In addition, KEYTRUDA plus LENVIMA reduced the risk of disease progression or death by 53% (HR=0.47 [95% CI: 0.38-0.57]), with a median progression-free survival (PFS) of 23.9 months ( 95% CI: 20.8). -27.7) versus 9.2 months (95% CI: 6.0-11.0) for sunitinib; The objective response rate (ORR) was 71.3% (95% CI: 66.6-76.0) and the complete response rate (CR) was 18.3% for KEYTRUDA plus LENVIMA compared to an ORR of 36.7% ( 95% CI: 31.7-41.7). with a CR of 4.8% for sunitinib.
There were no new safety signals and the safety profile in the final OS analysis was consistent with the primary analysis. Grade ≥3 treatment-emergent adverse reactions (TRAEs) occurred in 74.1% of patients receiving KEYTRUDA plus LENVIMA compared to 60.3% of patients receiving sunitinib. The six most common all-grade TRAEs in patients in the KEYTRUDA plus LENVIMA arm were diarrhea (56.0%), hypertension (54.3%), hypothyroidism (44.9%), decreased appetite (35.5%) , fatigue (34.1%) and stomatitis (32.7%). In the sunitinib arm, the six most common TRAEs of any grade were diarrhea (45.3%), hypertension (40.3%), stomatitis (37.4%), palmar-plantar erythrodysesthesia (36.2%), fatigue (32.9%) and nausea. (28.2%). %).
"KEYTRUDA plus LENVIMA continues to demonstrate sustained clinical benefit as a first-line treatment for patients with advanced renal cell carcinoma, as evidenced by the clinically significant improvement in overall survival at four years of follow-up," said Dr. Thomas Hutson, D.O., Pharm.D., FACP, Director of the Urological Oncology Program and Co-Chair of the Urological Cancer Research and Treatment Center, Texas Oncology at Baylor Sammons Cancer Center. “In addition, these data also showed a clinically meaningful improvement in mean PFS and ORR over sunitinib. These results emphasize the important role of KEYTRUDA plus LENVIMA as standard first-line treatment for patients with advanced renal cell carcinoma.”
"Long-term follow-up data from the CLEAR/KEYNOTE-581 trial demonstrate that response to first-line treatment with KEYTRUDA plus LENVIMA was durable in many of these patients," said Dr. Gregory Lubiniecki, vice president of global clinical development at Merck Research Laboratories. "Through our joint clinical development program with Eisai, we are continuing our research to evaluate KEYTRUDA plus LENVIMA in other challenging cancers as we seek to help even more patients."
“In the final pre-specified analysis, KEYTRUDA plus LENVIMA continued to demonstrate clinically relevant performance in terms of PFS, ORR and OS, providing patients and their physicians with new information on how to treat people with advanced renal cell carcinoma,” said Corina Dutcus, MD, Senior Vice President, Clinical Development, Oncology, Eisai Inc. "These results are a testament to our unwavering commitment to people with advanced cancer, and we are grateful for the support of patients, families and caregivers for participating in these studies."
KEYTRUDA plus LENVIMA is approved in the US, EU, Japan and other countries for the treatment of advanced RCC and certain advanced endometrial cancers. Lenvatinib is marketed in the EU as KISPLYX for advanced RCC. Merck and Eisai are investigating the combination of KEYTRUDA and LENVIMA under LEAP (NASTYnwatynibAzdPEmbrolizumab) in a variety of cancers, including but not limited to endometrial cancer, hepatocellular carcinoma, non-small cell lung cancer, RCC, head and neck cancer, gastric cancer and esophageal cancer in multiple clinical trials.
Study design and additional data from CLEAR/KEYNOTE-581
The CLEAR/KEYNOTE-581 trial is a phase 3 multicenter, randomized, open-label study (ClinicalTrials.gov,NCT02811861) to evaluate LENVIMA in combination with KEYTRUDA or in combination with everolimus versus sunitinib as first-line treatment in patients with advanced renal cell carcinoma. The main efficacy results were PFS as assessed by independent radiological review (IRC) according to the solid tumor response assessment criteria version 1.1 (RECIST v1.1) and OS. Other efficacy results included IRC-validated ORR, health-related quality of life (HRQoL), and safety.
1,069 patients were enrolled and randomized 1:1:1 to KEYTRUDA (200 mg IV every 3 weeks for up to 24 months) plus LENVIMA (20 mg orally once daily) or LENVIMA (18 mg orally once daily) plus everolimus (5 mg orally once daily) daily) or sunitinib (50 mg orally once daily for four weeks followed by two weeks off). KEYTRUDA was administered for up to 35 cycles (approximately two years) or until protocol discontinuation criteria were met. After completion of the two-year combination therapy, LENVIMA could be administered as monotherapy until protocol-defined treatment discontinuation criteria were met.
This final, pre-specified OS analysis was event-driven and driven by approximately 304 target OS events across the two treatment arms (149 events in the 355 patients who received KEYTRUDA plus LENVIMA versus 159 events in the 357 patients who received sunitinib).
The median duration of response was 26.7 months (95% CI: 22.8-34.6) for KEYTRUDA plus LENVIMA compared to 14.7 months (95% CI: 9.4-18.2) for sunitinib.
Efficacy results were consistent across all Memorial Sloan Kettering Cancer Center (MSKCC) predefined risk groups (Favourable, Moderate, and Low) and International Metastatic RCC Database Consortium (IMDC) risk groups. In Memorial Sloan Kettering Cancer Center (MSKCC) predefined risk groups (favourable, moderate, and poor), OS and PFS were improved with KEYTRUDA plus LENVIMA compared to sunitinib. The interpretation of OS in patients at favorable risk is limited due to the small number of events.
Fewer patients treated with KEYTRUDA plus LENVIMA received further cancer treatments (181 patients out of 355, 51.0%) compared to patients treated with sunitinib (246 patients out of 357, 68.9%), i.e. 56 patients (15, 8%). and 195 patients (54.6%) who subsequently received PD-1/PD-L1 checkpoint inhibitors, respectively. In an exploratory analysis using a 2-step model, KEYTRUDA plus LENVIMA reduced the risk of death by 45% compared to sunitinib when additional anticancer agents were added (HR = 0.55 [95% CI: 0.44-0.69] ).
Over Niercelcarcinoom (RCC)
It is estimated that in 2020, more than 431,000 new cases of kidney cancer were diagnosed worldwide and more than 179,000 people died from the disease [GLOBOCAN, 2020]. Renal cell carcinoma is by far the most common form of kidney cancer; About nine out of ten kidney cancer diagnoses are RCC [AD, 2020]. Renal cell carcinomas are about twice as common in men as in women [ACS, 2023]. Most cases of kidney cancer are discovered incidentally during imaging studies for other abdominal conditions [American Family Physician, 2019]. About 30% of patients with renal cell carcinoma already have metastases at diagnosis.American Family Physician, 2019]. Survival is highly dependent on disease stage at diagnosis, with a 5-year survival rate of 15% in patients with metastatic disease.ACS, 2023].
By Injection KEYTRUDA (pembrolizumab), 100 mg
KEYTRUDA is a programmed death receptor 1 (PD-1) therapy that increases the ability of the body's immune system to recognize and fight cancer cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands PD-L1 and PD-L2, activating T cells that can target cancer cells as well as healthy cells.
Merck has the industry's largest clinical research program in immuno-oncology. There are currently more than 1,600 studies evaluating KEYTRUDA in various cancer types and treatment contexts. The KEYTRUDA clinical program aims to understand the role of KEYTRUDA in various cancers and to identify factors that can predict the likelihood that a patient will benefit from KEYTRUDA treatment, including testing of various biomarkers.
Selected Indications of KEYTRUDA (pembrolizumab) in the US
niercelcarcinoom
KEYTRUDA in combination with axitinib is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC).
KEYTRUDA in combination with LENVIMA is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma.
KEYTRUDA is indicated for the adjuvant treatment of renal cell carcinoma patients at moderate to high risk of recurrence after nephrectomy or after nephrectomy and resection of metastatic lesions.
Additional selected KEYTRUDA indications in the United States can be found under selected Important Safety Information.
Selected important safety information for KEYTRUDA
Serious and fatal immune-related side effects
KEYTRUDA is a monoclonal antibody belonging to a class of drugs that bind to PD-1 or PD-L1, blocking the PD-1/PD-L1 signaling pathway, reversing the suppression of the immune response and possibly the peripheral cause of tolerance is interrupted by immune-mediated side effects. Immune-related side effects, which can be serious or fatal, can occur in any organ system or tissue, affect more than one body system at a time, and occur at any time after treatment is started or stopped. Important immune-related side effects listed here may not include all possible serious and fatal immune-related side effects.
