Carisma Therapeutics to Present Latest Data from Phase 1 Clinical Trial of Engineered Macrophage Therapy at 2022 ASCO Annual Meeting

On May 26, 2022 Carisma Therapeutics Inc., a clinical stage biopharmaceutical company focused on discovering and developing innovative immunotherapies, reported that two presentations including findings of its lead candidate, CT-0508, accepted for presentation at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting taking place in Chicago, June 3-7 (Press release, Carisma Therapeutics, MAY 26, 2022, View Source [SID1234615141]). The company will present the latest data from its landmark CT-0508 chimeric antigen receptor macrophage (CAR-M) trial for patients with advanced metastatic HER2 overexpressing solid tumors, reaffirming safety and feasibility of its proprietary engineered cell therapy platform. Clinical trial design for phase 1 study of adenovirally transduced autologous macrophages, a second CT-0508 study, was also accepted for presentation.

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In the abstract "A Phase 1, first-in-human (FIH) study of the anti-HER2 CAR Macrophage CT-0508 in subjects with HER2 overexpressing solid tumors," Kim A. Reiss, MD, principal investigator of the Phase 1 clinical trial and an Assistant Professor of Hematology-Oncology at the Perelman School of Medicine at the University of Pennsylvania (Penn), will present an update on the ongoing clinical trial. The findings are the first clinical data of genetically engineered macrophages in humans and demonstrate that CT-0508 was well tolerated after infusion and there were no dose-limiting toxicities reported to date in the current study. CT-0508 was also successfully manufactured using macrophages obtained from heavily pre-treated, advanced solid tumor patients and showed high chimeric antigen receptor (CAR) expression, viability, and purity. The data provide the first clinical demonstration of the CAR-M mechanism of action, exhibiting tumor infiltration, remodeling of the solid tumor microenvironment, and early indications of T-cell activation.

"This additional patient data reinforces the potential of the CAR-M platform, which may have applicability across other therapeutic areas in addition to HER2 over expressing cancers," said Debora Barton, MD, Chief Medical Officer at Carisma Therapeutics. "We look forward to continuing the CT-0508 clinical trial to further observe how our CAR-M therapy can potentially address the unmet needs of patients with hard-to-treat cancers."

Also accepted for presentation at the ASCO (Free ASCO Whitepaper) Annual Meeting is, "A phase 1, first-in-human (FIH) study of adenovirally transduced autologous macrophages engineered to contain an anti-HER2 chimeric antigen receptor (CAR) in subjects with HER2 overexpressing solid tumors," overview of the design of the Phase 1 clinical trial, also presented by Dr. Reiss.

Both of the abstracts will be presented at the 2022 ASCO (Free ASCO Whitepaper) Annual Meeting in the "Developmental Therapeutics—Immunotherapy" poster session on June 5.

Editor’s Note: Carisma has licensed certain Penn-owned intellectual property from the University of Pennsylvania, and Penn’s Perelman School of Medicine receives sponsored research and clinical trial funding from the company. Penn may also be entitled to receive additional financial benefits from technologies licensed and optioned to Carisma in the future. In addition, Penn is a co-founder of the company and holds equity interests in Carisma.

About CT-0508
CT-0508 is a human epidermal growth factor receptor 2 (HER2) targeted chimeric antigen receptor macrophage (CAR-M). It is being evaluated in a landmark Phase 1 multi-center clinical trial that focuses on patients with recurrent or metastatic HER2-overexpressing solid tumors whose cancers do not have approved HER2-targeted therapies or who do not respond to treatment. We are selecting participants who have tumors of any anatomical origin, but with the commonality of overexpressing the HER2 receptor on the cell surface, which is the target for our CAR-M. The Phase 1 clinical trial is first-of-its-kind, marking the first time that engineered macrophages are being studied in humans. The trial continues to enroll patients at five U.S. sites, including Penn; the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill; City of Hope in Duarte, California; University of Texas MD Anderson Cancer Center in Houston, Texas; and Sarah Cannon Research Institute at Tennessee Oncology – Nashville.

Rutgers Cancer Institute of New Jersey and RWJBarnabas Health to Present Expansive, Diverse and Compelling New Cancer Research at the 2022 ASCO Annual Meeting

On May 26, 2022 Physician-scientists from Rutgers Cancer Institute of New Jersey and RWJBarnabas Health reported that it will present intriguing data from their innovative cancer clinical research program at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, to be held both in person in Chicago and online from June 3-7 (Press release, Rutgers Cancer Institute of New Jersey, MAY 26, 2022, View Source [SID1234615140]). A total of 14 presentations, including 13 abstracts and one education session, have been accepted, highlighting research advances in several types of cancer, including leukemia, lymphoma, lung cancer and colorectal cancer.

