Agendia Presents Data from the FLEX Real World Evidence Trial in Seven Posters at ASCO 2022, Showcasing the Power of Its 30,000-Patient Breast Cancer Genome Project

On June 5, 2022 Agendia, Inc., a commercial-stage company focused on improving outcomes for breast cancer patients worldwide by providing physicians and patients with next-generation diagnostic and information solutions to inform optimized treatment decision-making, reported it will present seven posters derived from the company’s FLEX Trial, the real-world, multicenter, prospective, observational breast cancer study at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (ASCO) (Free ASCO Whitepaper) 2022 (Press release, Agendia, JUN 5, 2022, View Source [SID1234615578]).

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One of Agendia’s posters, selected for the oral discussion session, titled Whole transcriptomic analysis of HR+ breast cancer in Black women classified as basal-type by BluePrint [Reid, S., et al.], will present findings from a racially-diverse cohort and resulting transcriptomic analyses suggesting hormone receptor-positive (HR+)/Basal tumors are biologically similar to triple-negative breast cancer (TNBC) tumors, regardless of race, demonstrating the importance of subtyping a tumor’s biology to determine optimal treatment course. BluePrint also identified racial disparities in the proportion of HR+/Basal tumors, showing a near doubling of such tumors among Black women, underscoring the need for diverse representation in clinical trials, a hallmark of the FLEX Trial.

"Leveraging the BluePrint assay, we are able to uncover new gene expression insights for HR+/Basal breast cancer tumors, which traditionally are more aggressive, higher grade, and disproportionally impact Black women compared to White women," said Sonya Reid, MD, MPH, Department of Medicine, Vanderbilt University Medical Center. "The FLEX Trial’s robust collection of diverse patient genomic profiles uniquely allows for sub-studies analyses like these to take place, helping researchers better support their patients from all racial and ethnic backgrounds with further classification of breast cancer tumors."

These data build on findings presented at San Antonio Breast Cancer Symposium 2021, also authored by Dr. Reid, that showed MammaPrint and BluePrint more robustly identify differences in more aggressive breast cancers in Black and White women beyond clinical factors, highlighting the fundamental importance of genomic classification and personalized treatment planning.

In addition, Agendia will present several sub-studies highlighting the FLEX Trial’s approach to cancer research by accelerating impactful data generation, aimed at redefining cancer care. The company believes this patient-centric design and national network of participating sites backed by Agendia will allow its investigator-initiated sub-studies to produce important results with the potential to drive science forward, like those being shared at ASCO (Free ASCO Whitepaper) 2022:

Clinical implications for patients with discordant Oncotype and MammaPrint results [Socoteanu, M., et al.] recalls findings from the IMPACT trial, which demonstrated MammaPrint and BluePrint inform treatment planning and increase physician confidence. In an effort to examine consistency among genomic tests, researchers analyzed therapy implications for patients who received both results from MammaPrint and BluePrint as well as OncotypeDx within the FLEX Trial:
Of 722 patients, 49% were observed to have discordant results with the potential of negative clinical impact. This includes 27% who may be undertreated, 6% potentially overtreated, and 10% who may not be given the option to decrease endocrine therapy to two years based on MammaPrint Ultra Low genomic risk assessment. Of 114 concordant MammaPrint High Risk tumors, 14% were genomically classified as Basal, and likely require more aggressive chemo than typically used in estrogen receptor-positive (ER+) breast cancers.
Together, these analyses showed more than half the patients in this cohort were at potential risk for undertreatment or overtreatment, had they received an OncotypeDx test as a standalone test. Discordance between OncotypeDx Recurrence Scores and MammaPrint with BluePrint results, most often yields the potential for undertreatment if the Recurrence Score is relied upon for treatment decision-making, putting a significant amount of risk on the patient since undertreatment may result in an incurable metastatic recurrence.
Whole transcriptome analysis of tumors with discordant Oncotype and MammaPrint results in the FLEX trial [Socoteanu, M., et al.] also looked at the differences in quality of results from OncotypeDx Recurrence Scores in comparison to MammaPrint results, this time by evaluating the genomic diversity within each test’s classification. The analysis found a high amount of genomic diversity within the OncotypeDx Recurrence Score Intermediate group, while conversely showing MammaPrint further classifies cases into more genomically rich and distinct categories, allowing for more precise treatment pathways based on the individual tumor.
Investigation of a genomic signature for transcription factor MAF gene amplification and lack of bisphosphonate benefit in early breast cancer [Nasrazadani, A. et al.] provides whole transcriptome analyses suggesting breast cancer tumors with mesenchymal aponeurotic fibrosarcoma (MAF) gene amplifications – a biomarker associated with shortened survival and lack of bisphosphate benefit when related to bone metastases in breast cancer – may be identified by a unique gene expression pattern. In this study, researchers used the MammaPrint/BluePrint platform to identify a set of 57 genes that could potentially predict MAF amplification status which could enable a woman’s care team to potentially anticipate a lack of benefit from adjuvant bisphosphonate treatment. Additionally, these results show mining the complete genome more thoroughly provides expanded insights and can shed light on new biomarkers previously unknown.
Distribution of breast cancer molecular subtypes within receptor classifications: Lessons from the I-SPY2 trial and FLEX Registry [Cha, J., et al.] proposes that the breast cancer research community drive science forward and work with the NCI’s Surveillance, Epidemiology, and End Results (SEER) Program to update its immunohistochemical (IHC) labels to avoid overlap with molecular subtype nomenclature and incorporate more modern classifications when available. Study results show the SEER Program database using IHC labels is not accurately identifying genomic subtypes via its annotations. In fact, the categorizations in the population-based registry were discordant with MammaPrint and BluePrint results in 52% of I-SPY2 Trial cases and 43% of FLEX Trial cases, emphasizing the growing importance of molecular subtyping to inform treatment and epidemiological research.
Defining transcriptomic profiles of early-stage mucinous breast cancers: A FLEX sub study [Sivapiragasam, A., et al.] revealed although mucinous breast cancer (MuBC), a rare subtype of invasive ductal carcinoma (IDC) accounts for less than 2% of all breast cancers, it often is expected to have low clinical risk and a favorable prognosis, however new genomic testing showed half of the patients observed in the study were in fact classified as MammaPrint High Risk. Through the examination of transcriptomic profiles, the findings demonstrated MammaPrint Low Risk MuBC is biologically different from MammaPrint Low Risk IDC providing new evidence as to why there are more favorable prognoses. Results also indicated MammaPrint High Risk MuBC and High Risk IDCs are highly genomically similar and could benefit from chemotherapy, providing additional clarity to guide specific treatment among these breast cancer subtypes.
FLEX, the 30,000 breast cancer transcriptome project: A platform for early breast cancer research using full-genome arrays paired with clinical data [Ma, C., et al.] shares data from the 38 investigator-initiated sub-studies – including five investigating racial disparities – approved within the FLEX Real World Evidence Trial (NCT03053193). Since the trial’s inception in 2017, FLEX has enrolled 10,000 patients at over 109 sites with a diverse data set designed to meet the needs of historically under-represented patients with breast cancer.
"These new findings presented at ASCO (Free ASCO Whitepaper) 2022 show the breadth of the FLEX research platform to identify and evaluate the many different complexities of a breast cancer biology at diagnosis that may facilitate more precise and individualized treatment recommendations," said William Audeh, MD, Chief Medical Officer at Agendia. "Agendia’s commitment to expanding our understanding of breast cancer to improve outcomes for women with breast cancer is astounding, exemplified by the FLEX Real World Evidence Trial. FLEX has the significant potential to broaden the application of genomic information through assays such as MammaPrint, BluePrint, and new proprietary Agendia signatures, which could lead to practice-changing models within breast cancer care aimed at improved outcomes for women with breast cancer."

