On June 20, 2023 UroGen Pharma Ltd. (Nasdaq: URGN), a biotech company dedicated to developing and commercializing innovative solutions that treat urothelial and specialty cancers, reported the results of a sub-analysis from the first post-commercial utilization review of JELMYTO (mitomycin) for pyelocalyceal solution (Press release, UroGen Pharma, JUN 20, 2023, View Source [SID1234632801]). This is the first study to compare modes of administration for JELMYTO, an approved treatment for low-grade upper tract urothelial cancer (LG-UTUC) in adult patients. Findings from the study titled, Route of Administration for UGN-101 and Impact on Oncological and Safety Outcomes, are published in the European Urology Focus online.

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In this sub-analysis, 136 renal units were treated in 132 patients (43% via antegrade and 57% via retrograde) with at least one dose of JELMYTO. Investigators reported that the overall rate of stricture occurrence was lower with the antegrade approach (12%) compared to retrograde group (32%). Although no significant difference in response was observed, the antegrade group showed a higher complete response (CR) rate of 60% compared to 48% in the retrograde group (p=0.1). Partial response (PR) rates were also favorable, with 60% CR and 32% PR for antegrade administration, and 48% CR and 28% PR for retrograde administration. In this study, survival outcomes are reported per patient and treatment, complications and recurrence outcomes are reported per renal unit.

In the OLYMPUS clinical study, data were generated for the retrograde administration of JELMYTO. In that study population, ureteric obstruction was reported in 58% (n=41) of patients receiving JELMYTO, including 17% (n=12) of patients who experienced Grade 3 obstruction.

"These results are encouraging because they add to recent evidence that suggests the antegrade mode of administration of JELMYTO may have potential advantages," said Jennifer Linehan, M.D., Associate Professor of Urology and Urologic Oncology, St. Joseph’s Cancer Institute, Providence Specialty Medical Group, Santa Monica, CA. "Since JELMYTO was approved for both retrograde and antegrade administration, physicians and patients should have more confidence in choosing antegrade when evaluating the pros and cons of each treatment approach."

Mark Schoenberg, M.D., Chief Medical Officer, UroGen, shared similar sentiments, saying, "We are pleased to see the growing body of evidence that may give physicians and patients more confidence when choosing between two modes of administration for JELMYTO. It’s good to have options to choose from based on personal preferences."

While acknowledging the limitations of the study, such as its retrospective design and potential treatment bias, the researchers highlighted the need for further investigation into patient-reported tolerability, quality of life, cost analysis, long-term safety and treatment durability. To address some of these areas, investigators are currently enrolling patients in the prospective and retrospective uTRACT Registry, which aims to capture data in a large-scale, standardized manner and provide more comprehensive insights into patient outcomes following JELMYTO treatment, including long-term follow-up.

About UTUC

Approximately 5-7% of urothelial cancer occurs in the upper lining of the kidney, called the calyx and renal pelvis. It can also occur in one or both of the ureter(s), the tubes that lead from the kidneys to the bladder. Cancer in the renal pelvis or ureter(s) is called upper tract. LG-UTUC is usually not very aggressive and is slow to spread but has a high recurrence rate. High-grade UTUC can be more aggressive. It may spread to other parts of the urinary tract or to other parts of the body.

JELMYTO is approved for the treatment of adults with LG-UTUC. LG-UTUC is a rare disease managed by endoscopic methods and radical nephroureterectomy. Endoscopic resection and laser ablation attempt to preserve the kidney, though there is a high risk of recurrence that may eventually necessitate removal of the kidney. Although kidney removal is the gold standard for treatment of high-grade UTUC, it may be over-treatment in LG-UTUC, as kidney removal offers similar five-year survival as kidney-sparing procedures but is associated with significant morbidity. JELMYTO is efficacious as a primary chemoablative therapy in patients with LG-UTUC.