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"Our passionate team of dedicated, globally recognized physicians and translational researchers is at the vanguard of transforming cancer management, working to develop new treatments, enhance patient care and professional support, and most importantly improve patient outcomes for the multitude of cancers we diagnose and treat," said Andrew M. Evens, DO, MSc, FACP, Associate Director, Clinical Services, Rutgers Cancer Institute; and System Director, Medical Oncology and Oncology Lead, Combined Medical Group, RWJBarnabas Health. "The high-powered lineup of valuable data to be unveiled at this year’s ASCO (Free ASCO Whitepaper) Annual Meeting reflects the command of medicine, technical expertise and leading-edge thinking that are the hallmarks of our cancer research program. The presentations will include significant findings on a number of key cancer treatment strategies, including the use of combination therapies for difficult-to-treat cancers, as well as the impact of social media on the emotional health of oncology professionals," added Dr. Evens, who is also Associate Vice Chancellor, Clinical Innovation and Data Analytics, Rutgers Biomedical and Health Sciences.

Highlights of the accepted abstracts include the following:

Results of an electronic survey of SWOG Cancer Research Network and Children’s Oncology Group members designed to assess the impact of social media on the emotional health and burnout of pediatric and adult oncology professionals. While social media engagement is common in oncology for patients and support groups to advance education and support, the impact on oncology professionals is unknown. The purpose of this survey, developed and piloted by adult and pediatric oncologists, was to evaluate professional social media use and its potential associations with wellness and burnout.
In an updated analysis of ECHELON-1, researchers studied overall survival of first-line brentuximab vedotin plus chemotherapy in patients with stage III/IV classical Hodgkin lymphoma. To date, an overall survival benefit has rarely been shown in first-line classical Hodgkin lymphoma (cHL) and a meaningful improvement in overall survival without the need for escalation of therapy or use of bleomycin would represent a significant advance in optimizing outcomes for these patients.
Initial findings of the phase 2, open-label DELPHINUS study of daratumumab in pediatric and young adult patients with relapsed/refractory T-cell acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL). While current treatments provide a promising prognosis for pediatric ALL and LL, up to 25% of patients will be refractory to or relapse after frontline treatment. This trial seeks to determine the efficacy and safety of daratumumab, a human monoclonal antibody approved to treat multiple myeloma, when used in combination with standard chemotherapy in this patient population.
Updated data from the dose escalation part of a phase 1b, multicenter study of subasumstat in combination with pembrolizumab in patients with relapsed/refractory, checkpoint inhibitor (CPI)-exposed, non-squamous non-small-cell lung cancer or microsatellite-stable colorectal cancer. SUMOylation is a post-translational modification with a role in limiting type 1 interferon (IFN-1)-dependent immune responses. Subasumstat is a small-molecule inhibitor of SUMOylation with the potential to increase antitumor immunity and overcome tumor resistance to CPI by inducing IFN-1 signaling. Preclinical data suggest that subasumstat enhances antigen cross-presentation, promoting T cell dependent antitumor responses; subasumstat plus an anti-PD-1 CPI has shown synergistic tumor growth inhibition and activation of CD8+ T cells and natural killer cells in synergistic mouse models.

Biotheryx to Present Preclinical Data for Its Dual Protein Degrader BTX-1188 at the 2022 American Society of Clinical Oncology Annual Meeting

On May 26, 2022 Biotheryx, Inc., a clinical stage company discovering and developing a portfolio of innovative small molecule targeted protein degraders (TPDs) in areas of high unmet medical need, reported that its abstract highlighting supportive preclinical data for its lead asset BTX-1188, a potentially first-in-class, dual protein degrader of GSPT1 and IKZF1/3, will be presented in a poster at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting taking place June 3-7, 2022, in Chicago, Illinois and virtually (Press release, BioTheryX, MAY 26, 2022, View Source [SID1234615139]).

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"Our distinctive PRODEGY platform is designed to enable the discovery and development of a broad range of targeted protein degrader molecules and BTX-1188 is the first of our pipeline to enter the clinic," said Leah Fung, Ph.D., Chief Scientific Officer of Biotheryx. "BTX-1188 is a molecular glue that was rationally designed to degrade GSPT1 and IKZF1/3. The data being presented at ASCO (Free ASCO Whitepaper) 2022 support the ongoing Phase 1 clinical trial evaluating BTX-1188 in patients with hematologic and solid tumor cancers and demonstrate what we believe to be our ability to design first-in-class molecular glues with the potential to improve clinical outcomes for patients with cancer and other serious diseases."

"We are leveraging our deep expertise with the modulation of Cereblon, the only clinically and commercially validated E3 ligase, to design innovative targeted protein degraders with the potential to address significant unmet medical need," said Philippe Drouet, President and Chief Executive Officer of Biotheryx. "We look forward to presenting these pre-clinical data from our lead program, BTX-1188, at ASCO (Free ASCO Whitepaper) 2022."

