On December 4, 2023 NANOBIOTIX (Euronext: NANO – NASDAQ: NBTX – "Nanobiotix" or the "Company"), a late-clinical stage biotechnology company pioneering physics-based approaches to expand treatment possibilities for patients with cancer, reported the closing of the previously announced subscription by Johnson & Johnson Innovation – JJDC, Inc. ("JJDC") for 901,256 additional ordinary shares of the Company, in the form of restricted American Depositary Shares ("ADSs"), for an aggregate amount of $4.8 million, equivalent to €4.6 million1 (the "Remaining Placement Amount", and the subscription transaction being the "Remaining Placement"), following the approval by the French Ministry of Economy of JJDC Remaining Placement on November 22, 2023, in accordance with the French foreign investment control rules (Press release, Nanobiotix, DEC 4, 2023, View Source [SID1234638129]).

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As previously announced, pursuant to an existing securities purchase agreement, JJDC was obligated to subscribe, subject to any required regulatory approvals, for $25.0 million of the Company’s restricted ADSs (the "Placement Amount"), exempt from the registration requirements of the Securities Act of 1933, as amended. Pursuant to French foreign investment control rules, the Placement Amount as initially agreed was reduced, such that JJDC had initially subscribed for 3,762,923 restricted ADSs (representing, together with JJDC’s existing stake, 9.99% of the then outstanding voting rights of the Company’s capital stock, as of the issuance date thereof) for gross proceeds to the Company of $20.2 million (the "Initial Placement"). The subscription by JJDC of the Remaining Placement Amount was conditioned upon the approval of the French Ministry of Economy.

Form of the Remaining Placement

The Remaining Placement was carried out by way of a share capital increase for an aggregate amount of $4.8 million (issue premium included) decided on November 22, 2023 by the Company’s Executive Board pursuant to the delegation granted to it by the Company’s combined shareholders’ meeting held on June 27, 2023 in its 25th resolution in accordance with Article L. 225-138 of the French Commercial Code (Code de commerce) through the issuance of 901,256 additional ordinary shares, €0.03 nominal value per share of the Company (each an "Ordinary Share"), in the form of restricted ADSs reserved to a specific investor meeting the criteria defined by the shareholders’ meeting in the 25th resolution – i.e., an industrial company, institution or entity operating in the healthcare or biotechnology sector, either directly or through a controlled company or a company by which they are controlled, where applicable when entering into a commercial agreement, financing contract or partnership with the Company.

The subscription price per Ordinary Share and per ADS of the Remaining Placement is equivalent to the subscription price per Ordinary Share and per ADS of the Initial Placement. The subscription price per Ordinary Share is equal to the volume weighted average price of the Ordinary Shares on the regulated market of Euronext in Paris ("Euronext") over the last three trading sessions preceding the pricing of the Remaining Placement (i.e. November 22, 21 and 20, 2023), less a discount of 8,88%, in accordance with the 25th resolutions of the Company’s combined shareholders’ meeting held on June 27, 2023.

The Company intends to use the net proceeds from the Remaining Placement as described in the Company’s press release dated November 6, 2023.

As of November 30th, 2023, the Company had cash and cash equivalents of €77.2 million (unaudited). The Company believes that the net proceeds from the Remaining Placement, together with its cash and cash equivalents, will be sufficient to meet its working capital requirements for operations until the end of the first quarter 2025, and, assuming the receipt from Janssen Pharmaceutica NV (‘‘Janssen’’) of the first milestone payment under the Company’s License Agreement with Janssen dated July 7, 2023, into mid’2025.

The Company’s estimates of the period of time through which its financial resources are expected to be adequate to meet its working capital requirements are forward-looking statements and involve risks and uncertainties, and actual results could vary materially and negatively as a result of a number of factors, as described under "Special Note Regarding Forward-Looking Statements" below.

Dilution

The 901,256 Ordinary Shares (in the form of restricted ADSs) that have been subscribed by JJDC in the context of the Remaining Placement represent a dilution of approximately 1,95% of the outstanding share capital of the Company (on a non-diluted basis). On an illustrative basis, a shareholder which held 1% of the Company’s share capital before the Remaining Placement holds a stake of0,98% after closing of the Remaining Placement.