About JELMYTO

JELMYTO (mitomycin) for pyelocalyceal solution is a mitomycin-containing reverse thermal gel containing 4 mg mitomycin per mL gel indicated for primary chemoablative treatment of LG-UTUC in adults. It is recommended for primary treatment of biopsy-proven LG-UTUC in patients deemed appropriate candidates for renal-sparing therapy. JELMYTO is a viscous liquid when cooled and becomes a semi-solid gel at body temperature. The drug slowly dissolves over four to six hours after instillation and is removed from the urinary tract by normal urine flow and voiding. It is approved for administration in a retrograde manner via ureteral catheter or antegrade through nephrostomy tube. The delivery system allows the initial liquid to coat and conform to the upper urinary tract anatomy. The eventual semisolid gel allows for chemoablative therapy to remain in the collecting system for four to six hours without immediately being diluted or washed away by urine flow.

APPROVED USE FOR JELMYTO

JELMYTO is a prescription medicine used to treat adults with a type of cancer of the lining of the upper urinary tract including the kidney called low-grade Upper Tract Urothelial Cancer (LG-UTUC).

IMPORTANT SAFETY INFORMATION

You should not receive JELMYTO if you have a hole or tear (perforation) of your bladder or upper urinary tract.

Before receiving JELMYTO, tell your healthcare provider about all your medical conditions, including if you:

are pregnant or plan to become pregnant. JELMYTO can harm your unborn baby. You should not become pregnant during treatment with JELMYTO. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with JELMYTO. Females who are able to become pregnant: You should use effective birth control (contraception) during treatment with JELMYTO and for 6 months after the last dose. Males being treated with JELMYTO: If you have a female partner who is able to become pregnant, you should use effective birth control (contraception) during treatment with JELMYTO and for 3 months after the last dose.
are breastfeeding or plan to breastfeed. It is not known if JELMYTO passes into your breast milk. Do not breastfeed during treatment with JELMYTO and for 1 week after the last dose.
Tell your healthcare provider if you take water pills (diuretic).
How will I receive JELMYTO?

Your healthcare provider will tell you to take a medicine called sodium bicarbonate before each JELMYTO treatment.
You will receive your JELMYTO dose from your healthcare provider 1 time a week for 6 weeks. It is important that you receive all 6 doses of JELMYTO according to your healthcare provider’s instructions. If you miss any appointments, call your healthcare provider as soon as possible to reschedule your appointment. Your healthcare provider may recommend up to an additional 11 monthly doses.
JELMYTO is given to your kidney through a tube called a catheter.
During treatment with JELMYTO, your healthcare provider may tell you to take additional medicines or change how you take your current medicines.
After receiving JELMYTO:

JELMYTO may cause your urine color to change to a violet to blue color. Avoid contact between your skin and urine for at least 6 hours.
To urinate, males and females should sit on a toilet and flush the toilet several times after you use it. After going to the bathroom, wash your hands, your inner thighs, and genital area well with soap and water.
Clothing that comes in contact with urine should be washed right away and washed separately from other clothing.
JELMYTO may cause serious side effects, including:

Swelling and narrowing of the tube that carries urine from the kidney to the bladder (ureteric obstruction). If you develop swelling and narrowing, and to protect your kidney from damage, your healthcare provider may recommend the placement of a small plastic tube (stent) in the ureter to help the kidney drain. Tell your healthcare provider right away if you develop side pain or fever during treatment with JELMYTO.
Bone marrow problems. JELMYTO can affect your bone marrow and can cause a decrease in your white blood cell, red blood cell, and platelet counts. Your healthcare provider will do blood tests prior to each treatment to check your blood cell counts during treatment with JELMYTO. Your healthcare provider may need to temporarily or permanently stop JELMYTO if you develop bone marrow problems during treatment with JELMYTO.
The most common side effects of JELMYTO include: urinary tract infection, blood in your urine, side pain, nausea, trouble with urination, kidney problems, vomiting, tiredness, stomach (abdomen) pain.

