On February 12, 2021 Exelixis, Inc. (NASDAQ: EXEL) reported positive final data for a phase 1 trial sponsored and conducted by the U.S. National Cancer Institute (NCI), including seven expansion cohorts, evaluating cabozantinib in combination with either nivolumab or nivolumab plus ipilimumab in patients with refractory metastatic genitourinary (GU) tumors . The data will be presented as part of the Rapid Abstract Session: Urothelial Carcinoma and Rare Tumors from 2:15 p.m. – 3:05 p.m. PT on Friday, February 12 at the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper)’s Genitourinary Cancers Symposium (ASCO GU), which is being held virtually, February 11-13, 2021.

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In the study, cabozantinib in combination with either nivolumab alone (n=64) or nivolumab plus ipilimumab (n=56) demonstrated an objective response rate (ORR) for all evaluable patients (n=108) of 38%, with an 11.1% complete response (CR) rate per the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

For the 33 patients with previously treated metastatic urothelial carcinoma (UC), the ORR was 42.4%, and the CR rate was 21%. The ORR for the 16 patients with previously treated metastatic renal cell carcinoma (RCC) was 62.5%. The ORR was 20% for patients with urachal adenocarcinoma (n=15), 85.7% for squamous cell carcinoma of the bladder (n=7) and 44.4% for penile carcinoma (n=9).

The median overall survival for the entire population was 15.9 months. Median progression-free survival was 5.5 months, and median duration of response was 22.8 months.

"We see a significant level of anti-tumor activity with an acceptable tolerability profile for the combination of cabozantinib with nivolumab or nivolumab and ipilimumab for this early phase trial across a broad range of GU malignancies," said Andrea Apolo, M.D., Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health and the principal investigator of the trial. "This phase 1 study’s early results provided important information for the development of the phase 3 CheckMate -9ER study sponsored by Bristol Myers Squibb, of cabozantinib plus nivolumab versus sunitinib that recently reported improved progression-free survival, overall response, and overall response rate, leading to last month’s U.S. approval of the combination therapy of cabozantinib and nivolumab in first-line advanced renal cell carcinoma. The additional activity seen in other GU tumors support further research into the potential of cabozantinib combinations with immune checkpoint inhibitors in other advanced, intractable GU cancers."

"These clinical data were the result of a productive collaboration between the investigators leading the trial, NCI-CTEP, the trial sponsor, and both Exelixis and Bristol Myers Squibb. We would like to thank the patients who generously agreed to participate in the trial," said Gisela Schwab, M.D., President, Product Development and Medical Affairs and Chief Medical Officer, Exelixis. "The combination of cabozantinib with immune checkpoint inhibitors continues to demonstrate positive outcomes for patients with difficult-to-treat advanced genitourinary malignancies such as renal cell and urothelial carcinomas. Going forward, we will continue our work to uncover the potential of cabozantinib in combination with immunotherapies to provide further treatment options to patients with cancer in need."

Treatment-related grade 3 or 4 adverse events (>5% of patients) observed in the doublet cabozantinib and nivolumab group included fatigue (13%), hypertension (13%), dehydration (6%) and thromboembolic event (6%). Immune-related grade 3 or 4 adverse events (>5% of patients) were not observed in this group. Treatment-related grade 3 or 4 adverse events (>5% of patients) observed in the triplet cabozantinib plus nivolumab and ipilimumab group included fatigue (16%), hypertension (11%), dehydration (5.3%) and thromboembolic event (5.3%). Immune-related grade 3 or 4 adverse events (>5% of patients) for this group included hepatitis (7%) and colitis (7%).

About the Trial

The trial was sponsored by the U.S. NCI through Cooperative Research and Development Agreements between the NCI’s Cancer Therapy Evaluation Program (CTEP), Division of Cancer Treatment and Diagnosis, and both Exelixis and Bristol Myers Squibb. Andrea Apolo, M.D., of the NCI’s Genitourinary Malignancies Branch, is the principal investigator. The trial was conducted by the NCI and includes centers from its Experimental Therapeutics Clinical Trials Network.

This open label, non-randomized phase 1 trial was divided into two parts: a dose-escalation phase and an expansion cohort phase. The primary endpoint of the phase 1 trial was to determine the dose-limiting toxicity and recommended doses of the doublet and triplet combinations for later stage clinical studies. The secondary endpoint is ORR as assessed per RECIST version 1.1.