Patients should be carefully monitored for signs and symptoms that may be clinical signs of underlying immune-related adverse reactions. Early detection and treatment are essential to ensure the safe use of anti-PD-1/PD-L1 therapy. Assess liver enzymes, creatinine and thyroid function at the start of treatment and periodically during treatment. In TNBC patients treated with KEYTRUDA neoadjuvant, baseline blood cortisol levels should be monitored prior to surgery and as clinically appropriate. If immune-related side effects are suspected, investigations should be initiated to rule out alternative causes, including infection. Start medical treatment immediately, possibly including specialist advice.
Depending on the severity of the immune-related adverse reaction, treatment with KEYTRUDA should be interrupted or permanently discontinued. If treatment with KEYTRUDA has to be interrupted or discontinued, systemic corticosteroid therapy (prednisone 1 to 2 mg/kg/day or equivalent) should generally be initiated until recovery to Grade 1 or less. If improvement is Grade 1 or less, begin tapering corticosteroids and continue tapering for at least 1 month. Other systemic immunosuppressants should be considered for patients whose side effects are not controlled with corticosteroid therapy.
Immune-mediated pneumonia
KEYTRUDA can cause immune-mediated pneumonia. The incidence is higher in patients who have previously received radiotherapy to the chest. Immune-related pneumonitis occurred in 3.4% (94/2,799) of KEYTRUDA-treated patients, including fatal reactions (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%). Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and discontinuation in 0.9% (26). All patients who were refused treatment were restarted on KEYTRUDA after symptoms improved; Of these, 23% relapsed. Pneumonia resolved in 59% of the 94 patients.
Pneumonia occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA monotherapy, with Grade 3-4 occurring in 2.3% of patients. Patients received high doses of corticosteroids for an average of 10 days (range: 2 days to 53 months). The incidence of pneumonia was similar in patients with and without prior chest irradiation. Pneumonia led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of patients who developed pneumonia, 42% discontinued KEYTRUDA, 68% discontinued KEYTRUDA, and 77% improved.
Pneumonia occurred in 7% (41/580) of adult patients with resectable NSCLC who received KEYTRUDA monotherapy in the adjuvant setting of NSCLC, including fatal pneumonia (0.2%), Grade 4 (0.3%), and Grade 3 (1%). side effects. Patients received high doses of corticosteroids for an average of 10 days (range: 1 day to 2.3 months). Pneumonitis led to discontinuation of KEYTRUDA in 26 (4.5%) patients. Of patients who developed pneumonia, 54% discontinued KEYTRUDA, 63% discontinued KEYTRUDA, and 71% improved.
Colitis with decreased immunity
KEYTRUDA can cause immune-mediated colitis, which may include diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-resistant immune-mediated colitis. In corticosteroid-resistant colitis, repeated testing for infection should be considered to rule out alternative causes. Immune-related colitis occurred in 1.7% (48/2799) of patients treated with 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 immunosuppressive therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and discontinuation in 0.5% (13). All patients who were refused treatment were restarted on KEYTRUDA after symptoms improved; Of these, 23% relapsed. Colitis resolved in 85% of the 48 patients.
Hepatotoxicity and immune-mediated hepatitis
KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients treated with 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 immunosuppressive therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and discontinuation in 0.3% (9). All patients who were refused treatment were restarted on KEYTRUDA after symptoms improved; None of them had a relapse. Hepatitis resolved in 79% of the 19 patients.
KEYTRUDA met axitinib
KEYTRUDA in combination with axitinib may cause hepatotoxicity. Liver enzymes should be checked before starting treatment and regularly during treatment. Consider more frequent monitoring compared to monotherapy. In case of elevated liver enzymes, treatment with KEYTRUDA and axitinib should be discontinued and corticosteroids considered if necessary. Grade 3 and 4 elevations in alanine aminotransferase (ALT) (20%) and aspartate aminotransferase (AST) (13%) were more frequently observed with KEYTRUDA in combination with axitinib than with KEYTRUDA alone. Fifty-nine percent of patients with elevated ALT received systemic corticosteroids. In patients with ALT ≥ 3 times the upper limit of normal (ULN) (Grade 2-4, n=116), ALT decreased to Grade 0-1 in 94%. Of the 92 patients who were re-administered KEYTRUDA (n=3) or axitinib (n=34) alone or both (n=55), one patient received axitinib and 24 patients received both. Subsequently, all patients with ALT recurrence ≥3 ULN recovered from the event.
Immunological endocrinopathies
adrenal insufficiency
KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or greater, treat symptomatically, including hormone replacement therapy, as clinically indicated. Suspend KEYTRUDA based on severity. Adrenal insufficiency, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%). Systemic corticosteroids were required in 77% (17/22) of patients; Of these, most continued to receive systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUD in <0.1% (1) and discontinuation in 0.3% (8). All patients who were refused treatment were restarted on KEYTRUDA after symptoms improved.
Inflammation of the pituitary gland
KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis may present with acute mass effect symptoms such as headache, photophobia or visual field disturbances. Hypophysitis can cause hypopituitarism. Begin hormone replacement as directed. Depending on the severity, KEYTRUDA should be discontinued or discontinued altogether. Hypophysitis occurred in 0.6% (17/2799) of KEYTRUDA-treated patients, 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, most continued to receive systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and discontinuation in 0.3% (7). All patients who were refused treatment were restarted on KEYTRUDA after symptoms improved.
thyroid disorders
KEYTRUDA can cause immune-mediated thyroid disease. Thyroiditis can occur with or without endocrinopathy. Hyperthyroidism can be followed by hypothyroidism. Initiate hormone replacement therapy for hypothyroidism or initiate pharmacotherapy for hyperthyroidism as clinically indicated. Depending on the severity, KEYTRUDA should be discontinued or discontinued altogether. Thyroid inflammation, including Grade 2 (0.3%), occurred in 0.6% (16/2799) of patients treated with KEYTRUDA. None discontinued treatment, but KEYTRUDA was discontinued in <0.1%(1) of patients.
Hyperthyroidism occurred in 3.4% (96/2799) of patients treated with KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). This resulted in a permanent discontinuation of KEYTRUD in <0.1% (2) and discontinuation in 0.3% (7). All patients who were refused treatment were restarted on KEYTRUDA after symptoms improved. Hypothyroidism occurred in 8% (237/2799) of KEYTRUDA-treated patients, including Grade 3 (0.1%) and Grade 2 (6.2%). This resulted in permanent discontinuation of KEYTRUD in <0.1% (1) and discontinuation in 0.5% (14). All patients who were refused treatment were restarted on KEYTRUDA after symptoms improved. Most patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1,185 patients with HNSCC and occurred in 16% of patients receiving KEYTRUDA alone or in combination with platinum and FU, including Grade 3 hypothyroidism (0.3%). The incidence of new or worsening hypothyroidism was higher in the 389 adult patients with cHL (17%) who received KEYTRUDA monotherapy, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism. The incidence of new or worsening hyperthyroidism was higher in the 580 patients who underwent NSCLC resection and occurred in 11% of patients who received KEYTRUDA alone as adjuvant therapy, including Grade 3 hyperthyroidism (0.2%). The incidence of new or worsening hypothyroidism was higher in 580 patients with resection of NSCLC and occurred in 22% of patients receiving KEYTRUDA monotherapy as adjunctive therapy (KEYNOTE-091), including Grade 3 hypothyroidism (0.3%).
Type 1 diabetes (DM), possibly associated with diabetic ketoacidosis
Patients should be monitored for hyperglycaemia or other signs and symptoms of diabetes. Initiate insulin therapy as clinically indicated. Suspend KEYTRUDA based on severity. Type 1 diabetes occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. This resulted in permanent treatment discontinuation in <0.1%(1) of patients and KEYTRUDA discontinuation in <0.1%(1). All patients who were refused treatment were restarted on KEYTRUDA after symptoms improved.
Immune-mediated nephritis with renal dysfunction
KEYTRUDA can cause immune-mediated inflammation of the kidneys. Immune-related nephritis occurred in 0.3% (9/2799) of patients treated with KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1% ) responses). Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and discontinuation in 0.1% (3). All patients who were refused treatment were restarted on KEYTRUDA after symptoms improved; None of them had a relapse. Nephritis resolved in 56% of the 9 patients.
Immune-related dermatological side effects
KEYTRUDA may cause a skin rash or immune-mediated dermatitis. Anti-PD-1/PD-L1 treatment has been associated with exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis. Mild to moderate non-squamous rashes can be treated with topical emollients and/or topical corticosteroids. Depending on the severity, KEYTRUDA should be discontinued or discontinued altogether. Immune-related dermatologic adverse reactions occurred in 1.4% (38/2,799) of KEYTRUDA-treated patients, 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 of KEYTRUDA in 0.1% (2) and discontinuation of KEYTRUDA in 0.6% (16) of patients. All patients who were refused treatment were restarted on KEYTRUDA after symptoms improved; Of these, 6% fell back. Reactions resolved in 79% of 38 patients.