Key Highlights from BTX-1188 Preclinical Results

BTX-1188 has shown deep and durable degradation of GSPT1 and IKZF1/3 and inhibition of MYC in several types of hematologic and solid tumor cell lines, including lymphoma, diffuse large B-cell lymphoma, non-small cell lung cancer and glioma.
BTX-1188 has shown inhibition of pro-inflammatory cytokines and enhancement of immune stimulatory cytokines, owing to IKZF1/3 degradation, which may prevent the known systemic inflammatory dose-limiting toxicities associated with pure GSPT1 degradation (Uy 2019)[1].
BTX-1188 potently inhibits tumor cell proliferation and tumor growth in ex vivo and in vivo models of acute myeloid leukemia (AML) and in in vitro and in vivo models of lung, breast and ovarian cancer.
These preclinical results support the ongoing Phase 1 clinical evaluation of BTX-1188 in patients with AML and certain solid tumors, especially in MYC-dependent cancers.
Details for the BTX-1188 ASCO (Free ASCO Whitepaper) 2022 poster presentation are as follows:

Title: BTX-1188, a first-in-class dual degrader of GSPT1 and IKZF1/3, for treatment of acute myeloid leukemia (AML) and solid tumors
Presenter: Aparajita Hoskote Chourasia, Ph.D.
Abstract Number: 7025
Poster Number: 256
Session: Hematologic Malignancies—Leukemia, Myelodysplastic Syndromes, and Allotransplant
Date and Time: Saturday, June 4, 2022 at 9:00 a.m. CT (10:00 a.m. ET)

This poster presentation will be available on the ASCO (Free ASCO Whitepaper) Meeting website. Following the presentation at the meeting, a PDF copy of the poster will be available in the "Publications and Presentations" section of Biotheryx’s website.

About BTX-1188

Biotheryx’s lead molecular glue drug candidate BTX-1188 is a dual protein degrader which was designed to degrade GSPT1, a promising cancer target, and IKZF1/3 (also known as Ikaros/Aiolos), both clinically validated anti-inflammatory and immunomodulatory targets. Prior literature has demonstrated that degradation of GSPT1 can result in antitumor activity in difficult-to-treat tumors such as acute myeloid leukemia (AML) and in solid tumors, including those that overexpress oncogenic transcription factors, such as MYC, however, prior clinical research by others has shown that administration of a GSPT1-only degrader was associated with dose-limiting toxicities related to the release of pro-inflammatory cytokines. BTX-1188 was specifically designed as a potent degrader of GSPT1 that can also directly block inflammation by degrading IKZF1/3. In preclinical studies conducted by Biotheryx, administration of BTX-1188 led to complete eradication of tumors and extended survival in xenograft models of AML. BTX-1188 also led to potent cell killing in a number of cell lines derived from solid tumors. BTX-1188 is currently being evaluated in a Phase 1 dose-escalation trial in patients with hematologic and solid tumor malignancies.

Delfi Diagnostics to Present at 2022 ASCO Annual Meeting on Multiple Applications for its Next-Generation Liquid Biopsy Platform

On May 26, 2022 Delfi Diagnostics, a pioneering developer of a new class of high-performance, affordable liquid biopsy tests for early cancer detection, reported that it will present updates at the 2022 annual meeting of the American Society for Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago June 3-7 describing multiple applications for its next-generation liquid biopsy platform (Press release, Delfi Diagnostics, MAY 26, 2022, View Source [SID1234615138]).

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"Delfi has made incredible progress on our screening program over the past year. Additionally, we have identified several new potential applications for our technology that we are continuing to explore," said Victor Velculescu, MD, PhD, Delfi’s founder and CEO. "We are excited to share these updates with ASCO (Free ASCO Whitepaper)’s members as we pursue multiple applications on the Delfi platform."

Delfi will present a trial-in-progress update on DELFI-L101, a prospective, case-control study to train and test classifiers for lung cancer detection. Additionally, it will present data showing that Delfi’s Tumor Fraction score, DELFI-TFTM, strongly correlates with mutant allele frequency and could serve as a useful tool to monitor tumor burden in patients with advanced cancer.

EMD Serono to Present Latest Research From Oncology Portfolio at ASCO 2022

On May 26, 2022 EMD Serono, the healthcare business of Merck KGaA, Darmstadt, Germany, in the US and Canada, reported the latest research representing the Company’s innovative oncology portfolio has been accepted for presentation at this year’s American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, June 3-7, 2022 (Press release, EMD Serono, MAY 26, 2022, View Source [SID1234615137]). Data encompass Company-sponsored, investigator-sponsored, and external collaboration studies.

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Abstracts to be shared at the meeting include data for the Company’s licensed medicines BAVENCIO (avelumab), TEPMETKO (tepotinib) and its oncology pipeline. The presentations span key tumor types including advanced urothelial carcinoma (UC), advanced renal cell carcinoma (RCC), metastatic non-small cell lung cancer (NSCLC), metastatic colorectal cancer (CRC), and head and neck cancer (SCCHN).