Once the recommended doses were determined for the combinations of cabozantinib plus nivolumab and of cabozantinib plus nivolumab and ipilimumab, the trial enrolled seven subsequent expansion cohorts. The cabozantinib plus nivolumab expansion cohorts included patients with UC, RCC, bladder adenocarcinoma and other rare metastatic GU tumors. The cabozantinib plus nivolumab and ipilimumab expansion cohorts included UC, RCC and penile carcinoma. The objectives of the trial were to determine the clinical activity, safety and tolerability of both combinations in multiple metastatic GU tumors.

The recommended phase 2 doses determined for the combination of cabozantinib plus nivolumab were cabozantinib 40 mg daily and 3 mg/kg of nivolumab every two weeks. The recommended phase 2 doses determined for the combination of cabozantinib plus nivolumab and ipilimumab were cabozantinib 40 mg daily, 3 mg/kg of nivolumab every two weeks and 1 mg/kg ipilimumab every three weeks.

More information about the trial is available at ClinicalTrials.gov.

About Genitourinary Cancers

Genitourinary cancers are those that affect the urinary tract, bladder, kidneys, ureter, prostate, testicles, penis or adrenal glands — parts of the body involved in reproduction and excretion — and include RCC, castration-resistant prostate cancer (CRPC) and UC.1

The American Cancer Society’s (ACS) 2021 statistics cite kidney cancer as among the top ten most commonly diagnosed forms of cancer among both men and women in the U.S.2 Clear cell RCC is the most common type of kidney cancer in adults.3 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 13%.2 Approximately 32,000 patients in the U.S. and over 71,000 worldwide will require systemic treatment for advanced kidney cancer in 2021, with nearly 15,000 patients in need of a first-line treatment in the U.S.4

According to the ACS, in 2021, approximately 250,000 new cases of prostate cancer will be diagnosed, and 34,000 people will die from the disease.2 Prostate cancer that has spread beyond the prostate and does not respond to androgen-suppression therapies — a common treatment for prostate cancer — is known as metastatic CRPC.5 Researchers estimate that in 2020, 43,000 people were diagnosed with metastatic CRPC, which has a median survival of less than two years.6,7,8

Urothelial cancers encompass carcinomas of the bladder, ureter and renal pelvis at a ratio of 50:3:1, respectively.9 Bladder cancer occurs mainly in older people, with 90% of patients aged 55 or older.10 With an estimated 84,000 new cases expected to be diagnosed in 2021, bladder cancer accounts for about 5% of all new cases of cancer in the U.S. each year.11 It is the fourth most common cancer in men.2

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; and for patients with advanced RCC as a first-line treatment in combination with nivolumab. CABOMETYX tablets have also received regulatory approvals in the European Union and additional countries and regions worldwide. In 2016, Exelixis granted Ipsen exclusive rights for the commercialization and further clinical development of cabozantinib outside of the United States 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 United States.

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 and HCC studies. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage. 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 36% (17% 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. Discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis.

Diarrhea: Diarrhea occurred in 63% of CABOMETYX patients. Grade 3 diarrhea occurred in 11% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 diarrhea, Grade 3 diarrhea that cannot be managed with standard antidiarrheal treatments, or Grade 4 diarrhea.

Palmar-Plantar Erythrodysesthesia (PPE): PPE occurred in 44% 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.

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 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 7% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. 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.

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 is observed. 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.

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, decreased appetite, PPE, nausea, hypertension, vomiting, weight decreased, constipation, and dysphonia.

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

DRUG INTERACTIONS

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

Strong CYP3A4 Inducers: If coadministration with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage. Avoid St. John’s wort.

USE IN SPECIFIC POPULATIONS

Lactation: Advise women not to breastfeed during CABOMETYX treatment and for 4 months after the final dose.

Hepatic Impairment: In patients with moderate hepatic impairment, reduce the CABOMETYX dosage. Avoid CABOMETYX in patients with severe hepatic impairment.