You are encouraged to report negative side effects of prescription drugs to the U.S. Food and Drug Administration. Visit www.fda.gov/medwatch or call 1-800-FDA-1088. You may also report side effects to UroGen Pharma at 1-855-987-6436.

Please click here for JELMYTO Full Prescribing Information, including the Patient Information, for additional information and here for the Nephrostomy Administration Guide.

On June 20, 2023 Ultragenyx Pharmaceutical Inc. (NASDAQ: RARE), a biopharmaceutical company focused on the development and commercialization of novel therapies for rare and ultra-rare diseases, reported the grant of 20,405 restricted stock units of the company’s common stock to 16 newly hired non-executive officers of the company (Press release, Ultragenyx Pharmaceutical, JUN 20, 2023, View Source [SID1234632800]). The awards were approved by the compensation committee of the company’s board of directors and granted under the Ultragenyx Employment Inducement Plan, with a grant date of June 16, 2023, as an inducement material to the new employees entering into employment with Ultragenyx in accordance with Nasdaq Listing Rule 5635(c)(4).

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The restricted stock units vest over four years, with 25% of the underlying shares vesting on each anniversary of the grant date, subject to the employee being continuously employed by the company as of such vesting dates.

On June 20, 2023 TRACON Pharmaceuticals (NASDAQ: TCON), a clinical stage biopharmaceutical company utilizing a cost-efficient, CRO-independent product development platform to advance its pipeline of novel targeted cancer therapeutics and to partner with other life science companies, reported the positive results of a six-month independent data monitoring committee (IDMC) review for the ongoing ENVASARC Phase 2 pivotal trial (Press release, Tracon Pharmaceuticals, JUN 20, 2023, View Source [SID1234632799]).

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The IDMC reviewed interim safety and efficacy data from more than 80 patients equally randomized into cohort C of single agent envafolimab or cohort D of envafolimab given in combination with Yervoy. Patients in cohort C who had at least two on study CT scans continued to demonstrate a double-digit ORR assessed by investigator and blinded independent central review. Envafolimab was well tolerated without a single > grade 2 drug related adverse event. A planned interim analysis in the third quarter will be conducted after the 46th patient treated with envafolimab has completed a minimum of 12 weeks of efficacy evaluations and includes a futility rule that is currently being exceeded based on available data.

"We are pleased with the single agent activity of envafolimab that continues to generate a double-digit ORR, as well as the safety data showing envafolimab is well tolerated," said James Freddo, M.D., TRACON’s Chief Medical Officer. "We believe the current response rate indicates that we remain on track to achieve the primary endpoint of the study of a minimum 11.25% objective response rate. We remain excited by the emerging data and for envafolimab’s potential to become a differentiated treatment for sarcoma patients."

The combination of envafolimab with Yervoy did not demonstrate synergy when compared to single agent envafolimab and the Company will terminate enrollment in cohort D. This is expected to result in a reduction in trial costs and acceleration of the timeline to final ENVASARC data.

Enrollment of the separate trial of TRACON’s CTLA-4 antibody YH001 with envafolimab and doxorubicin will continue, based on multiple responses seen in the Phase 1 portion of the trial to date using a higher dose of the CTLA-4 antibody. Phase 1 is designed to determine the optimal dose of YH001 in combination with envafolimab and doxorubicin, and the Company expects to report trial data at the Connective Tissue Oncology Society (CTOS) annual meeting in November.

"Achieving a double-digit ORR with a well-tolerated safety profile positions envafolimab to become a potentially compelling treatment option for patients with the refractory sarcoma subtypes of UPS and MFS," said Charles Theuer, M.D., Ph.D., TRACON’s Chief Executive Officer. "The sole approved treatment for these patients is Votrient, which achieved a 4% ORR and carries a black box warning for fatal liver toxicity."