"We look forward to coming together with the scientific community at ASCO (Free ASCO Whitepaper) 2022, where we will share the latest data from our portfolio, which demonstrate our determination to make a real difference in the lives of patients with some of the most challenging cancers," said Victoria Zazulina, Head of Development Unit, Oncology, for the Healthcare business of Merck KGaA, Darmstadt, Germany.

Select presentations include:

BAVENCIO (avelumab): New analyses of long-term data from the Phase III JAVELIN Bladder 100 study of BAVENCIO as first-line maintenance treatment in advanced UC, including data from subgroups defined by best response to first-line chemotherapy and in patients who did or did not receive second-line treatment after BAVENCIO maintenance.
TEPMETKO (tepotinib): Data for the oral MET inhibitor TEPMETKO include two poster presentations from the VISION trial reporting efficacy, safety and quality-of-life results of TEPMETKO in Asian patients with METex14 skipping NSCLC, and updated efficacy and safety results of TEPMETKO and exploratory biomarker analyses in patients with NSCLC with high-level MET amplification enrolled into Cohort B of the VISION trial based on liquid biopsy.
Berzosertib: Results from research collaborations assessing the intravenous ataxia telangiectasia-mutated and Rad3-related protein kinase (ATR) inhibitor berzosertib, including the National Cancer Institute’s (NCI) Cancer Therapy Evaluation Program 9938 Phase I study of berzosertib plus irinotecan in patients with advanced solid tumors and NCI single-arm Phase II data of berzosertib plus topotecan in patients with relapsed extra-pulmonary small cell neuroendocrine carcinomas.
Below is a selection of key Merck KGaA, Darmstadt, Germany-related abstracts accepted for presentation at ASCO (Free ASCO Whitepaper) 2022:

Title

Lead Author

Abstract/#

Session Title/Date/Time

BAVENCIO (avelumab)

Avelumab first-line (1L) maintenance for advanced urothelial carcinoma (aUC): long-term outcomes from JAVELIN Bladder 100 in subgroups defined by response to 1L chemotherapy

BP Valderrama

4559

Genitourinary Cancer—Kidney and Bladder

Saturday, June 4, 2022

1:15 PM-4:15 PM CDT

Long-term outcomes in patients with advanced urothelial carcinoma (UC) who received avelumab first-line (1L) maintenance with or without second-line (2L) treatment: exploratory analyses from JAVELIN Bladder 100

J Bellmunt

4560

Genitourinary Cancer—Kidney and Bladder

Saturday, June 4, 2022

1:15 PM-4:15 PM CDT

TEPTMETKO (tepotinib)

Tepotinib in Asian patients with advanced NSCLC with MET exon 14 (METex14) skipping

T Kato

9120

Lung Cancer—Non-Small Cell Metastatic

Monday, June 6, 2022

8:00 AM-11:00 AM CDT

Clinical response to tepotinib according to circulating tumor (ct) DNA biomarkers in patients with advanced NSCLC with high-level MET amplification (METamp) detected by liquid biopsy (LBx)

X Le

9121

Lung Cancer—Non-Small Cell Metastatic

Monday, June 6, 2022

8:00 AM-11:00 AM CDT

Pipeline

Berzosertib (M6620)*

Targeting genomic instability in extrapulmonary small cell neuroendocrine cancers: a phase II study with ATR inhibitor berzosertib and topotecan

N Takahashi

8518

Lung Cancer—Non-Small Cell Local-Regional/Small Cell/Other Thoracic Cancers

Monday, June 6, 2022

Live discussion: 12:26 PM CDT

NCI 9938: Phase I clinical trial of ATR inhibitor berzosertib (M6620, VX-970) in combination with irinotecan in patients with advanced solid tumors

LC Villaruz

3012

Developmental Therapeutics—Molecularly Targeted Agents and Tumor Biology

Sunday, June 5, 2022

Live Discussion: 4:42 PM CDT

*These studies are sponsored by the National Cancer Institute (NCI), part of the National Institutes of Health, under its Cooperative Research and Development Agreement with Merck KGaA, Darmstadt, Germany for M6620.

Merck KGaA, Darmstadt, Germany is a science-led organization dedicated to delivering transformative medicines with the goal of making a meaningful difference in the lives of people affected by cancer. Our oncology research efforts aim to leverage our synergistic portfolio in oncogenic pathways, immuno-oncology, and DNA Damage Response (DDR) to tackle challenging tumor types in gastrointestinal, genitourinary, and thoracic cancers. Our curiosity drives our pursuit of treatments for even the most complex cancers, as we work to illuminate a path to scientific breakthroughs that transform patient outcomes. Learn more at www.emdseronooncology.com.

About BAVENCIO (avelumab)
BAVENCIO is a human anti-programmed death ligand-1 (PD-L1) antibody. BAVENCIO has been shown in preclinical models to engage both the adaptive and innate immune functions. By blocking the interaction of PD-L1 with PD-1 receptors, BAVENCIO has been shown to release the suppression of the T cell-mediated antitumor immune response in preclinical models.7-9 In November 2014, Merck KGaA, Darmstadt, Germany and Pfizer announced a strategic alliance to co-develop and co-commercialize BAVENCIO.

