First Ever Phase 1B Trial of NK Cells with IL-2 and VACTOSERTIB

On June 24, 2022 Chimeric Therapeutics Ltd (ASX:CHM) reported the first ever trial studying NK cells in combination with IL-2 and Vactosertib, using Chimeric’s CORE NK platform cells (Press release, Chimeric Therapeutics, JUN 24, 2022, View Source [SID1234616225]).

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The Phase 1B investigator-initiated trial has been approved by the US Food and Drug Administration (FDA) and will enrol 12 patients at UH Seidman Cancer Center in Ohio, with either locally advanced or metastatic colorectal cancer or relapsed/refractory blood cancers.

Chimeric’s CORE NK platform is a novel NK cell therapy platform of ex-vivo expanded non-HLA*-matched universal donor NK cells.

Safety and early efficacy demonstrated
The CORE NK platform was studied in a Phase 1A clinical trial demonstrating safety and an early efficacy signal in patients with metastatic colorectal cancer and refractory haematological malignancies.

The new study seeks to build upon responses observed during the initial CORE NK clinical trial, by co-administering the CORE NK cells with subcutaneous IL-2 and oral Vactosertib.

Study looks at combination
IL-2 is known to activate NK cells by stimulating proliferation and enhancing function.

Vactosertib is an oral TGF-β receptor inhibitor that can potentially disrupt the TGF-β signalling pathway, which has been shown to limit the effectiveness of immune therapies like NK cells.

"Vactosertib has never been used in combination with NK cells in the clinic, but it has been used in humans in other clinical trials," said UH Seidman oncologist Dr J Eva Selfridge, assistant professor at Case Western Reserve University School of Medicine in Ohio, who will lead the upcoming trial.

NK cells can "actually make it into the tumours"
"The goal of using it in this trial is to disrupt the TGF-β signaling pathway that is so strong in colorectal cancer and cells. We want to shut down that TGF-β signaling pathway so that the NK cells can actually make it into the tumours. Once they’re there, they have a chance of being active instead of just being silenced right away."

Dr. Selfridge says she is hopeful this new clinical trial at UH Seidman Cancer Center will present patients with more and better options for treatment and care: "T cell-directed immunotherapy is only available for 5% or less of cancer patients, but immunotherapy is really the only way we have to cure people with metastatic disease," she said.

"We’re just beginning our study, but ultimately the goal is to find immune therapies that work long-term."

Busy clinical pipeline
The study adds to CHM’s busy clinical pipeline, with now four clinical trials in progress or planned within 9 months.

"With the initial positive results seen in the Phase 1A clinical trial with our CORE NK Platform cells, we have been eager to accelerate the development opportunities for it," said Chimeric CEO Jennifer Chow.

"This study looks to combine novel therapeutics to overcome the challenges that are commonly thought to limit disease responses to NK cells.

"We hope that this combination will allow us to see more complete responses in patients with difficult to treat diseases, like the one seen in the Phase 1A study that has resulted in complete tumour eradication for more than 15 months now."

New Survey Offers Perspective on Mental and Emotional Journey for Patients Diagnosed with Slow-Growing Blood Cancer

On June 24, 2022 AbbVie reported findings from the newly launched Emotional Impact Report, a survey of more than 300 chronic lymphocytic leukemia (CLL) patients, caregivers and healthcare providers (HCPs), which uncovered insights about the emotional journey associated with a CLL diagnosis (Press release, AbbVie, JUN 24, 2022, View Source [SID1234616232]).

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CLL is a slow-growing form of blood cancer in which the bone marrow makes too many lymphocytes, a type of white blood cell.1 CLL progresses much slower than other forms of leukemia and many do not experience symptoms for several years. This leads to disease management with an approach called "watch and wait" in which the disease progression is monitored until treatment is deemed necessary.2

A CLL diagnosis can take a mental and emotional toll on patients, caregivers and HCPs and the Emotional Impact Report seeks to better understand that impact, raise awareness of the need for additional support and the importance of considering overall Quality of Life when making treatment decisions.3

Among a sample of 111 CLL patients, emotions ranged from angry and bitter to optimistic and grateful. For those CLL patients who were newly diagnosed and/or told by their HCP to watch and wait, many may feel hopeful (41%) and optimistic (36%), expressing they are looking forward to the future success of their treatment and their long-term prognosis. And once patients first receive treatment, many (42%) feel positive, including mentions of feeling confident, satisfied, or relieved as they see the medication working. Others mention feeling anxious, never knowing when they will need treatment again and not knowing what is next, further reinforcing the variation and complexity of emotions experienced by CLL patients.

