On January 29, 2021 Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported first-time data from the Phase 3 KEYNOTE-598 study evaluating KEYTRUDA, Merck’s anti-PD-1 therapy, in combination with ipilimumab (Yervoy) compared with KEYTRUDA monotherapy as first-line treatment for patients with metastatic non-small cell lung cancer (NSCLC) without EGFR or ALK genomic tumor aberrations and whose tumors express PD-L1 (tumor proportion score [TPS] ≥50%) (Press release, Merck & Co, JAN 29, 2021, View Source [SID1234574419]). Results of the study showed that the addition of ipilimumab to KEYTRUDA did not improve overall survival (OS) or progression-free survival (PFS) but added toxicity compared with KEYTRUDA monotherapy in these patients. The median OS was 21.4 months for patients randomized to KEYTRUDA in combination with ipilimumab versus 21.9 months for those randomized to KEYTRUDA monotherapy (HR=1.08 [95% CI, 0.85-1.37]; p=0.74). Additionally, the median PFS was 8.2 months for patients in the combination arm versus 8.4 months for those in the KEYTRUDA monotherapy arm (HR=1.06 [95% CI, 0.86-1.30]; p=0.72).

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"In KEYNOTE-598, the addition of ipilimumab to KEYTRUDA did not improve overall survival or progression-free survival, and patients who received the combination were more likely to experience serious side effects than those who received KEYTRUDA monotherapy," said Dr. Michael Boyer, chief clinical officer and conjoint chair of thoracic oncology, Chris O’Brien Lifehouse, Camperdown, NSW, Australia. "KEYTRUDA monotherapy remains a standard of care for the first-line treatment of certain patients with metastatic non-small cell lung cancer whose tumors express PD-L1."

"As a leader in lung cancer, we are pursuing a broad clinical program to better understand the potential of KEYTRUDA-based combinations to improve survival outcomes for patients with this devastating disease," said Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. "KEYNOTE-598 is the first head-to-head study designed to answer the question of whether combining KEYTRUDA with ipilimumab provided additional clinical benefits beyond treatment with KEYTRUDA alone in certain patients with metastatic non-small cell lung cancer. The results are clear – the combination did not add clinical benefit but did add toxicity."

These results were presented in the Presidential Symposium at the IASLC 2020 World Conference on Lung Cancer hosted by the International Association for the Study of Lung Cancer on Friday, Jan. 29 and published in the Journal of Clinical Oncology. As previously announced in Nov. 2020, the study was discontinued due to futility based on the recommendation of an independent Data Monitoring Committee (DMC), which determined the benefit/risk profile of KEYTRUDA in combination with ipilimumab did not support continuing the trial. The DMC also advised that patients in the study discontinue treatment with ipilimumab/placebo.

KEYNOTE-598 Study Design and Additional Data (Late-Breaking Abstract #PS01.09)

KEYNOTE-598 (ClinicalTrials.gov, NCT03302234) is a randomized, double-blind, Phase 3 trial designed to evaluate KEYTRUDA in combination with ipilimumab compared to KEYTRUDA monotherapy as first-line treatment for patients with metastatic NSCLC without EGFR or ALK genomic tumor aberrations and whose tumors express PD-L1 (TPS ≥50%). The dual primary endpoints are OS and PFS. Secondary endpoints include objective response rate (ORR), duration of response (DOR) and safety.

The study enrolled 568 patients who were randomized 1:1 to receive KEYTRUDA (200 mg intravenously [IV] on Day 1 of each three-week cycle for up to 35 cycles) in combination with ipilimumab (1 mg/kg IV on Day 1 of each six-week cycle for up to 18 cycles); or KEYTRUDA (200 mg IV on Day 1 of each three-week cycle for up to 35 cycles) as monotherapy. Non-binding futility criteria for the study were based on restricted mean survival time (RMST), an alternative outcome measure estimated as the area under the survival curve through a fixed timepoint. The pre-specified criteria were differences in RMST for KEYTRUDA in combination with ipilimumab and KEYTRUDA monotherapy of ≤0.2 at the maximum observation time and ≤0.1 at 24 months of follow-up.