The following table presents, to the Company’s knowledge, the expected allocation of the Company’s share capital following the closing of the Remaining Placement:

Situation before the Remaining Placement Situation after the Remaining Placement
Shareholders

Number of shares % of share capital % of theoretical voting rights(1) Number of shares % of share capital % of theoretical voting rights(1)
Non-diluted Non-diluted Diluted (2) Non-diluted Diluted (2) Non-diluted Non-diluted Diluted (2) Non-diluted Diluted (2)
Invus Public Equities Advisors, LLC (A) 4 375 004 9.5% 7.9% 9.1% 7.6% 4 375 004 9.3% 7.7% 9.0% 7.5%
Baillie Gifford & Co (B) 2 821 261 6.1% 5.1% [·]5.9% [·]4.9% 2 821 261 6.0% 5.0% 5.8% 4.8%
JJDC (C) 4 722 560 [·]10.2% [·]8.5% [·]9.8% 8.2% 5 623 816 11.9% 11.5% 11.5% 11.2%
Qatar Holding LLC (D) 4 298 507 9.3% 7.7% ·]9.0% 7.5% 4 298 507 9.1% 7.6% 8.8% 7.4%
Total (A) + (B) + (C)+(D) 16 217 332 35.1% 29.1% 33.8% 28.2% 17 118 588 36.3% 31.8% 35.0% 30.9%
Laurent Levy 1 139 060 2.5% 5.4% 4.1% 6.6% 1 139 060 2.4% 5.3% 4.0% 6.5%
Bart Van Rhijn – 0.8% - 0.8% - - 0.8% - 0.7%
Anne-Juliette Hermant 140 000 0.3% 0.8% 0.3% 0.7% 140 000 0.3% 0.8% 0.3% 0.7%
Other managers and employees 166 273 0.4% 3.3% 0.5% 3.4% 166 273 0.4% 3.3% 0.5% 3.3%
Total Management and employees 1 445 333 3.1% 10.2% 4.9% 11.5% 1 445 333 3.1% 10.1% 4.8% 11.3%
Other(3) 28 547 289 61.7% 60.6% 61.3% 60.2% 28 547 289 60.6% 58.0% 60.1% 57.8%
Treasury shares 22 118 - - - - 22 118 - - - -
Total 46 232 072 100% 100% 100% 100% 47 133 328 100% 100% 100% 100%
(1) The calculations are based on the assumption of the exercise of all the share warrants (BSA), founders share warrants (BSPCE) and stock options as well as the definitive acquisition of all free shares (AGA).
(2) Double voting rights are granted to all fully paid-up ordinary shares of the Company registered in the name of the same shareholder for at least two years. ADSs do not carry double voting rights.
(3) Including institutional investors holding, prior to the Remaining Placement, 2.7% of the Company’s share capital and 2.6% of its voting rights (2.2% and 2.2% respectively on a fully diluted basis), and after the completion of the Remaining Placement, 2.6% of the Company’s share capital and 2.5% of its voting rights (2.2% and 2.1% respectively on a fully diluted basis).

Risk Factors

[The Company draws attention to the risk factors related to the Company and its activities presented in section 1.5 of the 2022 universal registration document of the Company filed with the French Financial Markets Authority (Autorité des Marchés Financiers – the "AMF") under number D.23-0332 on April 24, 2023, as updated in section 2.4 of the first amendment to the Company’s 2022 universal registration document filed with the AMF under number D.23-0332-A01 on November 1st, 2023 and by a second amendment to the Company’s 2022 universal registration document filed with the AMF under number D.23-0332-A02 on November 3rd, 2023, which are available free of charge on the Company’s website at View Source, as well as on the AMF’s website at www.amf-france.org.]

Settlement and Delivery – Documentation

The Ordinary Shares issued in the Remaining Placement has been admitted to trading on Euronext on December 4, 2023, on the same trading line as the existing ordinary shares of the Company, under the ticker symbol "NANO" and the ISIN code FR0011341205.

The ADSs to be issued in the Remaining Placement are expected to be listed on the Nasdaq Global Select Market under the ticker symbol "NBTX" on December 6, 2023.