"These findings highlight the ups and downs CLL patients can go through from potentially waiting to start treatment to the prospect of being on continuous therapy," said Ahmed Kotb, vice president, US medical affairs, oncology, AbbVie. "But patients don’t have to navigate a disease like CLL on their own. Based on insights from the Emotional Impact Report, there is an opportunity for increased dialogue between patients and their physicians to set treatment goals and understand available treatment options."

Furthermore, HCPs understand the importance of talking to their patients about the emotional impact of CLL. In fact, 71% said they are likely to discuss the emotional impact of CLL with their patients. Specifically, 90% recognize that a patient’s emotional well-being has an impact on their treatment plan. Physicians cited specific impacts, including adherence to treatment, ability to cope with treatment and how they respond to treatment. HCPs recognize that treating a CLL patient differs from treating other cancer patients, in that CLL is treated similarly to the way a chronic disease is treated, which increases the need to consider Quality of Life when making treatment decisions.

Among a sample of 100 caregivers, most (81%) feel positively about caring for someone with CLL and feel it is their duty to help their loved one. Yet, nearly three in four state that being a caregiver is more difficult than expected. As one caregiver noted, the biggest reason why they are nervous in their role is because they don’t know what’s going to happen from one minute to the next.

This U.S.-based survey was conducted between March 11 – April 7, 2022, and responses were obtained from 313 participants, which included 111 CLL patients, 100 caregivers and 102 HCPs. The online survey was sponsored by AbbVie and developed in consultation with C Space.

To learn more about CLL, navigating a diagnosis and understanding treatment goals, visit CLLCancer.com.

About Chronic Lymphocytic Leukemia
CLL is one of the two most common forms of leukemia in adults and is a type of cancer that can develop from cells in the bone marrow that later mature into certain white blood cells (called lymphocytes).1 While these cancer cells start in the bone marrow, they later spread into the blood. In 2019, there were approximately 200,766 people with CLL living in the United States with more than 20,000 new cases expected in 2022.4 CLL is predominately a disease of the elderly, with a median age at diagnosis of 65 to 70 years and is more common among men than women.5

About the Survey
Participants in the 31-35-question self-administered online survey included three groups, each with its own set and number of survey questions: patients, caregivers, and physicians who specialize in treating cancer. The patient group (n = 111) and the caregiver group (n = 100) included adults ages 18 and older from the U.S., and the physician group (n = 102) included board-certified hematologic oncologists, hematologists or medical oncologists who had treated at least five patients with CLL in the previous 12 months in the U.S. All surveys were completed between March 11, 2022, and April 7, 2022. Using the field services of C Space, the surveys asked both qualitative and quantitative questions. This online survey is not based on a probability sample and therefore no estimate of theoretical sampling error can be calculated.

About C Space
C Space is a global customer agency, that builds customers into the ways companies work.

Working with some of the world’s best-known brands – including Walmart, McDonald’s, IKEA and more – C Space builds the world’s most relevant brands by unlocking the power of human relationships. By building ongoing relationships with customers, brands can stay relevant, deliver superior experiences, and build loyalty. C Space’s customized customer programs are tailored based on specific business needs and include private online communities, in-person live events, visual storytelling, co-creation workshops, and business consulting.

Headquartered in Boston, C Space also has offices in London, New York, Tokyo, San Francisco, and Mexico City. C Space is a part of the Interbrand Group.

European Commission Approves KEYTRUDA® (pembrolizumab) as Adjuvant Treatment for Adult and Adolescent Patients (?12 Years of Age) With Stage IIB or IIC Melanoma Following Complete Resection

On June 24, 2022 Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported that the European Commission (EC) has approved KEYTRUDA, Merck’s anti-PD-1 therapy, as monotherapy for the adjuvant treatment of adults and adolescents aged 12 years and older with stage IIB or IIC melanoma and who have undergone complete resection (Press release, Merck & Co, JUN 24, 2022, View Source [SID1234616233]). Additionally, the EC approved expanding the indications for KEYTRUDA in advanced (unresectable or metastatic) melanoma and stage III melanoma (as adjuvant treatment following complete resection) to include adolescent patients aged 12 years and older.