Other immune-related side effects
The following clinically significant immune-related adverse reactions have been reported with a frequency of <1% (unless stated otherwise) in patients receiving KEYTRUDA or other anti-PD-1/PD-L1 agents. Serious or fatal cases have been reported for some of these side effects.Heart/vessel:myocarditis, pericarditis, vasculitis;nervous system:Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve palsy, autoimmune neuropathy;Eyepiece:Uveitis, iritis and other toxic eye inflammation can occur. In some cases, retinal detachment can occur. Visual impairments can range in severity, up to and including blindness. If uveitis occurs in conjunction with other immune-mediated adverse reactions, Vogt-Koyanagi-Harada-like syndrome should be considered as it may require treatment with systemic steroids to reduce the risk of permanent vision loss.gastrointestinal:pancreatitis including increased amylase and lipase levels in serum, gastritis, duodenitis;Musculoskeletal system and connective tissue:myositis/polymyositis, rhabdomyolysis (and related sequelae including renal failure), arthritis (1.5%), polymyalgia rheumatica;Documentary:hypoparathyreoïdie;Hematological/immunological:Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, organ transplant rejection.
Infusion-related reactions
KEYTRUDA can cause serious or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which were reported in 0.2% of 2,799 patients receiving KEYTRUDA. Watch for signs and symptoms of infusion-related reactions. For Grade 1 or 2 reactions, stop or slow the rate of infusion. For Grade 3 or 4 reactions, stop the infusion and permanently discontinue KEYTRUDA.
Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)
Fatal and other serious complications can occur in patients receiving allogeneic HSCT before or after anti-PD-1/PD-L1 treatment. Transplant complications include hyperacute graft versus host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease with reduced intensity after conditioning, and steroid-requiring febrile syndrome (with no identified infectious cause). These complications can occur despite the use of interventional therapy between anti-PD-1/PD-L1 treatment and allogeneic HSCT. Patients should be carefully monitored for signs of these complications and prompt action taken. The benefit-risk balance of using anti-PD-1/PD-L1 therapy before or after allogeneic HSCT should be considered.
Increased mortality in patients with multiple myeloma
In multiple myeloma studies, the addition of KEYTRUDA to the thalidomide analogue and dexamethasone resulted in increased mortality. Treatment of these patients with anti-PD-1/PD-L1 therapy in this combination is not recommended outside of controlled studies.
Embryo-Fetal Toxicity
Due to its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Make women aware of this potential danger. Women of childbearing potential should have their pregnancy status assessed before starting treatment with KEYTRUDA and advised to use effective contraception during treatment and for 4 months after the last dose.
side effects
In KEYNOTE-006, KEYTRUDA was discontinued due to adverse events in 9% of 555 patients with advanced melanoma; Adverse reactions that led to permanent treatment discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reactions (0.4%), polyneuropathy (0.4%), 0.4%) and heart failure (0.4%). The most common adverse reactions (≥20%) associated with KEYTRUDA are fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).
In study KEYNOTE-054, when KEYTRUDA was administered as monotherapy to patients with stage III melanoma, KEYTRUDA treatment was permanently discontinued in 14% of 509 patients due to adverse reactions; The most common (≥1%) were pneumonia (1.4%), colitis (1.2%) and diarrhea (1%). Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. The most common adverse reaction (≥20%) associated with KEYTRUDA was diarrhea (28%). In the KEYNOTE-716 trial, when KEYTRUDA was administered as monotherapy to patients with stage IIB or IIC melanoma, the patients with stage IIB or IIC melanoma experienced adverse reactions similar to those observed in the 1,011 patients with stage III melanoma in the KEYNOTE-054 trial. study.
In the KEYNOTE-189 trial, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients receiving concomitant pemetrexed and platinum chemotherapy in patients with metastatic non-squamous NSCLC. The most common adverse reactions leading to permanent discontinuation of KEYTRUDA were pneumonia (3%) and acute renal failure (2%). The most common adverse reactions (≥20%) associated with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%). vomiting (24%), cough (21%), shortness of breath (21%) and fever (20%).
In study KEYNOTE-407, KEYTRUDA was discontinued due to adverse reactions in 15% of 101 patients who received concomitant carboplatin and paclitaxel or protein-bound paclitaxel in metastatic squamous cell NSCLC. The most common serious adverse reactions reported in at least 2% of patients were febrile neutropenia, pneumonia, and urinary tract infections. Adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 except that an increased incidence of alopecia (47% vs. 36%) and peripheral neuropathy (31% vs. 25%) was observed with placebo. ) and chemotherapy arms in KEYNOTE-407.
In KEYNOTE-042, KEYTRUDA treatment was discontinued due to adverse events in 19% of 636 patients with advanced NSCLC; The most common are pneumonia (3%), death from unknown cause (1.6%) and pneumonia (1.4%). The most common serious adverse reactions reported in at least 2% of patients were pneumonia (7%), pneumonia (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; pneumonia was the most common (1.8%). The most common adverse reactions (≥20%) were decreased appetite (25%), fatigue (25%), dyspnoea (23%) and nausea (20%).
Adverse reactions observed in KEYNOTE-091 were generally similar to those observed in other NSCLC patients receiving KEYTRUDA alone, with the exception of hypothyroidism (22%), hyperthyroidism (11%), and pneumonia (7%). There were two fatal side effects of myocarditis.
In KEYNOTE-048, KEYTRUDA monotherapy was discontinued due to adverse reactions 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 study KEYNOTE-048, KEYTRUDA was discontinued due to adverse reactions in 16% of 276 patients with HNSCC when KEYTRUDA was administered in combination with platinum (cisplatin or carboplatin) and FU chemotherapy. The most common adverse reactions leading to permanent discontinuation of KEYTRUDA were pneumonia (2.5%), pneumonia (1.8%), and septic shock (1.4%). The most common adverse reactions (≥20%) were nausea (51%), fatigue (49%), constipation (37%), vomiting (32%), mucositis (31%), diarrhea (29%), decreased appetite (29 %), stomatitis (26%) and cough (22%).
In KEYNOTE-012, KEYTRUDA was discontinued in 17% of 192 HNSCC patients due to adverse events. Serious side effects occurred in 45% of patients. The most common serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnoea, confusional state, vomiting, pleural effusion and respiratory failure. The most common adverse reactions (≥20%) were fatigue, decreased appetite and dyspnoea. Adverse reactions observed in HNSCC patients were generally similar to those seen in melanoma or NSCLC patients receiving KEYTRUDA alone, with the exception of an increased incidence of facial edema and new or worsening hypothyroidism.
In KEYNOTE-204, KEYTRUDA treatment was discontinued due to adverse events in 14% of 148 patients with cHL. Serious adverse events occurred in 30% of patients receiving KEYTRUDA; These ≥ 1% were pneumonia, pneumonia, fever, myocarditis, acute kidney injury, febrile neutropenia, and sepsis. Three patients died from causes other than disease progression: two from complications following allogeneic HSCT and one from an 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 study KEYNOTE-087, KEYTRUDA was discontinued in 5% of 210 cHL patients due to adverse events. Serious adverse events occurred in 16% of patients; These ≥ 1% were pneumonia, pneumonia, fever, dyspnoea, GVHD and herpes zoster. Two patients died from causes other than disease progression: one from GVHD after subsequent allogeneic HSCT and one 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 treatment was discontinued due to adverse events in 8% of 53 patients with PMBCL. Serious adverse events 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 starting treatment. The most common adverse reactions (≥20%) were musculoskeletal pain (30%), upper respiratory tract infection and fever (28% each), cough (26%), fatigue (23%) and dyspnoea (21%).
In KEYNOTE-869, when KEYTRUDA was administered in combination with enfortumab vedotin to patients with locally advanced or muUC who were ineligible for cisplatin-based chemotherapy (n=121), fatal adverse events occurred in 5% of patients, including sepsis (1.6%), bullous dermatitis (0.8%), myasthenia gravis (0.8%), and pneumonia (0.8%). Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA in combination with enfortumab vedotin; Serious adverse reactions in ≥2% of patients were acute kidney injury (7%), urinary tract infection (7%), sepsis urosepsis (5%), hematuria (3.3%), pneumonia (3.3%), lungs (3, 3%). , sepsis (3.3%), anemia (2.5%), diarrhea (2.5%), hypotension (2.5%), myasthenia gravis (2.5%), myositis (2.5%) and urinary retention (2.5%). Permanent discontinuation of KEYTRUDA occurred in 32% of patients. The most common adverse reactions (≥2%) leading to permanent discontinuation of KEYTRUDA were pneumonia (5%), peripheral neuropathy (5%), rash (3.3%), and myasthenia gravis (2.5%). The most common adverse reactions (≥20%) reported in patients treated with KEYTRUDA in combination with enfortumab vedotin were rash (71%), peripheral neuropathy (65%), fatigue (60%), alopecia (52%), weight decreased (48%), diarrhea (45%), pruritus (40%), decreased appetite (38%), nausea (36%), dysgeusia (35%), urinary tract infection (30%), constipation (27%), edema (26%), dry eyes (25%), dizziness (23%), joint pain (23%) and dry skin (21%).
