interactions

Advise patients to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, dietary and herbal products.
Inform patients to avoid proton pump inhibitors and H2 receptor antagonists while taking LUMAKRAS.
If coadministration with an acid-reducing agent cannot be avoided, inform patients to take LUMAKRAS 4 hours before or 10 hours after a locally acting antacid.

Please see LUMAKRAS full Prescribing Information.

On August 21, 2023 Alligator Bioscience (Nasdaq Stockholm: ATORX) reported that the European Medicines Agency (EMA) has granted Orphan Designation to its lead asset mitazalimab for the treatment of pancreatic cancer (Press release, Alligator Bioscience, AUG 21, 2023, View Source [SID1234634593]).

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Mitazalimab is a monoclonal antibody targeting CD40 designed to sensitize tumors to chemotherapy and induce immune-mediated tumor killing by activating dendritic cells, B cells, and macrophages. Mitazalimab is currently being evaluated in OPTIMIZE-1, a Phase 2 open-label, multi-center study to assess its safety and efficacy in combination with chemotherapy, mFOLFIRINOX, in previously untreated patients with metastatic pancreatic ductal adenocarcinoma (NCT04888312).

In May 2023, the U.S. Food and Drug Administration (FDA) granted orphan drug designation to mitazalimab for the treatment of pancreatic cancer.

"We are very pleased that the European Medicines Agency has granted orphan designation to our lead asset mitazalimab in the treatment of pancreatic cancer," said Søren Bregenholt, CEO of Alligator Bioscience. "It is our second orphan designation this year following the FDA’s decision to grant us ODD in May, meaning mitazalimab now has stronger commercial protection through market exclusivity in these two key markets. This latest designation adds to the momentum we are building in our efforts to bring this promising drug candidate to market."

To qualify for the EMA’s orphan designation, a medicine must be intended for the treatment, prevention or diagnosis of rare, life-threatening or chronically debilitating diseases that affect fewer than five in 10,000 persons in the EU. Medicines that meet these criteria are eligible for financial and regulatory incentives that include 10 years of marketing exclusivity in the EU after product approval.

In June 2023, Alligator announced a second set of strong interim results from OPTIMIZE-1, in which mitazalimab combined with mFOLFIRINOX showed deepening of tumor response and increase in objective response rate (ORR) to 57% (from initially reported 52% ORR in 23 patients) and demonstrated an interim ORR of 44% in the full study cohort (57 patients) that is expected to further improve with longer follow up. A median duration of response (DoR) of 8.7 months , as per the Response Evaluation Criteria in Solid Tumors (RECIST 1.1), was also reported. This compares very strongly with an ORR of 31.6% and DOR of 5.9 months reported in a similar patient population treated with standard of care[1].

OPTIMIZE-1 is on track for top-line readout in early Q1 2024.

On August 21, 2023 Adamis Pharmaceuticals Corporation (NASDAQ: ADMP), a commercial-stage biopharmaceutical company, reported financial results for the second quarter ended June 30, 2023, and provided an update on recent corporate developments (Press release, Adamis Pharmaceuticals, AUG 21, 2023, View Source [SID1234634592]).

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Q2 2023 Corporate Highlights

· In May, the Company closed the merger with DMK Pharmaceuticals Corporation (DMK), a private, clinical-stage biotechnology company at the forefront of endorphin-inspired drug design focused on developing novel treatments for opioid use disorder and other neuro-based diseases. Ebrahim Versi, MD, PhD, CEO of DMK, was named CEO of Adamis and Chairman of the Board of Directors. David J. Marguglio, previously Chief Executive Officer of Adamis, assumed the role of President and Chief Operating Officer of the combined company. Changes to the composition of the Board of Directors were also made.

· In June, management participated in the White House Roundtable with Opioid Reversal Product Manufacturers hosted by White House Office of National Drug Control Policy Director, Dr. Rahul Gupta, White House Domestic Policy Council Advisor Neera Tanden, U.S. Assistant Secretary for Health Admiral Rachel Levine, and U.S. Assistant Secretary for Mental Health and Substance Use Dr. Miriam E. Delphin-Rittmon. While in Washington, D.C., management also met individually with 12 members and/or staff of the House of Representatives and Senate, from both parties, and discussed the opioid crisis and potential ways it could be mitigated.

· Also in June, the Company announced that its wholly owned subsidiary DMK was the recipient of a grant from the National Institute of Alcohol Abuse and Alcoholism (NIAAA) of the National Institutes of Health (NIH) to support the development of a novel bifunctional small molecule for the treatment of alcohol use disorder.