As of data cut-off, the median study follow-up was 20.6 months. Findings showed the median OS was 21.4 months for patients randomized to KEYTRUDA in combination with ipilimumab (n=284) versus 21.9 months for those randomized to KEYTRUDA monotherapy (n=284) (HR=1.08 [95% CI, 0.85-1.37]; p=0.74). The differences in RMST for KEYTRUDA in combination with ipilimumab and KEYTRUDA monotherapy were -0.56 at the maximum observation time and -0.52 at 24 months, meeting the futility criteria for the trial and confirming the benefit/risk profile of the combination did not support continuing the study. Additionally, the median PFS was 8.2 months for patients randomized to KEYTRUDA in combination with ipilimumab versus 8.4 months for those randomized to KEYTRUDA monotherapy (HR=1.06 [95% CI, 0.86-1.30]; p=0.72). In both arms of the study, ORR was 45.4%; the median DOR was 16.1 months for patients randomized to KEYTRUDA in combination with ipilimumab versus 17.3 months for those randomized to KEYTRUDA monotherapy.

No new safety signals for KEYTRUDA monotherapy were observed. Treatment-related adverse events (TRAEs) occurred in 76.2% of patients treated with KEYTRUDA in combination with ipilimumab versus 68.3% of patients treated with KEYTRUDA monotherapy. Of these TRAEs, 35.1% vs. 19.6% were Grade 3-5, 27.7% vs. 13.9% were serious, 6.0% vs. 3.2% led to discontinuation of ipilimumab or placebo, 19.1% vs. 7.5% led to discontinuation of both drugs and 2.5% vs. 0.0% (no patients) led to death. Additionally, immune-mediated adverse events (AEs) and infusion reactions occurred in 44.7% of patients treated with KEYTRUDA in combination with ipilimumab versus 32.4% of patients treated with KEYTRUDA monotherapy. Of these immune-mediated AEs, 20.2% vs. 7.8% were Grade 3-5, 19.1% vs. 7.1% were serious, 1.8% vs. 1.1% led to discontinuation of ipilimumab or placebo, 12.1% vs. 4.3% led to discontinuation of both drugs and 2.1% vs. 0.0% (no patients) led to death.

About Lung Cancer

Lung cancer, which forms in the tissues of the lungs, usually within cells lining the air passages, is the leading cause of cancer death worldwide. Each year, more people die of lung cancer than die of colon and breast cancers combined. The two main types of lung cancer are non-small cell and small cell. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for about 85% of all cases. Small cell lung cancer (SCLC) accounts for about 10% to 15% of all lung cancers. Before 2014, the five-year survival rate for patients diagnosed in the U.S. with NSCLC and SCLC was estimated to be 5% and 6%, respectively.

About KEYTRUDA (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-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 1,300 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 patients with melanoma with involvement of lymph node(s) following complete resection.

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.

Small Cell Lung Cancer

KEYTRUDA is indicated for the treatment of patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least 1 other prior line of therapy. 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 confirmatory trials.

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 cisplatin-containing chemotherapy and whose tumors express PD-L1 (CPS ≥10), as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) 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, or
colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.
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 first-line treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).

Gastric Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. 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 recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.

Cervical Cancer

KEYTRUDA 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. 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.

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 patients with advanced renal cell carcinoma (RCC).

Tumor Mutational Burden-High

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) that is not curable by surgery or radiation.

Triple-Negative Breast Cancer

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

This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

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 programmed death receptor-1 (PD-1) or the programmed death ligand 1 (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. 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). 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 treatments 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, 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-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%).

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

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 metastatic urothelial carcinoma. 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 metastatic urothelial carcinoma. 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.

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

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

In KEYNOTE-158, KEYTRUDA was discontinued due to adverse reactions in 8% of 98 patients with 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 hepatocellular carcinoma (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%).

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 cSCC were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

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%).

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.

On January 29, 2021 Myovant Sciences (NYSE: MYOV), a healthcare company focused on redefining care for women and for men, reported it will host a webcast and conference call to discuss corporate updates and financial results for its third fiscal quarter 2020, ended December 31, 2020 (Press release, Myovant Sciences, JAN 29, 2021, https://investors.myovant.com/news-releases/news-release-details/myovant-sciences-host-third-fiscal-quarter-2020-earnings [SID1234574422]). The webcast and conference call will be held at 8:30 a.m. Eastern Time / 5:30 a.m. Pacific Time on February 11, 2021.

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Investors and the general public may access a live webcast of the call by visiting the investor relations page of Myovant’s website at investors.myovant.com. Institutional investors and analysts may also participate in the conference call by dialing 1-800-532-3746 in the U.S. or +1-470-495-9166 from outside the U.S.

A replay of the webcast, along with the earnings press release and presentation slides, will be archived on Myovant’s investor relations website.