In KEYNOTE-052, KEYTRUDA treatment was discontinued due to adverse reactions in 11% of 370 locally advanced or mucous patients. Serious adverse events occurred in 42% of patients; These ≥2% were urinary tract infections, haematuria, 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 events in 8% of 266 locally advanced or mucous patients. The most common adverse reaction leading to permanent discontinuation of KEYTRUDA was pneumonia (1.9%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients; These ≥2% were urinary tract infections, pneumonia, anemia and pneumonia. The most common adverse reactions (≥20%) in patients receiving KEYTRUDA were fatigue (38%), musculoskeletal pain (32%), pruritus (23%), decreased appetite (21%), nausea (21%), and rash ( 20%). %). %). %).
In KEYNOTE-057, KEYTRUDA treatment was discontinued due to adverse events in 11% of 148 patients with high-risk NMIBC. The most common adverse reaction leading to permanent discontinuation of KEYTRUDA was pneumonia (1.4%). Serious adverse events occurred in 28% of patients; These ≥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%).
The adverse reactions observed in patients with MSI-H or dMMR-CRC were similar to those observed in patients with melanoma or NSCLC who received KEYTRUDA alone.
In KEYNOTE-158 and KEYNOTE-164, the adverse events observed in patients with MSI-H or dMMR were similar to those in patients with other solid tumors who received KEYTRUDA alone.
In the KEYNOTE-811 study, KEYTRUDA was discontinued due to adverse reactions in 6% of 217 patients with locally advanced, unresectable, or metastatic HER2+ gastric cancer or GEJ adenocarcinoma when KEYTRUDA was administered in combination with trastuzumab, a fluoropyrimidine and platinum-based chemotherapy regimen . The most common adverse reaction leading to permanent treatment discontinuation was pneumonia (1.4%). In the KEYTRUDA arm, compared to placebo, there was a ≥5% difference in the incidence of diarrhea and nausea between patients treated with KEYTRUDA and standard of care (53% vs. 44%) (49% vs. 44%).
The most common adverse reactions (reported in ≥20%) in patients receiving KEYTRUDA in combination with chemotherapy were fatigue/asthenia, nausea, constipation, diarrhoea, decreased appetite, rash, vomiting, cough, dyspnoea, pyrexia, alopecia, neuropathy peripheral, stomatitis , headache, weight loss, abdominal pain, joint pain, muscle pain and insomnia.
In the KEYNOTE-590 study, KEYTRUDA was discontinued when KEYTRUDA was co-administered with cisplatin and fluorouracil in patients with metastatic or locally advanced esophageal cancer or GEJ (tumors with an epicenter 1 to 5 centimeters above the GEJ) who are not eligible for surgical intervention. resection or definitive radiochemotherapy were due to side effects in 15% of 370 patients. The most common adverse reactions leading to permanent discontinuation of KEYTRUDA (≥1%) were pneumonia (1.6%), acute renal failure (1.1%), and pneumonia (1.1%). The most common adverse reactions (≥20%) of 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%).
The side effects seen in patients with esophageal cancer who received KEYTRUDA alone were similar to those seen in patients with melanoma or NSCLC who received KEYTRUDA alone.
In the KEYNOTE-826 study, when KEYTRUDA was administered in combination with paclitaxel and cisplatin or paclitaxel and carboplatin, with or without bevacizumab (n=307), patients with first-line persistent, recurrent, or metastatic PD-L1 tumor-independent cervical cancer found that 4.6 % of patients not receiving chemotherapy, except when used concomitantly as a radiation sensitizer, had fatal adverse events, including 3 cases of hemorrhage, 2 cases of unexplained sepsis, and 1 case of acute myocardial infarction, any cardiac disease, autoimmune disease, encephalitis, cardiac arrest, stroke, femur fracture with perioperative pulmonary embolism, intestinal perforation and pelvic infection. Serious adverse events occurred in 50% of patients receiving KEYTRUDA in combination with chemotherapy with or without bevacizumab; These ≥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 leading to permanent treatment discontinuation (≥1%) was colitis (1%).
In 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%), leucopenia (24%), hypothyroidism (22%) and decreased appetite (21%).
In 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%), and nausea (40%) . . diarrhea (36%), constipation (28%), arthralgia (27%), vomiting (26%), hypertension and urinary tract infection (24% each), and rash (22%).
In KEYNOTE-158, KEYTRUDA treatment was discontinued due to adverse reactions in 8% of 98 patients with previously treated recurrent or metastatic cervical cancer. Serious adverse events occurred in 39% of patients receiving KEYTRUDA; The most common were anemia (7%), fistulas, bleeding and infections [other than 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 in HCC patients were generally similar to those in melanoma or NSCLC patients receiving KEYTRUDA monotherapy, with the exception of an increased incidence of ascites (8% Grade 3-4) and immune-mediated hepatitis (2.9%) . . Laboratory abnormalities (Grades 3-4) that occurred more frequently included elevated AST (20%), ALT (9%), and hyperbilirubinaemia (10%).
Of the 50 MCC patients enrolled in KEYNOTE-017, the adverse events observed in MCC patients were generally similar to those seen in melanoma or NSCLC patients who received KEYTRUDA alone. Laboratory abnormalities (Grades 3-4) that occurred more frequently were elevated AST (11%) and hyperglycaemia (19%).
In the KEYNOTE-426 study, when KEYTRUDA was administered in combination with axitinib, fatal adverse events occurred in 3.3% of 429 patients. Serious adverse reactions occurred in 40% of patients, the most common (≥1%) being hepatotoxicity (7%), diarrhea (4.2%), acute kidney injury (2.3%), dehydration (1%) and pneumonia (1%). ). Permanent discontinuation due to an adverse reaction occurred in 31% of patients; KEYTRUDA alone (13%), axitinib alone (13%), and combination (8%); The most common were hepatotoxicity (13%), diarrhoea/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%), erythrodysaesthesia palmar-plantar (28%), nausea (28%), stomatitis/mucositis (27%), dysphonia (25%), rash (25%), cough (21%), and constipation (21%).
In the KEYNOTE-581 study, in which KEYTRUDA was administered in combination with LENVIMA to patients with advanced RCC (n=352), fatal adverse events occurred in 4.3% of patients. Serious adverse events occurred in 51% of patients; The most common (≥2%) were bleeding (5%), diarrhea (4%), hypertension, myocardial infarction, pneumonia and vomiting (3% each), acute kidney injury, hypoadrenocorticism, dyspnea, and pneumonia (2). % everyone).
Permanent discontinuation of KEYTRUD, LENVIM, or both due to an adverse reaction occurred in 37% of patients; 29% KEYTRUDA only, 26% LENVIMA only, and 13% both. The most common adverse reactions (≥2%) leading to permanent discontinuation of KEYTRUDA, LENVIMA, or the combination were pneumonia, myocardial infarction, hepatotoxicity, acute kidney injury, rash (each 3%), and diarrhea (2%).
The most common adverse reactions (≥20%) observed with KEYTRUDA in combination with LENVIMA were fatigue (63%), diarrhea (62%), musculoskeletal disorders (58%), hypothyroidism (57%), hypertension (56%), stomatitis (43%), decreased appetite (41%), rash (37%), nausea (36%), weight loss, dysphonia and proteinuria (30% each), palmar-plantar erythrodysaesthesia syndrome (29%), abdominal pain and bleeding adverse reactions (27 each %), vomiting (26%), constipation and hepatotoxicity (25% each), headache (23%), and acute kidney injury (21%).
In the KEYTRUDA-564 trial, when KEYTRUDA was administered as monotherapy in the adjuvant treatment of renal cell carcinoma, 20% of patients receiving KEYTRUDA experienced serious adverse reactions; Serious adverse reactions (≥1%) were acute kidney injury, adrenal insufficiency, pneumonia, colitis, and diabetic ketoacidosis (1% each). Fatal side effects occurred in 0.2%, including 1 case of pneumonia. Of 488 patients, 21% discontinued KEYTRUDA due to adverse events; The most common (≥1%) were ALT elevation (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%).
In the KEYNOTE-775 study, when KEYTRUDA was administered in combination with LENVIMA to patients with advanced endometrial cancer with pMMR or non-MSI-H (n=342), fatal adverse reactions occurred in 4.7% of patients. Serious side effects occurred in 50% of these patients; The most common (≥3%) were hypertension (4.4%) and urinary tract infections (3.2%).