About Envafolimab

Envafolimab (KN035), a single-domain antibody against PD-L1 invented by Alphamab Oncology and licensed by TRACON, is the first approved subcutaneously injected PD-(L)1 inhibitor. Envafolimab was approved by the Chinese NMPA in November 2021 in adult patients with MSI-H/dMMR advanced solid tumors who failed systemic treatment and have no satisfactory alternative treatment options. In December 2019, Alphamab Oncology, 3D Medicines and TRACON entered into a collaboration whereby TRACON has the right to develop and commercialize envafolimab in soft tissue sarcoma in North America. Envafolimab is currently being studied in the ENVASARC Phase 2 pivotal trial in the United States sponsored by TRACON and a Phase 3 pivotal trial in combination with gemcitabine and oxaliplatin in advanced biliary tract cancer patients in China sponsored by TRACON’s corporate partners, Alphamab Oncology and 3D Medicines. TRACON has received orphan drug designation from the U.S. Food and Drug Administration for envafolimab for patients with soft tissue sarcoma and fast track designation from the U.S. Food and Drug Administration for envafolimab (KN035) for patients with locally advanced, unresectable or metastatic undifferentiated pleomorphic sarcoma (UPS) and myxofibrosarcoma (MFS) who have progressed on one or two prior lines of chemotherapy.

About ENVASARC (NCT04480502)

The ENVASARC pivotal trial is a multicenter, open label, randomized, non-comparative, parallel cohort study at 30 top cancer centers in the United States and the United Kingdom that began dosing in December 2020. ENVASARC is enrolling patients with UPS or MFS who have progressed following one or two lines of prior treatment and have not received an immune checkpoint inhibitor. A total of 80 patients will receive treatment with single agent envafolimab at 600 mg every three weeks. The primary endpoint is objective response rate by central review with duration of response a key secondary endpoint.

On June 20, 2023 Seagen Inc. (NASDAQ: SGEN) reported that the clinical research cooperative German Hodgkin Study Group (GHSG) reported results showing that a phase 3 trial of ADCETRIS in combination with chemotherapy – a regimen called BrECADD (brentuximab vedotin [ADCETRIS], etoposide, cyclophosphamide, doxorubicin [Adriamycin], dacarbazine, and dexamethasone) – met its co-primary endpoints of non-inferior efficacy and superior tolerability versus a highly efficacious yet chemotherapy-intense treatment regimen of escalated BEACOPP (bleomycin, etoposide, doxorubicin (Adriamycin), cyclophosphamide, vincristine, procarbazine, and prednisone), which is an international standard of care in the frontline advanced classical Hodgkin lymphoma (cHL) setting and commonly used in Europe (Press release, Seagen, JUN 20, 2023, View Source [SID1234632798]). Both study arms used PET scans to guide treatment decisions. The data results of the HD21 study were presented in a late-breaking session at the 17th International Conference on Malignant Lymphoma (ICML) in Lugano, Switzerland on June 17.

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An interim analysis at 40 months showed an unprecedented 94.9% 3-year progression-free survival (PFS) (99% CI: 92.8, 97.1) for patients treated with the ADCETRIS combination of BrECADD versus 92.3% for eBEACOPP (99% CI: 89.7, 94.9). 12-month post-treatment safety data were consistent with previously presented HD21 data results at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2022 Annual Meeting.

ADCETRIS + AVD chemotherapy (Adriamycin, vinblastine, dacarbazine) is a U.S. standard of care in advanced-stage cHL and is the only targeted therapy inclusive regimen that has a proven statistically significant overall survival benefit at 6-years of follow-up compared to ABVD, reducing risk of death by 41% for these patients.i,ii ADCETRIS is approved for seven indications in the U.S. and six indications in Europe, where Takeda has commercialization rights.