Latest Data of InnoCare’s Orelabrutinib for the Treatment of SLE Presented at LBA Session of EULAR 2022

On June 5, 2022 InnoCare Pharma (HKEX: 09969), a leading biotech company, reported that Professor Zhanguo Li, the leading PI, has presented latest data of BTK inhibitor orelabrutinib for the treatment of Systemic Lupus Erythematosus (SLE) at the just-concluded EULAR 2022 European Congress of Rheumatology (Press release, InnoCare Pharma, JUN 5, 2022, View Source [SID1234615577]). The abstract was selected as late-breaking oral presentation.

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Late-breaking Oral Presentation:

Orelabrutinib, an irreversible inhibitor of Bruton’s tyrosine kinase (BTK), for the treatment of SLE: results of a randomized, double-blind, placebo-controlled, phase Ib/IIa dose-finding study
Abstract Number: LB0005

The study is aimed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), preliminary efficacy and biomarkers of orelabrutinib in patients with mild to moderate SLE who received standard of care therapy.

The study randomized 60 patients with 55 patients who completed 12-week treatment. Baseline disease characteristics were generally balanced across treatment groups. Orelabrutinib was generally well tolerated in patients with SLE.

The plasma exposure of orelabrutinib (AUC and Cmax) was proportionally increased with doses. Nearly complete BTK occupancy was achieved at all dose levels, and the occupancy lasted for 24 hours.

In all evaluable patients, the SLE Response Index (SRI)-4 response rates at week 12 were 50.0%(7/14), 61.5%(8/13) and 64.3%(9/14) in patients treated with orelabrutinib at 50mg, 80mg and 100mg respectively, compared with 35.7%(5/14) in patients treated with placebo, which indicated a trend of dose-dependent improvement.

Among the small cohort of subgroup of patients with SLEDAI-2K≥8 at screening, SRI-4 response occurred in 70%(7/10), 70%(7/10) and 66.7%(6/9) of patients who received orelabrutinib at 50mg, 80mg and 100mg, respectively, compared with 30%(3/10) who received placebo.

A biological signal of reduced proteinuria, anti-dsDNA and IgG, total B cells and increased complements C4 were also observed following orelabrutinib administration.

Professor Zhanguo Li said, "Orelabrutinib was generally well tolerated in patients with SLE. We are encouraged by the preliminary results suggesting trends in efficacy and supporting further studies in longer-term trials and larger cohorts of SLE patients."

More information can be found at EULAR official website.

About Orelabrutinib

Orelabrutinib is a highly selective BTK inhibitor developed by InnoCare for the treatment of cancers and autoimmune diseases.

On Dec. 25 2020, orelabrutinib received conditional approval from the China National Medical Products Administration (NMPA) in two indications: the treatment of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) /small lymphocytic lymphoma (SLL), and the treatment of patients with relapsed/refractory mantle cell lymphoma (MCL). At the end of 2021, orelabrutinib was included into National Reimbursement Drug list to benefit more lymphoma patients.

In addition to the approved indications, multi-center, multi-indication clinical trials are underway in the US and China with orelabrutinib as monotherapy or in combination therapies.

Orelabrutinib was granted as Breakthrough Therapy Designation for the treatment of r/r MCL by U.S. Food and Drug Administration (FDA).

In addition, orelabrutinib is also being evaluated in global phase II studies for the treatment of Multiple Sclerosis (MS), and clinical trials for the treatment of SLE, Primary Immune Thrombocytopenia (ITP) and Neuromyelitis Optica Spectrum Disorder (NMOSD) in China.

Merus Presents Clinical Data on Zenocutuzumab (Zeno) in NRG1-fusion (NRG1+) Cancer at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting (Oral Abstract)

On June 5, 2022 Merus N.V. (Nasdaq: MRUS) ("Merus", "the Company", "we", or "our"), a clinical-stage oncology company developing innovative, full-length multispecific antibodies (Biclonics and Triclonics), reported interim efficacy data as of an April 12, 2022 data cutoff date, from the phase 1/2 eNRGy trial and Early Access Program (EAP) of the bispecific antibody Zeno in patients with NRG1+ cancer presented virtually by Lead Author, Dr. Alison Schram of Memorial Sloan Kettering Cancer Center (MSKCC) at the 2022 ASCO (Free ASCO Whitepaper) Annual meeting (Press release, Merus, JUN 5, 2022, View Source [SID1234615570]).

