Moderna and Merck announce mRNA-4157 (V940), an investigational personalized neoantigen therapy in combination with KEYTRUDA® (pembrolizumab) demonstrating superior recurrence-free survival in patients with high-risk stage III/IV melanoma after melanoma h (2023)

April 16, 2023 11:05 a.m. ET

CAMBRIDGE, MA & RAHWAY, New Jersey, April 16, 2023 - Moderna, Inc. (Nasdaq: MRNA),a biotechnology company pioneering messenger RNA (mRNA) therapies and vaccines, and Merck (NYSE:MRK), known as MSD outside the US and Canada, today announced the first presentation of detailed results from Phase 2b KEYNOTE-942/ mRNA - Study 4157 Announced -P201 evaluating mRNA-4157 (V940), an investigational personalized neoantigen (INT) therapy, in combination with KEYTRUDA, Merck's anti-PD-1 therapy, in patients with high-risk resected melanoma ( stage III/IV). In the general intent-to-treat population, adjunctive treatment with mRNA-4157 (V940) in combination with KEYTRUDA showed a statistically significant and clinically significant improvement in relapse-free survival (RFS) and reduced the risk of recurrence or death by 44% ( HR = 0.56 [95% CI, 0.309-1.017]; one-sided p-value = 0.0266) compared to KEYTRUDA alone.

These results will be presented at the 2023 American Association for Cancer Research (AACR) Annual Meeting and Press Conference (Abstract #CT001). Also presented are data from a subgroup analysis of KEYNOTE-942/mRNA-4157-P201 (Abstract # CT224) evaluating mRNA-4157 (V940) in combination with KEYTRUDA in patients based on tumor mutational burden (TMB) status.

"Today's results provide further encouragement for the potential of mRNA as a personalized neoantigen therapy to positively impact patients with high-risk resected melanoma," said Dr. Kyle Holen, M.D., senior vice president and chief of development, therapeutics and oncology. Modern. "The strongly observed reduction in the risk of recurrence-free survival suggests that this combination may be a new means of potentially extending the lives of patients with high-risk melanoma. We look forward to starting the Phase 3 melanoma study soon and expanding the testing for lung cancer and beyond.”

"The KEYNOTE-942 data demonstrate the potential of mRNA-4157 (V940) in combination with KEYTRUDA to improve recurrence-free survival when administered to patients with high-risk resected melanoma," said Dr. Eliav Barr, senior vice president. Head of Global Clinical Development and Chief Medical Officer, Merck Research Laboratories; “These data support the potential of mRNA-4157 (V940) in combination with KEYTRUDA to help target melanoma earlier and warrant testing the combination in a larger Phase 3 study. in a variety of other early-stage cancers".

Based on data from KEYNOTE-942/mRNA-4157-P201, the US Food and Drug Administration and the European Medicines Agency granted mRNA-4157 (V940) treatment status or PRIME regimen for adjunctive use in patients in combination with KEYTRUDA with high-risk melanoma after complete resection. Additional data from KEYNOTE-942/mRNA-4157-P201 will be presented at an upcoming medical meeting and published in a peer-reviewed publication. Companies had already announced positive data from this study in December 2022.

Additional Efficacy and Safety Data for KEYNOTE-942/mRNA-4157-P201 (Abstract #CT001)

In KEYNOTE-942/mRNA-4157-P201, 107 patients received mRNA-4157 (V940) in combination with KEYTRUDA and 50 patients were treated with KEYTRUDA alone. Relapse or death was reported in 22.4% of patients (n=24/107) in the combination arm compared to 40% of patients (n=20/50) receiving KEYTRUDA alone at a median follow-up of 23 and 24 months. e The 12-month RFS rate was 83.4% (95% CI, 74.7-89.3) and 77.1% (95% CI, 62.5-86.6) in the combination and arm of control. The 18-month RFS rate was 78.6% (95% CI, 69.0-85.6) and 62.2% (95% CI, 46.9-74.3) in the combination and control arms , respectively.

Adverse events reported with mRNA-4157 (V940) in KEYNOTE-942 were consistent with those previously seen in a Phase 1 clinical study. The safety profile of KEYTRUDA was consistent with results from previous studies. The number of patients reporting Grade ≥ 3 treatment-emergent adverse events was similar between arms (25% and 18%, respectively). The most common adverse reactions of any grade attributable to mRNA-4157 (V940) or the combination of mRNA-4157 (V940) and KEYTRUDA were fatigue (60.6%), injection site pain (55.8%) and chills. (50.0%).