On January 29, 2021 Astellas Pharma Inc. (TSE: 4503, President and CEO: Kenji Yasukawa, "the Company") reported the financial results for the first nine months (April 1, 2020 – December 31, 2020) of the fiscal year 2020 (FY2020) ending March 31, 2021 (Press release, Astellas, JAN 29, 2021, View Source [SID1234574380]).

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1. Qualitative information on consolidated financial results for the first nine months of FY2020 (1) Business performance
Consolidated financial results (core basis) in the first nine months of FY2020 are shown in the table below.

Revenue, core operating profit and core profit decreased across the board. Revenue-Sales of main products XTANDI for the treatment of prostate cancer and XOSPATA for the treatment of acute myeloid leukemia continued to grow.

In addition, growth of the co-promotion revenue of PADCEV for the treatment of urothelial cancer, which was launched in the United States in December 2019, contributed to revenue.

-Moreover, sales of Betanis / Myrbetriq / BETMIGA for the treatment of overactive bladder ("OAB") showed steady progress, and new product group in Japan achieved sales growth, including those of EVENITY for the treatment of osteoporosis, Suglat and SUJANU Combination Tablets for the treatment of diabetes mellitus.
-However, revenue decreased mainly due to the loss of market exclusivity of Vesicare for the treatment of OAB in Europe and Celecox for the treatment of inflammation and pain in Japan, and the termination of sales agreements for Symbicort for the treatment of asthma, human vaccines of KM Biologics Co., Ltd. and Micardis family for the treatment of hypertension. Sales were also negatively impacted due to the spread of COVID-19.

As a result of the above, revenue in the first nine months of FY2020 decreased by 4.8% compared to those in the corresponding period of the previous fiscal year ("year-on-year") to ¥940.9 billion. Core operating profit / Core profit-Gross profit decreased by 1.8% year-on-year to ¥753.2 billion.

The cost-to-revenue ratio fell by 2.5 percentage points year-on-year to 20.0%, mainly due to changes in product mix.-Selling, general and administrative expenses increased by 2.7% year-on-year to ¥363.0 billion.

There was a decrease in expenses due to refraining from promotional activities, etc. due to the spread of COVID-19, but total selling, general and administrative expenses increased due to the increase of co-promotion fees associated with the growth of sales of XTANDI in the United States, and there was a one-off reducing factor on expenses from a reversal of loss allowances in the corresponding period of the previous fiscal year.-Research and development (R&D) expenses increased by 5.7% year-on-year to ¥168.8 billion.

There was a decrease in development expenses due to the impact of the spread of COVID-19 on the execution of a portion of clinical trials, but total R&D expenses increased due to an increase in development expenses for key post-POC pipeline projects, and the addition of R&D expenses from Audentes Therapeutics, Inc., which was acquired in January 2020. The R&D cost-to-revenue ratio was up 1.8 percentage points year-on-year to 17.9%.-Amortisation of intangible assets increased by 12.0% year-on-year to ¥17.3 billion.

As a result of the above, core operating profit decreased by 13.6% year-on-year to ¥203.7 billion, and core profit decreased by 13.1% year-on-year to ¥166.6 billion. 3 Impact of exchange rate on financial results The exchange rates for the yen in the first nine months of FY2020 are shown in the table below. The resulting impacts were a ¥7.3 billion decrease in revenue and a ¥3.6 billion decrease in core operating profit compared with if the exchange rates of the first nine months of FY2019 were applied.

Average rate First nine months
Consolidated financial results on a full basis in the first nine months of FY2020 are shown in the table below. Revenue, operating profit, profit before tax and profit decreased across the board. The full basis financial results include "Other income," "Other expenses," which are excluded from the core basis financial results. In the first nine months of FY2020, "Other income" was ¥7.0 billion (¥15.1 billion in the same period of the previous fiscal year) and "Other expenses" was ¥51.3 billion (¥13.4 billion in the same period of the previous fiscal year).

As "Other expenses," the Company recorded impairment losses of ¥30.2 billion in relation to the termination of development for the anti-TIGIT antibody ASP8374/PTZ-201 in the first six months of FY2020, and as a result, the decrease in profit was larger compared to the financial results on a core basis. * Prograf: Includes Advagraf, Graceptor, and ASTAGRAF XL.-Sales of XTANDI increased by 15.0% year-on-year to ¥342.7 billion. Sales increased in all regions of Japan, United States, Established Markets, Greater China, and International.-Sales of XOSPATA increased by 80.7% year-on-year to ¥17.6 billion. This was due to its sales growing in Japan and United States in addition to the contribution of its sales in Established Markets, where it was launched in November 2019.-Co-promotion revenue of PADCEV amounted to ¥9.4 billion in United States.-Sales of Betanis / Myrbetriq / BETMIGA increased by 1.0% year-on-year to ¥122.3 billion.