BAVENCIO Approved Indications
BAVENCIO (avelumab) is indicated in the US for the maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) that has not progressed with first-line platinum-containing chemotherapy. BAVENCIO is also indicated for the treatment of patients with locally advanced or metastatic UC who have disease progression during or following platinum-containing chemotherapy, or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy

BAVENCIO in combination with axitinib is indicated in the US for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

In the US, the FDA granted accelerated approval for BAVENCIO for the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials.

BAVENCIO is currently approved for at least one indication for patients in more than 50 countries.

BAVENCIO Important Safety Information from the US FDA-Approved Label
BAVENCIO can cause severe and fatal immune-mediated adverse reactions in any organ system or tissue and at any time after starting treatment with a PD-1/PD-L1 blocking antibody, including after discontinuation of treatment.

Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

No dose reduction for BAVENCIO is recommended. For immune-mediated adverse reactions, withhold or permanently discontinue BAVENCIO depending on severity. In general, withhold BAVENCIO for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue BAVENCIO for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating corticosteroids. In general, if BAVENCIO requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic corticosteroids (eg, endocrinopathies and dermatologic reactions) are discussed in subsequent sections.

BAVENCIO can cause immune-mediated pneumonitis, including fatal cases. Monitor patients for signs and symptoms of pneumonitis and evaluate suspected cases with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold BAVENCIO for Grade 2 and permanently discontinue for Grade 3 or Grade 4 pneumonitis. Immune-mediated pneumonitis occurred in 1.2% (21/1738) of patients, including fatal (0.1%), Grade 4 (0.1%), Grade 3 (0.3%) and Grade 2 (0.6%) adverse reactions. Systemic corticosteroids were required in all (21/21) patients with pneumonitis.

BAVENCIO can cause immune-mediated colitis. The primary component of immune-mediated colitis consisted of diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Withhold BAVENCIO for Grade 2 or Grade 3, and permanently discontinue for Grade 4 colitis. Immune-mediated colitis occurred in 1.5% (26/1738) of patients, including Grade 3 (0.4%) and Grade 2 (0.7%) adverse reactions. Systemic corticosteroids were required in all (26/26) patients with colitis.

BAVENCIO can cause hepatotoxicity and immune-mediated hepatitis. Withhold or permanently discontinue BAVENCIO based on tumor involvement of the liver and severity of aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total bilirubin elevation. Immune-mediated hepatitis occurred with BAVENCIO as a single agent in 0.9% (16/1738) of patients, including fatal (0.1%), Grade 3 (0.6%), and Grade 2 (0.1%) adverse reactions. Systemic corticosteroids were required in all (16/16) patients with hepatitis.

BAVENCIO in combination with INLYTA can cause hepatotoxicity with higher than expected frequencies of Grade 3 and 4 ALT and AST elevation compared to BAVENCIO alone. Consider more frequent monitoring of liver enzymes as compared to when the drugs are used as monotherapy. Withhold or permanently discontinue both BAVENCIO and INLYTA based on severity of AST, ALT, or total bilirubin elevation, and consider administering corticosteroids as needed. Consider rechallenge with BAVENCIO or INLYTA, or sequential rechallenge with both BAVENCIO and INLYTA, after recovery. In patients treated with BAVENCIO in combination with INLYTA in the advanced RCC trials, increased ALT and increased AST were reported in 9% (Grade 3) and 7% (Grade 4) of patients. Immune-mediated hepatitis was reported in 7% of patients including 4.9% with Grade 3 or 4 immune-mediated hepatitis. Thirty-four patients were treated with corticosteroids and one patient was treated with a non-steroidal immunosuppressant.

BAVENCIO can cause primary or secondary immune-mediated adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement, as clinically indicated. Withhold BAVENCIO for Grade 3 or Grade 4 endocrinopathies until clinically stable or permanently discontinue depending on severity. Immune-mediated adrenal insufficiency occurred in 0.5% (8/1738) of patients, including Grade 3 (0.1%) and Grade 2 (0.3%) adverse reactions. Systemic corticosteroids were required in all (8/8) patients with adrenal insufficiency.

BAVENCIO can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement, as clinically indicated. Withhold BAVENCIO for Grade 3 or Grade 4 endocrinopathies until clinically stable or permanently discontinue depending on severity. Immune-mediated pituitary disorders occurred in 0.1% (1/1738) of patients, which was a Grade 2 (0.1%) adverse reaction.