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The approval of KEYTRUDA for the adjuvant treatment of patients with resected stage IIB or IIC melanoma was based on results from the Phase 3 KEYNOTE-716 trial, in which KEYTRUDA significantly prolonged recurrence-free survival (RFS), reducing the risk of disease recurrence or death by 39% (HR=0.61 [95% CI, 0.45-0.82]; p=0.00046) compared to placebo in this patient population at a median follow-up of 20.5 months. KEYTRUDA in this adjuvant setting also significantly prolonged distant metastasis-free survival (DMFS), reducing the risk of distant metastasis by 36% (HR=0.64 [95% CI, 0.47-0.88]; p=0.00292) compared to placebo in this patient population at a median follow-up of 26.9 months.

"When melanoma recurs, patients often have a significantly worse long-term prognosis, especially if the cancer returns or spreads to distant sites," said Dr. Alexander Eggermont, chief scientific officer, Princess Máxima Center for Pediatric Oncology, the Netherlands. "This approval further reinforces the important role of adjuvant therapy for patients 12 years and older with completely resected stage IIB and IIC melanoma who now have a treatment option that has demonstrated the potential to significantly reduce the risk of their cancer returning."

The safety of KEYTRUDA monotherapy has been evaluated in 7,631 patients across tumor types. The incidences of immune-related adverse reactions were 36.1% for all Grades and 8.9% for Grades 3-5 for KEYTRUDA monotherapy in the adjuvant setting (n=1,480). No new immune-related adverse reactions were identified for KEYTRUDA monotherapy in the adjuvant setting.

"Melanoma continues to be a public health burden in Europe, claiming more than 26,000 lives in 2020, with rates rising annually," said Dr. Scot Ebbinghaus, vice president, global clinical development, Merck Research Laboratories. "KEYTRUDA has become the first anti-PD-1 adjuvant treatment option approved in the EU for patients 12 years and older across stage IIB, IIC and III melanoma following complete resection, based on data that show the potential of KEYTRUDA to help reduce the risk of recurrence, including as distant metastases, in these patients. This approval furthers our commitment to finding new effective options for even more patients with melanoma."

This approval allows marketing of KEYTRUDA for this indication in all 27 European Union (EU) member states plus Iceland, Lichtenstein, Norway and Northern Ireland. In the EU, KEYTRUDA was previously approved for the treatment of adult patients with advanced (unresectable or metastatic) melanoma and for the adjuvant treatment of adult patients with stage III melanoma and lymph node involvement who have undergone complete resection.

About KEYNOTE-716
The approval was based on data from KEYNOTE-716 (ClinicalTrials.gov, NCT03553836), 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 for pediatric patients [up to 200 mg]) or placebo every three weeks for approximately one year until disease recurrence or unacceptable toxicity. The primary endpoint is RFS, and secondary endpoints include DMFS and overall survival.

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 of melanoma diagnosed worldwide in 2020, and melanoma is the leading cause of skin cancer deaths, with more than 57,000 deaths from the disease worldwide in 2020. In Europe, it is estimated there were more than 150,000 new cases of melanoma diagnosed and more than 26,000 deaths from the disease in 2020.

The recurrence rates for resected melanoma are estimated to be 32-46% for patients with stage IIB and IIC disease and 39-74% for patients with stage III disease. The five-year survival rates 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 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.

Calithera Biosciences Announces First Patient Enrolled in Phase 2 Clinical Trial of Mivavotinib in Relapsed/Refractory non-GCB (ABC) Diffuse Large B-Cell Lymphoma

On June 23, 2022 Calithera Biosciences, Inc. (Nasdaq: CALA), a clinical-stage, precision-oncology biopharmaceutical company, reported that the first patient has been enrolled in a multicenter phase 2 clinical trial evaluating its spleen tyrosine kinase (SYK) inhibitor mivavotinib (CB-659) in patients with relapsed/refractory non-germinal center B-cell like (non-GCB) diffuse large B-cell lymphoma (DLBCL), a DLBCL subpopulation that primarily comprises patients with activated B-cell like disease (ABC) (Press release, Calithera Biosciences, JUN 23, 2022, View Source [SID1234616206]).