"Our mission in Hodgkin lymphoma is to cure patients with a first-line treatment that reduces the risk of cancer returning as much as possible so patients can go on with their lives," said Professor Dr. med. Peter Borchmann, Assistant Medical Director, Department of Hematology and Oncology at the University Hospital of Cologne, Germany and Head of the Lymphoma Program, Head of the German Hodgkin Study Group and Trial Chairman of the HD21 study. "The mature results of this study demonstrate 3-year efficacy never previously observed in a phase 3 trial in advanced cHL and suggest that the BrECADD regimen may be the most effective therapy regimen currently available in advanced cHL."

"We are enthusiastic about these strong and durable efficacy outcomes and tolerability findings of an ADCETRIS based chemotherapy regimen compared to an international standard chemotherapy. We are evaluating these results to determine next steps," said Roger Dansey, President of Research and Development and Chief Medical Officer at Seagen.

Results from the GHSG’s HD21 Trial

Among 1,482 patients at median follow up of 40 months, an intent-to-treat analysis showed:

3-year PFS was 94.9% for BrECADD vs. 92.3% for eBEACOPP (HR=0.63 [99% CI: 0.37, 1.07])
1-year PFS was 97.5% for BrECADD (99% CI: 96, 99)
3-year overall survival was 98.5% in both treatment arms
12-month post-treatment safety information was available for 95 percent of patients (n=1,395), which showed the rate of grade ≥2 peripheral neuropathy was lower with BrECADD (1.9%) vs. eBEACOPP (2.7%) with most patients having no or low (grade 1) peripheral neuropathy (98.1% for BrECADD vs. 97.3% for eBEACOPP).

Preservation of fertility potential was indicated by measurement of follicle-stimulating hormone (FSH) and was available for 597 patients. Preservation of fertility potential was numerically favorable for the BrECADD arm vs. eBEACOPP. Mean FSH levels were 29.4 and 31.8 after 4 and 6 cycles, respectively for eBEACOPP, and 18.3 and 20.5 after 4 and 6 cycles, respectively, for BrECADD. Persistently elevated FSH is associated with impaired gonadal function. Additional analysis is required to understand the significance of these findings.

Please see Important Safety Information, including a BOXED WARNING for progressive multifocal leukoencephalopathy (PML), for ADCETRIS below.

About the HD21 Study

The GHSG’s phase 3 HD21 trial in advanced cHL enrolled 1,500 patients from 9 countries between July 2016 and August 2020. The median age was 34 years old (range 18-61), and 47 percent were considered high-risk with an international prognostic index ≥3. 59% of patients received four cycles of therapy and 41% received six cycles of therapy. Patients were randomized in a 1:1 ratio to PET2-guided 4-6 cycles of either BrECADD or eBEACOPP. PET2 and PFS events were assessed by blinded panel review. Non-inferiority of the primary efficacy endpoint PFS was defined as absolute difference <6% at five years corresponding to an HR of BrECADD vs eBEACOPP <1.69. The study was funded by Takeda.

About Hodgkin Lymphoma

Lymphoma is a general term for a group of cancers that originate in the lymphatic system affecting a type of white blood cell called lymphocytes. There are two major categories of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. Hodgkin lymphoma is distinguished by the presence of Reed-Sternberg cells that usually have a protein called CD30 on their surface. Approximately 8,830 cases of classical Hodgkin lymphoma will be diagnosed in the United States during 2023 and 900 people will die from the disease.iii According to the International Agency for Research on Cancer in 2020, over 83,000 people worldwide were diagnosed with Hodgkin lymphoma and approximately 23,000 people died from this cancer.iv

About The German Hodgkin Study Group

For over 30 years, the German Hodgkin Study Group (GHSG) has been committed to optimizing diagnostics, therapy and follow-up care in Hodgkin lymphoma. The GHSG’s Trial Coordination Center belongs to the Department of Internal Medicine at the University of Cologne. It recruits patients from across Europe, and over 15,000 patients have participated in its clinical trials. With the results of its large-scale controlled, prospective and randomized trials for all stages of Hodgkin lymphoma, the GHSG has contributed decisively to the great progress in Hodgkin lymphoma therapy over the years. The GHSG’s latest trials aim to reduce adverse effects of therapy while maintaining cure rates.