While sales grew in United States, Established Markets and Greater China, sales decreased in Japan and International due to decreased demand, etc. associated with the reduction of patient visits to hospitals/clinics as a result of the impact of the spread of COVID-19.-Sales of Vesicare decreased by 31.8% year-on-year to ¥24.7 billion mainly due to the impact of the effect of generic drugs resulting from the loss of market exclusivity for the drug in Europe.

-Sales of Prograf decreased by 5.4% year-on-year to ¥138.3 billion. While sales grew in Greater China, sales decreased in other regions.
-In Japan, new product group sales continued to increase, including those of EVENITY, Suglat and SUJANU Combination Tablets. On the other hand, the main factors for the decrease in sales were the loss of market exclusivity for Celecox and the termination of sales agreements for Symbicort, human vaccines of KM Biologics Co., Ltd. and Micardis family.

-In United States, sales of pharmacologic stress agent Lexiscan decreased due to decreased demand associated with the reduction of patient visits to hospitals/clinics as a result of the impact of the spread of COVID-19, mainly in the first three months of FY2020. 6 Revenue by region is shown in the table below. Revenue in United States increased, and revenue in Established Markets achieved similar levels year on year. On the other hand, revenue in Japan, Greater China and International decreased.

(2) Financial position i. Assets, equity and liabilities In the first three months of FY2020, the consolidated statement of financial position as of March 31, 2020 was retrospectively revised due to adjustments of fair value of assets acquired and liabilities assumed for Audentes Therapeutics, Inc., which was acquired in January 2020.

As a result, goodwill increased, and intangible assets and deferred tax liabilities decreased in comparison to the figures prior to the retrospective adjustment. The Company is still in the process of finalizing the fair value measurement as of December 31, 2020. An overview of the consolidated statement of financial position as of December 31, 2020 and the main changes from the end of the previous fiscal year after the retrospective adjustment are shown below. Assets Total assets as of December 31, 2020 saw a decrease of ¥18.3 billion compared to the end of the previous fiscal year to ¥2,296.8 billion.

As of December 31, 2020: ¥1,433.5 billion (a decrease of ¥14.1 billion)-Property, plant and equipment decreased by ¥13.4 billion compared to the end of the previous fiscal year to ¥255.2 billion.-Goodwill decreased by ¥10.5 billion compared to the end of the previous fiscal year to ¥267.8 billion, and intangible assets decreased by ¥27.6 billion compared to the end of the previous fiscal year to ¥697.2 billion. Intangible assets decreased mainly due to the recording of impairment losses in relation to the termination of development for the anti-TIGIT antibody ASP8374/PTZ-201 in the first six months of FY2020.

As of December 31, 2020: ¥863.3 billion (a decrease of ¥4.2 billion)-Cash and cash equivalents decreased by ¥11.9 billion compared to the end of the previous fiscal year to ¥306.5 billion.

Equity Total equity as of December 31, 2020 saw an increase of ¥79.4 billion compared to the end of the previous fiscal year to ¥1,368.6 billion, making the ratio of equity attributable to owners of the parent to gross assets 59.6%.-While profit stood at ¥132.9 billion, the Company paid ¥76.2 billion of dividends of surplus. 8 Liabilities Total liabilities decreased by ¥97.8 billion compared to the end of the previous fiscal year to ¥928.2 billion.

As of December 31, 2020: ¥292.4 billion (an increase of ¥65.1 billion)-Other financial liabilities increased by ¥69.7 billion compared to the end of the previous fiscal year to ¥199.0 billion mainly due to converting ¥80.0 billion from short-term borrowings to long-term borrowings in the first three months of FY2020.