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In a retrospective analysis of prior phase 1/2 studies in patients with DLBCL, patients with non-GCB DLBCL who received mivavotinib had a response rate of 53%, as compared to a response rate of 22% in patients with GCB DLBCL. Additionally, recent preclinical studies have shown enhanced SYK activity, and greater sensitivity to SYK inhibition, in DLBCL tumor-cell lines with mutations in MYD88 and CD79b genes. A significant fraction of patients with non-GCB DLBCL have tumors that harbor these mutations, and this subset of patients is known to have poorer outcomes with standard-of-care therapies.

"Mivavotinib has demonstrated potential to be a first-to-market approach for non-GCB DLBCL, including the genetic subset of patients harboring MYD88 and/or CD79 mutations," said Susan Molineaux, PhD, president and chief executive officer of Calithera. "This study will advance understanding of how our novel biomarker-driven approach could help address this high unmet therapeutic need, and we look forward to sharing data by the first quarter of 2023."

The phase 2 clinical trial (NCT05319028) is an open-label study of mivavotinib monotherapy in patients with relapsed/refractory non-GCB DLBCL. The main study objectives are to confirm previously seen single-agent activity in non-GCB DLBCL patients, evaluate activity according to MYD88/CD79b mutational status, and refine dose/schedule in this patient population. Approximately 50 non-GCB DLBCL patients, with or without MYD88/CD79b mutations, will be randomized 1:1 to one of two oral dose/schedule cohorts: a continuous dosing schedule (100 mg QD) or an induction dosing schedule (120 mg QD x 14 days, then 80 mg QD starting Day 15).

Centrally assessed ctDNA-based liquid next-generation sequencing (NGS) will be performed after randomization to ascertain MyD88/CD79b mutation status. The primary endpoints of the study are overall response rate as assessed by an independent radiology review committee and safety. Key secondary endpoints include duration of response, progression-free survival, and complete response.

Data from the trial could position Calithera to initiate a study with registrational intent in biomarker-specific DLBCL populations.

RedHill Biopharma Announces Q1/22 Highlights: On Track for Positive Cash from Operations in H2/22

On June 23, 2022 RedHill Biopharma Ltd. (Nasdaq: RDHL) ("RedHill" or the "Company"), a specialty biopharmaceutical company, reported its first quarter 2022 financial results and operational highlights, targeting positive cash from operations1 to start during H2/22 and recent implementation of a comprehensive cost reduction plan, expected to generate operational cost savings of approximately $50 million over the next 18 months (Press release, RedHill Biopharma, JUN 23, 2022, View Source [SID1234616222]).

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Dror Ben-Asher, RedHill’s Chief Executive Officer, said: "To address the current market realities and operating landscape, RedHill is being decisive about controlling its own destiny and is highly focused on achieving earlier profitability, targeting positive cash from operations to start during H2/221. Our comprehensive cost reduction plan is expected to generate operational cost savings of approximately $50 million over the next 18 months. The majority of these savings result from an approximately one-third reduction of the U.S. commercial team workforce, returning to pre-pandemic levels, streamlined operational expenditure including selling, general and administrative (SG&A) expenses and refining the Company’s R&D strategy to rely mostly on external funding sources based on the promising clinical data generated to date. On behalf of RedHill and its Board of Directors, I would like to express my profound and respectful gratitude to the colleagues who are departing RedHill. We value and are extremely grateful for your immense contributions and dedication which enabled RedHill to build a first-class U.S. commercial organization and launch three innovative products that help patients in need. While difficult, the changes we have made as part of our cost reduction plan were necessary given the current realities."

Mr. Ben-Asher continued: "Improved financial stability resulting from cost savings, a commercial basket including three FDA-approved proprietary drugs, continued prescription growth and healthy sales, improved managed care coverage and the amended credit agreement with HCR, positions RedHill for further growth. To that end, RedHill is in non-binding discussions to acquire a synergetic U.S. FDA-approved, patented GI drug currently generating dozens of millions of dollars, which, if materialized, will help expedite and increase cash generation."