The Remaining Placement is not subject to a prospectus requiring an approval from the AMF / French Financial Market Authority (Autorité des Marchés Financiers) (the "AMF").

On December 4, 2023 IDEAYA Biosciences, Inc. (Nasdaq:IDYA), a precision medicine oncology company committed to the discovery and development of targeted therapeutics, reported that it has entered into a clinical study collaboration and supply agreement with Gilead Sciences, Inc. (Gilead) to evaluate the efficacy and safety of IDE397, its investigational, potential first-in-class, small molecule MAT2A inhibitor, in combination with Gilead’s sacituzumab-govitecan-hziy ("Trodelvy"), a Trop-2 directed antibody-drug conjugate (ADC), in a Phase 1 clinical trial (Press release, Ideaya Biosciences, DEC 4, 2023, View Source [SID1234638128]).

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"We are pleased to collaborate with Gilead to evaluate this potential first-in-class Trop-2 directed ADC and MAT2A clinical combination in MTAP-deletion bladder cancer. MTAP-deletion prevalence in bladder cancer is approximately 26% and this patient population represents a high unmet medical need, as there are no approved therapies for MTAP-deletion bladder cancer," said Darrin Beaupre, M.D., Ph.D., Chief Medical Officer, IDEAYA Biosciences.

"We are delighted to enter into this clinical collaboration with Gilead that advances our multi-pronged strategy designed to deliver maximal benefit to MTAP-deletion solid tumor patients. We believe the strong mechanistic rationale of this combination, and the monotherapy efficacy observed by both agents in MTAP-deletion bladder cancer, may enable this combination to be differentiated and studied in an earlier-line clinical setting," said Yujiro Hata, President and Chief Executive Officer, IDEAYA Biosciences.

IDE397 is a potent and selective small molecule inhibitor targeting methionine adenosyltransferase 2a (MAT2A), in patients having solid tumors with methylthioadenosine phosphorylase (MTAP) deletion. The MTAP deletion patient population is estimated to represent approximately 15% of solid tumors, including approximately 19% of squamous NSCLC and 26% of bladder cancer. Sacituzumab govitecan, commercialized under the brand name Trodelvy, is a Trop-2 directed antibody-drug conjugate currently approved in the U.S. for the treatment of HR+/HER2- metastatic breast cancer, metastatic triple-negative breast cancer and metastatic urothelial cancer.

IDEAYA is evaluating IDE397 in an ongoing Phase 1/2 clinical trial. The company has initiated and is actively enrolling patients into monotherapy expansion in squamous NSCLC and bladder cancer and collaborating with Amgen in a Phase 1 combination study with AMG 193, Amgen’s MTA-Cooperative PRMT5 inhibitor.

Under the clinical study collaboration and supply agreement, Gilead will provide drug supply to IDEAYA, which will be the sponsor of the Phase 1 clinical combination trial. IDEAYA and Gilead each retain all commercial rights to their respective compounds, including as monotherapy or as combination therapies.

On December 4, 2023 GT Biopharma, Inc. (NASDAQ: GTBP), a clinical stage immuno-oncology company focused on developing innovative therapeutics based on the Company’s proprietary natural killer (NK) cell engager, TriKE platform, reported the submission of an Investigational New Drug (IND) application with the US Food and Drug Administration (FDA) for the development of GTB-3650, a 2nd generation nanobody TriKE for the treatment of patients with CD33+ leukemia, including relapsed/refractory acute myelogenous leukemia (AML) and high-risk myelodysplastic syndrome (MDS) (Press release, GT Biopharma, DEC 4, 2023, View Source [SID1234638127]).

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"Today’s announcement is an important milestone for GT Biopharma, and we look forward to advancing GTB-3650 for treatment of CD33+ leukemia. We are excited to expeditiously move this molecule into the clinic as we execute on our clinical objectives in 2024," stated Michael Breen, GT Biopharma’s Executive Chairman, Board of Directors and Interim Chief Executive Officer.

