Epirubicin Hydrochloride

KEYTRUDA plus LENVIMA is the first and only combination for the first-line treatment of advanced renal cell carcinoma (RCC) with data in both clear cell and non-clear cell RCC in the US label NUTLEY, N.J., June 27, 2024 /PRNewswire/ -- Eisai today announced a label update for LENVIMA, the orally available multiple receptor tyrosine kinase inhibitor discovered by Eisai, in the United States to include clinical efficacy data for the first-line treatment of advanced non-clear cell renal cell carcinoma (nccRCC). This update is based on data from KEYNOTE-B61, a Phase 2, single-arm trial evaluating KEYTRUDA® (pembrolizumab), Merck's anti-PD-1 therapy, plus LENVIMA for the first-line treatment of adult patients with advanced nccRCC. While the label now includes efficacy data on the non-clear cell population, the approved indication for KEYTRUDA plus LENVIMA for the first-line treatment of adult patients with advanced RCC is unchanged. Merck, known as MSD outside of the United States and Canada, received an updated label for KEYTRUDA including this data as well. KEYTRUDA plus LENVIMA is the first and only immunotherapy and tyrosine kinase inhibitor (IO plus TKI) combination with data in both clear cell and non-clear cell advanced RCC in the FDA-approved label. KEYNOTE-B61 was a Phase 2, single-arm, multicenter trial that enrolled 160 patients with previously untreated nccRCC to investigate an immune checkpoint inhibitor in combination with a TKI. The major efficacy outcome measure was objective response rate (ORR) as assessed by blinded independent central review (BICR) using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Additional efficacy outcome measures included duration of response (DOR) as assessed by BICR using RECIST 1.1. The ORR was 51% (95% CI, 43-59), with a complete response rate of 8% and a partial response rate of 42%, for patients who received KEYTRUDA plus LENVIMA. The median DOR was 19.5 months (range: 1.5+, 23.5+ (+ denotes ongoing response)). No new safety signals were observed. "Non-clear cell RCC is an aggressive, challenging-to-treat disease, and our goal is to address those unmet needs and advance care for these patients," said Dr. Takashi Owa, Chief Scientific Officer, Senior Vice President, Eisai Co., Ltd. "The addition of efficacy data from the KEYNOTE-B61 trial reinforces the important role of KEYTRUDA plus LENVIMA as a frontline treatment option for adult patients with advanced RCC regardless of histology. We are proud to realize this development through our collaboration with Merck to improve the lives of more people affected by cancer, and we are grateful to the patients and investigators whose involvement made this advancement possible." About KEYNOTE-B61 KEYNOTE-B61 is a multicenter, single-arm Phase 2 trial (ClinicalTrials.gov, NCT04704219) evaluating KEYTRUDA plus LENVIMA for the first-line treatment of adult patients with advanced/metastatic non-clear cell RCC that enrolled 160 patients. Among the 160 patients, 158 patients received LENVIMA (20 mg orally once daily) in combination with KEYTRUDA (400 mg every six weeks) for up to 24 months or until unacceptable toxicity or disease progression. LENVIMA could be continued as a single agent beyond 24 months until unacceptable toxicity or disease progression. Administration of LENVIMA with KEYTRUDA was permitted beyond RECIST-defined disease progression if the patient was considered by the investigator to be deriving clinical benefit. Among the 158 treated patients, the baseline characteristics were: median age of 60 years (range: 24 to 87 years); 71% male; 86% White, 8% Asian, and 3% Black; <1% Hispanic or Latino; 22% and 78% of patients had a baseline KPS of 70 to 80 and 90 to 100, respectively; histologic subtypes were 59% papillary, 18% chromophobe, 4% translocation, <1% medullary, 13% unclassified, and 6% other; patient distribution by IMDC risk categories was 35% favorable, 54% intermediate, and 10% poor. Common sites of metastases in patients were lymph node (65%), lung (35%), bone (30%), and liver (21%). The major efficacy outcome measure was ORR as assessed by BICR using RECIST 1.1. Additional efficacy outcome measures included DOR as assessed by BICR using RECIST 1.1. About Renal Cell Carcinoma (RCC) In the U.S., it is estimated there will be approximately 81,610 new cases of kidney cancer diagnosed and approximately 14,390 deaths from the disease in 2024. Approximately nine out of ten kidney cancer diagnoses are renal cell carcinoma, making RCC the most common type of kidney cancer. Renal cell carcinoma is about twice as common in men than in women. Most cases of RCC are discovered incidentally during imaging tests for other abdominal diseases. Renal cell carcinoma can be classified into two subgroups: clear cell RCC, which makes up about 75% of cases, and non-clear cell RCC, which makes up about 25% of cases. About LENVIMA® (lenvatinib); available as 10 mg and 4 mg capsules LENVIMA, discovered and developed by Eisai, is an orally available multiple receptor tyrosine kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). LENVIMA inhibits other kinases that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1-4, the platelet derived growth factor receptor alpha (PDGFRA), KIT, and RET. In syngeneic mouse tumor models, LENVIMA decreased tumor-associated macrophages, increased activated cytotoxic T cells, and demonstrated greater antitumor activity in combination with an anti-PD-1 monoclonal antibody compared to either treatment alone. LENVIMA® (lenvatinib) Indications in the U.S. For the treatment of adult patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory 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 one prior anti-angiogenic therapy For the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC) In combination with pembrolizumab, for the treatment of patients with advanced endometrial carcinoma (EC) that is mismatch repair proficient (pMMR), as determined by an FDA-approved test, or not microsatellite instability-high (MSI-H), who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation Selected Safety Information for LENVIMA Warnings and Precautions Hypertension. In differentiated thyroid cancer (DTC), hypertension occurred in 73% of patients on LENVIMA (44% grade 3-4). In advanced renal cell carcinoma (RCC), hypertension occurred in 42% of patients on LENVIMA + everolimus (13% grade 3). Systolic blood pressure ≥160 mmHg occurred in 29% of patients, and 21% had diastolic blood pressure ≥100 mmHg. In unresectable hepatocellular carcinoma (HCC), hypertension occurred in 45% of LENVIMA-treated patients (24% grade 3). Grade 4 hypertension was not reported in HCC. Serious complications of poorly controlled hypertension have been reported. Control blood pressure prior to initiation. Monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly thereafter during treatment. Withhold and resume at reduced dose when hypertension is controlled or permanently discontinue based on severity. Cardiac Dysfunction. Serious and fatal cardiac dysfunction can occur with LENVIMA. Across clinical trials in 799 patients with DTC, RCC, and HCC, grade 3 or higher cardiac dysfunction occurred in 3% of LENVIMA-treated patients. Monitor for clinical symptoms or signs of cardiac dysfunction. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity. Arterial Thromboembolic Events. Among patients receiving LENVIMA or LENVIMA + everolimus, arterial thromboembolic events of any severity occurred in 2% of patients in RCC and HCC and 5% in DTC. Grade 3-5 arterial thromboembolic events ranged from 2% to 3% across all clinical trials. Among patients receiving LENVIMA with KEYTRUDA, arterial thrombotic events of any severity occurred in 5% of patients in CLEAR, including myocardial infarction (3.4%) and cerebrovascular accident (2.3%). Permanently discontinue following an arterial thrombotic event. The safety of resuming after an arterial thromboembolic event has not been established, and LENVIMA has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months. Hepatotoxicity. Across clinical studies enrolling 1,327 LENVIMA-treated patients with malignancies other than HCC, serious hepatic adverse reactions occurred in 1.4% of patients. Fatal events, including hepatic 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% discontinued due to hepatic failure. Monitor liver function prior to initiation, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Monitor patients with HCC closely for signs of hepatic failure, including hepatic encephalopathy. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity. Renal Failure or Impairment. Serious including fatal renal failure or impairment can occur with LENVIMA. Renal impairment was reported in 14% and 7% of LENVIMA-treated patients in DTC and HCC, respectively. Grade 3-5 renal failure or impairment occurred in 3% of patients with DTC and 2% of patients with HCC, including 1 fatal event in each study. In RCC, renal impairment or renal failure was reported in 18% of LENVIMA + everolimus–treated patients (10% grade 3). Initiate prompt management of diarrhea or dehydration/hypovolemia. Withhold and resume at reduced dose upon recovery or permanently discontinue for renal failure or impairment based on severity. Proteinuria. In DTC and HCC, proteinuria was reported in 34% and 26% of LENVIMA-treated patients, respectively. Grade 3 proteinuria occurred in 11% and 6% in DTC and HCC, respectively. In RCC, proteinuria occurred in 31% of patients receiving LENVIMA + everolimus (8% grade 3). Monitor for proteinuria prior to initiation and periodically during treatment. If urine dipstick proteinuria ≥2+ is detected, obtain a 24-hour urine protein. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity. Diarrhea. Of the 737 LENVIMA-treated patients in DTC and HCC, diarrhea occurred in 49% (6% grade 3). In RCC, diarrhea occurred in 81% of LENVIMA + everolimus–treated patients (19% grade 3). Diarrhea was the most frequent cause of dose interruption/reduction, and diarrhea recurred despite dose reduction. Promptly initiate management of diarrhea. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity. Fistula Formation and Gastrointestinal Perforation. Of the 799 patients treated with LENVIMA or LENVIMA + everolimus in DTC, RCC, and HCC, fistula or gastrointestinal perforation occurred in 2%. Permanently discontinue in patients who develop gastrointestinal perforation of any severity or grade 3-4 fistula. QT Interval Prolongation. In DTC, QT/QTc interval prolongation occurred in 9% of LENVIMA-treated patients and QT interval prolongation of >500 ms occurred in 2%. In RCC, QTc interval increases of >60 ms occurred in 11% of patients receiving LENVIMA + everolimus and QTc interval >500 ms occurred in 6%. In HCC, QTc interval increases of >60 ms occurred in 8% of LENVIMA-treated patients and QTc interval >500 ms occurred in 2%. Monitor and correct electrolyte abnormalities at baseline and periodically during treatment. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Withhold and resume at reduced dose upon recovery based on severity. Hypocalcemia. In DTC, grade 3-4 hypocalcemia occurred in 9% of LENVIMA-treated patients. In 65% of cases, hypocalcemia improved or resolved following calcium supplementation with or without dose interruption or dose reduction. In RCC, grade 3-4 hypocalcemia occurred in 6% of LENVIMA + everolimus–treated patients. In HCC, grade 3 hypocalcemia occurred in 0.8% of LENVIMA-treated patients. Monitor blood calcium levels at least monthly and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue depending on severity. Reversible Posterior Leukoencephalopathy Syndrome (RPLS). Across clinical studies of 1,823 patients who received LENVIMA as a single agent, RPLS occurred in 0.3%. Confirm diagnosis of RPLS with MRI. Withhold and resume at reduced dose upon recovery or permanently discontinue depending on severity and persistence of neurologic symptoms. Hemorrhagic Events. Serious including fatal hemorrhagic events can occur with LENVIMA. In DTC, RCC, and HCC clinical trials, hemorrhagic events, of any grade, occurred in 29% of the 799 patients treated with LENVIMA as a single agent or in combination with everolimus. The most frequently reported hemorrhagic events (all grades and occurring in at least 5% of patients) were epistaxis and hematuria. In DTC, grade 3-5 hemorrhage occurred in 2% of LENVIMA-treated patients, including 1 fatal intracranial hemorrhage among 16 patients who received LENVIMA and had CNS metastases at baseline. In RCC, grade 3-5 hemorrhage occurred in 8% of LENVIMA + everolimus–treated patients, including 1 fatal cerebral hemorrhage. In HCC, grade 3-5 hemorrhage occurred in 5% of LENVIMA-treated patients, including 7 fatal hemorrhagic events. Serious tumor-related bleeds, including fatal hemorrhagic events, occurred in LENVIMA-treated patients in clinical trials and in the postmarketing setting. In postmarketing surveillance, serious and fatal carotid artery hemorrhages were seen more frequently in patients with anaplastic thyroid carcinoma (ATC) than other tumors. Safety and effectiveness of LENVIMA in patients with ATC have not been demonstrated in clinical trials. Consider the risk of severe or fatal hemorrhage associated with tumor invasion or infiltration of major blood vessels (eg, carotid artery). Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity. Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction. LENVIMA impairs exogenous thyroid suppression. In DTC, 88% of patients had baseline thyroid stimulating hormone (TSH) level ≤0.5 mU/L. In patients with normal TSH at baseline, elevation of TSH level >0.5 mU/L was observed post baseline in 57% of LENVIMA-treated patients. In RCC and HCC, grade 1 or 2 hypothyroidism occurred in 24% of LENVIMA + everolimus–treated patients and 21% of LENVIMA-treated patients, respectively. In patients with normal or low TSH at baseline, elevation of TSH was observed post baseline in 70% of LENVIMA-treated patients in HCC and 60% of LENVIMA + everolimus–treated patients in RCC. Monitor thyroid function prior to initiation and at least monthly during treatment. Treat hypothyroidism according to standard medical practice. Impaired Wound Healing. Impaired wound healing has been reported in patients who received LENVIMA. Withhold LENVIMA for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of LENVIMA 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. Perform an oral examination prior to treatment with LENVIMA and periodically during LENVIMA treatment. Advise patients regarding good oral hygiene practices and to consider having preventive dentistry performed prior to treatment with LENVIMA and throughout treatment with LENVIMA. Avoid invasive dental procedures, if possible, while on LENVIMA treatment, particularly in patients at higher risk. Withhold LENVIMA for at least 1 week prior to scheduled dental surgery or invasive dental procedures, if possible. For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk of ONJ. Withhold LENVIMA if ONJ develops and restart based on clinical judgement of adequate resolution. Embryo ‐ Fetal Toxicity. Based on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm when administered to pregnant women. In animal reproduction studies, oral administration of LENVIMA during organogenesis at doses below the recommended clinical doses resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits. Advise pregnant women of the potential risk to a fetus; and advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for 30 days after the last dose. Adverse Reactions In 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%), decreased weight (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 reactions led to dose reductions in 68% of LENVIMA-treated patients; 18% discontinued LENVIMA. The most common adverse reactions (≥10%) resulting in dose reductions were hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhea (10%); the most common adverse reactions (≥1%) resulting in discontinuation of LENVIMA were hypertension (1%) and asthenia (1%). In RCC, the most common adverse reactions (≥20%) observed in LENVIMA + KEYTRUDA-treated patients were fatigue (63%), diarrhea (62%), musculoskeletal pain (58%), hypothyroidism (57%), hypertension (56%), stomatitis (43%), decreased appetite (41%), rash (37%), nausea (36%), decreased weight (30%), dysphonia (30%), proteinuria (30%), palmar-plantar erythrodysesthesia syndrome (29%), abdominal pain (27%), hemorrhagic events (27%), vomiting (26%), constipation (25%), hepatotoxicity (25%), headache (23%), and acute kidney injury (21%). Fatal adverse reactions occurred in 4.3% of patients receiving LENVIMA in combination with KEYTRUDA, including cardio-respiratory arrest (0.9%), sepsis (0.9%), and one case (0.3%) each of arrhythmia, autoimmune hepatitis, dyspnea, hypertensive crisis, increased blood creatinine, multiple organ dysfunction syndrome, myasthenic syndrome, myocarditis, nephritis, pneumonitis, ruptured aneurysm and subarachnoid hemorrhage. Serious adverse reactions occurred in 51% of patients receiving LENVIMA and KEYTRUDA. Serious adverse reactions in ≥2% of patients were hemorrhagic events (5%), diarrhea (4%), hypertension (3%), myocardial infarction (3%), pneumonitis (3%), vomiting (3%), acute kidney injury (2%), adrenal insufficiency (2%), dyspnea (2%), and pneumonia (2%). Permanent discontinuation of LENVIMA, KEYTRUDA, or both due to an adverse reaction occurred in 37% of patients; 26% LENVIMA only, 29% KEYTRUDA only, and 13% both drugs. The most common adverse reactions (≥2%) leading to permanent discontinuation of LENVIMA, KEYTRUDA, or both were pneumonitis (3%), myocardial infarction (3%), hepatotoxicity (3%), acute kidney injury (3%), rash (3%), and diarrhea (2%). Dose interruptions of LENVIMA, KEYTRUDA, or both due to an adverse reaction occurred in 78% of patients receiving LENVIMA in combination with KEYTRUDA. LENVIMA was interrupted in 73% of patients and both drugs were interrupted in 39% of patients. LENVIMA was dose reduced in 69% of patients. The most common adverse reactions (≥5%) resulting in dose reduction or interruption of LENVIMA were diarrhea (26%), fatigue (18%), hypertension (17%), proteinuria (13%), decreased appetite (12%), palmar-plantar erythrodysesthesia (11%), nausea (9%), stomatitis (9%), musculoskeletal pain (8%), rash (8%), increased lipase (7%), abdominal pain (6%), and vomiting (6%), increased ALT (5%), and increased amylase (5%). In RCC, the most common adverse reactions (≥30%) observed in LENVIMA + everolimus–treated patients 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%), dyspnea (35%), rash (35%), decreased weight (34%), hemorrhagic events (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%), and dyspnea (5%). Adverse reactions led to dose reductions or interruption in 89% of patients. The most common adverse reactions (≥5%) resulting in dose reductions were diarrhea (21%), fatigue (8%), thrombocytopenia (6%), vomiting (6%), nausea (5%), and proteinuria (5%). Treatment discontinuation 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%), decreased weight (31%), abdominal pain (30%), palmar-plantar erythrodysesthesia syndrome (27%), proteinuria (26%), dysphonia (24%), hemorrhagic events (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 reductions or interruption in 62% of patients. The most common adverse reactions (≥5%) resulting in dose reductions were fatigue (9%), decreased appetite (8%), diarrhea (8%), proteinuria (7%), hypertension (6%), and palmar-plantar erythrodysesthesia syndrome (5%). Treatment discontinuation due to an adverse reaction occurred in 20% of patients. The most common adverse reactions (≥1%) resulting in discontinuation of LENVIMA were fatigue (1%), hepatic encephalopathy (2%), hyperbilirubinemia (1%), and hepatic failure (1%). In endometrial carcinoma, the most common adverse reactions (≥20%) observed in LENVIMA + KEYTRUDA-treated patients were hypothyroidism (67%), hypertension (67%), fatigue (58%), diarrhea (55%), musculoskeletal disorders (53%), nausea (49%), decreased appetite (44%), vomiting (37%), stomatitis (35%), decreased weight (34%), abdominal pain (34%), urinary tract infection (31%), proteinuria (29%), constipation (27%), headache (26%), hemorrhagic events (25%), palmar‐plantar erythrodysesthesia (23%), dysphonia (22%), and rash (20%). Fatal adverse reactions occurred in 4.7% of those treated with LENVIMA and KEYTRUDA, including 2 cases of pneumonia, and 1 case of the following: acute kidney injury, acute myocardial infarction, colitis, decreased appetite, intestinal perforation, lower gastrointestinal hemorrhage, malignant gastrointestinal obstruction, multiple organ dysfunction syndrome, myelodysplastic syndrome, pulmonary embolism, and right ventricular dysfunction. Serious adverse reactions occurred in 50% of patients receiving LENVIMA and KEYTRUDA. Serious adverse reactions with frequency ≥3% were hypertension (4.4%), and urinary tract infection (3.2%). Discontinuation of LENVIMA due to an adverse reaction occurred in 26% of patients. The most common (≥1%) adverse reactions leading to discontinuation of LENVIMA were hypertension (2%), asthenia (1.8%), diarrhea (1.2%), decreased appetite (1.2%), proteinuria (1.2%), and vomiting (1.2%). Dose reductions of LENVIMA due to adverse reactions occurred in 67% of patients. The most common (≥5%) adverse reactions resulting in dose reduction of LENVIMA were hypertension (18%), diarrhea (11%), palmar-plantar erythrodysesthesia syndrome (9%), proteinuria (7%), fatigue (7%), decreased appetite (6%), asthenia (5%), and weight decreased (5%). Dose interruptions of LENVIMA due to an adverse reaction occurred in 58% of these patients. The most common (≥2%) adverse reactions leading to interruption of LENVIMA were hypertension (11%), diarrhea (11%), proteinuria (6%), decreased appetite (5%), vomiting (5%), increased alanine aminotransferase (3.5%), fatigue (3.5%), nausea (3.5%), abdominal pain (2.9%), weight decreased (2.6%), urinary tract infection (2.6%), increased aspartate aminotransferase (2.3%), asthenia (2.3%), and palmar-plantar erythrodysesthesia (2%). Use in Specific Populations Because of the potential for serious adverse reactions in breastfed children, advise women to discontinue breastfeeding during treatment and for 1 week after the last dose. LENVIMA may impair fertility in males and females of reproductive potential. No dose adjustment is recommended for patients with mild (creatine clearance [CLcr] 60-89 mL/min) or moderate (CLcr 30-59 mL/min) renal impairment. LENVIMA concentrations may increase in patients with DTC, RCC, or EC and severe (CLcr 15-29 mL/min) renal impairment. Reduce the dose for patients with DTC, RCC, or endometrial carcinoma 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 for patients with HCC and mild hepatic impairment (Child-Pugh A). There is no recommended dose for patients with HCC with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment. No dose adjustment is recommended for patients with DTC, RCC, or endometrial carcinoma and mild or moderate hepatic impairment. LENVIMA concentrations may increase in patients with DTC, RCC, or endometrial carcinoma and severe hepatic impairment. Reduce the dose for patients with DTC, RCC, or endometrial carcinoma and severe hepatic impairment. Please see Prescribing Information for LENVIMA (lenvatinib) at . Selected KEYTRUDA® (pembrolizumab) Indications in the U.S. Renal Cell Carcinoma KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC). KEYTRUDA, in combination with LENVIMA, is indicated for the first-line treatment of adult patients with advanced RCC. KEYTRUDA is indicated for the adjuvant treatment of patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions. See additional selected KEYTRUDA indications in the U.S. after the Selected Important Safety Information. Selected Important Safety Information for KEYTRUDA Severe and Fatal Immune-Mediated Adverse Reactions KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the 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. For patients with TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate. Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy. Immune-Mediated Pneumonitis KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients. Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution. Pneumonitis occurred in 7% (41/580) of adult patients with resected NSCLC who received KEYTRUDA as a single agent for adjuvant treatment of NSCLC, including fatal (0.2%), Grade 4 (0.3%), and Grade 3 (1%) adverse reactions. Patients received high-dose corticosteroids for a median duration of 10 days (range: 1 day to 2.3 months). Pneumonitis led to discontinuation of KEYTRUDA in 26 (4.5%) of patients. Of the patients who developed pneumonitis, 54% interrupted KEYTRUDA, 63% discontinued KEYTRUDA, and 71% 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. The incidence of new or worsening hyperthyroidism was higher in 580 patients with resected NSCLC, occurring in 11% of patients receiving KEYTRUDA as a single agent as adjuvant treatment, including Grade 3 (0.2%) hyperthyroidism. The incidence of new or worsening hypothyroidism was higher in 580 patients with resected NSCLC, occurring in 22% of patients receiving KEYTRUDA as a single agent as adjuvant treatment (KEYNOTE-091), including Grade 3 (0.3%) hypothyroidism. Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in <0.1% (1) and withholding of KEYTRUDA in <0.1% (1) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Immune-Mediated Nephritis With Renal Dysfunction KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and withholding in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Nephritis resolved in 56% of the 9 patients. Immune-Mediated Dermatologic Adverse Reactions KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with anti– PD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients. Other Immune-Mediated Adverse Reactions The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA or were reported with the use of other anti–PD-1/PD-L1 treatments. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) 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, when KEYTRUDA was administered as a single agent to patients with stage III melanoma, KEYTRUDA was permanently discontinued due to adverse reactions in 14% of 509 patients; the most common (≥1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. The most common adverse reaction (≥20%) with KEYTRUDA was diarrhea (28%). In KEYNOTE-716, when KEYTRUDA was administered as a single agent to patients with stage IIB or IIC melanoma, adverse reactions occurring in patients with stage IIB or IIC melanoma were similar to those occurring in 1011 patients with stage III melanoma from KEYNOTE-054. In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (≥20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%). In KEYNOTE-407, when KEYTRUDA was administered with carboplatin and either paclitaxel or paclitaxel protein-bound in metastatic squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 15% of 101 patients. The most frequent serious adverse reactions reported in at least 2% of patients were febrile neutropenia, pneumonia, and urinary tract infection. Adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs 36%) and peripheral neuropathy (31% vs 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407. In KEYNOTE-042, KEYTRUDA was discontinued due to adverse reactions in 19% of 636 patients with advanced NSCLC; the most common were pneumonitis (3%), death due to unknown cause (1.6%), and pneumonia (1.4%). The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%). The most common adverse reaction (≥20%) was fatigue (25%). In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC; the most common was pneumonitis (1.8%). The most common adverse reactions (≥20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%). In KEYNOTE-671, adverse reactions occurring in patients with resectable NSCLC receiving KEYTRUDA in combination with platinum-containing chemotherapy, given as neoadjuvant treatment and continued as single-agent adjuvant treatment, were generally similar to those occurring in patients in other clinical trials across tumor types receiving KEYTRUDA in combination with chemotherapy. The most common adverse reactions (reported in ≥20%) in patients receiving KEYTRUDA in combination with chemotherapy were fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia, peripheral neuropathy, mucosal inflammation, stomatitis, headache, weight loss, abdominal pain, arthralgia, myalgia, insomnia, palmar- plantar erythrodysesthesia, urinary tract infection, and hypothyroidism. In the neoadjuvant phase of KEYNOTE-671, when KEYTRUDA was administered in combination with platinum-containing chemotherapy as neoadjuvant treatment, serious adverse reactions occurred in 34% of 396 patients. The most frequent (≥2%) serious adverse reactions were pneumonia (4.8%), venous thromboembolism (3.3%), and anemia (2%). Fatal adverse reactions occurred in 1.3% of patients, including death due to unknown cause (0.8%), sepsis (0.3%), and immune-mediated lung disease (0.3%). Permanent discontinuation of any study drug due to an adverse reaction occurred in 18% of patients who received KEYTRUDA in combination with platinum-containing chemotherapy; the most frequent adverse reactions (≥1%) that led to permanent discontinuation of any study drug were acute kidney injury (1.8%), interstitial lung disease (1.8%), anemia (1.5%), neutropenia (1.5%), and pneumonia (1.3%). Of the KEYTRUDA-treated patients who received neoadjuvant treatment, 6% of 396 patients did not receive surgery due to adverse reactions. The most frequent (≥1%) adverse reaction that led to cancellation of surgery in the KEYTRUDA arm was interstitial lung disease (1%). In the adjuvant phase of KEYNOTE-671, when KEYTRUDA was administered as a single agent as adjuvant treatment, serious adverse reactions occurred in 14% of 290 patients. The most frequent serious adverse reaction was pneumonia (3.4%). One fatal adverse reaction of pulmonary hemorrhage occurred. Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 12% of patients who received KEYTRUDA as a single agent, given as adjuvant treatment; the most frequent adverse reactions (≥1%) that led to permanent discontinuation of KEYTRUDA were diarrhea (1.7%), interstitial lung disease (1.4%), increased aspartate aminotransferase (1%), and musculoskeletal pain (1%). Adverse reactions observed in KEYNOTE-091 were generally similar to those occurring in other patients with NSCLC receiving KEYTRUDA as a single agent, with the exception of hypothyroidism (22%), hyperthyroidism (11%), and pneumonitis (7%). Two fatal adverse reactions of myocarditis occurred. 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-A39, when KEYTRUDA was administered in combination with enfortumab vedotin to patients with locally advanced or metastatic urothelial cancer (n=440), fatal adverse reactions occurred in 3.9% of patients, including acute respiratory failure (0.7%), pneumonia (0.5%), and pneumonitis/ILD (0.2%). Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA in combination with enfortumab vedotin; the serious adverse reactions in ≥2% of patients were rash (6%), acute kidney injury (5%), pneumonitis/ILD (4.5%), urinary tract infection (3.6%), diarrhea (3.2%), pneumonia (2.3%), pyrexia (2%), and hyperglycemia (2%). Permanent discontinuation of KEYTRUDA occurred in 27% of patients. The most common adverse reactions (≥2%) resulting in permanent discontinuation of KEYTRUDA were pneumonitis/ILD (4.8%) and rash (3.4%). The most common adverse reactions (≥20%) occurring in patients treated with KEYTRUDA in combination with enfortumab vedotin were rash (68%), peripheral neuropathy (67%), fatigue (51%), pruritus (41%), diarrhea (38%), alopecia (35%), weight loss (33%), decreased appetite (33%), nausea (26%), constipation (26%), dry eye (24%), dysgeusia (21%), and urinary tract infection (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. In KEYNOTE-158 and KEYNOTE-164, adverse reactions occurring in patients with MSI-H or dMMR cancer were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent. In KEYNOTE-811, when KEYTRUDA was administered in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, KEYTRUDA was discontinued due to adverse reactions in 6% of 217 patients with locally advanced unresectable or metastatic HER2+ gastric or GEJ adenocarcinoma. The most common adverse reaction resulting in permanent discontinuation was pneumonitis (1.4%). In the KEYTRUDA arm versus placebo, there was a difference of ≥5% incidence between patients treated with KEYTRUDA versus standard of care for diarrhea (53% vs 44%) and nausea (49% vs 44%). In KEYNOTE-859, when KEYTRUDA was administered in combination with fluoropyrimidine- and platinum-containing chemotherapy, serious adverse reactions occurred in 45% of 785 patients. Serious adverse reactions in >2% of patients included pneumonia (4.1%), diarrhea (3.9%), hemorrhage (3.9%), and vomiting (2.4%). Fatal adverse reactions occurred in 8% of patients who received KEYTRUDA including infection (2.3%) and thromboembolism (1.3%). KEYTRUDA was permanently discontinued due to adverse reactions in 15% of patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (≥1%) were infections (1.8%) and diarrhea (1.0%). The most common adverse reactions (reported in ≥20%) in patients receiving KEYTRUDA in combination with chemotherapy were peripheral neuropathy (47%), nausea (46%), fatigue (40%), diarrhea (36%), vomiting (34%), decreased appetite (29%), abdominal pain (26%), palmar-plantar erythrodysesthesia syndrome (25%), constipation (22%), and weight loss (20%). In KEYNOTE-590, when KEYTRUDA was administered with cisplatin and fluorouracil to patients with metastatic or locally advanced esophageal or GEJ (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma who were not candidates for surgical resection or definitive chemoradiation, KEYTRUDA was discontinued due to adverse reactions in 15% of 370 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (≥1%) were pneumonitis (1.6%), acute kidney injury (1.1%), and pneumonia (1.1%). The most common adverse reactions (≥20%) with KEYTRUDA in combination with chemotherapy were nausea (67%), fatigue (57%), decreased appetite (44%), constipation (40%), diarrhea (36%), vomiting (34%), stomatitis (27%), and weight loss (24%). Adverse reactions occurring in patients with esophageal cancer who received KEYTRUDA as a monotherapy were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy. In KEYNOTE-A18, when KEYTRUDA was administered with CRT (cisplatin plus external beam radiation therapy [EBRT] followed by brachytherapy [BT]) to patients with FIGO 2014 Stage III-IVA cervical cancer, fatal adverse reactions occurred in 1.4% of 292 patients, including 1 case each (0.3%) of large intestinal perforation, urosepsis, sepsis, and vaginal hemorrhage. Serious adverse reactions occurred in 30% of patients; those ≥1% included urinary tract infection (2.7%), urosepsis (1.4%), and sepsis (1%). KEYTRUDA was discontinued for adverse reactions in 7% of patients. The most common adverse reaction (≥1%) resulting in permanent discontinuation was diarrhea (1%). For patients treated with KEYTRUDA in combination with CRT, the most common adverse reactions (≥10%) were nausea (56%), diarrhea (50%), vomiting (33%), urinary tract infection (32%), fatigue (26%), hypothyroidism (20%), constipation (18%), decreased appetite and weight loss (17% each), abdominal pain and pyrexia (12% each), hyperthyroidism, dysuria, rash (11% each), and pelvic pain (10%). In KEYNOTE-826, when KEYTRUDA was administered in combination with paclitaxel and cisplatin or paclitaxel and carboplatin, with or without bevacizumab (n=307), to patients with persistent, recurrent, or first-line metastatic cervical cancer regardless of tumor PD-L1 expression who had not been treated with chemotherapy except when used concurrently as a radio- sensitizing agent, fatal adverse reactions occurred in 4.6% of patients, including 3 cases of hemorrhage, 2 cases each of sepsis and due to unknown causes, and 1 case each of acute myocardial infarction, autoimmune encephalitis, cardiac arrest, cerebrovascular accident, femur fracture with perioperative pulmonary embolus, intestinal perforation, and pelvic infection. Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA in combination with chemotherapy with or without bevacizumab; those ≥3% were febrile neutropenia (6.8%), urinary tract infection (5.2%), anemia (4.6%), and acute kidney injury and sepsis (3.3% each). KEYTRUDA was discontinued in 15% of patients due to adverse reactions. The most common adverse reaction resulting in permanent discontinuation (≥1%) was colitis (1%). For patients treated with KEYTRUDA, chemotherapy, and bevacizumab (n=196), the most common adverse reactions (≥20%) were peripheral neuropathy (62%), alopecia (58%), anemia (55%), fatigue/asthenia (53%), nausea and neutropenia (41% each), diarrhea (39%), hypertension and thrombocytopenia (35% each), constipation and arthralgia (31% each), vomiting (30%), urinary tract infection (27%), rash (26%), leukopenia (24%), hypothyroidism (22%), and decreased appetite (21%). For patients treated with KEYTRUDA in combination with chemotherapy with or without bevacizumab, the most common adverse reactions (≥20%) were peripheral neuropathy (58%), alopecia (56%), fatigue (47%), nausea (40%), diarrhea (36%), constipation (28%), arthralgia (27%), vomiting (26%), hypertension and urinary tract infection (24% each), and rash (22%). In KEYNOTE-158, KEYTRUDA was discontinued due to adverse reactions in 8% of 98 patients with previously treated recurrent or metastatic cervical cancer. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA; the most frequent included anemia (7%), fistula, hemorrhage, and infections [except urinary tract infections] (4.1% each). The most common adverse reactions (≥20%) were fatigue (43%), musculoskeletal pain (27%), diarrhea (23%), pain and abdominal pain (22% each), and decreased appetite (21%). In KEYNOTE-394, KEYTRUDA was discontinued due to adverse reactions in 13% of 299 patients with previously treated hepatocellular carcinoma. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was ascites (2.3%). The most common adverse reactions in patients receiving KEYTRUDA (≥10%) were pyrexia (18%), rash (18%), diarrhea (16%), decreased appetite (15%), pruritis (12%), upper respiratory tract infection (11%), cough (11%), and hypothyroidism (10%). In KEYNOTE-966, when KEYTRUDA was administered in combination with gemcitabine and cisplatin, KEYTRUDA was discontinued for adverse reactions in 15% of 529 patients with locally advanced unresectable or metastatic biliary tract cancer. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA (≥1%) was pneumonitis (1.3%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 55% of patients. The most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were decreased neutrophil count (18%), decreased platelet count (10%), anemia (6%), decreased white blood cell count (4%), pyrexia (3.8%), fatigue (3.0%), cholangitis (2.8%), increased ALT (2.6%), increased AST (2.5%), and biliary obstruction (2.3%). In KEYNOTE-017 and KEYNOTE-913, adverse reactions occurring in patients with MCC (n=105) were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a single agent. In KEYNOTE-426, when KEYTRUDA was administered in combination with axitinib, fatal adverse reactions occurred in 3.3% of 429 patients. Serious adverse reactions occurred in 40% of patients, the most frequent (≥1%) were hepatotoxicity (7%), diarrhea (4.2%), acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%). Permanent discontinuation due to an adverse reaction occurred in 31% of patients; KEYTRUDA only (13%), axitinib only (13%), and the combination (8%); the most common were hepatotoxicity (13%), diarrhea/colitis (1.9%), acute kidney injury (1.6%), and cerebrovascular accident (1.2%). The most common adverse reactions (≥20%) were diarrhea (56%), fatigue/asthenia (52%), hypertension (48%), hepatotoxicity (39%), hypothyroidism (35%), decreased appetite (30%), palmar-plantar erythrodysesthesia (28%), nausea (28%), stomatitis/mucosal inflammation (27%), dysphonia (25%), rash (25%), cough (21%), and constipation (21%). In KEYNOTE-581, when KEYTRUDA was administered in combination with LENVIMA to patients with advanced renal cell carcinoma (n=352), fatal adverse reactions occurred in 4.3% of patients. Serious adverse reactions occurred in 51% of patients; the most common (≥2%) were hemorrhagic events (5%), diarrhea (4%), hypertension, myocardial infarction, pneumonitis, and vomiting (3% each), acute kidney injury, adrenal insufficiency, dyspnea, and pneumonia (2% each). Permanent discontinuation of KEYTRUDA, LENVIMA, 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%) resulting in permanent discontinuation of KEYTRUDA, LENVIMA, or the combination were pneumonitis, myocardial infarction, hepatotoxicity, acute kidney injury, rash (3% each), 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 erythrodysesthesia syndrome (29%), abdominal pain and hemorrhagic events (27% each), vomiting (26%), constipation and hepatotoxicity (25% each), headache (23%), and acute kidney injury (21%). In KEYNOTE-564, when KEYTRUDA was administered as a single agent for the adjuvant treatment of renal cell carcinoma, serious adverse reactions occurred in 20% of patients receiving KEYTRUDA; the serious adverse reactions (≥1%) were acute kidney injury, adrenal insufficiency, pneumonia, colitis, and diabetic ketoacidosis (1% each). Fatal adverse reactions occurred in 0.2% including 1 case of pneumonia. Discontinuation of KEYTRUDA due to adverse reactions occurred in 21% of 488 patients; the most common (≥1%) were increased ALT (1.6%), colitis (1%), and adrenal insufficiency (1%). The most common adverse reactions (≥20%) were musculoskeletal pain (41%), fatigue (40%), rash (30%), diarrhea (27%), pruritus (23%), and hypothyroidism (21%). In KEYNOTE-868, when KEYTRUDA was administered in combination with chemotherapy (paclitaxel and carboplatin) to patients with advanced or recurrent endometrial carcinoma (n=759), serious adverse reactions occurred in 35% of patients receiving KEYTRUDA in combination with chemotherapy, compared to 19% of patients receiving placebo in combination with chemotherapy. Fatal adverse reactions occurred in 1.6% of patients receiving KEYTRUDA in combination with chemotherapy, including COVID-19 (0.5%) and cardiac arrest (0.3%). KEYTRUDA was discontinued for an adverse reaction in 14% of patients. Adverse reactions occurring in patients treated with KEYTRUDA and chemotherapy were generally similar to those observed with KEYTRUDA alone or chemotherapy alone, with the exception of rash (33% all Grades; 2.9% Grades 3-4). In KEYNOTE-775, when KEYTRUDA was administered in combination with LENVIMA to patients with advanced endometrial carcinoma that was pMMR or not MSI-H (n=342), fatal adverse reactions occurred in 4.7% of patients. Serious adverse reactions occurred in 50% of these patients; the most common (≥3%) were hypertension (4.4%) and urinary tract infections (3.2%). Discontinuation of KEYTRUDA due to an adverse reaction occurred in 15% of these patients. The most common adverse reaction leading to discontinuation of KEYTRUDA (≥1%) was increased ALT (1.2%). The most common adverse reactions for KEYTRUDA in combination with LENVIMA (reported in ≥20% 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 infections (31%), proteinuria (29%), constipation (27%), headache (26%), hemorrhagic events (25%), palmar-plantar erythrodysesthesia (23%), dysphonia (22%), and rash (20%). Adverse reactions occurring in patients with MSI-H or dMMR endometrial carcinoma who received KEYTRUDA as a single agent were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a single agent. Adverse reactions occurring in patients with TMB-H cancer were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent. Adverse reactions occurring in patients with recurrent or metastatic cSCC or locally advanced cSCC were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy. In KEYNOTE-522, when KEYTRUDA was administered with neoadjuvant chemotherapy (carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide) followed by surgery and continued adjuvant treatment with KEYTRUDA as a single agent (n=778) to patients with newly diagnosed, previously untreated, high-risk early-stage TNBC, fatal adverse reactions occurred in 0.9% of patients, including 1 each of adrenal crisis, autoimmune encephalitis, hepatitis, pneumonia, pneumonitis, pulmonary embolism, and sepsis in association with multiple organ dysfunction syndrome and myocardial infarction. Serious adverse reactions occurred in 44% of patients receiving KEYTRUDA; those ≥2% were febrile neutropenia (15%), pyrexia (3.7%), anemia (2.6%), and neutropenia (2.2%). KEYTRUDA was discontinued in 20% of patients due to adverse reactions. The most common reactions (≥1%) resulting in permanent discontinuation were increased ALT (2.7%), increased AST (1.5%), and rash (1%). The most common adverse reactions (≥20%) in patients receiving KEYTRUDA were fatigue (70%), nausea (67%), alopecia (61%), rash (52%), constipation (42%), diarrhea and peripheral neuropathy (41% each), stomatitis (34%), vomiting (31%), headache (30%), arthralgia (29%), pyrexia (28%), cough (26%), abdominal pain (24%), decreased appetite (23%), insomnia (21%), and myalgia (20%). In KEYNOTE-355, when KEYTRUDA and chemotherapy (paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin) were administered to patients with locally recurrent unresectable or metastatic TNBC who had not been previously treated with chemotherapy in the metastatic setting (n=596), fatal adverse reactions occurred in 2.5% of patients, including cardio-respiratory arrest (0.7%) and septic shock (0.3%). Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA in combination with chemotherapy; the serious reactions in ≥2% were pneumonia (2.9%), anemia (2.2%), and thrombocytopenia (2%). KEYTRUDA was discontinued in 11% of patients due to adverse reactions. The most common reactions resulting in permanent discontinuation (≥1%) were increased ALT (2.2%), increased AST (1.5%), and pneumonitis (1.2%). The most common adverse reactions (≥20%) in patients receiving KEYTRUDA in combination with chemotherapy were fatigue (48%), nausea (44%), alopecia (34%), diarrhea and constipation (28% each), vomiting and rash (26% each), cough (23%), decreased appetite (21%), and headache (20%). Lactation Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 4 months after the last dose. Pediatric Use In KEYNOTE-051, 173 pediatric patients (65 pediatric patients aged 6 months to younger than 12 years and 108 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 25 months). Adverse reactions that occurred at a ≥10% higher rate in pediatric patients when compared to adults were pyrexia (33%), leukopenia (31%), vomiting (29%), neutropenia (28%), headache (25%), abdominal pain (23%), thrombocytopenia (22%), Grade 3 anemia (17%), decreased lymphocyte count (13%), and decreased white blood cell count (11%). Geriatric Use Of the 564 patients with locally advanced or metastatic urothelial cancer treated with KEYTRUDA in combination with enfortumab vedotin, 44% (n=247) were 65-74 years and 26% (n=144) were 75 years or older. No overall differences in safety or effectiveness were observed between patients 65 years of age or older and younger patients. Patients 75 years of age or older treated with KEYTRUDA in combination with enfortumab vedotin experienced a higher incidence of fatal adverse reactions than younger patients. The incidence of fatal adverse reactions was 4% in patients younger than 75 and 7% in patients 75 years or older. Additional Selected KEYTRUDA Indications in the U.S. Melanoma KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma. KEYTRUDA is indicated for the adjuvant treatment of adult and pediatric (12 years and older) patients with Stage IIB, IIC, or III melanoma following complete resection. 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. KEYTRUDA is indicated for the treatment of patients with resectable (tumors ≥4 cm or node positive) NSCLC in combination with platinum-containing chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery. KEYTRUDA, as a single agent, is indicated for adjuvant treatment following resection and platinum-based chemotherapy for adult patients with Stage IB (T2a ≥4 cm), II, or IIIA NSCLC. 