· In July, the Company committed to an unrestricted research grant to the Leiden University Medical Center Anesthesia and Pain Research Unit, to fund a ZIMHI clinical study by Albert Dahan, MD, PhD, a world expert on opioid-induced respiratory depression, otherwise known as an opioid overdose. The objective of the work will be to assess the efficacy of the Company’s ZIMHI product compared to 4mg of intranasal naloxone, which is comparable to NARCAN, and the respective number of doses required to reverse fentanyl-induced respiratory depression.

Recent Corporate Updates

· On August 4, 2023, the Company announced the closing of a public offering of 5,930,000 units at a public offering price of $1.35, with each unit consisting of one share of common stock (or pre-funded warrant in lieu thereof) and one warrant to purchase one share of common stock. The Company received gross proceeds of approximately $8.0 million before deducting fees and other estimated offering expenses at the closing, and has received additional proceeds resulting from exercises after the closing date of some of the warrants issued in the transaction.

Q2 2023 Financial Highlights

· Revenues for the second quarter ending June 30, 2023 were $0.0 million compared to $0.0 million for the same period in 2022. Revenues were negligible in both periods because no manufacturing of commercial products occurred in the second quarter in 2023 or 2022. Revenues for the six months ending June 30, 2023 and 2022 were approximately $1.5 million and $1.2 million, respectively. The increase was due to higher manufacturing demand for ZIMHI in the first quarter of 2023 versus 2022.

· Selling, general and administrative (SG&A) expenses for the three months ending June 30, 2023 were $4.0 million compared to $4.2 million for the second quarter of 2022. SG&A expenses for the first six months ending June 30, 2023 and 2022 were $8.8 million and $7.6 million, respectively. The increase was primarily attributable to approximately $1.3 million in transaction costs associated with the DMK merger.

· Research and development (R&D) expense for the second quarter of 2023 was $0.4 million compared to $3.2 million in the second quarter of the prior year. R&D expense for the first six months of 2023 was $1.7 million, compared to $7.5 million in the same period in 2022. The decline in both periods was due to terminating the clinical development activity related to a previous product candidate.

· Net loss for the combined (continued and discontinued) operations for the second quarter of 2023 was $8.6 compared to a net loss of $8.4 million in the second quarter of 2022. The increase was primarily attributable to a charge of $6.5 million for DMK’s in-process research and development acquired in the merger. Net loss for the six months ended June 30, 2023 and 2022 was $17.5 million and $18.8 million, respectively.

· Cash and cash equivalents as of June 30, 2023, were approximately $0.6 million. Additional cash infusions subsequent to the close of the second quarter include net proceeds of approximately $1.8 million from the sale of assets related to the discontinued US Compounding operations and net proceeds of approximately $7.0 million from the Company’s equity financing transaction that occurred in August.

On August 21, 2023 Actinium Pharmaceuticals, Inc. (NYSE AMERICAN: ATNM) (Actinium or the Company), a leader in the development of targeted radiotherapies, reported two abstracts accepted for oral and poster presentation at the upcoming European Association of Nuclear Medicine (EANM) 2023 Congress, which will be held in Vienna, September 9-13, 2023 (Press release, Actinium Pharmaceuticals, AUG 21, 2023, View Source [SID1234634591]). The EANM oral presentation, reflecting the potentially paradigm changing Iomab-B SIERRA data in facilitating transplants for people with AML who are currently not considered for transplant, represents the fifth oral presentation at prestigious medical conferences globally in 2023 including TCT, EBMT, SNMMI, and EHA (Free EHA Whitepaper).

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Details of the EANM oral presentation:

Presentation Title: "Safety and dosimetry evaluation of personalized dose I131-apamistamab prior to HCT in the phase 3 SIERRA trial for patients with relapsed/refractory acute myeloid leukemia (R/R AML)"
Session: Theranostics Track – Oncology & Theranostics Committee / EARL – Featured Session: Old but Novel Techniques
Date and Time: September 10, 3:00pm CET

Details of the EANM e-poster presentation:

All e-posters will be accessible for viewing for the entirety of the conference.

e-Poster Title: Feasibility of high-dose targeted radiation with I131-apamistamab in patients with relapsed/refractory AML: Dosimetry and radiation safety experience from the phase 3 SIERRA trial
e-Poster Number: EP-0608
Session Title: C: Therapy Clinical Study -> C1 Oncological Therapy Clinical Study -> C15 Other Oncological Treatments