About ADCETRIS

ADCETRIS is an antibody-drug conjugate (ADC) comprised of a CD30-directed monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seagen’s proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-positive tumor cells.

ADCETRIS is approved in seven indications in the U.S.:

Adult patients with previously untreated Stage III/IV cHL in combination with doxorubicin, vinblastine, and dacarbazine (2018)
Pediatric patients 2 years and older with previously untreated high risk cHL in combination with doxorubicin, vincristine, etoposide, prednisone and cyclophosphamide (2022)
Adult patients with cHL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation (2015)
Adult patients with cHL after failure of auto-HSCT or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates (2011)
Adult patients with previously untreated systemic anaplastic large cell lymphoma (sALCL) or other CD30-expressing peripheral T-cell lymphomas (PTCL), including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified, in combination with cyclophosphamide, doxorubicin, and prednisone (2018)
Adult patients with sALCL after failure of at least one prior multi-agent chemotherapy regimen. (2011)
Adult patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) after prior systemic therapy (2017)
ADCETRIS has marketing authorization in more than 70 countries for relapsed or refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma. ADCETRIS received conditional marketing authorization from the European Commission in October 2012. Its approved indications in Europe are for:

Adult patients with previously untreated CD30-positive Stage IV Hodgkin lymphoma in combination with AVD
Adult patients with CD30-positive Hodgkin lymphoma at increased risk of relapse or progression following ASCT.
Adult patients with relapsed or refractory CD30-positive Hodgkin lymphoma following ASCT or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option.
Adult patients with relapsed or refractory sALCL
Adult patients with previously untreated sALCL in combination with CHP
Adult patients with CD30-positive cutaneous T-cell lymphoma (CTCL) after at least one prior systemic therapy
Seagen and Takeda jointly develop ADCETRIS. Under the terms of the collaboration agreement, Seagen has U.S. and Canadian commercialization rights, and Takeda has rights to commercialize ADCETRIS in the rest of the world. Seagen and Takeda are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where Takeda is solely responsible for development costs.

ADCETRIS (brentuximab vedotin) for injection U.S. Important Safety Information

BOXED WARNING

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML): JC virus infection resulting in PML, and death can occur in ADCETRIS-treated patients.

CONTRAINDICATION

Contraindicated with concomitant bleomycin due to pulmonary toxicity (e.g., interstitial infiltration and/or inflammation).

WARNINGS AND PRECAUTIONS

Peripheral neuropathy (PN): ADCETRIS causes PN that is predominantly sensory. Cases of motor PN have also been reported. ADCETRIS-induced PN is cumulative. Monitor for symptoms such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness. Patients experiencing new or worsening PN may require a delay, change in dose, or discontinuation of ADCETRIS.

Anaphylaxis and infusion reactions: Infusion-related reactions (IRR), including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an IRR occurs, interrupt the infusion and institute appropriate medical management. If anaphylaxis occurs, immediately and permanently discontinue the infusion and administer appropriate medical therapy. Premedicate patients with a prior IRR before subsequent infusions. Premedication may include acetaminophen, an antihistamine, and a corticosteroid.

Hematologic toxicities: Fatal and serious cases of febrile neutropenia have been reported with ADCETRIS. Prolonged (≥1 week) severe neutropenia and Grade 3 or 4 thrombocytopenia or anemia can occur with ADCETRIS.

Administer G-CSF primary prophylaxis beginning with Cycle 1 for adult patients who receive ADCETRIS in combination with chemotherapy for previously untreated Stage III/IV cHL or previously untreated PTCL, and pediatric patients who receive ADCETRIS in combination with chemotherapy for previously untreated high risk cHL.