As of December 31, 2020: ¥635.8 billion (a decrease of ¥162.9 billion)-As of December 31, 2020, the balance of bonds amounted to ¥165.0 billion. Other financial liabilities decreased by ¥156.2 billion compared to the end of the previous fiscal year to ¥189.5 billion due to the conversion from short-term borrowings to long-term borrowings stated above, repayments, etc.ii. Cash flow Cash flows from operating activities Net cash flows from operating activities in the first nine months of FY2020 increased by ¥54.9 billion year-on-year to ¥225.1 billion

.-Income tax paid decreased by ¥20.0 billion year-on-year to ¥10.5 billion. Cash flows from investing activities Net cash flows used in investing activities in the first nine months of FY2020 was ¥67.7 billion, a decrease in outflow of ¥6.7 billion year-on-year. Cash flows from financing activities Net cash flows used in financing activities in the first nine months of FY2020 was ¥171.3 billion, an increase in outflow of ¥46.1 billion year-on-year.

-While proceeds from long-term borrowings amounted to ¥80.0 billion, the balance of bonds and short-term borrowings decreased by ¥161.0 billion. Dividends paid increased by ¥2.6 billion year-on-year to ¥76.2 billion.

As a result, cash and cash equivalents totaled ¥306.5 billion as of December 31, 2020, a decrease of ¥11.9 billion compared to the end of the previous fiscal year.(3) Consolidated business forecasts for FY2020 and other forward-looking statements The Company’s business forecasts are presented on a core basis and full basis. The consolidated full-year business forecasts for FY2020 are shown below.

The Company has left its business forecasts unchanged from the consolidated full-year business forecasts announced in October 2020.Business Combinations For the nine months ended 31 December 2020 Audentes Therapeutics, Inc. On 15 January 2020, Audentes Therapeutics, Inc. became a consolidated subsidiary of the Company through a cash tender offer followed by a merger. During the three months ended 30 June 2020, further facts came to light and additional analysis was performed on the fair value measurement of the assets acquired and liabilities assumed at the acquisition date. As a result, the provisional fair values were adjusted as follows.

The initial accounting for the business combination is incomplete as of 31 December 2020 as Astellas Pharma Inc. and its subsidiaries are still in the process of finalizing the fair value measurement.Goodwill mainly comprises the value of expected synergies arising from the acquisition and future economic benefits, which is not separately recognised. Financial assets at FVTOCI (debt instruments) are included in "Other financial assets" in the condensed interim consolidated statement of financial position.

Along with this adjustment, the Company retrospectively revised the corresponding balances in the condensed interim consolidated statement of financial position as of 31 March 2020. As a result, intangible assets and deferred tax liabilities decreased by 13,734 million yen and 2,992 million yen respectively, and goodwill increased by 10,743 million yen.

On January 29, 2021 AstraZeneca and Daiichi Sankyo Company reported that its datopotamab deruxtecan (Dato-DXd; DS-1062) and Enhertu (trastuzumab deruxtecan) showed encouraging results from both antibody drug conjugates (ADCs) in patients with advanced or metastatic non-small cell lung cancer (NSCLC) (Press release, AstraZeneca, JAN 29, 2021, View Source [SID1234574402]). The data were presented today in two oral presentations during the World Conference on Lung Cancer (WCLC), hosted by the International Association for the Study of Lung Cancer (IASLC).

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Updated results from the TROPION-PanTumor01 Phase I trial showed promising clinical activity for datopotamab deruxtecan, a TROP2-directed ADC, in patients with advanced or metastatic NSCLC.

Additionally, an interim analysis of the HER2-overexpressing cohort of the DESTINY-Lung01 Phase II trial showed preliminary evidence of antitumour activity for Enhertu, a HER2-directed ADC, in patients with metastatic NSCLC.

Lung cancer is the leading cause of cancer death among both men and women, and accounts for about one-fifth of all cancer deaths globally, with 80-85% classified as NSCLC.1-3 For patients with metastatic disease, prognosis is particularly poor, as only 6-10% live five years beyond diagnosis.4 Currently, there are no TROP2-directed or HER2-directed medicines approved for the treatment of NSCLC.

Cristian Massacesi, Senior Vice President, Head of Late-Stage Development, Oncology R&D, said: "Antibody drug conjugates have transformative potential for the targeted treatment of advanced lung cancer, and the early data for datopotamab deruxtecan and Enhertu suggest a promising durable benefit in patients who have limited treatment options. Both are potent ADCs, and we look forward to further clinical data from these development programmes in patients with lung cancer."

Antoine Yver, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo, said: "Developing innovative therapies for patients with lung cancer, including those that target TROP2 and HER2, are important as few treatment options remain once progression occurs in the metastatic setting following treatment with platinum-based chemotherapy and immune checkpoint inhibitors. We are encouraged by these preliminary results, which may indicate a durability of effect of datopotamab deruxtecan. We remain committed with AstraZeneca to our bold development plan, particularly the ongoing pivotal Phase III trial of datopotamab deruxtecan monotherapy in patients with metastatic non-small cell lung cancer."