On February 12, 2021 Astellas Pharma Inc. (TSE: 4503, President and CEO: Kenji Yasukawa, Ph.D., "Astellas") and Seagen Inc. (Nasdaq: SGEN) reported primary results from the phase 3 EV-301 trial comparing PADCEV (enfortumab vedotin-ejfv) to chemotherapy in adult patients with locally advanced or metastatic urothelial cancer who were previously treated with platinum-based chemotherapy and a PD-1/L1 inhibitor (Press release, Astellas, FEB 12, 2021, View Source [SID1234575028]). At the time of pre-specified interim analysis, patients who received PADCEV in the trial lived a median of 3.9 months longer than those who received chemotherapy. Median overall survival was 12.9 vs. 9.0 months, respectively (HR=0.70 [95 percent Confidence Interval (CI): 0.56-0.89], p=0.001). For patients in the PADCEV arm of the trial, maculopapular rash, fatigue and decreased neutrophil count were the most frequent Grade 3 or greater treatment-related adverse events (TRAEs) occurring in more than 5 percent of patients.

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Urothelial cancer is the most common type of bladder cancer and can also be found in the renal pelvis, ureter and urethra.1

The findings were published in the New England Journal of Medicine and presented during the virtual scientific program of the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Genitourinary Cancers Symposium (ASCO GU) (Abstract 393).

"Improving survival is especially meaningful in patients who have had their cancer progress following chemotherapy or other treatment," said Daniel P. Petrylak, M.D., Professor of Medicine and of Urology, Yale Cancer Center, and corresponding author of the published study.

"Enfortumab vedotin is the first medicine to reduce the risk of death compared to chemotherapy in patients with locally advanced or metastatic urothelial cancer who have received a platinum-containing chemotherapy and an immunotherapy," said Professor Thomas Powles, M.D., Director, Barts Cancer Centre, Queen Mary University of London, who presented results at ASCO (Free ASCO Whitepaper) GU.

Patients who received PADCEV in the trial also showed improvement in the following secondary endpoints:

Median progression-free survival, which is the time without progression of cancer, was 5.6 months for PADCEV vs. 3.7 months for chemotherapy (HR=0.62 [95 percent CI: 0.51-0.75]; p<0.00001).
Overall response rate, the percentage of patients with either complete or partial response, was 40.6 percent vs. 17.9 percent of patients in the chemotherapy arm (p<0.001).
Disease control rate (DCR), which is the percentage of patients who have achieved complete response, partial response or had stable disease, was 71.9 percent for PADCEV and 53.4 percent for chemotherapy (p<0.001).
Other safety findings included:

Rates of serious TRAEs were comparable between treatment arms (23 percent of patients receiving PADCEV vs. 23 percent receiving chemotherapy).
Grade 3 or greater TRAEs were experienced by approximately 50 percent of patients in both study arms. Grade 3 or greater TRAEs occurring in more than 5 percent of patients receiving PADCEV were maculopapular rash (occurring in 7 percent of patients receiving PADCEV vs. 0 percent of patients receiving chemotherapy), fatigue (6 percent vs. 4.5 percent) and decreased neutrophil count (6 percent vs. 13 percent).
"Patients who received PADCEV lived longer than those who received chemotherapy – an important finding, especially in light of the high unmet need faced by people with advanced urothelial cancer," said Andrew Krivoshik, M.D., Ph.D., Senior Vice President and Oncology Therapeutic Area Head, Astellas.

"Since its accelerated approval by the FDA in late 2019, physicians have adopted PADCEV into their practice, and these confirmatory results provide additional evidence of its benefit for people living with advanced bladder cancer," said Roger Dansey, M.D., Chief Medical Officer, Seagen.

Results of EV-301 are expected to be submitted to the U.S. Food and Drug Administration by the end of March as the confirmatory trial following the drug’s accelerated approval in 2019. The results of EV-301 will also be included in submissions to global health authorities.

About Urothelial Cancer
Urothelial cancer is the most common type of bladder cancer (90 percent of cases) and can also be found in the renal pelvis (where urine collects inside the kidney), ureter (tube that connects the kidneys to the bladder) and urethra.1 Globally, approximately 549,000 new cases of bladder cancer and 200,000 deaths are reported annually.2

About the EV-301 Trial
The EV-301 trial (NCT03474107) is a global, multicenter, open-label, randomized phase 3 trial designed to evaluate enfortumab vedotin versus physician’s choice of chemotherapy (docetaxel, paclitaxel or vinflunine) in approximately 600 patients with locally advanced or metastatic urothelial cancer who were previously treated with a PD-1/L1 inhibitor and platinum-based therapies. The primary endpoint is overall survival and secondary endpoints include progression-free survival, overall response rate, duration of response and disease control rate, as well as assessment of safety/tolerability and quality-of-life parameters.