Micha Ben Chorin, Chief Financial Officer at RedHill, added: "RedHill’s commercial team has further strengthened Movantik’s share of the growing PAMORA class to approximately 74%, and Talicia’s approximately 13% quarterly growth further consolidates its position as the leading U.S. brand for H. pylori eradication. The Company’s disciplined cost control measures reduced Q1/22 cash used in operating activities by more than 70% to approximately $4 million, compared to approximately $15 million in Q4/21. Despite the challenging market conditions, RedHill is on its way to achieving company-wide positive cash from operations1 this year, and this, along with the envisaged growth drivers from the pipeline and potential acquisitions, could boost cash generation and further improve cash flow. We are confident that RedHill is well positioned for continuing growth."

Mr. Ben-Asher further remarked: "Turning to R&D, in reliance of promising clinical and other data we generated to date, we expect external funding for much of our promising R&D programs, through grants, industry partnerships and participation in platform studies. COVID-19, included in a broader category of ‘pandemic preparedness’, remains an area of high interest and need for novel oral therapeutics such as RedHill’s candidates. Regulatory feedback on opaganib, supportive of a confirmatory study has provided a pathway to potential opaganib submissions for approval in COVID-19. Most recently, opaganib further exhibited its variant-agnostic credentials by demonstrating potent in vitro efficacy against Omicron, while also showing, in a separate study, potent in vitro inhibition of influenza A H1N1, adding to evidence of opaganib’s broader antiviral potential and its promising applicability to ‘pandemic preparedness’. Meanwhile, RedHill’s 2nd COVID-19 therapeutic candidate, RHB-107, successfully met the Part A study primary outcome measure for its Phase 2/3-stage study in non-hospitalized COVID-19, showing, among other promising data, a 100% reduction in hospitalization due to COVID-19. Discussions are ongoing regarding potential external funding through grants, platform studies and other public, private and industry partnerships to support the opaganib and RHB-107 programs, as well as our ongoing Phase 3 study with RHB-204 for NTM disease."

Financial results for the quarter ended March 31, 2022 (Unaudited)[3]

Net Revenues for the first quarter of 2022 were $18.2 million, as compared to $22.1 million in the fourth quarter of 2021, the difference being attributable to typical cyclical trends in Movantik sales and increased gross to net deductions related mainly to increased formulary coverage.

Cost of Revenues for the first quarter of 2022 were $8.0 million, as compared to $19.3 million in the fourth quarter of 2021. The decrease was attributed to recognition of an approximately $9 million impairment related to the intangible asset of Aemcolo for travelers’ diarrhea in the previous quarter.

Gross Profit for the first quarter of 2022 was $10.2 million, as compared to $2.7 million in the fourth quarter of 2021. The increase was attributed to the impairment recognized in the previous quarter, as detailed above.

Research and Development Expenses for the first quarter of 2022 were $3.1 million, as compared to $5.9 million in the fourth quarter of 2021. The decrease was attributed to the ongoing optimization of R&D costs and completion of elements of the opaganib and RHB-107 development programs.

Selling, Marketing and General and Administrative Expenses for the first quarter of 2022 were $20.4 million, as compared to $17.6 million in the fourth quarter of 2021. The increase was mainly attributed to a one-off positive adjustment in quarter four of 2021 and expenses related to professional services and other related expenses in the first quarter of 2022.

Operating Loss for the first quarter of 2022 was $13.2 million, as compared to $20.7 million in the fourth quarter of 2021. The decrease was mainly attributed to the impairment recognized in the previous quarter, as detailed above.

Net Cash Used in Operating Activities for the first quarter of 2022 was $4.2 million, as compared to $14.9 million in the fourth quarter of 2021. The decrease was mainly due to changes in working capital and continued implementation of cost-reduction measures.

Net Cash Used in Financing Activities for the first quarter of 2022 was $4.9 million, as compared to Net Cash Provided by Financing Activities of $17.6 million in the fourth quarter of 2021, comprised mostly from proceeds of equity offerings completed in the fourth quarter of 2021. The additional decrease of $5 million was due to a reduction of Movantik acquisition liabilities.

Liquidity and Capital Resources

Cash Balance1 as of March 31, 2022, was $45.0 million, as compared to $54.2 million as of December 31, 2021.

On June 17, 2022, RedHill Biopharma Inc. signed an amendment to the HCR Credit Agreement reducing the revenue covenant to $75.0 million for the next two quarters, with a 0.5% increase in interest.

The license of opaganib[4] for COVID-19 by Kukbo for South Korea is expected to yield a $1.5 million upfront payment to RedHill and, in addition, up to $5.6 million in milestone payments plus royalties on net sales.