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 Cancer KEYTRUDA, in combination with enfortumab vedotin, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer. KEYTRUDA, as a single agent, is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma: who are not eligible for any platinum-containing chemotherapy, or who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. KEYTRUDA, as a single agent, 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, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC) as determined by an FDA-approved test. Gastric Cancer KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum containing chemotherapy, is indicated for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma 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 of this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. KEYTRUDA, in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma. Esophageal Cancer KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either: in combination with platinum- and fluoropyrimidine-based chemotherapy, or as a single agent after one or more prior lines of systemic therapy for patients with tumors of squamous cell histology that express PD-L1 (CPS ≥10) as determined by an FDA-approved test. Cervical Cancer KEYTRUDA, in combination with chemoradiotherapy (CRT), is indicated for the treatment of patients with FIGO 2014 Stage III-IVA cervical cancer. KEYTRUDA, in combination with chemotherapy, with or without bevacizumab, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. Hepatocellular Carcinoma KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) secondary to hepatitis B who have received prior systemic therapy other than a PD-1/PD-L1-containing regimen. Biliary Tract Cancer KEYTRUDA, in combination with gemcitabine and cisplatin, is indicated for the treatment of patients with locally advanced unresectable or metastatic biliary tract cancer (BTC). Merkel Cell Carcinoma KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). Endometrial Carcinoma KEYTRUDA, in combination with carboplatin and paclitaxel, followed by KEYTRUDA as a single agent, is indicated for the treatment of adult patients with primary advanced or recurrent endometrial carcinoma. KEYTRUDA, in combination with LENVIMA, is indicated for the treatment of adult patients with advanced endometrial carcinoma that is mismatch repair proficient (pMMR) as determined by an FDA-approved test or not MSI-H, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. KEYTRUDA, as a single agent, is indicated for the treatment of adult patients with advanced endometrial carcinoma that is MSI-H or dMMR, as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. Tumor Mutational Burden-High Cancer KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established. Cutaneous Squamous Cell Carcinoma KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC that is not curable by surgery or radiation. Triple-Negative Breast Cancer KEYTRUDA is indicated for the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery. KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test. Please see Prescribing Information for KEYTRUDA (pembrolizumab) at and Medication Guide for KEYTRUDA at . About the Merck and Eisai strategic collaboration In March 2018, Eisai and Merck, known as MSD outside the United States and Canada, through an affiliate, entered into a strategic collaboration for the worldwide co-development and co-commercialization of LENVIMA. Under the agreement, the companies will jointly develop, manufacture and commercialize LENVIMA, both as monotherapy and in combination with Merck's anti-PD-1 therapy KEYTRUDA. In addition to ongoing clinical studies evaluating the KEYTRUDA plus LENVIMA combination across several different tumor types, the companies have jointly initiated new clinical studies through the LEAP (LEnvatinib And Pembrolizumab) clinical program and are evaluating the combination in various tumor types across multiple clinical trials. Eisai's focus on cancer Eisai acknowledges "Oncology" as one of its key strategic areas, and will continue to focus on the discovery and development of anti-cancer drugs within drug discovery domains including "microenvironment", "proteostasis disruption", "cell lineage and cell differentiation", and "inflammation, hypoxia, oxidative stress and cell senescence" under the Deep Human Biology Learning (DHBL) drug discovery and development organization. Eisai aspires to discover innovative new drugs with new targets and mechanisms of action from these domains, with the aim of contributing to the cure of cancers. About Eisai Eisai's Corporate Concept is "to give first thought to patients and people in the daily living domain, and to increase the benefits that health care provides." Under this Concept [also known as our human health care (hhc) Concept], we aim to effectively achieve social good in the form of relieving anxiety over health and reducing health disparities. With a global network of R&D facilities, manufacturing sites and marketing subsidiaries, we strive to create and deliver innovative products to target diseases with high unmet medical needs, with a particular focus in our strategic areas of Neurology and Oncology. In addition, our continued commitment to the elimination of neglected tropical diseases (NTDs), which is a target (3.3) of the United Nations Sustainable Development Goals (SDGs), is demonstrated by our work on various activities together with global partners. For more information about Eisai, please visit (for global headquarters: Eisai Co., Ltd.), us.eisai.com (for U.S. headquarters: Eisai Inc.) or (for Europe, Middle East, Africa, Russia, Australia, and New Zealand headquarters: Eisai Europe Ltd.), and connect with us on Twitter (U.S. and global) and LinkedIn (for U.S. and EMEA). SOURCE Eisai Inc.

摘要 ：Claudin 18.2是一种紧密连接分子，主要在非恶性胃上皮细胞中发现，在恶性转化过程中，它在肿瘤细胞表面变得可接近，从而为癌症治疗提供了一个诱人的靶点。来自两个III期试验的数据测试了针对claudin 18.2的抗体zolbetuximab，已经建立了claudin 18.2阳性晚期胃癌作为一个独立的治疗亚群，从这种药剂添加到化疗中获益。这一发展大幅增加了有资格接受靶向治疗的患者百分比。此外，像高亲和力单克隆抗体、双特异性抗体、嵌合抗原受体T细胞和能够产生旁观者杀伤效应的抗体-药物偶联物等新的治疗方法，在表达claudin 18.2的胃癌患者中显示出相当的前景。这一新的发展来自于药物开发者超越了传统靶点，如驱动基因突变或生长因子。在这篇综述中，我们强调了生物学原理，并探讨了针对晚期胃癌患者中claudin 18.2的治疗方法的临床活性，并探索了将claudin 18.2靶向治疗扩展到其他claudin 18.2阳性实体瘤患者的潜力。 关键点 · Claudin 18.2几乎只在胃粘膜中表达，没有明确证据表明这种紧密连接蛋白在胃癌的致癌作用和/或增殖中发挥作用。 · 两项关键的III期试验测试了针对claudin 18.2的单克隆抗体zolbetuximab，已经证明在不可切除的胃癌患者中，无论是无进展生存期还是总生存期都有统计学上的显著改善，并确立了claudin 18.2作为一个经过验证的治疗靶点。 · 确定最佳治疗顺序，特别是对于那些可能符合多种靶向治疗或免疫治疗条件的患者，以及多种蛋白质生物标志物检测的可行性，将是zolbetuximab临床实施后讨论的主题。 · Claudin 18.2可能通过多种治疗方式被靶向，除了单克隆抗体外，还包括双特异性抗体、抗体-药物偶联物、嵌合抗原受体T细胞和基于mRNA的方法。 · Claudin 18.2靶向治疗的发展正在扩展，可能还会包括其他claudin 18.2阳性的癌症类型。 1. 引言 系统性化疗，通常是氟尿嘧啶类药物加上奥沙利铂（要么是卡培他滨加上奥沙利铂（CAPOX）方案，要么是亚叶酸（也称为亚叶酸）和5-氟尿嘧啶加上奥沙利铂（FOLFOX）方案），被认为是晚期胃癌（AGC）患者的标准治疗。尽管如此，AGC患者的预后仍然不佳，中位总生存期（OS）大约为14-17个月。各种HER2靶向治疗、VEGF靶向药物和抗PD-1抗体的组合，无论是单独使用还是与细胞毒性化疗联合使用，都已被批准作为AGC患者的一线治疗；然而，这些治疗的好处通常仅限于HER2阳性、PD-L1阳性或高微卫星不稳定性（MSI-H）的癌症患者，而且在疾病进展后，只有少数患者可能会接受这些治疗。这种缺乏有效的靶向治疗选择反映了缺乏可靶向的改变（HER2在15-25%的胃癌或胃食管结合部（GEJ）癌症中可检测到），以及受体酪氨酸激酶（RTKs）的异质性共表达，这限制了分子靶向治疗的使用范围至一部分患者。此外，尽管抗PD-1抗体纳武利尤单抗联合化疗已在几个国家被批准作为AGC患者的一线治疗，无论PD-L1表达如何，但好处主要限于微卫星不稳定性（MSI-H，通常<5%的患者）和/或PD-L1阳性（联合阳性评分（CPS）>5）的肿瘤患者（约占30-60%的患者），这通常反映在国家或地区指南中。因此，需要创新的治疗方法，这些方法对大多数AGC患者都有效，以进一步提高治疗效果。 Claudin 18.2靶向治疗的发展为这些挑战提供了一线希望。这种紧密连接蛋白由非恶性胃上皮表达，并在恶性转化过程中暴露在肿瘤细胞表面，使其成为靶向癌症治疗的一个可接近的目标。在III期SPOTLIGHT和GLOW试验中，zolbetuximab，一种抗claudin 18.2单克隆抗体，已被证明在与化疗联合使用时，可以改善先前未经治疗的表达高水平claudin 18.2的AGC患者的OS和无进展生存期（PFS）。此外，其他几种靶向claudin 18.2的药物正在进行早期阶段的试验，包括新型抗claudin 18.2抗体、双特异性抗体、抗体-药物偶联物（ADCs）和claudin 18.2特异性嵌合抗原受体（CAR）T细胞。Claudin 18.2在其他几种肿瘤类型中也有异位表达，包括胰腺癌，因此有潜力成为一个肿瘤不可知论的靶标。 在这篇综述中，我们描述了claudin 18.2在胃粘膜和癌变中的生物学作用，以及claudin 18.2靶向治疗的临床活性，包括基因组和免疫学方面的贡献。我们还讨论了zolbetuximab的即将纳入，这是第一个在III期试验中证明显著改善生存结果的靶向claudin 18.2的药物，到常规临床实践中。claudin 18.2靶向治疗的经验挑战了当前以基因组为重点的药物发现方法，并预计将引导我们超越仅针对致癌驱动改变，走向其他创新疗法。 2. Claudin 18.2的生物学作用 上皮细胞的基本功能是形成外部环境与下层组织之间的屏障。这种屏障功能由连接复合体支持，使上皮细胞能够形成一个连续且基本上不可渗透的屏障。连接复合体是细胞间隙中存在的多种结构的集体术语，负责确保细胞层的横向强度。这个复合体的组成部分包括紧密连接、粘附连接和桥粒。紧密连接位于侧膜的顶端（图1）。这些连接不仅作为物理屏障，通过紧密的细胞间连接最小化细胞旁渗透性，而且还包括孔隙，这些孔隙介导选择性的细胞旁运输，支持上皮细胞的极性。因此，紧密连接是一个复杂的分子组装，具有看似矛盾的性质，这在脊椎动物中是进化上保守的。紧密连接在20世纪70年代通过电子显微镜可视化，被称为扭曲的多条带状结构，称为“接吻点”。细胞生物学家长期以来一直对决定上皮细胞表型的基本原理感兴趣，勤奋地寻找涉及的分子。1998年，在发现闭锁蛋白之后，Furuse和Tsukita及其同事使用闭锁蛋白敲除小鼠模型成功表征了紧密连接组分中存在的新型小分子。他们将这种分子命名为claudin，源自拉丁语“claudere”，意为关闭。目前，已经鉴定出26个人类claudin家族成员，不同的claudin以组织特异性和电荷选择性的方式调节各种上皮膜的渗透性。2000年代之后，紧密连接的主要分子成分被确定为闭锁蛋白、claudin和连接粘附分子。CLDN18基因位于染色体3q22上，覆盖大约35 kb，包括六个外显子和五个内含子。已经鉴定出两种CLDN18剪接变体：异构体1（claudin 18.1）主要在非恶性肺泡上皮中表达，可能不在胃上皮中表达，或者表达极少，而异构体2（claudin 18.2）主要在胃上皮中表达。这些异构体在很大程度上是同质的，除了最靠近N末端的69个氨基酸，包括第一个细胞外环。 图1 | Claudin 18.2的结构、功能和表达模式。a，Claudin 18.2在非恶性胃黏膜中高度选择性表达，位于细胞间隙的最顶端，构成紧密连接复合体。b，Claudin 18.2是一种跨膜蛋白，具有两个细胞外环，它们与邻近细胞表面表达的claudin 18.2分子结合，形成选择性渗透屏障，使组织具有特异性的渗透性，并因此支持胃上皮细胞的极性。该图示出了治疗性单克隆抗体zolbetuximab的结合位点，以及用于确定claudin 18.2表达的各种诊断抗体的结合位点。ZO1，紧密连接蛋白1。 claudin 18.2剪接变体编码一个细胞表面蛋白，长度为264个氨基酸，分子量约为27 kDa。这种蛋白具有两个细胞外环，四个跨膜域和两个细胞质域。Zolbetuximab，一种首创的抗claudin 18.2单克隆抗体，特异性结合claudin 18.2的第一个细胞外环，其氨基酸序列与claudin 18.1不同。尽管zolbetuximab结合位点位于第一个细胞外环，但在关键性临床试验中用于诊断claudin 18.2阳性胃癌的43-14A抗体，识别位于C末端域的表位。因此，这种方法无法区分claudin 18.2和claudin 18.1的表达（图1）。由于胃上皮中claudin 18.1的缺乏或极少表达（图2），这种缺乏特异性不会影响胃癌患者样本中claudin 18.2的定量，尽管可能需要更特异性的抗体来定量其他组织样本中的生物标志物。通过在小鼠中敲除Cldn18后几天内诱发严重的胃炎，已经证明了claudin 18在紧密连接复合体的屏障功能中的作用，强调了claudin 18.2在防止细胞间隙H+泄漏中的贡献。胃的酸性环境提供了一个特定的背景，这证明了在胃上皮中高度限制特定claudin的表达。还报道了claudin的共表达和/或claudin表达模式的动态变化。例如，在小肠、结肠和直肠的非恶性粘膜中表达的claudin 3、4、7和9，都可以在肠上皮化生期间替代claudin 18.2。在由于慢性炎症引起的恶性转变期间，胃型claudin（claudin 18.2）可以被几种其他肠型claudin（claudin 3、4、6或7）之一替代。 3. 胃癌中的细胞癌变和claudin 18.2异常 紧密连接复合体，包括claudins，被假设在细胞癌变中具有抑制作用，类似于细胞粘附分子的肿瘤抑制功能。由于胚系CDH1突变导致的钙粘蛋白表达不足，已被广泛研究作为肿瘤发生的机制。同样，来自序列基因表达分析的数据显示，多种CLDN基因的表达在几种肿瘤类型中被下调。大约20-30%的胃癌表现出claudin 18.2表达的下调或丧失，以及在侵袭前沿claudin 18.2和Ki-67表达的相反模式，可能反映了从上皮细胞到间充质细胞表型的转变。claudin 18.2的下调还被认为是与癌细胞侵袭和增殖水平的增加有关，并且微小RNA miR-1303的减弱，一种CLDN18表达的潜在抑制因子，抑制了胃癌细胞的增殖。然而，支持CLDN18下调与胃癌发生相关性的证据仍然有限。使用Cldn18基因敲除小鼠模型的研究数据表明，由于紧密连接的破坏和随后的H+泄漏，从急性然后慢性胃炎中产生的多步骤肿瘤发生过程。由此产生的与炎症相关的细胞因子或趋化因子能够诱导细胞的去分化和Wnt信号通路的激活，以及获得伴随CD44表达的干细胞表型。这个过程似乎与幽门螺杆菌感染无关，尽管在感染幽门螺杆菌的Cldn18基因敲除小鼠中也观察到了肿瘤形成。 除了CLDN18表达的变化外，在胃癌患者中也检测到了涉及CLDN18的融合。根据癌症基因组图谱（TCGA）的数据，3%的胃癌患者和10%的弥漫型胃癌患者检测到CLDN18-ARHGAP融合基因。在另一项研究中，这些基因在15%的年轻胃癌患者（≤40岁）中被检测到。最常见的变体，CLDN18-ARHGAP26，是CLDN18的第5个外显子和ARHGAP26的第12个外显子之间的融合。这些融合破坏了连接复合体，可能是由于C末端结构域的丧失和与肌动蛋白调节蛋白相互作用的丧失，以及ARHGAP的Rho-GTP酶结构域的异常定位，这阻止了无附着点诱导的细胞死亡。然而，这个假设机制仍未得到验证。此外，涉及ARHGAP26的其他几种Rho-GTP酶表达融合（CTNND1-ARHGAP26和OCLN-ARHGAP26）在弥漫性胃癌中反复被识别出来，它们通过抑制小GTP酶RHOA的活性参与增殖的作用已被建议。RHOA的激活触发溶酶体膜的通透性，这种功能的丧失可以在携带功能丧失RHOA突变的细胞中观察到，也可以在包含RhoGAP结构域的融合中观察到。总之，没有确凿的证据表明claudin 18.2表达与细胞癌变之间存在直接联系。然而，由于异常claudin表达导致的紧密连接完整性的破坏导致细胞极性的丧失，分化受损和侵袭增加，可能有助于无序的增殖模式和细胞癌变。这些非恶性细胞和肿瘤细胞之间的极性差异以及由此导致的claudin 18.2表达分布的变化，从紧密连接到细胞膜上的表达，可能解释了针对claudin 18.2的疗法的特异性。基于这些观察和针对胃上皮细胞上存在的谱系特异性靶标的计算机辅助药物筛选的结果（类似于B细胞中的CD20），开发了具有活性Fc结构域的治疗性抗claudin 18.2抗体，能够参与抗体依赖性细胞介导的细胞毒性（ADCC）和补体依赖性细胞毒性（CDC）。 与HER2阳性癌症中的曲妥珠单抗不同，没有临床证据支持在更高染色强度（免疫组织化学（IHC）评分3+与2+）时zolbetuximab具有更大的临床活性。然而，表达更多claudin 18.2的肿瘤患者更有可能从zolbetuximab中获益（如FAST试验中claudin 18.2在>70%的肿瘤细胞上表达的患者的中位PFS为9.0个月，而claudin 18.2在40-69%的细胞上表达的患者的中位PFS为4.3个月）。在SPOTLIGHT和GLOW中选择了在75%的肿瘤细胞上claudin 18.2表达的最小水平≥2+的截止点，基于这些数据（见图2）。 4. claudin 18.2在其他肿瘤类型中的作用 众所周知，claudin 18.2在其他多种癌症类型中过度表达，包括其他消化道癌症（如食道癌、胰腺癌和结直肠癌）以及其他非消化道实体瘤（如非小细胞肺癌（NSCLC）和卵巢癌）。claudin 18.2的异常表达可能通过蛋白激酶C（PKC）或细胞外信号相关激酶（ERK）信号通路诱导。下游靶点活化蛋白AP-1已被证明可以增强胃、胰腺和胆管癌细胞中claudin 18.2 mRNAs的翻译，以及其他claudins的翻译。CLDN18的敲除也被证明可以抑制胆管腺癌异种移植模型中的细胞增殖和肿瘤生长。 图2 | 恶性转化过程中的claudin 18.2表达。a, 随着恶性潜力的增加，胃上皮细胞失去细胞极性，导致claudin 18.2表达的破坏。