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"We have made significant progress with enrollment in the eNRGy trial over the past year," said Dr. Andrew Joe, Chief Medical Officer at Merus. "And Zeno continues to demonstrate consistent efficacy in patients with multiple types of NRG1+ cancer. We believe Zeno has the potential to be both first in class and best in class as a tumor agnostic treatment for patients with NRG1+ cancer."

Dr. Schram added, "Zeno has led to durable responses in previously treated NRG1 fusion-positive cancer, with a median duration of response greater than 9 months and more than 25% of those responding continuing at 12 months. Additionally, Zeno has an extremely well tolerated safety profile. There are currently no approved therapies targeting NRG1 fusion-positive cancer and Zeno offers an important, potential new standard of care."

The reported data are from the phase 1/2 eNRGy trial and EAP which are assessing the safety and anti-tumor activity of Zeno monotherapy in NRG1+ cancer.

Key findings of the presentation include:

As of April 12, 2022, 110 patients were treated with Zeno
Efficacy was assessed in 79 evaluable patients with measurable disease having the opportunity for 6 months or more follow-up and who met the criteria for the primary analysis population
Median age was 59 years (range of 22-84); 59% were female
Median number of prior lines of systemic therapy was 2, (range of 0-8)
Qualifying NRG1 fusions included 26 distinct fusion partners
ORR per RECIST criteria as assessed by investigator was 34% (95% Cl; 24%-46%) across multiple tumor types
PDAC ORR 42% (8/19)
NSCLC ORR 35% (16/46)
Tumor shrinkage was observed in 70% of patients
Median time to response was 1.8 months, and median duration of exposure was 6.3 months
Median duration of response was 9.1 months, and 20/83 patients were continuing treatment as of the cutoff date
Strong safety profile with a low incidence of Grade 3 or higher treatment-related adverse events, including low rates of severe gastrointestinal and dermatologic toxicity, without clinically significant cardiotoxicity
The full presentation is available on the Publications page of our website.

Company Conference Call and Webcast Information
Merus will hold a conference call and webcast for investors on Sunday, June 5, 2022 at 6:00 p.m. CT to discuss the Zeno clinical data and provide a program update. A replay will be available after the completion of the call in the Investors and Media section of our website for a limited time.

Date: Sunday, June 5, 6:00 p.m. CT
Webcast link: available on our website
Dial-in: Toll-free: 18772601463/ International: 17066435907
Conference ID: 7194538

About the eNRGy Clinical Trial
Merus is currently enrolling patients in the phase 1/2 eNRGy trial to assess the safety and anti-tumor activity of Zeno monotherapy in NRG1+ cancer. The eNRGy trial consists of three cohorts: NRG1+ pancreatic cancer; NRG1+ non-small cell lung cancer; and NRG1+ cancer. Further details, including current trial sites, can be found at www.ClinicalTrials.gov and Merus’ trial website at www.nrg1.com or by calling 1-833-NRG-1234.

About Zeno
Zeno is an antibody-dependent cell-mediated cytotoxicity (ADCC)-enhanced Biclonics that utilizes the Merus Dock & Block mechanism to inhibit the neuregulin/HER3 tumor-signaling pathway in solid tumors with NRG1 gene fusions (NRG1+ cancer). Through its unique mechanism of binding to HER2 and potently blocking the interaction of HER3 with its ligand NRG1 or NRG1-fusion proteins, Zeno has the potential to be particularly effective against NRG1+ cancer. In preclinical studies, Zeno also potently inhibits HER2/HER3 heterodimer formation and tumor growth in models harboring NRG1 fusions.

Adjuvant Treatment With Merck’s KEYTRUDA® (pembrolizumab) Demonstrates Statistically Significant & Clinically Meaningful Improvement in Distant Metastasis-Free Survival in Patients With Resected Stage IIB or IIC Melanoma in Phase 3 KEYNOTE-716 Trial

On June 5, 2022 Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported distant metastasis-free survival (DMFS) results from the Phase 3 KEYNOTE-716 trial investigating KEYTRUDA, Merck’s anti-PD-1 therapy, versus placebo as adjuvant therapy for patients with resected stage IIB or IIC melanoma (Press release, Merck & Co, JUN 5, 2022, View Source [SID1234615565]). With a median follow-up of 27.4 months, KEYTRUDA demonstrated a statistically significant and clinically meaningful improvement in DMFS versus placebo (HR=0.64 [95% CI, 0.47-0.88]; p=0.0029). Median DMFS was not reached in either arm. These late-breaking data are being presented for the first time today at 10:45 a.m. ET during an oral abstract session at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (abstract #LBA9500).

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Additionally, at the median 27.4-month follow-up, KEYTRUDA continued to show a reduction in the risk of recurrence versus placebo (HR=0.64 [95% CI, 0.50-0.84]). According to Kaplan-Meier estimates, 81.2% of patients in the KEYTRUDA arm were recurrence-free at two years compared to 72.8% of patients in the placebo arm. A prespecified exploratory analysis of health-related quality of life (HRQoL) from KEYNOTE-716 will also be presented at ASCO (Free ASCO Whitepaper) 2022 on Monday, June 6 (abstract #9581), showing HRQoL was similar between the KEYTRUDA and placebo arms based on EORTC Quality of Life Questionnaire Core 30 or EQ-5D-5L VAS scores.

"Patients with stage IIB and IIC melanoma are at risk of seeing their cancer return and spread to distant sites," said Dr. Georgina Long, co-medical director, Melanoma Institute Australia (MIA), and chair, Melanoma Medical Oncology and Translational Research at MIA and Royal North Shore Hospital, University of Sydney. "The latest results from KEYNOTE-716 show the potential of pembrolizumab to help reduce distant recurrence in patients with resected stage IIB and IIC melanoma, and further highlight the important role of adjuvant therapy for these patients."

In the study, the safety profile of KEYTRUDA was consistent with previously reported studies in patients with solid tumors, and no new safety signals were observed at the time of DMFS analysis. Treatment-related adverse events Grade 3 or higher were observed in 17% of patients receiving KEYTRUDA versus 5% of patients receiving placebo. Immune-mediated events and infusion reactions were higher with KEYTRUDA (38% vs 9%, respectively).