In 15% of these patients, KEYTRUDA treatment was discontinued due to an adverse reaction. The most common adverse reaction leading to discontinuation of KEYTRUDA (≥1%) was ALT elevation (1.2%).
The most common adverse reactions of KEYTRUDA in combination with LENVIMA (reported in ≥20% of patients) were hypothyroidism and hypertension (67% each), fatigue (58%), diarrhea (55%), musculoskeletal disorders (53%), nausea ( 49%), decreased appetite (44%), vomiting (37%), stomatitis (35%), abdominal pain and weight loss (34% each), urinary tract infection (31%), proteinuria (29%), constipation (27%), headache (26%), haemorrhage (25%), palmar-plantar erythrodysaesthesia (23%), dysphonia (22%), and rash (20%).
The adverse reactions observed in patients with MSI-H or dMMR endometrial cancer receiving KEYTRUDA monotherapy were similar to those seen in patients with melanoma or NSCLC receiving KEYTRUDA monotherapy.
Patients with TMB-H cancer experienced side effects similar to those seen in patients with other solid tumors who received KEYTRUDA alone.
The adverse reactions observed in patients with recurrent or metastatic cSCC or locally advanced cSCC were similar to those observed in patients with melanoma or NSCLC receiving KEYTRUDA monotherapy.
In KEYNOTE-522, KEYTRUDA was administered with neoadjuvant chemotherapy (carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide), followed by surgery and continued adjuvant single KEYTRUDA therapy (n=778) in patients with newly diagnosed, previously untreated high in a early-stage risk TNBC, fatal adverse events occurred in 0.9% of patients, including 1 each for adrenal crisis, autoimmune encephalitis, hepatitis, pneumonia, pneumonia, pulmonary embolism, and sepsis associated with multiple organ dysfunction syndrome and myocardial infarction. Serious adverse events occurred in 44% of patients receiving KEYTRUDA; These ≥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%) leading to permanent treatment discontinuation were ALT elevations (2.7%), AST elevations (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%), stomatitis (34%), vomiting (31%), headache (30%), arthralgia (29%), fever (28%), cough (26%), abdominal pain (24%), decreased appetite ( 23%), insomnia (21%) and muscle pain (20%).
In study KEYNOTE-355, when KEYTRUDA and chemotherapy (paclitaxel, protein-bound paclitaxel or gemcitabine and carboplatin) were administered to patients with locally recurrent unresectable or metastatic TNBC who had not previously received chemotherapy for metastatic disease (n=596) W 2 Fatal events including Cardiac arrest (0.7%) and septic shock (0.3%) occurred in 5% of patients. Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA in combination with chemotherapy; Serious reactions occurring 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 leading to permanent treatment discontinuation (≥1%) were ALT elevations (2.2%), AST elevations (1.5%), and pneumonia (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 (each 28%), vomiting, and rash ( 26%), cough (23%), decreased appetite (21%) and headache (20%).
breastfeeding
Since serious side effects can occur in breastfed babies, we advise women not to breastfeed during treatment and for 4 months after the last dose.
Use in children
In study KEYNOTE-051, 173 children (65 children aged 6 months to less than 12 years and 108 children aged 12 to 17 years) received KEYTRUDA 2 mg/kg every 3 weeks. The mean duration of exposure was 2.1 months (range: 1 day to 25 months).
Adverse reactions occurring 10% more frequently in children than in adults were pyrexia (33%), leucopenia (31%), vomiting (29%), neutropenia (28%), headache (25%), abdominal pain (23%), thrombocytopenia (22 %), anemia (17%), decreased lymphocyte count (13%), and decreased white blood cell count (11%).
Other US Selected KEYTRUDA Indications
Melanoma
KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.
KEYTRUDA is indicated for the adjuvant treatment of adults and children (12 years and older) with stage IIB, IIC or III melanoma after 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 non-small cell lung cancer (NSCLC) without EGFR or ALK genomic abnormalities.
KEYTRUDA in combination with carboplatin and paclitaxel or protein-bound paclitaxel is indicated for the initial treatment of patients with metastatic squamous cell carcinoma (NSCLC).
KEYTRUDA is indicated as monotherapy for the first-line treatment of NSCLC patients with PD-L1 expression [Tumor Proportion Score (TPS) ≥ 1%] as determined by an FDA-cleared assay, without EGFR or ALK tumor genomic abnormalities, and is :
- Stage III where patients are not candidates for surgical resection or definitive chemoradiotherapy, or
- metastatic.
KEYTRUDA is indicated as monotherapy for the treatment of patients with metastatic NSCLC whose tumor expresses PD-L1 (TPS ≥ 1%) according to an FDA-cleared assay and whose disease progresses on or after platinum-based chemotherapy. Patients with EGFR or ALK tumor genomic abnormalities must have disease progression on an FDA-approved therapy for these abnormalities prior to treatment with KEYTRUDA.
KEYTRUDA is indicated as monotherapy for the adjuvant treatment of adult patients with stage IB (T2a ≥ 4 cm), stage II or IIIA NSCLC following resection and platinum-based chemotherapy.
Squamous cell carcinoma of the head and neck region
KEYTRUDA in combination with platinum and fluorouracil (FU) is indicated for the initial treatment of patients with metastatic or unresectable recurrent squamous cell carcinoma of the head and neck (HNSCC).
KEYTRUDA is indicated as monotherapy for the first-line treatment of patients with relapsed, metastatic, or unresectable HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-cleared assay.
KEYTRUDA monotherapy is indicated for the treatment of patients with relapsed or metastatic HNSCC with disease progression on or after platinum-based chemotherapy.
Classic 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 who have relapsed after at least 2 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 patients who have relapsed after two or more prior lines of therapy.
KEYTRUDA is not recommended for the treatment of patients with PMBCL in urgent need of cytoreductive therapy.
Urothelkarzinom
KEYTRUDA in combination with enfortumab vedotin is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma (mUC) who are unsuitable for cisplatin-based chemotherapy.
This indication has been approved through accelerated validation based on Tumor Response Rate and Durability of Response. Further acceptance of this indication may depend on verification and description of the clinical benefit in confirmatory studies.
KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC):
- who are not eligible for platinum-based chemotherapy or
- with disease progression during or after platinum-based chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-based chemotherapy.
KEYTRUDA, as monotherapy, is indicated for the treatment of patients with high-risk, Bacillus Calmette-Guerin-resistant, non-invasive myocardial (NMIBC) bladder cancer with carcinoma in situ, with or without papillary tumors, who chose to have previously inappropriate or not not undergo cystectomy for treatment.
Microsatellite instability - high or inconsistent repair deficiency in cancer
KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors with high microsatellite instability (MSI-H) or base mismatch repair deficiency (dMMR) as determined by an FDA-cleared test, following advanced treatment, when no satisfactory alternative, treatment options are available.
Microsatellite instability - high or inconsistent repair deficiency in colorectal cancer
KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic colorectal cancer (CRC) with MSI-H or dMMR, as confirmed by an FDA-cleared test.
stomach cancer
KEYTRUDA in combination with trastuzumab, fluoropyrimidine, and platinum-based chemotherapy is indicated for the initial treatment of patients with locally advanced, unresectable, or metastatic HER2-positive adenocarcinoma of the stomach or gastroesophageal junction (GEJ).
This indication has been approved through accelerated validation based on Tumor Response Rate and Durability of Response. Further acceptance of this indication may depend on verification and description of the clinical benefit in confirmatory studies.
esophageal cancer
KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic cancer of the esophagus or gastroesophageal junction (GEJ) (tumors with an epicenter 1 to 5 centimeters above the GEJ) who are candidates for surgical resection or definitive chemoradiotherapy:
- in combination with platinum-based chemotherapy and fluoropyrimidine, or
- as a single agent after one or more prior lines of systemic therapy in patients with squamous cell tumors with PD-L1-expressing histology (CPS ≥ 10) as determined by an FDA-cleared assay.
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-cleared test .
KEYTRUDA is indicated as monotherapy for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy and whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-cleared assay.
Hepatocellular carcinoma
KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) previously treated with sorafenib. This indication has been approved through accelerated validation based on Tumor Response Rate and Durability of Response. Further acceptance of this indication may depend on verification and description of the clinical benefit in confirmatory studies.
Merkelcelcarcinoom
KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication has been approved through accelerated validation based on Tumor Response Rate and Durability of Response. Further acceptance of this indication may depend on verification and description of the clinical benefit in confirmatory studies.
Endometriale plank
KEYTRUDA, in combination with LENVIMA, is indicated for the treatment of patients with advanced endometrial cancer that is capable of base mismatch repair (pMMR) or is not MSI-H as measured by an FDA-cleared assay and whose disease has progressed after previous systemic treatment. therapy and who are not eligible for surgery or radiotherapy.