On August 21, 2023 Exelixis, Inc. (Nasdaq: EXEL) and Ipsen (Euronext: IPN; ADR: IPSEY) reported that the global phase 3 CONTACT-02 pivotal trial met one of two primary endpoints, demonstrating a statistically significant improvement in progression-free survival (PFS) at the primary analysis (Press release, Exelixis, AUG 21, 2023, View Source [SID1234634583]). CONTACT-02 is evaluating cabozantinib (CABOMETYX) in combination with atezolizumab compared with a second novel hormonal therapy in patients with metastatic castration-resistant prostate cancer (mCRPC) and measurable soft tissue disease who have been previously treated with one novel hormonal therapy. At a prespecified interim analysis for the primary endpoint of overall survival (OS) that occurred at the same time as the primary analysis of PFS, a trend toward improvement of OS was observed; however, the data were immature and did not meet the threshold for statistical significance. Therefore, the trial will continue to the next analysis of OS as planned.

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The safety profile of the combination of cabozantinib and atezolizumab was consistent with the known safety profiles for each single medicine, and no new safety signals were identified with the combination.

"These positive findings from CONTACT-02 are highly encouraging given the need for additional, non-cytotoxic or non-chemotherapeutic treatment options for this patient population," said Neeraj Agarwal, M.D., FASCO, Professor and Presidential Endowed Chair of Cancer Research at Huntsman Cancer Institute, University of Utah and the global lead investigator of the trial. "Cabozantinib in combination with atezolizumab represents a potential new treatment modality for patients with metastatic castration-resistant prostate cancer, and we look forward to sharing the full data at a future medical meeting."

"Patients with metastatic castration-resistant prostate cancer face a poor prognosis of less than two years, and many who progress on a novel hormonal therapy are seeking alternative treatment options to chemotherapy," said Vicki L. Goodman, M.D., Executive Vice President, Product Development & Medical Affairs, and Chief Medical Officer, Exelixis. "We are pleased to report positive findings from the CONTACT-02 trial, in which cabozantinib in combination with an immune checkpoint inhibitor has demonstrated an efficacy benefit in another tumor type with significant unmet need. We look forward to discussing these findings with the U.S. Food and Drug Administration and to presenting further details at an upcoming medical meeting."

"With prostate cancer confirmed as the second most commonly occurring cancer in men globally, the need for innovative new therapies is extensive, especially for those whose cancer has progressed to the metastatic castration-resistant form," said Howard Mayer, Executive Vice President and Head of Research and Development at Ipsen. "These results represent the first positive phase 3 data of its kind for a tyrosine kinase inhibitor and immunotherapy combination in this indication. We will engage with regulatory authorities on these data and look forward to further exploring the potential treatment benefit for a patient population at such a challenging stage of disease."

About CONTACT-02
CONTACT-02 is a global, multicenter, randomized, phase 3, open-label study that enrolled 575 patients who were randomized 1:1 to the experimental arm of cabozantinib in combination with atezolizumab and the control arm of a second novel hormonal therapy (either abiraterone and prednisone or enzalutamide). The study included patients with mCRPC who have measurable visceral disease or measurable extrapelvic adenopathy who have been previously treated with one novel hormonal therapy. The two primary endpoints of the trial are PFS and OS. The secondary endpoint is objective response rate. The trial is sponsored by Exelixis and co-funded by Ipsen, Roche and Takeda Pharmaceutical Company Limited (Takeda). Takeda is conducting the trial in Japan. More information about CONTACT-02 is available at ClinicalTrials.gov.

About CRPC
Prostate cancer is the second most common cancer in men and the fourth most common cancer overall globally.1 In 2020, there were more than 1.4 million new cases of prostate cancer and about 375,300 deaths worldwide.1 Prostate cancer is considered mCRPC when it has spread beyond the prostate and does not respond to androgen-suppression therapies, a common treatment for prostate cancer.2 Men diagnosed with mCRPC often have a poor prognosis, with an estimated survival of 1-2 years.3

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 VEGFR-targeted therapy and who are radioactive iodine-refractory or ineligible. CABOMETYX tablets have also received regulatory approvals in over 60 countries outside the U.S. and Japan, including the European Union. 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 in combination with atezolizumab is not indicated as a treatment for mCRPC.

U.S. 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.

Please see accompanying full Prescribing Information View Source

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088.

EUROPEAN UNION IMPORTANT SAFETY INFORMATION

For detailed recommendations on the use of CABOMETYX in the European Union, please see the Summary of Product Characteristics.