TROPION-PanTumor01 trial results
In the TROPION-PanTumor01 Phase I trial, an objective response rate (ORR) ranging from 21 to 25%, as assessed by independent central review, was observed in 159 patients with advanced or metastatic NSCLC receiving different doses of datopotamab deruxtecan (4mg/kg, 6mg/kg or 8mg/kg), as of data cut-off on 4 September 2020. Thirty two confirmed complete or partial responses were seen, and an additional five complete or partial responses are still too early to confirm. Efficacy data were preliminary due to immaturity of follow-up across dose groups, but preliminary efficacy results may support durability of clinical activity. A disease control rate (DCR) ranging from 67 to 80% was observed with a median progression-free survival (PFS) ranging from 4.3 to 8.2 months across the three doses of datopotamab deruxtecan.

Alexander Spira, MD, PhD, FACP, Oncologist, Virginia Cancer Specialists, US Oncology Research and Johns Hopkins Oncology, said: "These updated preliminary results from TROPION-PanTumor01 are encouraging, as responses were seen across all three doses of datopotamab deruxtecan, underscoring the potential of targeting TROP2 with an antibody drug conjugate in advanced or metastatic non-small cell lung cancer. We look forward to seeing the results from the Phase III trial, which will further evaluate datopotamab deruxtecan versus chemotherapy, the current standard of care for patients with advanced disease that has progressed following treatment with platinum chemotherapy and immunotherapy."

Summary-of-TROPION-PanTumor01-results
The majority of patients across all three doses were previously treated with three or more prior lines of therapy including platinum-based chemotherapy (94%) or immunotherapy (84%). Median duration of follow-up was 7.4 months. As of data cut-off, 39% of patients remained on treatment with datopotamab deruxtecan.

Datopotamab deruxtecan demonstrated a manageable safety profile in the TROPION-PanTumor01 Phase I trial, which was consistent with what has been previously reported. Overall, the 4mg/kg and 6mg/kg doses were better tolerated than the 8mg/kg dose. The most common Grade 3 or greater treatment-emergent adverse events (TEAEs) included mucosal inflammation, anaemia, stomatitis and fatigue, with patients treated at the 8mg/kg dose experiencing higher rates overall. Fourteen cases (8%) of interstitial lung disease (ILD) occurred as determined by an independent adjudication committee. The majority of ILD cases (12/14) were observed with the 8mg/kg cohort, including three deaths (Grade 5). One Grade 3 ILD event was seen with the 4mg/kg dose and one Grade 2 ILD event was seen with the 6mg/kg dose.

Based on the efficacy and safety findings, the 6mg/kg dose has been identified as the recommended dose for the registrational TROPION-Lung01 Phase III trial.

DESTINY-Lung01 trial results
In the interim results of cohort 1 from the DESTINY-Lung01 Phase II trial the primary endpoint of confirmed ORR, assessed by independent central review, was 24.5% for extensively treated patients with HER2-overexpressing (defined as IHC3+ or IHC2+) metastatic NSCLC treated with Enhertu (6.4mg/kg) (n=49). Patients achieved a DCR of 69.4% with a median PFS of 5.4 months. After a median follow-up of 6.1 months, the estimated median duration of response (DoR) was 6.0 months, and the median overall survival (OS) was 11.3 months.

Patients were treated with a median of three prior lines of therapy with most receiving platinum-based chemotherapy (91.8%) or immunotherapy (73.5%). Median treatment duration was 18 weeks. As of data cut-off on 30 May 2020, 22% of patients remained on treatment with Enhertu.

Interim data (n=42) from the HER2-mutant (HER2m) metastatic NSCLC cohort of DESTINY-Lung01 were previously presented during the 2020 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) virtual meeting, and also featured as an encore presentation at WCLC. The results showed Enhertu achieved a clinically meaningful tumour response in patients with HER2m metastatic NSCLC.

The overall safety and tolerability profile of Enhertu was consistent with previous trials. In the HER2-overexpressing cohort of DESTINY-Lung01, the most common Grade 3 or greater TEAEs were decreased neutrophil count and fatigue. There were eight cases of treatment-related ILD or pneumonitis, as determined by an independent adjudication committee including two Grade 1, three Grade 2 and three deaths (Grade 5). In the HER2m cohort of DESTINY-Lung01, there were five cases of ILD or pneumonitis, as determined by an independent adjudication committee. All cases were Grade 2.