"Based on survival data, we know that patients with stage IIB and IIC melanoma have similar five-year outcomes as those with stage IIIB melanoma," said Dr. Scot Ebbinghaus, vice president, global clinical development, Merck Research Laboratories. "In KEYNOTE-716, treatment with KEYTRUDA after surgery improved both distant metastasis-free survival and recurrence-free survival compared to placebo in patients with stage IIB or IIC melanoma. These data are encouraging for the melanoma community and add to results from six positive pivotal studies for KEYTRUDA-based regimens in earlier stages of cancer."

In addition to KEYNOTE-716, the five other pivotal trials evaluating a KEYTRUDA-based regimen in patients with earlier stages of cancer met their primary endpoint(s). These trials include: KEYNOTE-091 in stage IB (≥4 centimeters) to IIIA non-small cell lung cancer; KEYNOTE-054 in stage III melanoma; KEYNOTE-564 in renal cell carcinoma; KEYNOTE-522 in triple-negative breast cancer; and KEYNOTE-057 in Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer.

Based on RFS results from KEYNOTE-716, the U.S. Food and Drug Administration approved KEYTRUDA for the adjuvant treatment of adult and pediatric (12 years and older) patients with stage IIB or IIC melanoma following complete resection in December 2021. With the approval, KEYTRUDA became the first anti-PD-1 adjuvant treatment option for patients (12 years and older) across completely resected stage IIB, IIC and III melanoma. The European Medicines Agency’s Committee for Medicinal Products for Human Use adopted a positive opinion based on KEYNOTE-716 in May 2022, and the data will be shared with additional health authorities globally.

A compendium of Merck’s presentations and posters is available here. Please visit View Source and @Merck on Twitter to keep up to date with ASCO (Free ASCO Whitepaper) news and updates.

KEYNOTE-716 study design and additional data
KEYNOTE-716 (ClinicalTrials.gov, NCT03553836) is a randomized, double-blind Phase 3 trial that enrolled 976 adult and pediatric patients (12 years and older) with resected stage IIB or IIC melanoma. Following complete surgical resection, patients were randomized to KEYTRUDA 200 mg for adult patients and 2 mg/kg (up to 200 mg) for pediatric patients or placebo every three weeks for approximately one year until disease recurrence or unacceptable toxicity. The primary endpoint was RFS, and secondary endpoints included DMFS and overall survival. Overall survival will continue to be followed for upcoming analyses.

As of data cutoff for the third interim analysis (Jan. 4, 2022), the median study follow-up was 27.4 months. Distant metastasis-free survival was defined as time from randomization to the first diagnosis of distant metastasis. In the KEYTRUDA arm, 12.9% (n=63/487) of patients experienced a DMFS event versus 19.4% (n=95/489) of patients in the placebo arm. The estimated two-year DMFS rates were 88.1% with KEYTRUDA versus 82.2% with placebo.

As previously announced, the study met the primary endpoint of RFS at the first interim analysis (HR=0.65 [95% CI, 0.46-0.92]; p=0.00658). At the third interim analysis, 19.5% (n=95/487) of patients who received KEYTRUDA experienced an RFS event versus 28.4% (n=139/489) of patients who received placebo. At two years, the estimated RFS rates were 81.2% with KEYTRUDA versus 72.8% with placebo.

About Merck’s research in melanoma
Melanoma, the most serious form of skin cancer, is characterized by the uncontrolled growth of pigment-producing cells. The rates of melanoma have been rising over the past few decades, with nearly 325,000 new cases diagnosed worldwide in 2020. In the U.S., skin cancer is one of the most common types of cancer diagnosed, and melanoma accounts for a large majority of skin cancer deaths. It is estimated there will be nearly 100,000 new cases of melanoma diagnosed and almost 8,000 deaths resulting from the disease in the U.S. in 2022.

The recurrence rates for resected melanoma are estimated to be 32-46% for patients with stage IIB and stage IIC disease and 39-74% for patients with stage III disease. The five-year survival rates (AJCC eighth edition) are estimated to be 87% for stage IIB, 82% for stage IIC, 93% for stage IIIA, 83% for stage IIIB, 69% for stage IIIC and 32% for stage IIID.

Merck is committed to delivering meaningful advances for patients with melanoma with KEYTRUDA and to continuing research in skin cancers through a broad clinical development program across investigational and approved medicines. KEYTRUDA has been established as an important treatment option for the adjuvant treatment of adult patients with resected stage III melanoma and is approved in over 90 countries based on the results from EORTC1325/KEYNOTE-054. KEYTRUDA is also approved worldwide for the treatment of patients with unresectable or metastatic melanoma.

About Merck’s early-stage cancer clinical program
Finding cancer at an earlier stage may give patients a greater chance of long-term survival. Many cancers are considered most treatable and potentially curable in their earliest stage of disease. Building on the strong understanding of the role of KEYTRUDA in later-stage cancers, Merck is studying KEYTRUDA in earlier disease states, with approximately 20 ongoing registrational studies across multiple types of cancer.

About KEYTRUDA (pembrolizumab) injection, 100 mg
KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industry’s largest immuno-oncology clinical research program. There are currently more than 1,700 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications in the U.S.
Melanoma
KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of adult and pediatric (12 years and older) patients with stage IIB, IIC, or III melanoma following complete resection.

See additional selected KEYTRUDA indications in the U.S. after the Selected Important Safety Information.

Selected Important Safety Information for KEYTRUDA
Severe and Fatal Immune-Mediated Adverse Reactions
KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the PD-1 or the PD-L1, blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of anti–PD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. For patients with TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. 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.

Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA 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 adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis
KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

Immune-Mediated Colitis
KEYTRUDA can cause immune-mediated colitis, which may present with 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. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients.

Hepatotoxicity and Immune-Mediated Hepatitis
KEYTRUDA as a Single Agent
KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients.

KEYTRUDA With Axitinib
KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT ≥3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT ≥3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT ≥3 ULN subsequently recovered from the event.

Immune-Mediated Endocrinopathies
Adrenal Insufficiency
KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Hypophysitis
KEYTRUDA 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 indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Thyroid Disorders
KEYTRUDA 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 or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in <0.1% (1) of patients.