The license of Talicia for H. pylori by Gaelan Medical for the United Arab Emirates, with $2.0 million upfront payment received, is anticipated to yield additional milestones and royalties on net sales.

Discussions with additional potential partners, for both in- and out-licensing partnerships, are ongoing including for potential acquisitions of additional synergetic commercial products with strong cash generation potential.

Commercial Highlights

Movantik (naloxegol)[5]

The Company’s focus and determination to drive both Movantik and the PAMORA class as a whole have delivered important results, with Movantik’s Q1/22 performance matching the record pace set in Q4/21. This represents an 8.6% increase in new prescriptions compared to Q1/21, more than doubling the already strong growth of the overall PAMORA class in the same period and contributing to a further increase in market share for Movantik, now up to almost 74% of the PAMORA class.

Nearly 92% of insurance plans provide access for Movantik – best-in-class coverage – and as of January 1, 2022, Movantik has been approved for inclusion as a preferred and unrestricted brand on a major National Medicare Part D formulary serving more than 10 million Americans. Movantik’s total commercial coverage now extends to 151 million American patients’ lives and has grown to 46 million Medicare lives, with over 93% coverage of Medicare Part D lives.

With best-in-class payer coverage, focused execution in the pain segment and continuing the PAMORA class market development, Movantik is well-positioned for continued growth in 2022 and beyond.

Talicia (omeprazole magnesium, amoxicillin and rifabutin)[6]

Talicia reached new TRx heights in Q1/22, growing a further 12.8% compared to the previous record levels set in Q4/21. This growth represents an 80% increase in new prescriptions from Q1/21, further cementing Talicia’s position as the most prescribed branded H. pylori therapy in the U.S. Significant increase in prescription volume in March of this year, coupled with a growing prescriber base, improving payor coverage and continuing promotional focus is expected to result in further growth acceleration.

Medi-Cal, California’s Medicaid Health Care program, which added Talicia last year to its Contract Drug List (CDL) for H. pylori treatment, with no prior authorization required, expanded coverage to 14 million beneficiaries on January 1, 2022. Florida Medicaid coverage started in April and another large Part D plan coverage became effective earlier this quarter. The Company also expects a major new coverage win to initiate July 1, 2022. As of May 2022, total Talicia coverage stood at nearly 200 million American lives, equating to seven out of ten lives.

Outside of the U.S., in January 2022, the Company announced that it had entered into an exclusive license agreement with Gaelan Medical Trade LLC, a wholly owned subsidiary of the Ghassan Aboud Group (GAG), for Talicia in the United Arab Emirates (UAE). Under the terms of the agreement, RedHill received an upfront payment of $2 million and is eligible for additional milestone payments as well as tiered royalties up to mid-teens on net sales of Talicia in the UAE if marketing authorization is received and Talicia is commercialized. Gaelan Medical received the exclusive rights to Talicia in the UAE, as well as a right of first refusal in relation to Talicia in the Gulf Cooperation Council region (Saudi Arabia, Kuwait, Qatar, Bahrain and Oman) for a pre-determined period.

Aemcolo (rifamycin)[7]

The Company continues to be ready for post-COVID-19 returning travel opportunities for Americans.

R&D Highlights

Opaganib (ABC294640)

COVID-19:

COVID-19, included in a broader category of ‘pandemic preparedness’, remains an area of high interest and need for novel oral therapeutics. Data from prespecified analyses of opaganib’s Phase 2/3 study (NCT04467840), announced in January and February 2022, demonstrated that opaganib improved viral RNA clearance, achieved faster time to recovery and reduced mortality in key subpopulations of moderate to severe hospitalized patients with COVID-19. Additionally, a post-hoc analysis identified a biomarker, the fraction of inspired oxygen (FiO2), to select patients that showed superior outcomes with opaganib vs. placebo. Opaganib also demonstrated potent in vitro efficacy against the Omicron SARS-CoV-2 variant and is expected to remain effective against sub-variants BA.2, XE and other emerging and future variants. Based on regulatory guidance, a positive confirmatory study constitutes the likely pathway to potential opaganib submissions for approval in the U.S., EU, and multiple other territories.

Data from the global Phase 2/3 study has now been published on MedRxiv and will also be the subject of a "Late-Breaker" oral presentation at the joint CDC / Task Force for Global Health-organized International Conference on Emerging Infectious Diseases, to be held in August.