On December 4, 2023 Geron Corporation (Nasdaq: GERN), a late-stage clinical biopharmaceutical company, reported publication in The Lancet of results from the IMerge Phase 3 trial investigating imetelstat versus placebo in patients with lower risk myelodysplastic syndromes (MDS) relapsed/refractory or ineligible for erythropoiesis stimulating agents (ESAs) (Press release, Geron, DEC 4, 2023, View Source [SID1234638126]). The publication is available online and will be available in print at a later date.

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"The Lancet’s publication of our IMerge Phase 3 manuscript is a strong validation of the importance of this study within the field, as well as a powerful way of reaching hematologists and other providers globally with these potentially practice-changing results," said Faye Feller, M.D., Executive Vice President, Geron’s Chief Medical Officer. "Based on the highly differentiated qualities of imetelstat reported in this study, we believe that, if approved by regulatory authorities, imetelstat could substantially improve the treatment paradigm in certain patients with lower risk MDS."

Imetelstat is currently under regulatory review by the U.S. Food and Drug Administration (FDA) and by the European Medicines Agency (EMA) for approval in transfusion dependent anemia in patients with lower risk MDS who have failed to respond or have lost response to or are ineligible for ESAs.

"I am pleased with the publication in The Lancet of what I believe are very powerful Phase 3 results with this unique mechanism of action, telomerase inhibition, where we see long-term and durable responses broadly across MDS subgroups. This includes lower risk MDS patients without ring sideroblasts (RS-), ESA-ineligible patients who have high serum EPO levels, and those with high transfusion burden, whose needs are not being met by today’s treatments," said Uwe Platzbecker, M.D., Department of Hematology, Cellular Therapy, Hemostaseology and Infectious Diseases, Leipzig University Hospital, Leipzig, Germany, who is the lead author on the manuscript and is an IMerge investigator. "With regards to the safety results, neutropenia and thrombocytopenia were predictable and manageable, with little to no significant clinical consequences. These adverse events commonly occurred in the first three cycles and frequently resolved within two weeks."

As previously reported, in the IMerge Phase 3 clinical trial, the primary endpoint of red blood cell transfusion independence (TI) for at least 8 consecutive weeks was significantly higher with imetelstat vs. best supportive care (placebo) (p<0.001), with median TI duration approaching one year for imetelstat 8-week TI responders. Mean hemoglobin levels in imetelstat-treated patients increased significantly (p<0.001) over time compared to placebo patients. For patients achieving 8-week TI, median increases in hemoglobin were 3.6 g/dL for imetelstat and 0.8 g/dL for placebo. Significant and clinically meaningful efficacy results were achieved across key MDS subgroups irrespective of ring sideroblast (RS) status, baseline transfusion burden and IPSS risk category. Patient-reported outcomes (PRO) data reported a sustained meaningful improvement in fatigue for imetelstat-treated patients vs. placebo. Treatment with imetelstat vs. placebo led to greater reduction in variant allele frequency (VAF) in certain genes commonly mutated in MDS, which was associated with longer TI duration and increase in hemoglobin levels. Consistent with prior imetelstat clinical experience, the most common adverse events were thrombocytopenia and neutropenia that were manageable and of short duration.

Click here to view The Lancet publication.

About IMerge Phase 3

The Phase 3 portion of the IMerge Phase 2/3 study is a double-blind, 2:1 randomized, placebo-controlled clinical trial to evaluate imetelstat in patients with IPSS Low or Intermediate-1 risk (lower risk) transfusion dependent MDS who were relapsed after, refractory to, or ineligible for, erythropoiesis stimulating agent (ESA) treatment, had not received prior treatment with either a HMA or lenalidomide and were non-del(5q). To be eligible for IMerge Phase 3, patients were required to be transfusion dependent, defined as requiring at least four units of packed red blood cells (RBCs), over an eight-week period during the 16 weeks prior to entry into the trial. The primary efficacy endpoint of IMerge Phase 3 is the rate of red blood cell transfusion independence (RBC-TI) lasting at least eight weeks, defined as the proportion of patients without any RBC transfusion for at least eight consecutive weeks since entry to the trial (8-week TI). Key secondary endpoints include the rate of RBC-TI lasting at least 24 weeks (24-week TI), the duration of TI and the rate of hematologic improvement erythroid (HI-E), which is defined under 2006 IWG criteria as a rise in hemoglobin of at least 1.5 g/dL above the pretreatment level for at least eight weeks or a reduction of at least four units of RBC transfusions over eight weeks compared with the prior RBC transfusion burden. A total of 178 patients were enrolled in IMerge Phase 3 across North America, Europe, Middle East and Asia.