BAVENCIO can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism, as clinically indicated. Withhold BAVENCIO for Grade 3 or Grade 4 endocrinopathies until clinically stable or permanently discontinue depending on severity. Thyroiditis occurred in 0.2% (4/1738) of patients, including Grade 2 (0.1%) adverse reactions. Hyperthyroidism occurred in 0.4% (7/1738) of patients, including Grade 2 (0.3%) adverse reactions. Systemic corticosteroids were required in 29% (2/7) of patients with hyperthyroidism. Hypothyroidism occurred in 5% (90/1738) of patients, including Grade 3 (0.2%) and Grade 2 (3.7%) adverse reactions. Systemic corticosteroids were required in 7% (6/90) of patients with hypothyroidism.

BAVENCIO can cause immune-mediated type I diabetes mellitus, which can present with diabetic ketoacidosis. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold BAVENCIO for Grade 3 or Grade 4 endocrinopathies until clinically stable or permanently discontinue depending on severity. Immune-mediated type I diabetes mellitus occurred in 0.1% (2/1738) of patients, including Grade 3 (0.1%) adverse reactions.

BAVENCIO can cause immune-mediated nephritis with renal dysfunction. Withhold BAVENCIO for Grade 2 or Grade 3, and permanently discontinue for Grade 4 increased blood creatinine. Immune-mediated nephritis with renal dysfunction occurred in 0.1% (1/1738) of patients, which was a Grade 2 (0.1%) adverse reaction. Systemic corticosteroids were required in this patient.

BAVENCIO can cause immune-mediated dermatologic adverse reactions, including rash or dermatitis. Exfoliative dermatitis including Stevens Johnson Syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis (TEN), has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold BAVENCIO for suspected and permanently discontinue for confirmed SJS, TEN, or DRESS. Immune-mediated dermatologic adverse reactions occurred in 5% (90/1738) of patients, including Grade 3 (0.1%) and Grade 2 (2.0%) adverse reactions. Systemic corticosteroids were required in 29% (26/90) of patients with dermatologic adverse reactions.

BAVENCIO can result in other immune-mediated adverse reactions. Other clinically significant immune-mediated adverse reactions occurred at an incidence of <1% in patients who received BAVENCIO or were reported with the use of other PD-1/PD-L1 blocking antibodies. For myocarditis, permanently discontinue BAVENCIO for Grade 2, Grade 3, or Grade 4. For neurological toxicities, withhold BAVENCIO for Grade 2 and permanently discontinue for Grade 3 or Grade 4.

BAVENCIO can cause severe or life-threatening infusion-related reactions. Premedicate patients with an antihistamine and acetaminophen prior to the first 4 infusions and for subsequent infusions based upon clinical judgment and presence/severity of prior infusion reactions. Monitor patients for signs and symptoms of infusion-related reactions, including pyrexia, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 infusion-related reactions. Permanently discontinue BAVENCIO for Grade 3 or Grade 4 infusion-related reactions. Infusion-related reactions occurred in 25% of patients, including three (0.2%) Grade 4 and nine (0.5%) Grade 3 infusion-related reactions. Eleven (92%) of the 12 patients with Grade ≥3 reactions were treated with intravenous corticosteroids.

Fatal and other serious complications of allogeneic hematopoietic stem cell transplantation (HSCT) can occur in patients who receive HSCT before or after being treated with a PD-1/PD-L1 blocking antibody. Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT.

BAVENCIO in combination with INLYTA can cause major adverse cardiovascular events (MACE) including severe and fatal events. Consider baseline and periodic evaluations of left ventricular ejection fraction. Monitor for signs and symptoms of cardiovascular events. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Permanently discontinue BAVENCIO and INLYTA for Grade 3-4 cardiovascular events. MACE occurred in 7% of patients with advanced RCC treated with BAVENCIO in combination with INLYTA compared to 3.4% treated with sunitinib in a randomized trial. These events included death due to cardiac events (1.4%), Grade 3-4 myocardial infarction (2.8%), and Grade 3-4 congestive heart failure (1.8%).

BAVENCIO can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to a fetus including the risk of fetal death. Advise females of childbearing potential to use effective contraception during treatment with BAVENCIO and for at least 1 month after the last dose of BAVENCIO. It is not known whether BAVENCIO is excreted in human milk. Advise a lactating woman not to breastfeed during treatment and for at least 1 month after the last dose of BAVENCIO due to the potential for serious adverse reactions in breastfed infants.

The most common adverse reactions (all grades, ≥20%) in patients with metastatic Merkel cell carcinoma (MCC) were fatigue (50%), musculoskeletal pain (32%), diarrhea (23%), nausea (22%), infusion-related reaction (22%), rash (22%), decreased appetite (20%), and peripheral edema (20%).

Selected treatment-emergent laboratory abnormalities (all grades, ≥20%) in patients with metastatic MCC were lymphopenia (49%), anemia (35%), increased aspartate aminotransferase (34%), thrombocytopenia (27%), and increased alanine aminotransferase (20%).