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in <0.1% (2) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 adult patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism.

Type 1 Diabetes Mellitus (DM), 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 KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in <0.1% (1) and withholding of KEYTRUDA in <0.1% (1) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Immune-Mediated Nephritis With Renal Dysfunction
KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and withholding in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Nephritis resolved in 56% of the 9 patients.

Immune-Mediated Dermatologic Adverse Reactions
KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with anti–PD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients.

Other Immune-Mediated Adverse Reactions
The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA or were reported with the use of other anti–PD-1/PD-L1 treatments. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions
KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)
Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after anti–PD-1/PD-L1 treatments. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between anti–PD-1/PD-L1 treatment and allogeneic HSCT. Follow patients closely for evidence of these complications and intervene promptly. Consider the benefit vs risks of using anti–PD-1/PD-L1 treatments prior to or after an allogeneic HSCT.

Increased Mortality in Patients With Multiple Myeloma
In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with an anti–PD-1/PD-L1 treatment in this combination is not recommended outside of controlled trials.

Embryofetal Toxicity
Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose.

Adverse Reactions
In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (≥20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).

In KEYNOTE-054, when KEYTRUDA was administered as a single agent to patients with stage III melanoma, KEYTRUDA was permanently discontinued due to adverse reactions in 14% of 509 patients; the most common (≥1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. The most common adverse reaction (≥20%) with KEYTRUDA was diarrhea (28%). In KEYNOTE-716, when KEYTRUDA was administered as a single agent to patients with stage IIB or IIC melanoma, adverse reactions occurring in patients with stage IIB or IIC melanoma were similar to those occurring in 1011 patients with stage III melanoma from KEYNOTE-054.

In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (≥20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%).

In KEYNOTE-407, when KEYTRUDA was administered with carboplatin and either paclitaxel or paclitaxel protein-bound in metastatic squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 15% of 101 patients. The most frequent serious adverse reactions reported in at least 2% of patients were febrile neutropenia, pneumonia, and urinary tract infection. Adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs 36%) and peripheral neuropathy (31% vs 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407.

In KEYNOTE-042, KEYTRUDA was discontinued due to adverse reactions in 19% of 636 patients with advanced NSCLC; the most common were pneumonitis (3%), death due to unknown cause (1.6%), and pneumonia (1.4%). The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%). The most common adverse reaction (≥20%) was fatigue (25%).

In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC; the most common was pneumonitis (1.8%). The most common adverse reactions (≥20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%).

In KEYNOTE-048, KEYTRUDA monotherapy was discontinued due to adverse events in 12% of 300 patients with HNSCC; the most common adverse reactions leading to permanent discontinuation were sepsis (1.7%) and pneumonia (1.3%). The most common adverse reactions (≥20%) were fatigue (33%), constipation (20%), and rash (20%).

In KEYNOTE-048, when KEYTRUDA was administered in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, KEYTRUDA was discontinued due to adverse reactions in 16% of 276 patients with HNSCC. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonia (2.5%), pneumonitis (1.8%), and septic shock (1.4%). The most common adverse reactions (≥20%) were nausea (51%), fatigue (49%), constipation (37%), vomiting (32%), mucosal inflammation (31%), diarrhea (29%), decreased appetite (29%), stomatitis (26%), and cough (22%).

In KEYNOTE-012, KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (≥20%) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of facial edema and new or worsening hypothyroidism.

In KEYNOTE-204, KEYTRUDA was discontinued due to adverse reactions in 14% of 148 patients with cHL. Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA; those ≥1% were pneumonitis, pneumonia, pyrexia, myocarditis, acute kidney injury, febrile neutropenia, and sepsis. Three patients died from causes other than disease progression: 2 from complications after allogeneic HSCT and 1 from unknown cause. The most common adverse reactions (≥20%) were upper respiratory tract infection (41%), musculoskeletal pain (32%), diarrhea (22%), and pyrexia, fatigue, rash, and cough (20% each).

In KEYNOTE-087, KEYTRUDA was discontinued due to adverse reactions in 5% of 210 patients with cHL. Serious adverse reactions occurred in 16% of patients; those ≥1% were pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from causes other than disease progression: 1 from GVHD after subsequent allogeneic HSCT and 1 from septic shock. The most common adverse reactions (≥20%) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%).

In KEYNOTE-170, KEYTRUDA was discontinued due to adverse reactions in 8% of 53 patients with PMBCL. Serious adverse reactions occurred in 26% of patients and included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. The most common adverse reactions (≥20%) were musculoskeletal pain (30%), upper respiratory tract infection and pyrexia (28% each), cough (26%), fatigue (23%), and dyspnea (21%).

In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in 11% of 370 patients with locally advanced or mUC. Serious adverse reactions occurred in 42% of patients; those ≥2% were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis. The most common adverse reactions (≥20%) were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%).

In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in 8% of 266 patients with locally advanced or mUC. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients; those ≥2% were urinary tract infection, pneumonia, anemia, and pneumonitis. The most common adverse reactions (≥20%) in patients who received KEYTRUDA were fatigue (38%), musculoskeletal pain (32%), pruritus (23%), decreased appetite (21%), nausea (21%), and rash (20%).

In KEYNOTE-057, KEYTRUDA was discontinued due to adverse reactions in 11% of 148 patients with high-risk NMIBC. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.4%). Serious adverse reactions occurred in 28% of patients; those ≥2% were pneumonia (3%), cardiac ischemia (2%), colitis (2%), pulmonary embolism (2%), sepsis (2%), and urinary tract infection (2%). The most common adverse reactions (≥20%) were fatigue (29%), diarrhea (24%), and rash (24%).

Adverse reactions occurring in patients with MSI-H or dMMR CRC were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

In KEYNOTE-811, when KEYTRUDA was administered in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, KEYTRUDA was discontinued due to adverse reactions in 6% of 217 patients with locally advanced unresectable or metastatic HER2+ gastric or GEJ adenocarcinoma. The most common adverse reaction resulting in permanent discontinuation was pneumonitis (1.4%). In the KEYTRUDA arm versus placebo, there was a difference of ≥5% incidence between patients treated with KEYTRUDA versus standard of care for diarrhea (53% vs 44%) and nausea (49% vs 44%).