About NSCLC
Lung cancer is the leading cause of cancer death among both men and women and accounts for about one-fifth of all cancer deaths.1 NSCLC accounts for approximately 80-85% of all lung cancers. 2,3 For patients with metastatic disease, prognosis is particularly poor, as only 6-10% live five years beyond diagnosis.4 The introduction of targeted therapies and checkpoint inhibitors in recent years has improved the treatment landscape for patients with advanced NSCLC; however, new approaches are needed for those who are not eligible for available treatments, or whose cancer continues to progress.5 Currently, there are no TROP2-directed or HER2-directed medicines approved for the treatment of NSCLC.

TROP2 (trophoblast cell-surface antigen 2) is a transmembrane glycoprotein that is overexpressed in many cancers.6 TROP2 expression has been associated with poor overall and disease-free survival in several types of solid tumours. TROP2 expression has been observed in up to 64% of adenocarcinoma and up to 75% of squamous cell carcinoma NSCLC.7-9

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumours, including lung, breast, gastric and colorectal cancers. HER2 overexpression is associated with a specific HER2 gene alteration known as HER2 amplification and is often associated with aggressive disease and poorer prognosis. It has been reported in up to one third of patients with NSCLC.10-12

Other HER2 gene alterations (called HER2 mutations) have been identified in NSCLC, specifically adenocarcinomas, as distinct molecular targets and have been reported in approximately 2-4% of patients with NSCLC.11,13-15 These acquired HER2 gene mutations have been independently associated with cancer cell growth and poor prognosis.13,14

About TROPION-PanTumor01
TROPION-PanTumor01 is a first-in-human, open-label, two-part, multicentre Phase I trial designed to evaluate the safety, tolerability and preliminary efficacy of datopotamab deruxtecan in patients with advanced solid tumours, including NSCLC and triple-negative breast cancer (TNBC), that are refractory to or relapsed from standard treatment — or for whom no standard treatment is available.

The first part of the trial (dose escalation) assessed the safety and tolerability of increasing doses of datopotamab deruxtecan to determine the maximum tolerated dose and/or recommended dose for expansion in patients with unresectable advanced NSCLC. The second part of the trial (dose expansion) is further assessing the safety and tolerability of datopotamab deruxtecan at selected dose levels (4mg/kg, 6mg/kg and 8mg/kg) in patients with NSCLC, and in patients with unresectable/advanced or metastatic TNBC.

Safety endpoints include dose-limiting toxicities and serious adverse events. Efficacy endpoints include ORR, DoR, DCR, time to response, PFS and OS. Pharmacokinetic, biomarker and immunogenicity endpoints also are being evaluated.16

About DESTINY-Lung01
DESTINY-Lung01 is a global, Phase II, open-label, multicentre, two-cohort trial evaluating the safety and efficacy of Enhertu in 170 patients with HER2m (6.4mg/kg) or HER2- overexpressing (defined as IHC3+ or IHC2+; 6.4mg/kg and 5.4mg/kg) unresectable and metastatic non-squamous NSCLC. Patients had progressed after one or more systemic therapies including chemotherapy, molecular targeted therapy or immunotherapy. The primary endpoint is ORR by independent central review. Key secondary endpoints include DoR, DCR, PFS and OS.17

Daiichi Sankyo Collaboration
Enhertu (trastuzumab deruxtecan; fam-trastuzumab deruxtecan-nxki in the US only) and datopotamab deruxtecan (Dato-DXd; DS-1062) are two lead DXd ADCs in the oncology pipeline of Daiichi Sankyo, and the most advanced programmes in AstraZeneca’s ADC scientific platform.

Each ADC is engineered using Daiichi Sankyo’s proprietary and portable DXd ADC technology to target and deliver chemotherapy inside cancer cells that express a specific cell surface antigen. Both Enhertu (a HER2-directed ADC) and datopotamab deruxtecan (a TROP2-directed ADC) consist of a monoclonal antibody attached to a topoisomerase I inhibitor payload, an exatecan derivative, via a stable tetrapeptide-based cleavable linker.

AstraZeneca and Daiichi Sankyo entered into a global collaboration to jointly develop and commercialise Enhertu in March 2019, and datopotamab deruxtecan in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is responsible for manufacturing and supply of Enhertu and datopotamab deruxtecan.

AstraZeneca in lung cancer
AstraZeneca has a comprehensive portfolio of approved and potential new medicines in late-stage development for the treatment of different forms of lung cancer spanning different histologies, several stages of disease, lines of therapy and modes of action.