KEYTRUDA is indicated as monotherapy for the treatment of patients with advanced endometrial cancer (MSI-H or dMMR based on an FDA-approved test) who have progressed after prior systemic therapy in any setting and who have not qualify for treatment. for surgery or radiotherapy.
Cancer mutation burden - high cancer
KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors with a high mutational burden (TMB-H) [≥10 mutations/megabase] as determined by an FDA-cleared assay who have progressed after prior treatment and who have no satisfactory alternative treatment options. This indication has been approved through accelerated validation based on Tumor Response Rate and Durability of Response. Further acceptance of this indication may depend on verification and description of the clinical benefit in confirmatory studies. The safety and efficacy of KEYTRUDA in pediatric patients with central nervous system TMB-H cancer have not been established.
Squamous cell carcinoma of the skin
KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the skin (cSCC) or locally advanced cSCC who cannot be treated with surgery or radiotherapy.
Triple negative breast cancer
KEYTRUDA is indicated for the treatment of patients with high-risk, triple-negative early stage breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment and will continue as monotherapy 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-cleared assay.
See prescribing information for KEYTRUDA (pembrolizumab) below http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.p... and Medication Guide for KEYTRUDA op http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_mg.p....
About LENVIMA (lenvatinib); available in 10mg and 4mg capsules
Discovered and developed by Eisai, LENVIMA is an orally available multi-receptor tyrosine kinase inhibitor that inhibits the kinase activity of the vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). LENVIMA inhibits other kinases involved in the pathogenesis of angiogenesis, tumor growth and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1-4, platelet-derived growth factor receptor alpha (PDGFRα), and KIT and RET. In syngeneic mouse tumor models, LENVIMA reduced the number of tumor-associated macrophages, increased activated cytotoxic T cells and, when combined with an anti-PD-1 monoclonal antibody, showed greater antitumor activity compared to either treatment alone.
LENVIMA (lenvatinib) indications in the US
- For the treatment of patients with locally recurrent or metastatic, progressive, radioiodine-resistant differentiated thyroid cancer (DTC)
- In combination with pembrolizumab for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC)
- In combination with everolimus for the treatment of adult patients with advanced renal cell carcinoma (RCC) following prior anti-angiogenic therapy
- For initial treatment of patients with inoperable hepatocellular carcinoma (HCC)
- In combination with pembrolizumab for the treatment of patients with advanced endometrial cancer (EC) who have remediable linkage errors (pMMR) or are not microsatellite unstable (MSI-H) by an FDA-cleared assay and whose disease has progressed after previous systemic therapy in any setting, not candidates for surgery or radiotherapy.
Selected safety information for LENVIMA
Warnings and Measures
Hypertension.In DTC (differentiated thyroid cancer), hypertension occurred in 73% of LENVIMA-treated patients (44% Grade 3-4). In RCC (renal cell carcinoma), hypertension occurred in 42% of patients receiving LENVIMA + everolimus (13% Grade 3). Twenty-nine percent of patients had systolic blood pressure ≥ 160 mmHg and 21% had diastolic blood pressure ≥ 100 mmHg. In HCC (hepatocellular carcinoma), hypertension occurred in 45% of LENVIMA-treated patients (24% Grade 3). Grade 4 hypertension has not been reported in HCC.
Serious complications of poorly controlled hypertension have been reported. Check your blood pressure before you start. Check your blood pressure after one week, then every two weeks for the first two months and then at least monthly during treatment. Once the high blood pressure is controlled, treatment should be discontinued and restarted at a reduced dose or permanently discontinued, depending on severity.
dysfunction of the heart.LENVIMA can cause serious and fatal heart problems. In clinical studies of 799 patients with DTC, RCC, and HCC, 3% of patients treated with LENVIMA had Grade 3 or greater cardiac dysfunction. Watch for clinical signs or signs of cardiac dysfunction. Discontinue treatment and resume treatment at a reduced dose upon recovery, or discontinue treatment permanently, depending on severity.
Arterial thromboembolic events.Of patients receiving LENVIMA or LENVIMA + everolimus, arterial thromboembolic events of any grade occurred in 2% of patients in RCC and HCC and 5% of patients in DTC. Grade 3-5 arterial thromboembolic events ranged from 2% to 3% in all clinical trials.
Among patients receiving LENVIMA with pembrolizumab, arterial thrombotic events of any grade, including myocardial infarction (3.4%) and cerebrovascular accident (2.3%), occurred in 5% of patients in the CLEAR study.
Permanently discontinue use after arterial thrombosis. The safety of re-treatment after arterial thromboembolism has not been established and LENVIMA has not been studied in patients who had an arterial thromboembolism within the previous 6 months.
hepatotoxicity.In clinical trials of 1,327 patients treated with LENVIMA with malignancies other than HCC, 1.4% of patients experienced serious hepatic adverse reactions. Fatal events, including liver failure, acute hepatitis and hepatorenal syndrome, occurred in 0.5% of patients. In HCC, hepatic encephalopathy occurred in 8% of LENVIMA-treated patients (5% Grade 3-5). Grade 3-5 hepatic failure occurred in 3% of LENVIMA-treated patients; 2% of patients discontinued LENVIMA due to hepatic encephalopathy and 1% due to hepatic failure.
Liver function should be monitored prior to treatment, then every 2 weeks for the first 2 months and then at least monthly during treatment. Patients with HCC should be carefully monitored for signs of hepatic impairment, including hepatic encephalopathy. Discontinue treatment and resume treatment at a reduced dose upon recovery, or discontinue treatment permanently, depending on severity.
Renal failure or renal impairment.Severe or fatal renal failure or renal impairment may occur during treatment with LENVIMA. Renal dysfunction was reported in 14% and 7% of patients treated with LENVIMA with DTC and HCC, respectively. Grade 3-5 renal failure or impairment, including one fatal event in each study, occurred in 3% of DTC patients and 2% of HCC patients. In RCC, renal dysfunction or renal failure was reported in 18% of patients treated with LENVIMA + everolimus (10% Grade 3).
Treat diarrhea or dehydration/hypovolaemia immediately. Discontinue use and resume treatment at a reduced dose upon recovery, or permanently discontinue treatment in case of renal insufficiency or renal dysfunction, depending on the severity.
proteinuria.For DTC and HCC, proteinuria was reported in 34% and 26% of patients treated with LENVIMA, respectively. Grade 3 proteinuria occurred in 11% and 6% of DTC and HCC patients, respectively. In RCC, proteinuria occurred in 31% of patients receiving LENVIMA + everolimus (8% Grade 3). Proteinuria should be monitored before starting treatment and regularly during treatment. If ≥2+ proteinuria is detected with a urine dipstick test, a 24-hour urine protein test should be performed. Discontinue treatment and resume treatment at a reduced dose upon recovery, or discontinue treatment permanently, depending on severity.
Diarrhea.Of the 737 patients treated with LENVIMA with DTC and HCC, 49% developed diarrhea (6% Grade 3). In RCC, 81% of patients treated with LENVIMA + everolimus experienced diarrhea (19% Grade 3). Diarrhea was the most common reason for dose interruption/reduction, with recurrent diarrhea despite dose reduction. Treat diarrhea immediately. Discontinue treatment and resume treatment at a reduced dose upon recovery, or discontinue treatment permanently, depending on severity.
fistula formation and perforation of the digestive tract.Of the 799 patients treated with LENVIMA or LENVIMA + everolimus for DTC, RCC, and HCC, 2% developed a GI fistula or perforation. Treatment should be permanently discontinued in patients who develop a Grade 3-4 gastrointestinal perforation or Grade 3-4 fistula.
QT prolongation.In the DTC, 9% of LENVIMA-treated patients experienced QT/QTc prolongation and 2% experienced QT prolongation > 500 msec. In renal cell carcinoma, 11% of patients receiving LENVIMA + everolimus had QTc prolongation > 60 msec and 6% of patients receiving QTc > 500 msec. In HCC, 8% of LENVIMA-treated patients had QTc prolongation > 60 msec and 2% > 500 msec.
Monitor and correct electrolyte abnormalities at the start and periodically during treatment. Monitor electrocardiograms in patients with congenital long QT syndrome, heart failure, bradyarrhythmias, or patients taking drugs that prolong the QT interval, including class Ia and III antiarrhythmics. Discontinue treatment and, upon recovery, resume treatment at reduced dose, depending on severity.
hypocalcemia.In the DTC, grade 3-4 hypocalcaemia occurred in 9% of LENVIMA-treated patients. In 65% of cases, hypocalcaemia improved or resolved with calcium supplementation with or without dose interruption or reduction. In RCC, Grade 3-4 hypocalcaemia occurred in 6% of patients treated with LENVIMA + everolimus. In HCC, Grade 3 hypocalcaemia occurred in 0.8% of LENVIMA-treated patients. Check your blood calcium levels at least once a month and supplement with calcium if necessary during treatment. Discontinue use and resume dose upon recovery or discontinue permanently depending on severity.