The most common adverse reactions (reported in ≥20%) in patients receiving KEYTRUDA in combination with chemotherapy were fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia, peripheral neuropathy, mucosal inflammation, stomatitis, headache, weight loss, abdominal pain, arthralgia, myalgia, and insomnia.

In KEYNOTE-590, when KEYTRUDA was administered with cisplatin and fluorouracil to patients with metastatic or locally advanced esophageal or GEJ (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma who were not candidates for surgical resection or definitive chemoradiation, KEYTRUDA was discontinued due to adverse reactions in 15% of 370 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (≥1%) were pneumonitis (1.6%), acute kidney injury (1.1%), and pneumonia (1.1%). The most common adverse reactions (≥20%) with KEYTRUDA in combination with chemotherapy were nausea (67%), fatigue (57%), decreased appetite (44%), constipation (40%), diarrhea (36%), vomiting (34%), stomatitis (27%), and weight loss (24%).

Adverse reactions occurring in patients with esophageal cancer who received KEYTRUDA as a monotherapy were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

In KEYNOTE-826, when KEYTRUDA was administered in combination with paclitaxel and cisplatin or paclitaxel and carboplatin, with or without bevacizumab (n=307), to patients with persistent, recurrent, or first-line metastatic cervical cancer regardless of tumor PD-L1 expression who had not been treated with chemotherapy except when used concurrently as a radio-sensitizing agent, fatal adverse reactions occurred in 4.6% of patients, including 3 cases of hemorrhage, 2 cases each of sepsis and due to unknown causes, and 1 case each of acute myocardial infarction, autoimmune encephalitis, cardiac arrest, cerebrovascular accident, femur fracture with perioperative pulmonary embolus, intestinal perforation, and pelvic infection. Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA in combination with chemotherapy with or without bevacizumab; those ≥3% were febrile neutropenia (6.8%), urinary tract infection (5.2%), anemia (4.6%), and acute kidney injury and sepsis (3.3% each).

KEYTRUDA was discontinued in 15% of patients due to adverse reactions. The most common adverse reaction resulting in permanent discontinuation (≥1%) was colitis (1%).

For patients treated with KEYTRUDA, chemotherapy, and bevacizumab (n=196), the most common adverse reactions (≥20%) were peripheral neuropathy (62%), alopecia (58%), anemia (55%), fatigue/asthenia (53%), nausea and neutropenia (41% each), diarrhea (39%), hypertension and thrombocytopenia (35% each), constipation and arthralgia (31% each), vomiting (30%), urinary tract infection (27%), rash (26%), leukopenia (24%), hypothyroidism (22%), and decreased appetite (21%).

For patients treated with KEYTRUDA in combination with chemotherapy with or without bevacizumab, the most common adverse reactions (≥20%) were peripheral neuropathy (58%), alopecia (56%), fatigue (47%), nausea (40%), diarrhea (36%), constipation (28%), arthralgia (27%), vomiting (26%), hypertension and urinary tract infection (24% each), and rash (22%).

In KEYNOTE-158, KEYTRUDA was discontinued due to adverse reactions in 8% of 98 patients with previously treated recurrent or metastatic cervical cancer. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA; the most frequent included anemia (7%), fistula, hemorrhage, and infections [except urinary tract infections] (4.1% each). The most common adverse reactions (≥20%) were fatigue (43%), musculoskeletal pain (27%), diarrhea (23%), pain and abdominal pain (22% each), and decreased appetite (21%).

Adverse reactions occurring in patients with HCC were generally similar to those in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of ascites (8% Grades 3-4) and immune-mediated hepatitis (2.9%). Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence were elevated AST (20%), ALT (9%), and hyperbilirubinemia (10%).

Among the 50 patients with MCC enrolled in study KEYNOTE-017, adverse reactions occurring in patients with MCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy. Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence were elevated AST (11%) and hyperglycemia (19%).

In KEYNOTE-426, when KEYTRUDA was administered in combination with axitinib, fatal adverse reactions occurred in 3.3% of 429 patients. Serious adverse reactions occurred in 40% of patients, the most frequent (≥1%) were hepatotoxicity (7%), diarrhea (4.2%), acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%). Permanent discontinuation due to an adverse reaction occurred in 31% of patients; KEYTRUDA only (13%), axitinib only (13%), and the combination (8%); the most common were hepatotoxicity (13%), diarrhea/colitis (1.9%), acute kidney injury (1.6%), and cerebrovascular accident (1.2%). The most common adverse reactions (≥20%) were diarrhea (56%), fatigue/asthenia (52%), hypertension (48%), hepatotoxicity (39%), hypothyroidism (35%), decreased appetite (30%), palmar-plantar erythrodysesthesia (28%), nausea (28%), stomatitis/mucosal inflammation (27%), dysphonia (25%), rash (25%), cough (21%), and constipation (21%).

In KEYNOTE-564, when KEYTRUDA was administered as a single agent for the adjuvant treatment of renal cell carcinoma, serious adverse reactions occurred in 20% of patients receiving KEYTRUDA; the serious adverse reactions (≥1%) were acute kidney injury, adrenal insufficiency, pneumonia, colitis, and diabetic ketoacidosis (1% each). Fatal adverse reactions occurred in 0.2% including 1 case of pneumonia. Discontinuation of KEYTRUDA due to adverse reactions occurred in 21% of 488 patients; the most common (≥1%) were increased ALT (1.6%), colitis (1%), and adrenal insufficiency (1%). The most common adverse reactions (≥20%) were musculoskeletal pain (41%), fatigue (40%), rash (30%), diarrhea (27%), pruritus (23%), and hypothyroidism (21%).

Adverse reactions occurring in patients with MSI-H or dMMR endometrial carcinoma who received KEYTRUDA as a single agent were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a single agent.

Adverse reactions occurring in patients with TMB-H cancer were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent.