About PADCEV (enfortumab vedotin-ejfv)
PADCEV was approved by the U.S. Food and Drug Administration (FDA) in December 2019 and is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and a platinum-containing chemotherapy before (neoadjuvant) or after (adjuvant) surgery or in a locally advanced or metastatic setting. PADCEV was approved under the FDA’s Accelerated Approval Program based on tumor response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.3

PADCEV is a first-in-class antibody-drug conjugate (ADC) that is directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer.3,4 Nonclinical data suggest the anticancer activity of PADCEV is due to its binding to Nectin-4 expressing cells followed by the internalization and release of the anti-tumor agent monomethyl auristatin E (MMAE) into the cell, which result in the cell not reproducing (cell cycle arrest) and in programmed cell death (apoptosis).4 PADCEV is co-developed by Astellas and Seagen.

PADCEV Important Safety Information

Warnings and Precautions

Hyperglycemia occurred in patients treated with PADCEV, including death and diabetic ketoacidosis (DKA), in those with and without pre-existing diabetes mellitus. The incidence of Grade 3-4 hyperglycemia increased consistently in patients with higher body mass index and in patients with higher baseline A1C. In one clinical trial, 8% of patients developed Grade 3-4 hyperglycemia. Patients with baseline hemoglobin A1C ≥8% were excluded. Closely monitor blood glucose levels in patients with, or at risk for, diabetes mellitus or hyperglycemia. If blood glucose is elevated (>250 mg/dL), withhold PADCEV.
Peripheral neuropathy (PN), predominantly sensory, occurred in 49% of the 310 patients treated with PADCEV in clinical trials; 2% experienced Grade 3 reactions. In one clinical trial, peripheral neuropathy occurred in patients treated with PADCEV with or without preexisting peripheral neuropathy. The median time to onset of Grade ≥2 was 3.8 months (range: 0.6 to 9.2). Neuropathy led to treatment discontinuation in 6% of patients. At the time of their last evaluation, 19% had complete resolution, and 26% had partial improvement. Monitor patients for symptoms of new or worsening peripheral neuropathy and consider dose interruption or dose reduction of PADCEV when peripheral neuropathy occurs. Permanently discontinue PADCEV in patients that develop Grade ≥3 peripheral neuropathy.
Ocular disorders occurred in 46% of the 310 patients treated with PADCEV. The majority of these events involved the cornea and included keratitis, blurred vision, limbal stem cell deficiency and other events associated with dry eyes. Dry eye symptoms occurred in 36% of patients, and blurred vision occurred in 14% of patients, during treatment with PADCEV. The median time to onset to symptomatic ocular disorder was 1.9 months (range: 0.3 to 6.2). Monitor patients for ocular disorders. Consider artificial tears for prophylaxis of dry eyes and ophthalmologic evaluation if ocular symptoms occur or do not resolve. Consider treatment with ophthalmic topical steroids, if indicated after an ophthalmic exam. Consider dose interruption or dose reduction of PADCEV for symptomatic ocular disorders.
Skin reactions occurred in 54% of the 310 patients treated with PADCEV in clinical trials. Twenty-six percent (26%) of patients had maculopapular rash and 30% had pruritus. Grade 3-4 skin reactions occurred in 10% of patients and included symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), bullous dermatitis, exfoliative dermatitis, and palmar-plantar erythrodysesthesia. In one clinical trial, the median time to onset of severe skin reactions was 0.8 months (range: 0.2 to 5.3). Of the patients who experienced rash, 65% had complete resolution and 22% had partial improvement. Monitor patients for skin reactions. Consider appropriate treatment, such as topical corticosteroids and antihistamines for skin reactions, as clinically indicated. For severe (Grade 3) skin reactions, withhold PADCEV until improvement or resolution and administer appropriate medical treatment. Permanently discontinue PADCEV in patients that develop Grade 4 or recurrent Grade 3 skin reactions.
Infusion site extravasation Skin and soft tissue reactions secondary to extravasation have been observed after administration of PADCEV. Of the 310 patients, 1.3% of patients experienced skin and soft tissue reactions. Reactions may be delayed. Erythema, swelling, increased temperature, and pain worsened until 2-7 days after extravasation and resolved within 1-4 weeks of peak. One percent (1%) of patients developed extravasation reactions with secondary cellulitis, bullae, or exfoliation. Ensure adequate venous access prior to starting PADCEV and monitor for possible extravasation during administration. If extravasation occurs, stop the infusion and monitor for adverse reactions.
Embryo-fetal toxicity PADCEV can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during PADCEV treatment and for 2 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with PADCEV and for 4 months after the last dose.
Adverse Reactions
Serious adverse reactions occurred in 46% of patients treated with PADCEV. The most common serious adverse reactions (≥3%) were urinary tract infection (6%), cellulitis (5%), febrile neutropenia (4%), diarrhea (4%), sepsis (3%), acute kidney injury (3%), dyspnea (3%), and rash (3%). Fatal adverse reactions occurred in 3.2% of patients, including acute respiratory failure, aspiration pneumonia, cardiac disorder, and sepsis (each 0.8%).