Reversible posterior leukoencephalopathy syndrome (RPLS).In clinical trials of 1,823 patients receiving LENVIMA alone, the incidence of RPLS was 0.3%. Confirm the diagnosis of RPLS with an MRI. Depending on the severity and persistence of neurological symptoms, interrupt and resume treatment at a reduced dose or discontinue completely upon recovery.
Hemorrhagic events.Serious bleeding, including fatal, can occur with the use of LENVIMA. In the DTC, RCC and HCC clinical trials, bleeding of any grade occurred in 29% of 799 patients treated with LENVIMA alone or in combination with everolimus. The most commonly reported haemorrhagic events (all grades and occurring in at least 5% of patients) were epistaxis and haematuria. In the DTC, Grade 3-5 bleeds occurred in 2% of patients treated with LENVIMA, including 1 fatal intracranial bleed in 16 patients receiving LENVIMA who had CNS metastases at baseline. In RCC, grade 3-5 haemorrhage, including 1 fatal cerebral haemorrhage, occurred in 8% of patients treated with LENVIMA + everolimus. In HCC, grade 3-5 bleeding occurred in 5% of LENVIMA-treated patients, including 7 fatal bleeding events. Serious tumor-related bleeding events, including fatal bleeding events, have occurred in patients treated with LENVIMA in clinical trials and post-marketing experience. In post-marketing experience, serious and fatal carotid artery haemorrhages were more frequently observed in patients with anaplastic thyroid carcinoma (ATC) than in other malignancies. The safety and efficacy of LENVIMA in patients with ATC have not been established in clinical trials.
The risk of serious or fatal bleeding associated with tumor invasion or infiltration of major blood vessels (e.g. carotid artery) should be considered. Discontinue treatment and resume treatment at a reduced dose upon recovery, or discontinue treatment permanently, depending on severity.
Decreased thyroid stimulating hormone suppression/thyroid dysfunction.LENVIMA interferes with exogenous thyroid suppression. In the DTC study, 88% of patients had baseline thyroid stimulating hormone (TSH) levels ≤ 0.5 mU/L. In patients with normal baseline TSH levels, 57% of LENVIMA-treated patients had post-baseline elevations in TSH levels > 0.5 mIU/L. In RCC and HCC, Grade 1 or 2 hypothyroidism occurred in 24% of patients treated with LENVIMA + everolimus and 21% of patients treated with LENVIMA, respectively. In patients with normal or low TSH levels at baseline, post-baseline TSH elevations were observed in 70% of HCC patients treated with LENVIMA and 60% of RCC patients treated with LENVIMA + everolimus.
Thyroid function should be checked before starting treatment and at least monthly during treatment. Hypothyroidism should be treated according to standard medical practice.
Decreased wound healing.Impaired wound healing has been reported in patients receiving LENVIMA. Discontinue administration of LENVIMA for at least 1 week before elective surgery. Do not administer for at least 2 weeks after major surgery and until the wound is sufficiently healed. The safety of resuming LENVIMA treatment after resolution of wound healing complications has not been established.
Osteonecrosis of the jaw (ONJ).ONJ has been reported in patients receiving LENVIMA. Concomitant exposure to other risk factors such as bisphosphonates, denosumab, dental disease or invasive dental procedures may increase the risk of ONJ.
An oral examination should be performed prior to treatment with LENVIMA and periodically during treatment with LENVIMA. Patients should be educated on good oral hygiene practices and preventive dental care should be considered prior to and during treatment with LENVIMA.
If possible, invasive dental procedures should be avoided during treatment with LENVIMA, especially in high-risk patients. If possible, you should stop using LENVIMA at least 1 week before a scheduled dental or invasive dental procedure. In patients requiring invasive dental procedures, discontinuation of bisphosphonate therapy may reduce the risk of ONJ.
Discontinue LENVIMA if ONJ develops and resume based on clinical assessment of adequate resolution.
Embryo-Fetal Toxicity.Based on the mechanism of action and data from animal reproduction studies, LENVIMA may cause fetal harm in pregnant women. In animal reproduction studies, oral administration of lenvatinib during organogenesis at doses below the recommended clinical dose in rats and rabbits resulted in embryotoxicity, foetotoxicity and teratogenicity. Pregnant women should be advised of the potential risk to the fetus and women of childbearing potential to use effective contraception during treatment with LENVIMA and for 30 days after the last dose.
side effects
For DTC, the most common adverse reactions (≥30%) observed in LENVIMA-treated patients were hypertension (73%), fatigue (67%), diarrhea (67%), arthralgia/myalgia (62%), decreased appetite (54 %). %)). %), weight decreased (51%), nausea (47%), stomatitis (41%), headache (38%), vomiting (36%), proteinuria (34%), palmar-plantar erythrodysesthesia syndrome (32%), abdominal pain (31% ) and dysphonia (31%). The most common serious adverse reactions (≥2%) were pneumonia (4%), hypertension (3%) and dehydration (3%). Adverse events resulted in dose reductions in 68% of LENVIMA-treated patients; 18% discontinued LENVIMA. The most common adverse reactions (≥10%) leading to dose reduction were hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhea (10%); The most common adverse reactions (≥1%) leading to discontinuation of LENVIMA were hypertension (1%) and asthenia (1%).
In the RCC, the most common adverse reactions (≥20%) observed in patients treated with LENVIMA + pembrolizumab were fatigue (63%), diarrhea (62%), musculoskeletal pain (58%), hypothyroidism (57%), hypertension (56%) %). ). %), stomatitis (43%), decreased appetite (41%), rash (37%), nausea (36%), weight decreased (30%), dysphonia (30%), proteinuria (30%), hand-foot syndrome erythrodysaesthesia syndrome (29%), abdominal pain (27%), bleeding (27%), vomiting (26%), constipation (25%), hepatotoxicity (25%), headache (23%), and acute kidney injury (21%). % . The most common serious adverse reactions (≥2%) were bleeding (5%), diarrhea (4%), hypertension (3%), myocardial infarction (3%), pneumonia (3%), vomiting (3%), acute renal failure ( 2%), adrenal insufficiency (2%), shortness of breath (2%), and pneumonia (2%). Fatal adverse events, including cardiac arrest (0.9%), sepsis (0.9%), and one case each (0.3%) of arrhythmias, autoimmune hepatitis, dyspnea and hypertensive crisis, blood creatinine increased, multi-organ dysfunction syndrome, myasthenic syndrome , myocarditis, nephritis, pneumonia, ruptured aneurysm and subarachnoid hemorrhage. Serious adverse reactions occurred in 51% of patients receiving LENVIMA and pembrolizumab. Serious adverse reactions occurring in ≥2% of patients were bleeding (5%), diarrhea (4%), hypertension (3%), myocardial infarction (3%), pneumonia (3%), vomiting (3%), acute trauma (2%), adrenal insufficiency (2%), shortness of breath (2%), and pneumonia (2%). 37% of patients permanently discontinued LENVIMA, pembrolizumab, or both due to an adverse reaction; 26% LENVIMA alone, 29% pembrolizumab alone, and 13% both drugs. The most common adverse reactions (≥2%) leading to permanent discontinuation of LENVIMA, pembrolizumab, or both were pneumonia (3%), myocardial infarction (3%), hepatotoxicity (3%), acute kidney injury (3%), and rash (3%) ) and diarrhea (2%). 78% of patients receiving LENVIMA in combination with pembrolizumab experienced interruptions in LENVIMA, pembrolizumab, or both due to an adverse reaction. 73% of patients discontinued LENVIMA and 39% of patients discontinued both drugs. The dose of LENVIMA was reduced in 69% of patients. The most common adverse reactions (≥5%) leading to dose reduction or discontinuation of LENVIMA were: diarrhea (26%), fatigue (18%), hypertension (17%), proteinuria (13%), decreased appetite (12%) erythrodysaesthesia hand-plantar (11%), nausea (9%), stomatitis (9%), musculoskeletal pain (8%), rash (8%), lipase increased (7%), abdominal pain (6%), and vomiting (6% ), increased ALT (5%) and increased amylase (5%).
In the RCC, the most common adverse reactions (≥30%) observed in patients treated with LENVIMA + everolimus were diarrhea (81%), fatigue (73%), arthralgia/myalgia (55%), decreased appetite (53% ), vomiting (48%), nausea (45%), stomatitis (44%), hypertension (42%), peripheral edema (42%), cough (37%), abdominal pain (37%), dyspnoea (35%) , rash (35%), weight loss (34%), bleeding (32%) and proteinuria (31%). The most common serious adverse reactions (≥5%) were renal failure (11%), dehydration (10%), anemia (6%), thrombocytopenia (5%), diarrhea (5%), vomiting (5%). Dyspnea (5%). Adverse reactions led to dose reduction or discontinuation in 89% of patients. The most common adverse reactions (≥5%) leading to dose reduction were diarrhea (21%), fatigue (8%), thrombocytopenia (6%), vomiting (6%), nausea (5%) and proteinuria (5%). . ). Discontinuation of treatment due to an adverse reaction occurred in 29% of patients.