A fatal adverse reaction (sepsis) occurred in one (0.3%) patient with locally advanced or metastatic urothelial carcinoma (UC) receiving BAVENCIO + best supportive care (BSC) as first-line maintenance treatment. In patients with previously treated locally advanced or metastatic UC, fourteen patients (6%) who were treated with BAVENCIO experienced either pneumonitis, respiratory failure, sepsis/urosepsis, cerebrovascular accident, or gastrointestinal adverse events, which led to death.

The most common adverse reactions (all grades, ≥20%) in patients with locally advanced or metastatic UC receiving BAVENCIO + BSC (vs BSC alone) as first-line maintenance treatment were fatigue (35% vs 13%), musculoskeletal pain (24% vs 15%), urinary tract infection (20% vs 11%), and rash (20% vs 2.3%). In patients with previously treated locally advanced or metastatic UC receiving BAVENCIO, the most common adverse reactions (all grades, ≥20%) were fatigue, infusion-related reaction, musculoskeletal pain, nausea, decreased appetite, and urinary tract infection.

Selected laboratory abnormalities (all grades, ≥20%) in patients with locally advanced or metastatic UC receiving BAVENCIO + BSC (vs BSC alone) as first-line maintenance treatment were blood triglycerides increased (34% vs 28%), alkaline phosphatase increased (30% vs 20%), blood sodium decreased (28% vs 20%), lipase increased (25% vs 16%), aspartate aminotransferase (AST) increased (24% vs 12%), blood potassium increased (24% vs 16%), alanine aminotransferase (ALT) increased (24% vs 12%), blood cholesterol increased (22% vs 16%), serum amylase increased (21% vs 12%), hemoglobin decreased (28% vs 18%), and white blood cell decreased (20% vs 10%).

Fatal adverse reactions occurred in 1.8% of patients with advanced renal cell carcinoma (RCC) receiving BAVENCIO in combination with INLYTA. These included sudden cardiac death (1.2%), stroke (0.2%), myocarditis (0.2%), and necrotizing pancreatitis (0.2%).

The most common adverse reactions (all grades, ≥20%) in patients with advanced RCC receiving BAVENCIO in combination with INLYTA (vs sunitinib) were diarrhea (62% vs 48%), fatigue (53% vs 54%), hypertension (50% vs 36%), musculoskeletal pain (40% vs 33%), nausea (34% vs 39%), mucositis (34% vs 35%), palmar-plantar erythrodysesthesia (33% vs 34%), dysphonia (31% vs 3.2%), decreased appetite (26% vs 29%), hypothyroidism (25% vs 14%), rash (25% vs 16%), hepatotoxicity (24% vs 18%), cough (23% vs 19%), dyspnea (23% vs 16%), abdominal pain (22% vs 19%), and headache (21% vs 16%).

Selected laboratory abnormalities (all grades, ≥20%) worsening from baseline in patients with advanced RCC receiving BAVENCIO in combination with INLYTA (vs sunitinib) were blood triglycerides increased (71% vs 48%), blood creatinine increased (62% vs 68%), blood cholesterol increased (57% vs 22%), alanine aminotransferase increased (ALT) (50% vs 46%), aspartate aminotransferase increased (AST) (47% vs 57%), blood sodium decreased (38% vs 37%), lipase increased (37% vs 25%), blood potassium increased (35% vs 28%), platelet count decreased (27% vs 80%), blood bilirubin increased (21% vs 23%), and hemoglobin decreased (21% vs 65%).

Please see full US Prescribing Information and Medication Guide available at View Source

About TEPMETKO (tepotinib)
TEPMETKO is a once-daily oral MET inhibitor that inhibits the oncogenic MET receptor signaling caused by MET (gene) alterations. Discovered and developed in-house at Merck KGaA, Darmstadt, Germany, TEPMETKO has a highly selective mechanism of action, with the potential to improve outcomes in aggressive tumors that have a poor prognosis and harbor these specific alterations.

TEPMETKO Approved Indications
TEPMETKO is a kinase inhibitor indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) harboring mesenchymal epithelial transition (MET) exon 14 skipping alterations. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials

TEPMETKO was the first oral MET inhibitor to receive a regulatory approval anywhere in the world for the treatment of advanced NSCLC harboring MET gene alterations, with its approval in Japan in March 2020. In February 2021, the U.S. Food and Drug Administration granted accelerated approval to TEPMETKO, making it the first and only once-daily oral MET inhibitor approved for patients in the U.S. with metastatic NSCLC with METex14 skipping alterations. In February 2022, the European Commission (EC) approved once-daily oral TEPMETKO as monotherapy for the treatment of adult patients with advanced non-small cell lung cancer (NSCLC) harboring alterations leading to mesenchymal-epithelial transition factor gene exon 14 (METex14) skipping, who require systemic therapy following prior treatment with immunotherapy and/or platinum-based chemotherapy.

TEPMETKO is available in a number of countries, and under review by various other regulatory authorities globally. To meet an urgent clinical need, TEPMETKO is also available in a pilot zone of China in line with the government policy to drive early access for innovative medicines approved outside of China.