Adverse reactions occurring in patients with recurrent or metastatic cSCC or locally advanced cSCC were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

In KEYNOTE-522, when KEYTRUDA was administered with neoadjuvant chemotherapy (carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide) followed by surgery and continued adjuvant treatment with KEYTRUDA as a single agent (n=778) to patients with newly diagnosed, previously untreated, high-risk early-stage TNBC, fatal adverse reactions occurred in 0.9% of patients, including 1 each of adrenal crisis, autoimmune encephalitis, hepatitis, pneumonia, pneumonitis, pulmonary embolism, and sepsis in association with multiple organ dysfunction syndrome and myocardial infarction. Serious adverse reactions occurred in 44% of patients receiving KEYTRUDA; those ≥2% were febrile neutropenia (15%), pyrexia (3.7%), anemia (2.6%), and neutropenia (2.2%). KEYTRUDA was discontinued in 20% of patients due to adverse reactions. The most common reactions (≥1%) resulting in permanent discontinuation were increased ALT (2.7%), increased AST (1.5%), and rash (1%). The most common adverse reactions (≥20%) in patients receiving KEYTRUDA were fatigue (70%), nausea (67%), alopecia (61%), rash (52%), constipation (42%), diarrhea and peripheral neuropathy (41% each), stomatitis (34%), vomiting (31%), headache (30%), arthralgia (29%), pyrexia (28%), cough (26%), abdominal pain (24%), decreased appetite (23%), insomnia (21%), and myalgia (20%).

In KEYNOTE-355, when KEYTRUDA and chemotherapy (paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin) were administered to patients with locally recurrent unresectable or metastatic TNBC who had not been previously treated with chemotherapy in the metastatic setting (n=596), fatal adverse reactions occurred in 2.5% of patients, including cardio-respiratory arrest (0.7%) and septic shock (0.3%). Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA in combination with chemotherapy; the serious reactions in ≥2% were pneumonia (2.9%), anemia (2.2%), and thrombocytopenia (2%). KEYTRUDA was discontinued in 11% of patients due to adverse reactions. The most common reactions resulting in permanent discontinuation (≥1%) were increased ALT (2.2%), increased AST (1.5%), and pneumonitis (1.2%). The most common adverse reactions (≥20%) in patients receiving KEYTRUDA in combination with chemotherapy were fatigue (48%), nausea (44%), alopecia (34%), diarrhea and constipation (28% each), vomiting and rash (26% each), cough (23%), decreased appetite (21%), and headache (20%).

Lactation
Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 4 months after the final dose.

Pediatric Use
In KEYNOTE-051, 161 pediatric patients (62 pediatric patients aged 6 months to younger than 12 years and 99 pediatric patients aged 12 years to 17 years) were administered KEYTRUDA 2 mg/kg every 3 weeks. The median duration of exposure was 2.1 months (range: 1 day to 24 months).

Adverse reactions that occurred at a ≥10% higher rate in pediatric patients when compared to adults were pyrexia (33%), vomiting (30%), leukopenia (30%), upper respiratory tract infection (29%), neutropenia (26%), headache (25%), and Grade 3 anemia (17%).

Additional Selected KEYTRUDA Indications in the U.S.
Non-Small Cell Lung Cancer
KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) ≥1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is:

stage III where patients are not candidates for surgical resection or definitive chemoradiation, or
metastatic.
KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Head and Neck Squamous Cell Cancer
KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma
KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.

Primary Mediastinal Large B-Cell Lymphoma
KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy.

KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma
KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC):

who are not eligible for any platinum-containing chemotherapy, or
who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
Non-muscle Invasive Bladder Cancer
KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High or Mismatch Repair Deficient Cancer
KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer
KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).

Gastric Cancer
KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Cancer
KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:

in combination with platinum- and fluoropyrimidine-based chemotherapy, or
as a single agent after one or more prior lines of systemic therapy for patients with tumors of squamous cell histology that express PD-L1 (CPS ≥10) as determined by an FDA-approved test.
Cervical Cancer
KEYTRUDA, in combination with chemotherapy, with or without bevacizumab, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test.

Hepatocellular Carcinoma
KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma
KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma
KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC).

KEYTRUDA is indicated for the adjuvant treatment of patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions.

Endometrial Carcinoma
KEYTRUDA, as a single agent, is indicated for the treatment of patients with advanced endometrial carcinoma that is MSI-H or dMMR, as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.

Tumor Mutational Burden-High Cancer
KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma
KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC that is not curable by surgery or radiation.

Triple-Negative Breast Cancer
KEYTRUDA is indicated for the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery.

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test.

Merck’s focus on cancer
Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, the potential to bring new hope to people with cancer drives our purpose and supporting accessibility to our cancer medicines is our commitment. As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the largest development programs in the industry across more than 30 tumor types. We also continue to strengthen our portfolio through strategic acquisitions and are prioritizing the development of several promising oncology candidates with the potential to improve the treatment of advanced cancers. For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.

HOOKIPA announces positive Phase 1 data and Phase 2 plans for HB-200 program for the treatment of advanced head and neck cancers at ASCO

On June 5, 2022 HOOKIPA Pharma Inc. (NASDAQ: HOOK, ‘HOOKIPA’), a company developing a new class of immunotherapeutics based on its proprietary arenavirus platform, reported positive Phase 1 results from its HB-200 program evaluating single-vector HB-201 and alternating 2-vector HB-202/HB-201 in advanced Human Papillomavirus 16-positive (HPV16+) head and neck cancer patients (Press release, Hookipa Pharma, JUN 5, 2022, View Source [SID1234615563]). HB-200 was generally well tolerated, rapidly induced a high magnitude of tumor-specific T cells and showed early anti-tumor activity in these difficult-to-treat patients. The company also announced the recommended Phase 2 dose for alternating 2-vector HB-202/HB-201, which showed superior immune and tumor response compared to single-vector HB-201. The data were presented in a poster presentation (abstract #2517) at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting.

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"We’re pleased to report the positive Phase 1 data on our novel arenaviral immunotherapies for advanced head and neck cancers, which highlight the ability of our platform technology to induce a high magnitude of potent, tumor-specific T cell responses," said Joern Aldag, Chief Executive Officer at HOOKIPA. "We’re encouraged by the superior immune response generated by alternating 2-vector immunotherapy, which resulted in an 80 percent disease control rate in patients who have failed several previous regimens. These results help focus our efforts as we move HB-202/HB-201 at the recommended Phase 2 dose into the Phase 2 portion of the trial. The findings on our alternating 2-vector technology also help inform our development plans across our oncology portfolio and especially for our HB-300 program in prostate cancer."