In HCC, the most common adverse reactions (≥20%) observed in LENVIMA-treated patients were hypertension (45%), fatigue (44%), diarrhea (39%), decreased appetite (34%), arthralgia/myalgia (31 %). ). . %), weight decreased (31%), abdominal pain (30%), palmar-plantar erythrodysaesthesia syndrome (27%), proteinuria (26%), dysphonia (24%), hemorrhage (23%), hypothyroidism (21%) %). ) and nausea (20%). The most common serious adverse reactions (≥2%) were hepatic encephalopathy (5%), hepatic failure (3%), ascites (3%) and decreased appetite (2%). Adverse reactions led to dose reduction or discontinuation in 62% of patients. The most common adverse reactions (≥ 5%) leading to dose reduction were fatigue (9%), decreased appetite (8%), diarrhea (8%), proteinuria (7%), hypertension (6%), and hand-foot discomfort. Erythrodysaesthesia syndrome (5%). Discontinuation of treatment due to an adverse reaction occurred in 20% of patients. The most common adverse reactions (≥1%) leading to discontinuation of LENVIMA were fatigue (1%), hepatic encephalopathy (2%), hyperbilirubinaemia (1%), and hepatic failure (1%).
In EC countries, the most common adverse reactions (≥20%) observed in patients treated with LENVIMA + pembrolizumab were hypothyroidism (67%), hypertension (67%), fatigue (58%), diarrhea (55%), musculoskeletal disorders (53). %), nausea (49%), decreased appetite (44%), vomiting (37%), stomatitis (35%), weight loss (34%), abdominal pain (34%), urinary tract infection (31%) %), proteinuria ( 29%), constipation (27%), headache (26%), bleeding (25%), palmar-plantar erythrodysaesthesia (23%), dysphonia (22%), and rash (20%). Fatal adverse events occurred in 4.7% of patients treated with LENVIMA and pembrolizumab, including 2 cases of pneumonia and 1 case of the following: acute kidney injury, acute myocardial infarction, colitis, decreased appetite, intestinal perforation, abdominal bleeding Gastro -Intestinal Cancer, Gastrointestinal Cancer - Disease Obstruction, Multiple Organ Dysfunction Syndrome, Myelodysplastic Syndrome, Pulmonary Embolism and Right Ventricular Dysfunction. Serious adverse reactions occurred in 50% of patients receiving LENVIMA and pembrolizumab. Serious adverse reactions with an incidence of ≥3% were hypertension (4.4%) and urinary tract infection (3.2%). 26% of patients discontinued LENVIMA treatment due to an adverse reaction. The most common adverse reactions (≥1%) leading to discontinuation of LENVIMA were hypertension (2%), asthenia (1.8%), diarrhea (1.2%), decreased appetite (1.2%), proteinuria (1 .2%), 2%). and vomiting (1.2%). %). In 67% of patients, the dose of LENVIMA was reduced due to side effects. The most common adverse reactions (≥5%) leading to dose reduction of LENVIMA were hypertension (18%), diarrhea (11%), palmar-plantar erythrodysaesthesia syndrome (9%), proteinuria (7%), and fatigue (7%). . decreased appetite (6%), asthenia (5%) and weight loss (5%). Dose interruptions of LENVIMA due to an adverse reaction occurred in 58% of these patients. The most common adverse reactions (≥2%) leading to LENVIMA treatment discontinuation were hypertension (11%), diarrhea (11%), proteinuria (6%), decreased appetite (5%), vomiting (5%), alanine aminotransferase increased (3.5%), fatigue (3.5%), nausea (3.5%), abdominal pain (2.9%), weight loss (2.6%), urinary tract infection (2.6%), increased aspartate aminotransferase (2.3%), weakness (2.3). %) and palmar-plantar erythrodysaesthesia (2%).
Use in specific populations
Since serious side effects can occur in breastfed babies, we recommend that women stop breastfeeding during treatment and for one week after the last dose. LENVIMA may impair fertility in men and women of childbearing potential.
No dose adjustment is recommended in patients with mild (CLcr 60-89 ml/min) or moderate (CLcr 30-59 ml/min) renal impairment. LENVIMA levels may be elevated in patients with DTC, RCC or EC and severe renal impairment (CLcr 15-29 ml/min). Reduce the dose in patients with DTC, RCC or EC and severe renal impairment. There is no recommended dose for patients with HCC and severe renal impairment. LENVIMA has not been studied in patients with end-stage renal disease.
No dose adjustment is recommended in HCC patients with mild hepatic impairment (Child-Pugh A). There is no recommended dose for HCC patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment. No dose adjustment is recommended in patients with DTC, RCC or EC and mild or moderate hepatic impairment. LENVIMA levels may be elevated in patients with DTC, RCC or EC and severe hepatic impairment. Reduce the dose in patients with DTC, RCC or EC and severe hepatic impairment.
See prescribing information for LENVIMA (lenvatinib) below. http://www.lenvima.com/pdfs/precribing-information.pdf.
About strategic cooperation between Merck and Eisai
In March 2018, Eisai and Merck, known outside the United States and Canada as MSD, entered into a strategic partnership through a subsidiary to jointly develop and commercialize LENVIMA globally. Under the terms of the agreement, the companies will jointly develop, manufacture and commercialize LENVIMA alone or in combination with Merck's anti-PD-1 therapy KEYTRUDA.
In addition to ongoing clinical trials evaluating the combination of KEYTRUDA and LENVIMA in several cancers, the companies have jointly initiated new clinical trials under the LEAP clinical program (LEnvatinib and pembrolizumab) and are evaluating the combination in several cancers in multiple clinical studies.
Merck targets cancer
Our goal is to turn breakthrough science into innovative cancer medicines to help people with cancer around the world. At Merck, our goal is to bring new hope to people living with cancer, and our commitment is to support access to our cancer medicines. With a focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the largest development programs in the industry spanning more than 30 cancer types. In addition, we continue to strengthen our portfolio through strategic acquisitions and prioritize the development of several promising cancer candidates that can improve the treatment of advanced cancers. For more information about our clinical oncology study, visitwww.merck.com/clinicaltrials.
Over Merck
At Merck, known as MSD outside the United States and Canada, we share a common goal: to harness the power of cutting-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity by developing essential medicines and vaccines. Our goal is to be the world's leading research-intensive biopharmaceutical company - and today we are at the forefront of research to deliver innovative healthcare solutions that accelerate the prevention and treatment of human and animal diseases. We support a diverse and inclusive global workforce and act responsibly every day to ensure a safe, sustainable and healthy future for all people and communities. For more information visitwww.merck.comand connect with usOn Twitter,Facebook,Instagram,youtubeILinkedin.
Eisai focuses on cancer
Eisai considers "oncology" as one of its key strategic areas and will continue to focus on anticancer drug discovery and development in areas such as "microenvironment", "interference with proteostasis", "cell lineage and cell differentiation". and "Inflammation, Hypoxia, Oxidative Stress and Cell Aging" from the Drug Discovery and Development Organization Deep Human Biology Learning (DHBL). Eisai aims to discover new, innovative drugs with new targets and mechanisms of action in these areas to help treat cancer.
Eisai
Eisai's business concept is to "put patients and people at the center of everyday life and enhance the benefits of healthcare". According to this concept [also known as ourpeople's health(hhk) Concept], we strive to achieve social well-being effectively by alleviating health problems and reducing health inequalities. With a global network of research and development centers, manufacturing facilities and marketing offices, we strive to develop and deliver innovative products to treat diseases with unmet medical needs, with a focus on our strategic areas of neurology and oncology.
Additionally,our continued commitment to eradicating neglected tropical diseases (NTDs),This is the goal (3.3) of the Sustainable Development Goals (SDGs) of the United Nations., is reflected in our work on various activities together with global partners.
For more information on Eisai, seewww.eisai.com(for Global Headquarters: Eisai Co., Ltd.),us.eisai.com(for US headquarters: Eisai Inc.) orwww.eisai.eu(Headquarters for Europe, Middle East, Africa, Russia, Australia and New Zealand: Eisai Europe Ltd.) and connect with us on Twitter (NAS.Iglobal) and LinkedIn (forNAS.IEMEA).
Merck & Co., Inc., Rahway, N.J., Forward-Looking Statement VS
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The Company does not undertake any obligation to publicly update any forward-looking statements, whether as a result of new information, future events or otherwise. Please refer to the Company's Annual Report on Form 10-K for the year ended December 31, 2022 and other filings by the Company with the Securities and Exchange Commission (SEC) available on the SEC's website (www.sec.gov).
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