Adverse reactions leading to discontinuation occurred in 16% of patients; the most common adverse reaction leading to discontinuation was peripheral neuropathy (6%). Adverse reactions leading to dose interruption occurred in 64% of patients; the most common adverse reactions leading to dose interruption were peripheral neuropathy (18%), rash (9%) and fatigue (6%). Adverse reactions leading to dose reduction occurred in 34% of patients; the most common adverse reactions leading to dose reduction were peripheral neuropathy (12%), rash (6%) and fatigue (4%).

The most common adverse reactions (≥20%) were fatigue (56%), peripheral neuropathy (56%), decreased appetite (52%), rash (52%), alopecia (50%), nausea (45%), dysgeusia (42%), diarrhea (42%), dry eye (40%), pruritus (26%) and dry skin (26%). The most common Grade ≥3 adverse reactions (≥5%) were rash (13%), diarrhea (6%) and fatigue (6%).

Lab Abnormalities
In one clinical trial, Grade 3-4 laboratory abnormalities reported in ≥5% were: lymphocytes decreased (10%), hemoglobin decreased (10%), phosphate decreased (10%), lipase increased (9%), sodium decreased (8%), glucose increased (8%), urate increased (7%), neutrophils decreased (5%).

Drug Interactions

Effects of other drugs on PADCEV Concomitant use with a strong CYP3A4 inhibitor may increase free MMAE exposure, which may increase the incidence or severity of PADCEV toxicities. Closely monitor patients for signs of toxicity when PADCEV is given concomitantly with strong CYP3A4 inhibitors.
Specific Populations

Lactation Advise lactating women not to breastfeed during treatment with PADCEV and for at least 3 weeks after the last dose.
Hepatic impairment Avoid the use of PADCEV in patients with moderate or severe hepatic impairment.
For more information, please see the full Prescribing Information for PADCEV here.

On February 12, 2021 VolitionRx Limited (NYSE AMERICAN: VNRX) ("Volition"), a multi-national epigenetics company that applies its Nucleosomics platform through its subsidiaries to develop simple, easy to use, cost-effective blood tests to help diagnose a range of cancers and other diseases, reported the closing of its underwritten public offering of 3,809,524 shares of its common stock (the "Offering") for gross proceeds of approximately $20 million, before deducting the underwriting commissions and other estimated offering expenses payable by Volition (Press release, VolitionRX, FEB 12, 2021, View Source [SID1234575045]). All of the shares in the Offering were sold by Volition. In addition, Volition has granted the underwriter for the Offering a 30-day option to purchase up to an additional 571,428 shares of its common stock.

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Cantor Fitzgerald & Co. acted as the sole book running manager of the Offering.

Volition intends to use the net proceeds of the Offering for general corporate purposes, which may include continued product development, clinical studies, product commercialization, working capital and other general corporate purposes, including potential strategic acquisitions.