On June 21, 2022, and adding to opaganib’s expanding patent suite, RedHill was granted an additional U.S. patent directed to a method for the treatment of COVID-19 in patients with moderate to severe COVID-19 related pneumonia using opaganib.

RedHill is pursuing multiple public and private external funding sources for our programs including grants in the U.S., UK and EU, government sponsored platform studies and industry partnerships. In March 2022, the Company announced that it had entered into an exclusive license agreement with Kukbo Co. Ltd., a South Korean corporation, for the exclusive rights to commercialize opaganib for the treatment of COVID-19 in South Korea. Under the terms of the agreement, RedHill is entitled to receive an upfront payment of $1.5 million and is eligible for $5.6 million in additional milestone payments, as well as low double-digit royalties on net sales of opaganib if marketing authorization is received and opaganib is commercialized.

Other indications under investigation:

Influenza A H1N1: Opaganib demonstrated potent in vitro inhibition of influenza A H1N1, at low concentrations and with no evidence of toxicity at these levels. The results were obtained in Normal Human Bronchial Epithelial Cells (NHBE) assay, the natural human target of the virus, making it a realistic model. These results add to previous data demonstrating antiviral activity in several in vitro and in vivo viral infection models including SARS-CoV-2, influenza and Ebola, providing further evidence of opaganib’s potential broad-spectrum antiviral effect. Discussions with NIH are ongoing regarding next steps for investigating opaganib’s broader antiviral potential and its promising applicability to ‘pandemic preparedness’.

Oncology:

The Company continues to advance opaganib’s development program in oncology with the cholangiocarcinoma (CCA) Phase 2 study analysis expected in Q3/2022

RHB-107 (upamostat)[8]

COVID-19:

In March 2022, the Company announced positive top-line results from Part A of the two- stage Phase 2/3 study of novel, once-daily, orally-administered, antiviral drug candidate, RHB-107. The study, evaluating RHB-107 for the treatment of non-hospitalized patients with symptomatic COVID-19 in the early course of the disease (NCT04723537), who do not require supplemental oxygen (the vast majority of COVID-19 patients) was predominantly conducted in the U.S. (60/61 patients) as well as South Africa.

Results showed that RHB-107 met the primary outcome measure, demonstrating a favorable safety and tolerability profile and showed a 100% reduction in hospitalization due to COVID-19, with zero patients (0/41) on the RHB-107 arms versus 15% (3/20) hospitalized due to COVID-19 on the placebo-controlled arm (nominal p-value=0.0317). The study also showed an approximately 88% reduction in reported new severe COVID-19 symptoms after treatment initiation, with only one patient in the RHB-107 treated group 2.4%, (1/41) versus 20% (4/20) of patients in the placebo-controlled arm. Further analysis of study data also showed a faster recovery from severe COVID-19 symptoms for patients in the RHB-107 arm, with a median of 3 days to recovery with RHB-107 vs. 8 days with placebo.

RHB 107’s unique human host-targeted, suggested antiviral mechanism is expected to act independently of viral spike protein mutations and remain effective against Omicron and sub-variants BA.2, XE and other emerging and future variants.

Next steps for the study are expected following ongoing discussions with regulators.

RHB-204 – Pulmonary Nontuberculous Mycobacteria (NTM) Disease[9]

A U.S. Phase 3 study is ongoing in the U.S. to evaluate the efficacy and safety of RHB-204 in adults with pulmonary NTM disease caused by Mycobacterium avium Complex (MAC) infection (NCT04616924). The waning of COVID-19 is expected to accelerate the advancement of the program

The study protocol provides for 6 months co-primary endpoint of sputum culture conversion (SCC) and clinical outcome (patient-reported outcomes – PRO) in a randomized placebo-controlled design, followed by open label active treatment with RHB-204 for 12 months from conversion.

RHB-204 has been granted Orphan Drug designation and QIDP status – providing for Fast Track and Priority Review and resulting in eligibility for 12 years post-approval market exclusivity.

Conference Call and Webcast Information:

The Company will host a conference call and webcast today, Thursday, June 23, 2022, at 8:30 a.m. EDT, during which it will present key highlights for the first quarter of 2022.

The webcast including slides will be broadcast live on the Company’s website, View Source, and will be available for replay for 30 days.