HB-200 Phase 1 results (NCT04180215)
Sixty-eight patients with advanced HPV16+ cancers were treated in the Phase 1 trial as of March 31, 2022. Fifty-four patients had advanced HPV16+ head and neck cancers with a median of three prior therapies (range of 1-11), including a checkpoint inhibitor regimen in 50 of the 54. Of these sixty-eight patients, five were continuing on treatment as of the cut-off date.

Safety
Phase 1 results showed HB-200 was generally well tolerated, with comparable safety between the single-vector HB-201 and alternating 2-vector HB-202/HB-201. The most common treatment-related side effects were flu-like symptoms, with only 8.8 percent of patients experiencing treatment-related side effects rated grade 3 or higher. This favorable tolerability profile in heavily pre-treated patients highlights the potential for combination with checkpoint inhibitors and other agents.

Anti-tumor activity
The poster presented at ASCO (Free ASCO Whitepaper) provided updated anti-tumor activity on 43 Phase 1 patients with HPV16+ HNSCC who received therapy intravenously every three weeks for the first five doses and every six weeks thereafter, which is the route and frequency selected for further evaluation in Phase 2 cohorts. The 43 patients were comprised of 20 persons who received single-vector HB-201 and 23 who received alternating 2-vector HB-202/HB-201.

While promising anti-tumor activity was shown in both groups, alternating 2-vector HB-202/HB-201 showed superior tumor response with 56 percent of treated patients showing target lesion shrinkage compared to 38 percent of HB-201 recipients. In addition, decreases in visceral lesions were predominantly seen in patients who received 2-vector therapy: 59 percent of patients on HB-202/HB-201 compared to 18 percent on HB-201. Further, HB-202/HB-201 demonstrated an 80 percent disease control rate, which compares favorably to historical disease control rates achieved by pembrolizumab in recurrent/metastatic HNSCC patients, specifically 35 percent overall and 40 percent in the HPV+ subset, based on peer-reviewed published data.1

T cell data
While both HB-201 and alternating 2-vector HB-202/HB-201 were highly immunogenic, HB-202/HB-201 induced superior immune response with 32 percent of recipients achieving tumor-specific T cell levels greater than 5 percent of the circulating T cell pool (7 percent of HB-201 recipients achieved this threshold). Tumor specific T cells are essential in eradicating cancer cells.

"Patients with advanced head and neck cancers have limited options," said Siqing Fu, M.D., Ph.D., professor of Investigational Cancer Therapeutics and principal investigator at The University of Texas MD Anderson Cancer Center, who presented the data at the ASCO (Free ASCO Whitepaper) meeting. "It’s encouraging to see a novel arenaviral immunotherapy demonstrate strong T cell response and anti-tumor activity in this difficult-to-treat population. I look forward to seeing future results from the Phase 2 portion in HPV16+ head and neck cancers, as well as in other types of cancer."

About HB-202/HB-201
HB-201 and HB-202/HB-201 are HOOKIPA’s lead oncology candidates engineered with the company’s proprietary replicating arenaviral vector platform. HB-201 is a single-vector compound that uses Lymphocytic Choriomeningitis Virus as its arenaviral backbone. HB-202 is a single-vector compound that uses Pichinde Virus as its arenaviral backbone. Both express the same antigen, an E7E6 fusion protein derived from HPV16. HB-202/HB-201 is an alternating 2-vector immunotherapy designed to further focus the immune response against the target antigen. In pre-clinical studies, alternating administration of HB-201 and HB-202 resulted in a ten-fold increase in immune response and better disease control than either compound alone. Both novel immunotherapy candidates, in combination with pembrolizumab, received Fast Track Designation from the U.S. Food and Drug Administration for the treatment of 1st-line advanced/metastatic HPV16+ head and neck cancers.

About the HB-200 trial (NCT04180215)
This Phase 1/2 clinical trial is an open-label trial evaluating single-vector HB-201 and alternating 2-vector HB-202/HB-201 for the treatment of advanced HPV16+ cancers who progressed on standard of care, including checkpoint inhibitors. The primary endpoint of Phase 1 was a recommended Phase 2 dose.

In Phase 1, HB-201 was evaluated at three dose levels, with two dosing schedules and two administration routes in 40 patients. HB-202/HB-201 was evaluated at four dose levels and two administration routes in 28 patients. Based on safety, anti-tumor activity and T cell response data, HB-202/HB-201 has been advanced for further development in Phase 2.

The Phase 2 part of the trial is open-label with primary endpoints of safety, tolerability and preliminary efficacy, defined by RECIST 1.1, for overall survival, progression-free survival and duration of response. Phase 2 is ongoing, evaluating HB-202/HB-201 alone in the post standard of care setting and in combination with pembrolizumab in 1st line and 2nd plus line settings. HB-201 in combination with pembrolizumab is being assessed for safety only in a small cohort. Initial results of HB-202/HB-201 in combination with pembrolizumab are anticipated in the second half of 2022 and will help inform the randomized Phase 2 trial of HB-202/HB-201 in combination with pembrolizumab planned for the first half of 2023. Initial results of HB-202/HB-201 as a post-standard of care treatment are expected in the first half of 2023.

About Human Papillomavirus-driven Cancers
Human Papillomavirus, or HPV, is a common viral infection estimated to cause about 5 percent of the worldwide cancer burden. This includes up to 60 percent of head and neck, 89 percent of cervical, 78 percent of vaginal, 88 percent of anal, 67 percent of vulvar and 50 percent of penile cancers.

While there are numerous HPV types associated with cancer, HPV16 is the most common cause of cancer. Most HPV infections are cleared from the body with no lasting consequences. However, in some cases, HPV DNA becomes integrated into chromosomal DNA. When host cells take up this DNA, they express the HPV E6 and E7 proteins. This uptake can potentially lead to cancer since expression of these proteins leads to alterations in cell cycle control, which in turn predisposes these cells to become cancerous.