Monitor complete blood counts prior to each ADCETRIS dose. Monitor more frequently for patients with Grade 3 or 4 neutropenia. Monitor patients for fever. If Grade 3 or 4 neutropenia develops, consider dose delays, reductions, discontinuation, or G-CSF prophylaxis with subsequent doses.

Serious infections and opportunistic infections: Infections such as pneumonia, bacteremia, and sepsis or septic shock (including fatal outcomes) have been reported in ADCETRIS-treated patients. Closely monitor patients during treatment for infections.

Tumor lysis syndrome: Patients with rapidly proliferating tumor and high tumor burden may be at increased risk. Monitor closely and take appropriate measures.

Increased toxicity in the presence of severe renal impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with severe renal impairment. Avoid use in patients with severe renal impairment.

Increased toxicity in the presence of moderate or severe hepatic impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with moderate or severe hepatic impairment. Avoid use in patients with moderate or severe hepatic impairment.

Hepatotoxicity: Fatal and serious cases have occurred in ADCETRIS-treated patients. Cases were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin, and occurred after the first ADCETRIS dose or rechallenge. Preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may increase the risk. Monitor liver enzymes and bilirubin. Patients with new, worsening, or recurrent hepatotoxicity may require a delay, change in dose, or discontinuation of ADCETRIS.

PML: Fatal cases of JC virus infection resulting in PML have been reported in ADCETRIS-treated patients. First onset of symptoms occurred at various times from initiation of ADCETRIS, with some cases occurring within 3 months of initial exposure. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider PML diagnosis in patients with new-onset signs and symptoms of central nervous system abnormalities. Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed.

Pulmonary toxicity: Fatal and serious events of noninfectious pulmonary toxicity, including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome, have been reported. Monitor patients for signs and symptoms, including cough and dyspnea. In the event of new or worsening pulmonary symptoms, hold ADCETRIS dosing during evaluation and until symptomatic improvement.

Serious dermatologic reactions: Fatal and serious cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with ADCETRIS. If SJS or TEN occurs, discontinue ADCETRIS and administer appropriate medical therapy.

Gastrointestinal (GI) complications: Fatal and serious cases of acute pancreatitis have been reported. Other fatal and serious GI complications include perforation, hemorrhage, erosion, ulcer, intestinal obstruction, enterocolitis, neutropenic colitis, and ileus. Lymphoma with pre-existing GI involvement may increase the risk of perforation. In the event of new or worsening GI symptoms, including severe abdominal pain, perform a prompt diagnostic evaluation and treat appropriately.

Hyperglycemia: Serious cases, such as new-onset hyperglycemia, exacerbation of pre-existing diabetes mellitus, and ketoacidosis (including fatal outcomes) have been reported with ADCETRIS. Hyperglycemia occurred more frequently in patients with high body mass index or diabetes. Monitor serum glucose and if hyperglycemia develops, administer anti-hyperglycemic medications as clinically indicated.

Embryo-fetal toxicity: Based on the mechanism of action and animal studies, ADCETRIS can cause fetal harm. Advise females of reproductive potential of this potential risk, and to use effective contraception during ADCETRIS treatment and for 2 months after the last dose of ADCETRIS. Advise male patients with female partners of reproductive potential to use effective contraception during ADCETRIS treatment and for 4 months after the last dose of ADCETRIS.

ADVERSE REACTIONS

The most common adverse reactions (≥20% in any study) are peripheral neuropathy, fatigue, nausea, diarrhea, neutropenia, upper respiratory tract infection, pyrexia, constipation, vomiting, alopecia, decreased weight, abdominal pain, anemia, stomatitis, lymphopenia, mucositis, thrombocytopenia, and febrile neutropenia.

DRUG INTERACTIONS

Concomitant use of strong CYP3A4 inhibitors has the potential to affect the exposure to monomethyl auristatin E (MMAE). Closely monitor adverse reactions.

USE IN SPECIAL POPULATIONS

Lactation: Breastfeeding is not recommended during ADCETRIS treatment.