The Offering was made pursuant to a "shelf" registration statement on Form S-3 (File No. 333-227248) previously filed by Volition with the Securities and Exchange Commission (the "SEC") on September 26, 2018 and declared effective by the SEC on September 28, 2018. The Offering was made only by means of a prospectus, including a prospectus supplement, forming a part of the effective registration statement. The final prospectus supplement relating to and describing the terms of the Offering was filed with the SEC on February 11, 2021 and is available on the SEC’s website at www.sec.gov. Copies of the final prospectus supplement and the accompanying prospectus relating to the Offering may also be obtained by contacting Cantor Fitzgerald & Co., Attn: Capital Markets, 499 Park Avenue, 6th floor, New York, NY 10022; Email: [email protected].

This press release shall not constitute an offer to sell or the solicitation of an offer to buy these securities, nor shall there be any sale of these securities in any state or other jurisdiction in which such offer, solicitation or sale would be unlawful prior to the registration or qualification under the securities laws of any such state or other jurisdiction.

On February 12, 2021 Heat Biologics, Inc. ("Heat") (Nasdaq:HTBX), a clinical-stage biopharmaceutical company focused on developing first-in-class therapies to modulate the immune system, including multiple oncology product candidates and a novel COVID-19 vaccine, reported that it will be presenting at the 2021 BIO CEO & Investor Digital Conference being held virtually between February 16-18, 2021 (Press release, Heat Biologics, FEB 12, 2021, View Source [SID1234575029]).

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A webcast of Heat’s presentation will be available on-demand to registered attendees beginning Tuesday, February 16th, and will be accessible for 30 days via the conference platform. Subsequent to the conference, the presentation will be made available on the investor relations section of Heat Biologics’ website at View Source

At the BIO CEO & Investor Digital Conference attendees will hear key biotech and pharma leaders discuss the most pertinent industry trends, the market outlook, and best practices for executive leadership. For more information about the BIO CEO & Investor Conference, please visit the conference website at View Source

On February 12, 2021 Enveric Biosciences, Inc. (NASDAQ: ENVB) ("Enveric" or the "Company"), a patient-first biotechnology company developing novel cannabinoid medicines to improve quality of life for cancer patients, reported the closing on February 11, 2021 of its previously announced registered direct offering of 3,007,026 shares of its common stock, at a purchase price of $4.27 per share for gross proceeds of approximately $12,840,000 (Press release, Enveric Biosciences, FEB 12, 2021, View Source [SID1234575046]). Enveric has also issued to the investors unregistered warrants to acquire 1,503,513 shares of common stock at $4.90 per share, exercisable immediately and terminating five years after the date of issuance.

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The net proceeds to Enveric from this offering are approximately $11.5 million after deducting financial advisory fees and other costs and expenses of the offering. Enveric intends to use the net proceeds from this offering for working capital and general corporate purposes.

Palladium Capital Group, LLC acted as a financial advisor to the Company.

The shares of common stock (but not the warrants or the shares of common stock underlying the warrants) were offered by Enveric pursuant to a "shelf" registration statement on Form S-3 (File No. 333-233260) previously filed with the Securities and Exchange Commission (the "SEC") on August 14, 2019, and declared effective by the SEC on November 19, 2019, and an additional registration statement on Form S-3 (File No. 333-252880) filed on February 9, 2021 pursuant to Rule 462(b), which became effective automatically upon filing. The offering of the shares of common stock was made only by means of a prospectus and prospectus supplement forming a part of the effective registration statement. Electronic copies of the prospectus supplement and accompanying prospectus may be obtained on the SEC’s website at View Source

The warrants described above were offered in a private placement under Section 4(a)(2) of the Securities Act of 1933, as amended (the "Act"), and Regulation D promulgated thereunder and, along with the shares of common stock underlying the warrants, have not been registered under the Act, or applicable state securities laws. Accordingly, the warrants and underlying shares of common stock may not be offered or sold in the United States except pursuant to an effective registration statement or an applicable exemption from the registration requirements of the Act and such applicable state securities laws. Enveric has agreed to register the shares of common stock issuable upon exercise of the warrants for resale pursuant to a customary registration rights agreement.

This press release shall not constitute an offer to sell or a solicitation of an offer to buy these securities, nor shall there be any sale of these securities in any state or other jurisdiction in which such offer, solicitation or sale would be unlawful prior to the registration or qualification under the securities laws of any such state or other jurisdiction.