AstraZeneca aims to address the unmet needs of patients with EGFRm tumours as a genetic driver of disease, which occur in 10-15% of NSCLC patients in the US and EU and 30-40% of NSCLC patients in Asia, with the approved medicines Iressa (gefitinib) and Tagrisso and its ongoing LAURA, NeoADAURA and FLAURA2 Phase III trials. AstraZeneca is committed to addressing tumour mechanisms of resistance through the ongoing SAVANNAH and ORCHARD Phase II trials, which test Tagrisso in combination with savolitinib, a selective inhibitor of c-MET receptor tyrosine kinase, along with other potential new medicines.

The Company is also evaluating the potential of ADCs to improve patient outcomes in NSCLC. Enhertu is in development for metastatic non-squamous HER2-overexpressing or HER2m NSCLC including trials in combination with other anticancer treatments. In addition, datopotamab deruxtecan is in early development for advanced NSCLC where TROP2 is overexpressed in the majority of tumours.

An extensive Immuno-Oncology development programme focuses on lung cancer patients without a targetable genetic mutation, which represent up to three quarters of all patients with lung cancer. Imfinzi, an anti-PDL1 antibody, is in development for patients with advanced disease (POSEIDON and PEARL Phase III trials) and for patients in earlier stages of disease, including potentially curative settings (MERMAID-1, MERMAID-2, AEGEAN, ADJUVANT BR.31, PACIFIC-2, PACIFIC-4, PACIFIC-5, and ADRIATIC Phase III trials) both as monotherapy and in combination with tremelimumab and/or chemotherapy. Imfinzi is also in development in the NeoCOAST, COAST and HUDSON Phase II trials in combination with potential new medicines from the early-stage pipeline, including Enhertu.

AstraZeneca in oncology
AstraZeneca has a deep-rooted heritage in oncology and offers a quickly growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With seven new medicines launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers.

By harnessing the power of six scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response, Antibody Drug Conjugates, Epigenetics, and Cell Therapies – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and, one day, eliminate cancer as a cause of death.

On January 29, 2021 Adamis Pharmaceuticals Corporation (Nasdaq: ADMP), a specialty biopharmaceutical company focused on developing and commercializing products in various therapeutic areas, including allergy, opioid overdose, respiratory and inflammatory disease, reported the pricing of its previously announced underwritten public offering of 40,540,540 shares of its common stock at a public offering price of $1.11 per share, resulting in gross proceeds of approximately $45,000,000, before deducting underwriting discounts and commissions and other estimated offering expenses payable by the company (Press release, Adamis Pharmaceuticals, JAN 29, 2021, View Source [SID1234574423]). All shares of common stock to be sold in the public offering are being sold by Adamis.

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The offering is expected to close on February 2, 2021, subject to the satisfaction of customary closing conditions. The company has also granted the underwriters a 30-day option to purchase up to 6,081,081 additional shares of its common stock to cover over-allotments, if any.

Raymond James & Associates, Inc. is acting as the sole book-running manager for the offering.

The company intends to use the net proceeds from this offering for general corporate purposes, which may include, without limitation, expenditures relating to research, development and clinical trials relating to its products and product candidates, capital expenditures, manufacturing, hiring additional personnel, acquisitions of new technologies or products, the payment, repayment, refinancing, redemption or repurchase of existing or future indebtedness, obligations or capital stock, and working capital.

The securities described above are being offered by the company pursuant to a "shelf" registration statement on Form S-3 (File No. 333-226100) previously filed with and declared effective by the Securities and Exchange Commission (the "SEC") on July 18, 2018. A preliminary prospectus supplement and the related prospectus have been filed with the SEC and are available on the SEC’s website at www.sec.gov. A final prospectus supplement and an accompanying prospectus related to the offering will be filed with the SEC and will be available on the SEC’s website located at www.sec.gov. When available, copies of the final prospectus supplement and the accompanying prospectus relating to this offering may be obtained by contacting Raymond James & Associates, Inc., Attention: Equity Syndicate, 880 Carillon Parkway, St. Petersburg, Florida, or by telephone at (800) 248-8863, or e-mail at [email protected].

Before investing in the offering, you should read in their entirety the prospectus supplement and the accompanying prospectus and the other documents that the company has filed with the SEC that are incorporated by reference in the prospectus supplement and the accompanying prospectus, which provide more information about the company and the offering.

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