在上皮-间充质转化期间，可能在侵袭前沿观察到claudin 18.2表达的下调。b, 用苏木精和伊红以及抗claudin 18（43-14A）抗体标记的非恶性胃粘膜的代表性图像。c, claudin 18阳性的肠型和弥漫型胃癌的代表性图像。 然而，据我们所知，这项研究提供了唯一的证据表明claudin 18.2直接激活增殖信号；因此，需要进一步的调查来确认这个假设。大部分证据表明，claudin 18.2的异常表达发生在恶性转化过程中。值得注意的是，在非胃癌中，特别是与结肠炎相关的结直肠腺癌中，claudin 18.2的表达与炎症有关。同样，由胃食管反流病引起的炎症，可能导致下食道腺癌，也可能促进claudin 18.2的表达（在一个队列中检测到18.4%的这些癌症中）。非胃癌中claudin 18.2的表达可能反映了一种独特的癌症亚型。例如，claudin 18.2阳性的NSCLCs往往是以缓慢增殖和缺乏甲状腺转录因子1表达为特征的早期肿瘤，而在结肠癌中，claudin 18.2的表达与CDX2（成熟的结肠上皮组织的已建立的生物标志物）之间观察到相反的关系。这些观察表明，不同癌症类型中claudin 18.2的表达与明显不同的表型特征相关，具有不同的临床意义。在来自上消化道的转移性卵巢粘液性癌中存在claudin 18.2的表达（56.6%的样本），但在来自下消化道的（0%）中不存在。 在胰腺导管腺癌（PDAC）中广泛观察到claudin 18.2的异常表达，以及在相关的癌前病变中，如导管内乳头状粘液性肿瘤和粘液性囊性肿瘤。来自几项研究的数据表明，在胰腺上皮内瘤变（PanIN）中表达claudin 18.2，这是另一种胰腺癌前病变，表明claudin 18.2的表达可能在PDAC的发展早期就发生。胃转录因子SOX2在从PanIN到PDAC进展的后期阶段中发挥更主导的作用。综合这些观察结果表明，胰腺上皮的胃型分化可能在恶性转化为高表达claudin 18.2的PDAC中起作用。在卵巢的癌前或边缘恶性病变中也报告了claudin 18.2的异常表达。 图3 | CLDN18–ARHGAP融合蛋白。据报道，CLDN18–ARHGAP融合蛋白可能源自CLDN18–ARHGAP26、CLDN18–ARHGAP6、CLDN18–ARHGAP10和CLDN18–ARHGAP42。CLDN18最常见的融合伴侣ARHGAP26，被认为会导致紧密连接复合体的破坏，因为claudin 18.2的C末端失去了PDZ结合基序，导致通过其他紧密连接蛋白如紧密连接蛋白1（ZO1）与细胞内肌动蛋白丝的相互作用丧失。这种破坏导致下游转化蛋白RHOA的失活，由于存在Rho GAP结构域，可能导致恶性转化。 从组织特异性claudin表达模式向恶性转化过程中claudin 18.2表达转变的生物学机制和后果仍然未知。针对胃癌的claudin 18.2靶向治疗的可用性也可能为其他实体瘤中过度表达claudin 18.2的亚群提供新的靶向治疗。值得注意的是，目前正在招募患者进行一项II期试验，以评估zolbetuximab联合化疗作为claudin 18.2阳性转移性PDAC患者一线治疗的疗效（NCT03816163）。 5. claudin 18.2阳性胃癌的临床病理特征 不同的研究已经描述了claudin 18.2在胃癌中的表达及其在预后上的含义，尽管使用了不同的商业可获得的抗体和阳性定义。如前所述，在SPOTLIGHT和GLOW试验中使用的43-14A抗claudin 18抗体识别了claudin 18.1和claudin 18.2的C末端。能够区分1型和2型的抗体对于胃癌样本的IHC分析并非必要，尽管对于非胃组织的claudin 18.2测试，更精确的诊断将至关重要。考虑到1型和2型有超过90%的肽同源性，并且在第一个外细胞域的51个氨基酸中只有8个不同，生产这种高度选择性的抗体是一个重大挑战。EPR1902/ab22512是一种商业上可获得的替代抗体，专门针对claudin 18.2，其表位位于1-100个氨基酸之内。然而，当使用两种抗体进行分析时，只有46.7%的样本被分类为具有相同水平的claudin 18.2表达，并且与43-14A相比，EPR1902/ab22512始终报告了更低的灵敏度。此外，已经使用了各种测量方法来定义阳性，如强度和/或染色区域的定性评估，以及H得分等半定量测量，这些通常不是可互换的。使用43-14A分析的样本的阳性标准定义为IHC得分>2+（意味着中等至强的膜染色强度）和在两个关键的III期试验中，≥75%的癌细胞表面积的染色。使用此截止点确定的claudin 18.2表达模式通常遵循U形模式，少数样本被分类为claudin 18.2阳性和claudin 18.2阴性之间的边缘。 在涉及4507名筛查患者的SPOTLIGHT和GLOW试验的联合分析中，38.4%的患者被认为是claudin 18.2阳性肿瘤。当排除HER2阳性癌症患者时，这个百分比增加到42.3%（SPOTLIGHT，41.9%；GLOW，42.9%）。在两项应用相同检测和诊断标准的回顾性研究中，已经证明了略低的阳性率（24.0%和33.4%）。在SPOTLIGHT和GLOW试验中，观察到白人（42.3%）和亚洲（36.4%）患者之间claudin 18.2阳性百分比的统计学显著差异（P=0.0004）。然而，报告的阳性率的区域差异是不一致的。例如，在MONO研究中，在德国和瑞士的多个中心进行，共筛查了268名患者，其中54名基于该研究中≥50%肿瘤细胞的claudin 18.2 IHC得分≥2+被认为符合条件。在这些患者中，有29名在≥70%的肿瘤细胞上IHC得分>2+。考虑到MONO中66名患者的claudin 18.2表达状态未知，这个队列中有10.8-35.4%的claudin 18.2阳性癌症。在FAST中，在中欧或东欧六个国家的中心进行，38.7%（334/686）的患者有claudin 18.2阳性疾病（定义为≥40%肿瘤细胞的IHC得分2+或3+）。在日本进行的一项回顾性研究中，使用与FAST相同的标准，报告了相似水平的claudin 18.2阳性（52%，135/262名患者）。来自先前研究的数据表明，亚洲患者（24%）的claudin 18.2阳性百分比低于欧洲（32%）或北美（34%）的患者。根据SPOTLIGHT和GLOW试验样本的生物标志物分析，中国大陆胃癌患者中claudin 18.2阳性的百分比（35.0%）与北美（37.7%）相似，但低于欧洲和中东（44.0%）。还观察到claudin 18.2表达与年龄或性别之间的统计学显著关联。在≤65岁的患者中观察到更高比例的claudin 18.2阳性肿瘤（40.9%），而不是>65岁的患者（34.3%），在≤75岁的患者中（39.0%）高于>75岁的患者（30.9%）。更高比例的女性患者有claudin 18.2阳性癌症（43.7%）而不是男性患者（36.9%）。在弥漫型组织学肿瘤中观察到更高比例的claudin 18.2阳性（48.3%）而不是肠型组织学肿瘤（38.8%）。值得注意的是，尽管已经报告了claudin 18.2状态与几个患者或临床特征之间的统计学显著关联，但大多数组之间claudin 18.2阳性的流行差异通常很小。此外，胃和GEJ癌症之间不存在一致的claudin 18.2阳性差异。 来自先前回顾性分析的数据表明，Borrmann 4型肿瘤中claudin 18.2阳性的一些富集（在未选择的队列中，28.6%的claudin 18.2阳性癌症，但只有17.1%的claudin 18.2阴性癌症）以及在印戒细胞癌（SRCC）组织学中（分别为20.5%和12.0%）。在另一项研究中，报告了64.8%的SRCCs（105中的68）为claudin 18.2阳性（定义为>40%癌细胞的≥2+染色强度）。与claudin 18.2过表达类似，CLDN18–ARHGAP融合在SRCCs中也更普遍，报告的患病率为1.4–8.8%。大多数研究的数据表明，claudin 18.2阳性癌症患者的预后与claudin 18.2阴性疾病患者的预后相似。 6. claudin 18.2阳性胃癌的基因组和免疫学特征 分子特征化方法的进步揭示了胃癌的独特分子特征。在TCGA分析中，研究人员提出了四种分子亚型：Epstein-Barr病毒（EBV）阳性、微卫星不稳定性（MSI）、基因组稳定（GS）和染色体不稳定性（CIN）肿瘤。在转化研究中，claudin 18.2表达一直被报道在EBV阳性胃癌中（70-84%），尽管一项研究的发现表明，这种亚型的癌症中只有26%的claudin 18.2阳性。关于claudin 18.2表达在其他TCGA胃癌亚型中的流行情况的数据有限，尽管IHC分析显示20.8%的错配修复缺陷（dMMR）癌症中表达claudin 18.2。其他研究报告了claudin 18.2阳性与MSI-H之间的有限关联，特别是对于表达高水平claudin 18.2的肿瘤。关于胃癌CIN亚型中claudin 18.2表达的数据更加有限，尽管这一亚群中ERBB2扩增的更高流行率以及这种扩增与claudin 18.2阳性的有限重叠意味着这一亚型的claudin 18.2表达水平适中。claudin 18.2在早期发病和/或弥漫型胃癌中的过度表达的主导地位表明与GS、微卫星稳定/上皮-间充质转化（MSS/EMT）或E-cadherin缺失TCGA簇的关联。然而，CDH1突变是GS亚型的特征性标志，在claudin 18.2阳性癌症中很少被检测到（在一项分析中的样本中为4%）。对几个公开可用数据集的生物信息学分析表明，在EBV阳性和MSS TP53阳性或TP53阴性的胃癌亚型中CLDN18水平更高。尽管存在这些关联，但这些分析中没有出现claudin 18.2过表达胃癌的独特分子特征。这一观察可能反映了claudin 18.2过表达源于启动子CpG岛的低甲基化。因此，可能需要结合表观基因组学的全面分析才能提供这样的分类。 EBV在感染胃上皮细胞后保持潜伏状态，可能通过甲基化沉默某些基因的转录，以防止产生来自病毒的免疫原性蛋白。这种潜伏状态反映在EBV阳性胃癌保留了与非恶性胃上皮相似的CLDN18和CLDN3表达谱的观察中。EBV相关胃癌的病因尚不清楚，但可能源于病毒感染和胃上皮细胞固有的一个或多个未识别因素的组合，可能是与维持胃上皮原始属性相关的因素，尽管需要进一步的调查来确认这个假设。 也探讨了claudin 18.2表达与其他生物标志物的关系。在具有不同阶段肿瘤的独立队列中，没有报告MSI-H和claudin 18.2表达之间的统计学显著关联。三项独立的回顾性分析确定了claudin 18.2和HER2表达的重叠，患者中有3.4-4.9%的人表达这两种蛋白，与claudin 18.2阴性肿瘤相比，较少的HER2阳性肿瘤也表达claudin 18.2。对SPOTLIGHT和GLOW数据的探索性分析表明，17.2%的claudin 18.2阳性AGCs也是PD-L1阳性（定义为CPS≥5），但由于几个可能的因素，包括使用不同的检测方法、回顾性分析和患者数量有限，研究之间观察到了一些变化。一项对1967名患者的样本进行的大规模分析显示，携带CDH1突变的肿瘤中claudin 18.2 mRNA水平更高，而其他研究提供了相互矛盾的结果。总的来说，claudin 18.2阳性胃癌没有独特的分子特征，这强调了在所有胃癌亚型中广泛筛查claudin 18.2表达的重要性。 图4 | 各类在研claudin 18.2靶向治疗的作用机制。各种claudin 18.2靶向治疗已经在临床试验中或正在进行测试。由于直接抑制目标蛋白缺乏临床活性，像zolbetuximab这样的单克隆抗体被设计成诱导抗体依赖性细胞介导的细胞毒性（ADCC）和/或补体依赖性细胞毒性（CDC），导致细胞死亡。双特异性T细胞引导分子或双特异性抗体旨在同时结合claudin 18.2以及其他目标蛋白，例如前者的CD3和其他一系列免疫相关目标蛋白，通常目的是将活跃的免疫细胞与肿瘤细胞紧密地靠近。针对claudin 18.2的抗体-药物偶联物（ADCs）旨在向表达claudin 18.2的癌细胞输送高毒性药物，这些药物随后能够在内吞和内体消化后（非可裂解链接物）或通过癌细胞特异性酶裂解链接物（可裂解链接物）释放有效载荷，导致癌细胞死亡，同时不损害周围非恶性细胞。针对claudin 18.2的第二代嵌合抗原受体（CAR）T细胞由CD8α铰链区域、CD28共刺激域和CD3ζ信号域组成。CAR T细胞经过基因改造，以识别和消除表达claudin 18.2的细胞。VH，免疫球蛋白重链可变区；VL，免疫球蛋白轻链可变区。 claudin 18.2阳性胃癌及其肿瘤微环境（TME）的免疫学特征也得到了评估。值得注意的是，自然杀伤（NK）细胞数量减少和中性粒细胞数量增加是claudin 18.2阳性胃癌的普遍特征，这一点在多项研究中得到了证实。转录分析还表明，在TME中，B细胞水平升高，调节性CD4+ T细胞、CD8+ T细胞和髓样树突状细胞数量有限，而关于巨噬细胞存在数据在研究中不一致。此外，对80个胃癌标本的多重IHC分析显示，在不表达免疫检查点及其相关配体（如PD-1、PD-L1、LAG3和TIM3）的claudin 18.2阳性肿瘤中，CD8+ T细胞的比例更高。这些发现表明，claudin 18.2阳性胃癌可能具有“冷”免疫学表型，免疫细胞浸润有限，TME免疫抑制，这与回顾性研究的数据一致，表明在claudin 18.2阳性胃癌患者中，抗PD-1或抗PD-L1抗体的活性与claudin 18.2阴性疾病患者相比相似或较差。这些免疫学特征也可能对选择新的claudin 18.2靶向治疗策略（如涉及ADCs和CAR T细胞的策略）具有意义。 关于携带CLDN18–ARHGAP融合的肿瘤的免疫表型，目前只有有限的数据。一项研究表明，通过激活PI3K/AKT–mTOR FAS信号通路的脂肪酸分泌可能有助于形成免疫抑制性的肿瘤微环境（TME），包围携带CLDN18–ARHGAP融合的胃癌细胞。这个结果尚未得到其他研究的支持，尽管所建议的机制与之前研究的数据一致，该研究展示了携带功能增益RHOAY42C突变的胃癌细胞具有类似的代谢特征，这些突变可能激活与CLDN18–ARHGAP融合相同的下游效应信号通路。因此，将免疫原性研究与对癌症代谢的见解结合起来，可能为如何应对免疫学上“冷”的胃癌提供新的视角。 7. 针对claudin 18.2的临床试验 7.1 针对claudin 18.2的单克隆抗体 7.1.1 Zolbetuximab Zolbetuximab，最初被称为IMAB362，结合在claudin 18.2的第一个外细胞环中的一个独特表位，其特异性由相对于claudin 18.1的八个变异氨基酸的存在决定。这种嵌合IgG1单克隆抗体包括一个活跃的Fc结构域，能够通过ADCC和CDC诱导抗肿瘤免疫反应。研究人员在I期研究中测试了zolbetuximab单药治疗不同剂量（补充信息）在表达不同水平claudin 18.2（从无检测表达到90%肿瘤细胞上的3+）的晚期胃癌或胃食管结合部（GEJ）癌症患者。胃肠道毒性是最常见的不良事件，尽管只有一名接受最高剂量（1000 mg/m^2）的患者出现了3级不良事件（呕吐），被认为是与治疗相关的。基于药代动力学和药效学数据，推荐的zolbetuximab II期剂量确定为每两周300-600 mg/m^2。使用来自患者和捐赠者的外周血单核细胞（PBMCs）的体外试验证实了zolbetuximab诱导ADCC和/或CDC的能力。随后的IIa期MONO研究在多个中心测试了这种剂量的zolbetuximab作为单药治疗，对象为表达claudin 18.2 ≥2+的晚期胃癌、GEJ或食道癌患者（表1）。在接受zolbetuximab的40名患者中，客观反应率（ORR）为10%，对于表达更高水平claudin 18.2的患者（定义为≥70%肿瘤细胞上的≥2+），增加到15%。3-4级呕吐（22%）和恶心（15%）是最常见的高级别不良事件，尽管在接受过胃切除术的患者中这两种都不那么频繁。这些事件中的许多出现在zolbetuximab最初的两次输注中，并且可以通过暂停或减少输注速率来管理。在日本进行的I期试验证实了zolbetuximab的毒性概况。FAST试验是一项随机II期试验，旨在评估zolbetuximab与表柔比星加奥沙利铂和卡培他滨（EOX）联合作为一线治疗的效果和安全性，共纳入了334名胃癌、GEJ或食道癌患者，这些患者的肿瘤细胞中≥40%表达≥2+ claudin 18.2（表1）。Zolbetuximab以800 mg/m^2的负荷剂量给药，随后在每个3周周期的第1天以600 mg/m^2给药。中位PFS（共同主要终点）在zolbetuximab加EOX组比EOX加安慰剂组显著更长。与组合疗法观察到中位OS（另一个共同主要终点）的类似显著改善（表1）。相比之下，来自探索性第三臂的数据，患者接受更高剂量的zolbetuximab（1000 mg/m^2）加EOX，与EOX加安慰剂相比，OS没有显著改善（中位9.6个月对8.3个月，风险比（HR）0.75，95%置信区间（CI）0.55–1.04；P=0.13）。预先指定的亚组分析显示，在≥70%肿瘤细胞表达claudin 18.2的患者中，获益富集（中位PFS 9.0个月对5.7个月，HR 0.38，95% CI 0.23–0.62；P<0.0005）。基于这些发现，进行了两项随机III期研究（SPOTLIGHT和GLOW），以进一步阐明这种剂量的zolbetuximab与标准化疗联合用于先前未经治疗的患者，这些患者患有HER2阴性、claudin 18.2阳性的局部晚期不可切除或转移性胃癌或GEJ癌症的疗效和安全性。在这两项试验中，使用自动免疫染色设备确定的75%的截止值被使用，这与FAST研究中使用的手动染色方法的70%的截止值相对应。选择背景化疗方案——SPOTLIGHT中的改良（m）FOLFOX6和GLOW中的CAPOX——反映了这两项试验中入组患者的地理分布。SPOTLIGHT的入组患者主要在亚洲之外（68.7%），一半的亚洲人群在日本的中心接受治疗。相反，62.1%的GLOW入组患者位于亚洲，主要是中国。在这两项试验中，中位PFS（主要终点）和中位OS的统计学显著改善都被观察到（表1）。ORR在治疗臂之间没有显著差异。与以前的研究类似，恶心和呕吐是zolbetuximab臂（表1）中主要的≥3级治疗相关不良事件（TRAEs）。两个研究中不良事件的总体发生率相似，尽管在SPOTLIGHT（11.4%）比GLOW（2.7%）中，导致中断zolbetuximab的TRAEs在两个臂之间的差异更大。根据来自SPOTLIGHT和GLOW的患者报告结果（PRO）数据，恶心和呕吐在zolbetuximab的最初几个周期中恶化，在接受六到八个周期后恢复到基线水平。在接受zolbetuximab加化疗与仅化疗治疗后，没有出现临床上有意义的全球健康状况或生活质量恶化。根据亚组分析的数据，亚洲种族的患者观察到PFS和OS的一致有利趋势，而GEJ癌症患者的预后较差。 CAPOX，卡培他滨加奥沙利铂；CI，置信区间；EOX，表柔比星加奥沙利铂和卡培他滨；GEJ，胃食管结合部；HR，风险比；mFOLFOX6，改良的5-氟尿嘧啶、亚叶酸和奥沙利铂；mOS，中位总生存期；mPFS，中位无进展生存期；ORR，客观反应率；TEAEs，治疗中出现的不良事件；vs，对比。a 免疫组化（IHC）得分在43-14A抗体检测下，≥50%的肿瘤细胞上≥2+。b 43-14A抗体染色的肿瘤细胞中，≥40%的细胞IHC得分≥2+。c 43-14A抗体染色的肿瘤细胞中，≥75%的细胞IHC得分≥2+。 这些结果表明，zolbetuximab在claudin 18.2阳性胃癌患者中持续改善生存结果，优化管理靶向胃肠道毒性将对这种药物的临床应用很重要。2023年7月6日，基于SPOTLIGHT和GLOW的数据，zolbetuximab被FDA授予优先审查地位，作为HER2阴性、claudin 18.2阳性胃癌或GEJ腺癌患者的一线治疗。正在进行的zolbetuximab疗效的进一步调查，包括与mFOLFOX6加nivolumab在ILUSTRO试验的4A/B队列中的组合（NCT03505320），反映了zolbetuximab的可接受耐受性以及来自临床前研究的数据，表明这种组合有希望的活性。在这个队列中，zolbetuximab每两周给药一次，基于zolbetuximab在以前研究中的药理学概况，支持每3周使用800/600 mg/m^2或每2周使用800/400 mg/m^2。 7.1.2 其他单克隆抗体 Osemitamab（也称为TST001）是一种差异化的重组人源化IgG1抗体，它具有高亲和力特异性结合claudin 18.2的细胞外结构域。由于Fc区的岩藻糖基化减少，Osemitamab具有增强的ADCC活性，导致在临床前研究中，即使在claudin 18.2表达有限的模型中，也比IMAB362类似物具有更强的ADCC、CDC和抗体依赖性细胞吞噬作用。I期研究的数据显示，这种药物与CAPOX联合给药通常耐受性良好，大多数患者只有1-2级不良事件，包括恶心、低白蛋白血症和呕吐。7名（17.9%）患者出现3级及以上不良事件，高血压是唯一在多于一名患者中观察到的事件。来自TranStar102试验（NCT04495296）C组的I/IIa期数据显示，Osemitamab联合CAPOX作为晚期胃癌或GEJ癌症患者的一线治疗，claudin 18.2表达≥1+的肿瘤细胞≥10%时，ORR为65.4%，中位PFS为9.5个月。正在TranStar102的其他两个队列中评估将Nivolumab添加到Osemitamab加CAPOX中，作为一线治疗（G组）或第三线或更晚线治疗（H组）。另一项I/IIa期试验（TranStar101; NCT04396821）正在评估不同剂量的Osemitamab单药治疗的安全性和有效性，随后是几个剂量扩展队列，包括胃癌或GEJ癌症患者的Osemitamab单药治疗；胃癌或GEJ癌症患者的Osemitamab加Nivolumab；PDAC或胆道癌症患者的Osemitamab单药治疗。 AB011是另一种重组人源化抗claudin 18.2抗体，I期试验的初步数据测试这种药物单独或与CAPOX联合用于晚期实体瘤患者，显示可管理的毒性和有希望的活性。在接受AB011加CAPOX的剂量递增臂中，70%（14/20）的患者出现3级及以上不良事件，包括中性粒细胞计数减少、贫血、低白蛋白血症、恶心和呕吐。该臂中确认的ORR和疾病控制率（DCR）分别为65.2%和100%。 MIL93是一种人源化去岩藻糖基化IgG1单克隆抗体，靶向claudin 18.2，具有增强的ADCC功能和高亲和力。这种抗体在体外显示出优于IMAB362类似物的活性。在中国六个中心进行的I期剂量递增研究中，研究人员报告说，每3周20毫克/千克的剂量具有可接受的毒性概况。尽管在未接受胃切除术的患者中，任何级别和3级及以上与MIL93相关的不良事件发生在94.1%和47.1%的患者中，但对于之前接受过胃切除术的患者，这些百分比分别下降到84.6%和15.4%。在17名未选择claudin 18.2的胃癌或GEJ癌症患者中，ORR和DCR分别为11.8%和41.2%。 ASKB589是一种人源化IgG1单克隆抗claudin 18.2抗体，也在体外研究中报告具有高亲和力，并能够比IMAB362类似物实现更强效的ADCC和/或CDC。