Please see the full Prescribing Information, including BOXED WARNING, for ADCETRIS here.

On June 20, 2023 erck (NYSE: MRK), known as MSD outside of the United States and Canada, reported topline results from the Phase 3 KEYNOTE-585 trial, investigating KEYTRUDA, Merck’s anti-PD-1 therapy, in combination with chemotherapy as neoadjuvant treatment, followed by adjuvant treatment with KEYTRUDA plus chemotherapy, then KEYTRUDA monotherapy in patients with locally advanced resectable gastric and gastroesophageal junction (GEJ) adenocarcinoma (Press release, Merck & Co, JUN 20, 2023, View Source [SID1234632797]). At a pre-specified interim analysis conducted by an independent Data Monitoring Committee, the study met one of its primary endpoints of pathological complete response (pCR) rate and demonstrated a statistically significant improvement in pCR rates compared with chemotherapy alone. For the primary endpoint of event-free survival (EFS), there was an improvement in the KEYTRUDA arm; however, results did not meet statistical significance per the pre-specified statistical analysis plan. The endpoint of overall survival (OS) was not formally tested since superiority was not reached for EFS. The safety profile of KEYTRUDA in this trial was consistent with that observed in previously reported studies. Results will be presented at an upcoming medical meeting.

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"While a statistically significant improvement in pathological complete response was observed in this study, we are disappointed that the KEYTRUDA regimen did not significantly improve event-free survival, a result that underscores the challenges in treating locally advanced resectable gastric cancer," said Dr. Scot Ebbinghaus, vice president, global clinical development, Merck Research Laboratories. "Innovative research in earlier stages of cancer is critical to help patients achieve better outcomes, and our efforts continue in earnest. We are grateful to the patients and investigators for their participation in this study."

Merck has an extensive clinical development program evaluating KEYTRUDA in gastrointestinal cancers and is continuing to study KEYTRUDA for multiple uses in gastric, hepatobiliary, esophageal, pancreatic and colorectal cancers.

About KEYNOTE-585
KEYNOTE-585 is a randomized, double-blind, Phase 3 trial (ClinicalTrials.gov, NCT03221426) evaluating KEYTRUDA in combination with chemotherapy (cisplatin plus capecitabine or cisplatin plus 5-fluorouracil) as neoadjuvant treatment, followed by adjuvant treatment with KEYTRUDA plus chemotherapy, then KEYTRUDA monotherapy for the treatment of patients with locally advanced resectable gastric and GEJ adenocarcinoma. The primary endpoints included EFS, defined as the time from randomization to the first occurrence of either radiographic disease progression, a local/distant recurrence, clinical progression or death from any cause; pCR rate, defined as a lack of all signs of cancer in tissue samples; and OS, defined as the time from randomization to death from any cause. Secondary endpoints included disease-free survival and safety. The trial enrolled 1,007 patients who were randomized 1:1 to receive three cycles of KEYTRUDA (200 mg every three weeks) in combination with chemotherapy as neoadjuvant treatment, followed by adjuvant treatment with three cycles of KEYTRUDA (200 mg every three weeks) plus chemotherapy, then KEYTRUDA monotherapy (200 mg every three weeks for up to 11 cycles) or neoadjuvant placebo plus chemotherapy, followed by adjuvant placebo plus chemotherapy, then placebo alone.

About gastric cancer
Gastric cancer – also called stomach cancer – is a type of cancer that begins in the stomach and tends to develop slowly over many years. Approximately 90-95% of gastric cancers are adenocarcinomas, which develop from cells in the innermost lining of the stomach (known as the mucosa). Gastric cancer is the fifth most diagnosed cancer and the fourth leading cause of cancer death worldwide, with approximately 1.1 million patients diagnosed and 768,000 patient deaths from the disease globally in 2020. In the U.S., it is estimated there will be approximately 26,500 patients diagnosed with gastric cancer and 11,000 patient deaths from the disease in 2023.