Merck KGaA, Darmstadt, Germany is also investigating the potential role of tepotinib in treating patients with NSCLC and acquired resistance due to MET amplification in the Phase II INSIGHT 2 study of tepotinib in combination with osimertinib in MET amplified, advanced or metastatic NSCLC harboring activating EGFR mutations that has progressed following first-line treatment with osimertinib.

Important Safety Information from the US FDA-Approved Label
TEPMETKO can cause interstitial lung disease (ILD)/pneumonitis, which can be fatal. Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis (eg, dyspnea, cough, fever). Immediately withhold TEPMETKO in patients with suspected ILD/pneumonitis and permanently discontinue if no other potential causes of ILD/pneumonitis are identified. ILD/pneumonitis occurred in 2.2% of patients treated with TEPMETKO, with one patient experiencing a Grade 3 or higher event; this event resulted in death.

TEPMETKO can cause hepatotoxicity, which can be fatal. Monitor liver function tests (including ALT, AST, and total bilirubin) prior to the start of TEPMETKO, every 2 weeks during the first 3 months of treatment, then once a month or as clinically indicated, with more frequent testing in patients who develop increased transaminases or total bilirubin. Based on the severity of the adverse reaction, withhold, dose reduce, or permanently discontinue TEPMETKO. Increased alanine aminotransferase (ALT)/increased aspartate aminotransferase (AST) occurred in 13% of patients treated with TEPMETKO. Grade 3 or 4 increased ALT/AST occurred in 4.2% of patients. A fatal adverse reaction of hepatic failure occurred in one patient (0.2%). The median time-to-onset of Grade 3 or higher increased ALT/AST was 30 days (range 1 to 178).

TEPMETKO can cause embryo-fetal toxicity. Based on findings in animal studies and its mechanism of action, TEPMETKO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential or males with female partners of reproductive potential to use effective contraception during treatment with TEPMETKO and for one week after the final dose.

Avoid concomitant use of TEPMETKO with dual strong CYP3A inhibitors and P-gp inhibitors and strong CYP3A inducers. Avoid concomitant use of TEPMETKO with certain P-gp substrates where minimal concentration changes may lead to serious or life-threatening toxicities. If concomitant use is unavoidable, reduce the P-gp substrate dosage if recommended in its approved product labeling.

Fatal adverse reactions occurred in one patient (0.4%) due to pneumonitis, one patient (0.4%) due to hepatic failure, and one patient (0.4%) due to dyspnea from fluid overload.

Serious adverse reactions occurred in 45% of patients who received TEPMETKO. Serious adverse reactions in >2% of patients included pleural effusion (7%), pneumonia (5%), edema (3.9%), dyspnea (3.9%), general health deterioration (3.5%), pulmonary embolism (2%), and musculoskeletal pain (2%).

The most common adverse reactions (≥20%) in patients who received TEPMETKO were edema, fatigue, nausea, diarrhea, musculoskeletal pain, and dyspnea.

Clinically relevant adverse reactions in <10% of patients who received TEPMETKO included ILD/pneumonitis, rash, fever, dizziness, pruritus, and headache.

Selected laboratory abnormalities (≥20%) from baseline in patients receiving TEPMETKO in descending order were: decreased albumin (76%), increased creatinine (55%), increased alkaline phosphatase (ALP) (50%), decreased lymphocytes (48%), increased alanine aminotransferase (ALT) (44%), increased aspartate aminotransferase (AST) (35%), decreased sodium (31%), decreased hemoglobin (27%), increased potassium (25%), increased gamma-glutamyltransferase (GGT) (24%), increased amylase (23%), and decreased leukocytes (23%).

The most common Grade 3 to 4 laboratory abnormalities (≥2%) in descending order were: decreased lymphocytes (11%), decreased albumin (9%), decreased sodium (8%), increased GGT (5%), increased amylase (4.6%), increased ALT (4.1%), increased AST (2.5%), and decreased hemoglobin (2%).

A clinically relevant laboratory abnormality in <20% of patients who received TEPMETKO was increased lipase in 18% of patients, including 3.7% Grades 3 to 4.

For more information about TEPMETKO, please see full Prescribing Information, and visit www.TEPMETKO.com.

About Berzosertib (M6620)
Berzosertib is an investigational, intravenous, potent and selective inhibitor of the ataxia telangiectasia and Rad3-related (ATR) protein that blocks ATR activity in cells. Berzosertib is the first ATR inhibitor evaluated in a randomized clinical trial in any tumor type, and it is the lead candidate in Merck KGaA, Darmstadt, Germany’s DNA Damage Response (DDR) inhibitor portfolio. It is currently being investigated in a number of internal and external studies with early phase I/II data in small cell lung cancer, ovarian cancer, and various solid tumors. Berzosertib, formerly known as VX-970, was licensed from Vertex Pharmaceuticals in 2017. Berzosertib is not approved for any use anywhere in the world.