目前正在进行一项I/II期试验，测试ASKB589与CAPOX和抗PD-1抗体Sintilimab联合作为一线治疗，用于claudin 18.2阳性（定义为任何肿瘤细胞上的≥1+膜染色强度）胃癌或GEJ腺癌患者。来自这项试验的初步数据显示有希望的抗肿瘤活性，15名疗效可评估患者中有80%的ORR和100%的DCR。3级及以上不良事件发生在11.5%的患者中。ASKB589目前正在与CAPOX加抗PD-1抗体Sintilimab联合在III期试验中进行测试，招募claudin 18.2阳性（肿瘤细胞≥40%）、晚期胃癌或GEJ癌症患者。 ZL-1211是另一种能够特异性、高亲和力结合claudin 18.2的人源化IgG1单克隆抗体。在ZL-1211的Fc区引入的位点特异性突变S239D和I332E赋予这种抗体高水平的ADCC和在小鼠异种移植模型中强大的抗肿瘤活性。正在进行的I/II期研究的初步结果测试这种药物用于先前治疗过的claudin 18.2阳性实体瘤患者，显示可接受的毒性概况，包括3级TEAEs在15.8%的患者中（3/19）。在9名疗效可评估的患者中，有3名病情缓解，没有人有部分缓解作为最佳总体反应。涉及claudin 18.2阳性胃癌或GEJ癌症患者的II期部分试验正在进行中。 7.1.3 双特异性抗体 双特异性抗体旨在同时结合位于同一或不同目标蛋白上的两个不同表位。因此，双特异性抗体的作用机制与单克隆抗体截然不同。双特异性抗体可以建立紧密的物理接近性，导致两个特定结合位点之间的相互作用，其中可以包括两种不同的细胞类型（反式结合）或在同一个细胞的膜上结合两个分子（顺式结合）。这种依赖性可以是时间上的（顺序发生的结合事件）或空间上的（同时发生的结合事件）。 7.1.4 双特异性T细胞引导分子 双特异性T细胞引导分子方法涉及通过将针对肿瘤特异性抗原的抗体与能够结合大多数T细胞的抗CD3抗体链接，创建双特异性抗体。这种双特异性抗体结合并激活T细胞，可能包括CD8+（细胞毒性）T细胞，并将其与目标表位靠近。这种活性可以通过CD8+ T细胞消除癌细胞。 Blinatumomab，一种针对CD19和CD3的首创双特异性抗体，在晚期急性淋巴细胞性白血病患者中取得成功，定义了使用双特异性抗体将T细胞重定向到肿瘤的概念。Gresonitamab、ASP2138、AZD5863和QLS31905都是设计用于结合claudin 18.2和CD3的在研双特异性抗体。Gresonitamab已在涉及AGC或PDAC患者的国际多中心I期研究中进行测试。这项研究已被列为完成，尽管到目前为止，据我们所知，结果尚未公开披露。QLS31905已在涉及大量预处理的晚期实体瘤患者的I期试验中进行测试。在52名安全人群中，任何级别和3级及以上TEAEs分别发生在51名（98.1%）和21名患者（40.4%）中。两名接受第二高剂量（每周350微克/千克）的患者出现3级及以上细胞因子释放综合征。在接受≥200微克/千克剂量的27名患者中，ORR和DCR分别为11.1%和63.0%。在胃癌或GEJ癌症患者中未观察到反应。测试ASP2138（NCT05365581）和AZD5863（NCT06005493）的I期研究正在进行中。 7.1.5 双特异性抗体靶向其他目标 Q-1802是一种人源化双特异性抗体，靶向claudin 18.2和PD-L1。Q-1802可能招募任何表达PD-L1的细胞，包括T细胞、巨噬细胞和NK细胞，有可能通过T细胞介导的细胞毒性、ADCP和ADCC诱导抗肿瘤活性。Q-1802还可能通过与树突状细胞上的PD-L1结合来促进抗原呈递。该药物正在一个开放标签、单臂I期试验中进行测试，该试验有两个阶段：剂量递增（Ia期）和剂量扩展（Ib期）（NCT04856150）。剂量递增阶段已经完成，剂量扩展阶段正在进行中，涉及胃癌、胰腺癌或胆道癌患者。使用高达20毫克/千克剂量的Q-1802未检测到剂量限制毒性。最常见的任何级别不良事件是恶心（62.1%）、呕吐（62.1%）和腹痛（27.6%），但只有三名患者（10.3%）观察到3级及以上的恶心和呕吐。七名患者发生了免疫相关不良事件，包括甲状腺功能异常、疲劳、皮疹和关节炎，大多数为1-2级。在九名剂量扩展队列患者中，两名部分缓解，四名病情稳定。 表达CD47“不要吃我”蛋白的细胞通过与主要在巨噬细胞上表达的跨膜糖蛋白SIRPα的相互作用逃避吞噬。然而，癌细胞能够利用这种先天免疫耐受机制逃避免疫监视。靶向CD47–SIRPα的研究正在测试中，涉及胃癌（NCT05002127）、结直肠癌（NCT05167409）或头颈癌（NCT04675294）等实体瘤患者的研究。PT886是一种新型双特异性抗体，靶向claudin 18.2和CD47。该药物正在一个开放标签的I期试验中进行测试，涉及晚期胃癌和GEJ腺癌或PDAC患者。 Givastomig（之前称为TJ-CD4B/ABL111）是一种创新的双特异性抗体，旨在同时靶向claudin 18.2和4-1BB，这是在活化的T细胞、NK细胞、树突状细胞、B细胞、单核细胞和中性粒细胞上表达的TNF受体家族共刺激受体。以前的数据显示givastomig能够结合表达有限claudin 18.2的肿瘤细胞，并且这种药物在体外具有优于抗4-1BB单克隆抗体的抗肿瘤活性。这种在低水平目标表达上的假定活性使givastomig成为一个有希望的候选药物，用于更广泛的人群。此外，这种药物只在与claudin 18.2结合时才激活T细胞，这避免了由于过度的非靶向T细胞激活引起的肝脏毒性，并减少了由于先天免疫激活引起的不良事件的风险。Givastomig目前正在美国和中国的中心进行I期试验（NCT04900818）。这项研究的初步数据显示三名患者（16.6%）部分缓解。常见的毒性包括1-2级恶心（22%）、疲劳（14%）和呕吐（12%），共报告了七次3级事件。这里描述的几种双特异性抗体靶向claudin 18.2和免疫检查点，可能反映了claudin 18.2阳性癌症的独特TME，其中包括更多的非耗竭CD8+ T细胞和CD4+ T细胞。因此，双特异性抗体可能不需要高水平的claudin 18.2表达就能实现强大的抗肿瘤活性。尽管没有直接的比较，但双特异性抗体通常似乎与zolbetuximab加化疗相比，血液学不良事件、恶心和呕吐的关联程度较轻，尽管如此，应该谨慎对待免疫相关不良事件的可能性。 7.2 CAR T cells 嵌合抗原受体（CAR）T细胞是一种革命性的发展，彻底改变了晚期B细胞恶性肿瘤患者的治疗，包括白血病和淋巴瘤。此外，这项技术在治疗实体瘤患者，包括胃肠道癌症方面的应用也正在取得进展。 CT041是一种靶向claudin 18.2的第二代CAR T细胞产品，包含CD8α铰链区、CD28共刺激域和CD3ζ信号域。临床前数据表明，在小鼠异种移植模型中，CT041展现了强大的抗肿瘤活性，且没有对非恶性胃组织或其他器官造成明显损伤。在I期研究中，CT041在转移性claudin 18.2阳性胃癌或胰腺腺癌患者中表现出相当的潜力（ORR 33.3%，中位PFS 130天）。基于这些有希望的结果，启动了第二项I期试验。该研究招募了37名经过大量预处理的晚期胃肠道癌症患者，其中包括28名胃癌患者、5名胰腺癌患者和4名肿瘤细胞表达claudin 18.2弱到强的其它癌症类型患者。所有患者和仅有胃癌患者的ORR分别为48.6%和57.1%，DCR分别为73.0%和75.0%。在最后的截止点，报告的中位PFS为3.7个月，6个月OS率为80.1%。清淋化疗导致的血液学毒性是最常报告的≥3级不良事件，发生在所有患者中。细胞因子释放综合征在94.6%的患者中观察到，大多数为1-2级。没有患者发展为免疫效应细胞相关神经毒性综合征（ICANS）。该研究目前正在进行中，CT041的进一步研究正在进行确认性的Ib/II期研究。 其他几种靶向claudin 18.2的CAR T细胞疗法目前正在早期阶段研究中进行测试，包括配备4-1BB共刺激域的第二代CAR LB1908，以及设计用于分泌特定细胞因子和趋化因子的第四代CAR T细胞RD07和CT048。基于这些有希望的数据和大量的研究活动，靶向claudin 18.2的CAR T细胞可能成为晚期claudin 18.2阳性胃肠道癌症患者的重要治疗方法。 CAR T细胞制造涉及患者自身免疫细胞的体外扩增和改造，需要在获取血样和治疗之间等待一段时间。CAR T细胞治疗的反应谱与大多数其他治疗不同，其主要特点是短期不良事件，很少有累积性或慢性毒性，尽管在少数患者中报告了继发性T细胞恶性肿瘤。此外，CAR T细胞治疗已被证明可以提供长期无治疗缓解，几乎不需要后续住院治疗，这对经过大量预处理的胃癌患者来说是一种新颖且非常受欢迎的体验。然而，大多数接受CAR T细胞治疗的实体瘤患者的反应目前并不像血液学恶性肿瘤患者那样持久，这可能反映了诸如肿瘤异质性程度和免疫抑制微环境存在等差异。此外，自体CAR T细胞的高成本可能限制了它们未来的实施。 7.3 抗体-药物偶联物（ADCs） 继针对HER2的ADC药物trastuzumab deruxtecan（T-DXd）取得成功后，ADCs正在深刻影响着治疗决策和药物开发模式。由于相当一部分胃食管结合部（GEJ）或胃癌患者呈claudin 18.2阳性（在GLOW和SPOTLIGHT数据综合分析中为38.4%），因此人们非常期待开发针对claudin 18.2的ADCs。这些药物有三个基本组成部分：一种针对肿瘤相关抗原的抗体、一种细胞毒素有效载荷和连接链接器。通过将细胞毒素有效载荷通过链接器与单克隆抗体偶联，ADCs结合了抗体的高度特异性和小分子的强细胞毒性。进入血液后，ADCs与肿瘤细胞表面表达的目标抗原结合。然后肿瘤细胞内吞ADCs，并随后被溶酶体酶裂解以释放细胞毒素小分子。这些小分子通过多种机制（包括破坏癌细胞DNA或微管）诱导细胞毒性，从而导致癌细胞死亡，理论上同时最小化对非恶性组织的毒性。 ADC开发正在蓬勃发展，尽管到目前为止，公开披露的临床数据仅有两种针对claudin 18.2的ADCs：SYSA1801和CMG901。其他大多数仍在早期临床测试中，包括TPX-4589/LM-302、RC118、SKB315、SOT102、TORL-2-307-ADC和JS107。 SYSA1801（也称为EO3021）是一种特异性针对claudin 18.2的ADC，使用单甲基auristatin E（MMAE）有效载荷，药物-抗体比（DAR）约为2。在一项正在进行的I期试验中，33名晚期、经过大量预处理的claudin 18.2阳性胃癌或胰腺癌患者，肿瘤细胞上claudin 18.2表达水平不一（≥1%），接受了递增剂量的SYSA1801单药治疗，最高剂量为3 mg/kg。在21名疗效可评估的患者中，ORR为38.1%，DCR为57.1%，在胃癌患者中增加至47.1%和64.7%。在接受3.0 mg/kg剂量的患者中，大多数患者出现恶心和呕吐，包括7名患者中的6名（85.7%）出现任何级别的恶心，7名中的3名（42.9%）出现3级及以上恶心，以及7名中的5名（71.4%）和2名（28.6%）出现呕吐。干眼症，也被认为与治疗相关，在33名患者中的7名（21.2%）中观察到。在3.0 mg/kg剂量下，未观察到3级及以上干眼症。尽管有这些额外的毒性，但在3.0 mg/kg剂量（ORR 20%）没有观察到活性增加。目前正在进行额外的剂量优化研究，测试2.0和2.5 mg/kg剂量，包括在中国以外地区（NCT05980416）。 CMG901（也称为AZD0901）由一种人源化IgG1抗claudin 18.2抗体组成，通过可被蛋白酶裂解的链接器与MMAE有效载荷偶联，DAR约为4。CMG901通过MMAE介导的细胞毒性以及旁观者杀伤效应、ADCC和CDC展示了强大的临床前活性。2023年11月，一项测试CMG901的I期试验的剂量递增和剂量扩展队列中，113名晚期、预处理的GEJ或胃癌患者的联合数据显示，2.2 mg/kg剂量的确认ORR为42%，2.6 mg/kg为24%，3.0 mg/kg为38%。这些ORR在几个亚组中保持一致，包括ECOG表现状态为1的患者、有腹膜转移的患者、接受过三次或更多先前治疗线的患者以及之前接受过抗PD-1抗体的患者。在整个队列中，最常见的任何级别和3级及以上血液学毒性分别是贫血（63%和13%）和中性粒细胞计数减少（52%和19%）。后一种事件与剂量相关，随着剂量的增加，任何级别的中性粒细胞计数减少和3级及以上中性粒细胞计数减少都有所增加，从2.2 mg/kg（41%和11%）到2.6 mg/kg（56%和22%），到3.0 mg/kg（68%和26%）。任何级别的非血液学毒性，包括呕吐、体重减轻、恶心和食欲减退，所有这些都发生在≥50%的患者中，尽管呕吐是这些事件中唯一在≥10%的患者中观察到的3级及以上形式。 细胞毒素有效载荷是ADCs的重要组成部分，对这类药物的治疗功效起着关键作用。CMG901和SYSA1801都具有MMAE有效载荷。T-DXd配备了不同的有效载荷（deruxtecan），尽管其他与特定药物相关的特征，包括DAR以及由不同的抗体、链接器和有效载荷组合创造的其他变化，都可能影响ADC的整体功效。CMG901和SYSA1801都具有可裂解的链接器。理想的链接器应在系统循环中保持高度稳定，因此避免小分子毒素过早释放，这可能会对非恶性组织或细胞造成损害。然而，有效的链接器还应促进在到达肿瘤细胞时快速有效的有效载荷释放。在这方面，配备不可裂解链接器的ADCs可能具有更具针对性的活动和更少的非靶向毒性。相反，可裂解链接器可能具有更大的抗肿瘤活性，包括能够靶向位于表达目标抗原细胞旁边的抗原阴性癌细胞，即旁观者效应。配备可裂解链接器的ADCs也可能更具毒性，因为链接器裂解后可能会发生非靶向有效载荷释放。随着链接器的不断优化、更有效载荷的探索以及连接技术的持续改进，预计许多新型ADCs将在未来几年进入临床实践。尽管充满热情，但目前的临床试验由于缺乏长期随访数据，对慢性毒性（如眼部毒性、肺炎和间质性肺病）的累积发生率和严重程度提供了有限的见解。因此，进行大规模样本研究和长期随访至关重要，以彻底调查这些潜在的严重毒性。 CMG901和SYSA1801都可能有靶向胃肠道毒性，与zolbetuximab所见类似，需要仔细管理。这些事件可能反映了ADCC或CDC的参与，反映了这些ADCs中包含的单克隆抗体的活性Fc区域。目前处于临床前开发的至少一种ADC，IBI-343，具有设计为减少这类毒性发生率的沉默Fc域。 7.4 其他方法 基于mRNA的药物提供了快速合成特定蛋白质或新抗原的潜力，没有基因疗法相关的基因整合和突变风险。 图5 | 建议使用针对claudin 18.2的多样化治疗方法。现有数据表明，有效性可能会因治疗剂类别的不同而有所不同，这意味着应为不同水平的靶标表达选择不同的claudin 18.2靶向疗法。抗体-药物偶联物（ADCs）即使在claudin 18.2表达水平最低的情况下也可能有效，而单克隆抗体应用于claudin 18.2表达水平高的肿瘤患者，并与细胞毒性剂联合使用。尽管如此，对claudin 18.2具有改进亲和力的新型抗体可能会扩大从这类疗法中获益的患者范围。双特异性T细胞引导剂和双特异性抗体在claudin 18.2表达水平较低时可能更有效，这可能取决于其他目标抗原。ADCC，抗体依赖性细胞介导的细胞毒性；CAR，嵌合抗原受体；CDC，补体依赖性细胞毒性；CRS，细胞因子释放综合征。 此外，进入细胞的外源性mRNA只有短暂的活性，并且可以被完全降解[137,138]。BNT141是一种创新的基于RNA的疗法，由两个假尿苷修饰的mRNA组成，编码针对claudin 18.2的抗体，这些mRNA被包裹在脂质纳米颗粒中，是这一类疗法中最早进入临床测试的产品之一。这种药剂在肝脏中优先积累，其中RNA进行翻译，随后蛋白质产物被释放到循环中，作为完全组装的抗claudin 18.2抗体。对BNT141的临床前评估表明，其剂量-暴露比率比传统的抗体对应物IMAB362更有利。这些数据还表明，BNT141的低剂量就足以在患者中实现生物学上相关的抗体暴露[139]。2020年12月启动了一项I/II期、开放标签、多中心试验（NCT04683939），测试BNT141，招募目标为48名患者，尽管这项研究在2023年10月由赞助商因未公开的原因中断[140]。 在mRNA基础疗法得以实施之前，需要进行大量的进一步研究和开发。 8. 针对claudin 18.2的疗法的临床实施 SPOTLIGHT和GLOW研究的成功结果引发了关于zolbetuximab临床实施的新问题。值得注意的是，38.4%的筛选患者被认为有claudin 18.2阳性癌症，这几乎是通常被诊断为HER2阳性疾病的患者的两倍。因此，预计晚期胃或GEJ癌症患者的一线治疗格局将发生重大变化。重要的是，zolbetuximab的监管批准应伴随着claudin 18.2表达的伴随诊断IHC测试的批准，以识别符合治疗条件的患者。基于IHC的检测是检测关键生物标志物的既定方法，包括胃癌患者中的HER2或PD-L1表达和dMMR蛋白。IHC测试claudin 18.2通常只需要一个额外的病理切片进行分析，因此，将此测试纳入诊断工作流程应该是可行的。事实上，我们在国家癌症中心医院的临床实践中，几乎所有胃癌患者的病理样本都同时测试了claudin 18.2。主要挑战包括安全有效地将化学修饰的mRNA传递给患者的靶细胞，以及在最小化任何非目标效应的同时最大化免疫原性[14,141]。重要的未解答问题包括如何确定最佳治疗剂量，以及最佳mRNA剂量和药代动力学参数在患者之间变化的程度。 东部（一个高容量、综合性癌症中心），并且结果通常在活检采样后大约1周内可获得[76]。这种简化的方法可以帮助确保符合条件的患者及时获得zolbetuximab。 目前，HER2阴性胃或GEJ癌患者的标准一线治疗涉及基于铂类-氟嘧啶的方案，无论是否加上抗PD-1抗体。然而，随着zolbetuximab的出现，讨论HER2阴性和claudin 18.2阳性肿瘤患者的首选一线治疗方法变得至关重要。具体来说，一个重要的问题出现了，即是否将抗PD-1抗体或zolbetuximab与化疗结合使用。由于缺乏直接比较，目前这个阶段没有明确的答案。尽管如此，对于PD-L1阴性或PD-L1低（CPS < 5）且claudin 18.2阳性的肿瘤患者，zolbetuximab可能是首选。这一建议反映了抗PD-1抗体在PD-L1 CPS <5肿瘤患者中的有限益处。相比之下，nivolumab或pembrolizumab在MSI-H肿瘤患者中的有效性显著增强，表明这些免疫检查点抑制剂之一加上化疗应该是这些患者的首选方案。对于具有重叠生物标记物表达的患者，如PD-L1 CPS >5和高水平claudin 18.2表达（SPOTLIGHT和GLOW研究中17.4%的患者），选择这两种方案之间的任何一种都可能成为合理的治疗选择。因此，一个考虑到每个患者偏好的共同决策过程，在确定最合适的治疗方法方面将变得越来越重要。其他生物标记物驱动疗法的疗效的新兴证据，如针对FGFR2b的疗法，可能会进一步复杂化携带多个重叠生物标记物的肿瘤患者的治疗选择。 由于claudin 18.2在非恶性胃黏膜上的限制性表达，恶心和呕吐是要考虑的相关靶向毒性。事实上，在SPOTLIGHT和GLOW中观察到的主要毒性是恶心和呕吐，导致一小部分患者停止治疗。有效管理这些毒性对于在临床实践中成功实施zolbetuximab至关重要。在III期试验中，建议使用NK-1或5-HT3抑制剂等抗呕剂。同时，应考虑尽可能避免或最小化使用皮质类固醇作为预防性抗呕剂，因为担心免疫抑制，这可能导致受损的ADCC或CDC。在III期试验中实施了建议在第一周期期间减慢输注速度的指导。在临床前研究中，对雪貂进行的zolbetuximab测试的组织学发现，其中呕吐和干呕都是常见的观察结果，表明胃黏膜迅速被侵蚀，尽管没有炎症细胞的浸润，并且损伤在给药后6小时内扩散到浆膜。基于这些观察结果，我们怀疑呕吐主要是由CDC介导的。在这个临床前模型中，皮质类固醇减少了胃毒性的范围。这项研究的数据还表明，fosaprepitant，无论是否加上ondansetron，都减少了雪貂的呕吐程度。来自SPOTLIGHT和GLOW的数据的探索性亚组分析表明，同时使用抗呕剂，减慢输注速度和剂量中断都可能减轻恶心和呕吐的发生率。值得注意的是，接受皮质类固醇的患者似乎没有减少PFS或OS。有必要对这些患者中最有效的抗呕剂进行前瞻性澄清。在zolbetuximab的前几个周期中，恶心和呕吐的发生率增加，尽管两种毒性的发生率在几次剂量后都下降到基线水平。根据SPOTLIGHT和GLOW的PRO数据，接受zolbetuximab加化疗并不会相对于接受化疗损害整体健康相关的生活质量。 尽管zolbetuximab已经在高度claudin 18.2阳性胃癌患者中显示出生存益处，但仍存在几个挑战，一旦zolbetuximab获批，就需要解决。正在进行zolbetuximab与免疫检查点抑制剂联合使用以及在围手术期设置中的有效性进一步调查，如II期ILUSTRO试验的第3和第4队列。优化管理以减少胃肠道毒性的发生率将是顺利进入临床实践的关键。 9. 结论 针对claudin 18.2的疗法的出现彻底改变了传统靶向治疗的方法，扩大了可能靶标的范围。大多数靶向治疗方法都集中在细胞膜表达的直接作用于癌细胞增殖的靶标上，如受体酪氨酸激酶（RTKs）。然而，通常在非恶性胃上皮细胞的细胞间隙中表达的claudin 18.2，在肿瘤细胞增殖中的作用有限。由癌症发生引起的紧密连接的破坏或细胞极性的丧失，使claudin 18.2成为一个可接近的癌症靶标。尽管没有明确的分子特征，但早期发病的、弥漫型和硬化型胃癌以及小细胞胃癌（SRCCs）比其他亚型更有可能表达claudin 18.2。两个关键的临床试验（SPOTLIGHT和GLOW）的积极结果确立了高度claudin 18.2阳性的胃癌（AGCs）作为一个独立的治疗亚组，可能会从将zolbetuximab添加到化疗中获益。新型高亲和力单克隆抗体具有改进的亲和力和更强的抗肿瘤活性，以及双特异性抗体和抗体-药物偶联物（ADCs）有潜力进一步提高这一亚组的疗效，并可能将claudin 18.2靶向疗法的好处扩展到那些表达水平较低的患者。因此，未来这一领域的发展可能会涉及不同系统治疗方式之间的竞争。我们建议根据claudin 18.2的表达水平（见图5）使用每种方法。对claudin 18.2的异位表达的进一步研究也可能使claudin 18.2靶向疗法扩展到患有胰腺导管腺癌（PDAC）和其他实体瘤的患者亚组。针对其他claudins的药剂也在研究中。例如，一项I期研究测试了一种针对claudin 6的ADC，配备了MMAE有效载荷（TORL-1-23），在经过大量预处理的卵巢癌或睾丸癌患者中显示出可接受的耐受性和令人鼓舞的抗肿瘤活性。最后，正在测试针对claudin 6的CAR T细胞，无论是否使用旨在放大claudin 6表达的RNA疫苗，在经过大量预处理的晚期实体瘤患者中进行测试。如果成功应用于claudin 18.2，这种方法可以使claudin 18.2靶向疗法的使用不受基线claudin 18.2表达的限制。总之，针对claudin 18.2的疗法是一种创新的治疗方法，有潜力改善claudin 18.2阳性实体瘤患者的治疗结果。 识别微信二维码，添加生物制品圈小编，符合条件者即可加入 生物制品微信群！ 请注明：姓名+研究方向！ 版 权 声 明 本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。