About Imetelstat

Imetelstat is a novel, first-in-class investigational telomerase inhibitor exclusively owned by Geron and being developed in hematologic malignancies. Data from non-clinical studies and clinical trials of imetelstat provide strong evidence that imetelstat targets telomerase to inhibit the uncontrolled proliferation of malignant stem and progenitor cells in myeloid hematologic malignancies resulting in malignant cell apoptosis and potential disease-modifying activity. Imetelstat has been granted Fast Track designation by the U.S. Food and Drug Administration for both the treatment of adult patients with transfusion dependent anemia due to Low or Intermediate-1 risk MDS that is not associated with del(5q) who are refractory or resistant to an erythropoiesis stimulating agent, and for adult patients with Intermediate-2 or High-risk myelofibrosis (MF) whose disease has relapsed after or is refractory to janus associated kinase (JAK) inhibitor treatment. Imetelstat is currently not approved by any regulatory authority.

On December 4, 2023 Exelixis, Inc. (Nasdaq: EXEL) reported the initiation of STELLAR-305, a phase 2/3 pivotal trial evaluating zanzalintinib in combination with pembrolizumab versus pembrolizumab alone in patients with previously untreated PD-L1-positive recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) (Press release, Exelixis, DEC 4, 2023, View Source [SID1234638125]).

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"We are excited to progress zanzalintinib, our next-generation multi-targeted tyrosine kinase inhibitor, into this population of patients who otherwise are relegated to immunotherapy plus chemotherapy, but may benefit from a chemo-free option," said Amy Peterson, M.D., Executive Vice President, Product Development & Medical Affairs, and Chief Medical Officer, Exelixis. "This study is based on encouraging data from a phase 2 investigator-initiated trial of cabozantinib and pembrolizumab and demonstrates our agility to move quickly into indications with sound rationale from our flagship asset."

STELLAR-305 is a global, multicenter, randomized, double-blind phase 2/3 study that will enroll patients with PD-L1-positive recurrent or metastatic SCCHN that is incurable with local therapies. Patients must not have received prior systemic therapy for recurrent or metastatic disease. Patients will be randomized 1:1 to receive zanzalintinib in combination with pembrolizumab or placebo in combination with pembrolizumab. The primary endpoints of the study are progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 by Blinded Independent Radiology Committee (BIRC) and overall survival. Secondary endpoints include PFS per RECIST 1.1 by investigator and objective response rate and duration of response per RECIST 1.1 by BIRC and by investigator.

STELLAR-305 is sponsored by Exelixis. More information about STELLAR-305 is available at ClinicalTrials.gov.

About Zanzalintinib

Zanzalintinib is a next-generation oral tyrosine kinase inhibitor that inhibits the activity of receptor tyrosine kinases implicated in cancer growth and spread, including VEGF receptors, MET, AXL and MER. These receptor tyrosine kinases are involved in both normal cellular function and in pathologic processes such as oncogenesis, metastasis, tumor angiogenesis and resistance to multiple therapies, including immune checkpoint inhibitors. With zanzalintinib, Exelixis sought to build upon its extensive experience with the target profile of cabozantinib, the company’s flagship medicine, while improving key characteristics, including pharmacokinetic half-life. Zanzalintinib is currently being developed for the treatment of advanced solid tumors, including genitourinary, colorectal and head and neck cancers.

About SCCHN

SCCHN 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, SCCHN 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 Approximately 50,000 new cases of SCCHN are diagnosed in the U.S. every year.1 SCCHN 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 SCCHN ranges from 4-35%.5

CABOMETYX 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, and constipation.

CABOMETYX in combination with nivolumab: diarrhea, fatigue, hepatotoxicity, PPE, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.

DRUG INTERACTIONS

Strong CYP3A4 Inhibitors: If coadministration with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage. Avoid grapefruit or grapefruit juice.

Strong 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

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