TMB subgroup analysis by KEYNOTE-942/mRNA-4157-P201 (#CT224)

Data from an exploratory subgroup analysis of KEYNOTE-942/mRNA-4157-P201 showed that an improvement in RFS was seen with mRNA-4157 (V940) in combination with KEYTRUDA compared to KEYTRUDA alone, regardless of TMB status. BMR was evaluated from tumor biopsies analyzed by whole exome sequencing (WES) and whole transcriptome sequencing. According to the WES Genome Score established for KEYTRUDA, high BMR was defined as ≥10 mut/Mb (175 mut/exome) assessed using the FoundationOne CDx Assay.

The RFS advantage of mRNA-4157 (V940) in combination with KEYTRUDA compared to KEYTRUDA alone observed in the intent-to-treat population persisted in both high TMB (HR = 0.65; 95% CI: 0.284-1.494) and non-TMB high (HR=0.59; 95% CI: 0.243-1.425) subpopulations. The association between TMB treatment outcome and mRNA-4157 (V940) will be investigated in future planned studies.

About mRNA-4157 (V940)

mRNA-4157 (V940) is an investigational new personalized neoantigen therapy based on ribonucleic acid (mRNA)¹consisting of a single synthetic mRNA encoding up to 34 neoantigens, designed and engineered based on the unique mutational signature of the patient's tumor DNA sequence. After administration into the body, algorithm-derived, RNA-encoded neoantigen sequences are endogenously translated and undergo native cellular antigen processing and presentation, a key step in adaptive immunity.

Personalized neoantigen therapies aim to activate the immune system to allow a patient to develop a personalized antitumor response specific to the tumor's mutational signature. mRNA-4157 (V940) is designed to stimulate an immune response by generating specific T-cell responses based on the unique mutational signature of a patient's tumor. KEYTRUDA is an immunotherapy that works by increasing the body's immune system's ability to recognize and fight cancer cells. Based on early clinical studies, combining mRNA-4157 (V940) with KEYTRUDA may provide additional benefits and enhance T cell-mediated destruction of cancer cells.

Sobre KEYNOTE-942/mRNA-4157-P201 (NCT03897881)

KEYNOTE-942 is an ongoing, randomized, open-label, Phase 2b study that enrolled 157 patients with high-risk stage III/IV melanoma. After complete surgical resection, patients were randomized 2:1 (stratified by stage) to receive mRNA-4157 (V940) (1 mg every 3 weeks for nine doses) and KEYTRUDA (200 mg every 3 weeks for up to 18 cycles [for approximately one year]) versus KEYTRUDA for only approximately one year until disease recurrence or unacceptable toxicity. The primary endpoint is RFS, defined as the time from the first dose of KEYTRUDA to the date of the first recurrence (local, regional, or distant metastases), new primary melanoma, or death from any cause in the intent-to-treat population. Secondary endpoints include survival and safety without distant metastases, and exploratory endpoints include the distribution of TMB expression in baseline tumor samples across study arms and its association with the primary endpoint of RFS.

Primary study selection criteria included: patients with resectable cutaneous melanoma metastatic to a lymph node and at high risk of recurrence, patients with complete resection within 13 weeks prior to the first dose of KEYTRUDA, patients without disease at baseline (after one surgery) with no locoregional recurrence or distant metastases and no clinical evidence of brain metastases, patients with sequenceable paraffin-embedded solid tumor (FFPE) sample, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and patients with organ and spinal cord function reported at screening.

about melanoma

Melanoma, the most serious form of skin cancer, is characterized by the uncontrolled growth of pigment-producing cells. Melanoma rates have increased in recent decades, with nearly 325,000 new cases diagnosed worldwide in 2020. In the United States, skin cancer is one of the most commonly diagnosed cancers, and melanoma is responsible for the vast majority of cancer deaths of skin. It is estimated that by 2022 there will be approximately 100,000 new cases of melanoma diagnosed and nearly 8,000 deaths from the disease in the United States. Five-year survival rates are estimated to be 60.3% for stage III and 16.2% for stage IV.

Via KEYTRUDA® (Pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-Programmed Death-1 (PD-1) receptor therapy that works by increasing the body's immune system's ability to recognize and fight cancer cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands PD-L1 and PD-L2, thereby activating T lymphocytes capable of attacking cancerous and healthy cells.

Merck has the industry's largest immuno-oncology clinical research program. There are currently over 1,600 studies evaluating KEYTRUDA in a variety of cancer types and treatment settings. The KEYTRUDA clinical program aims to understand the role of KEYTRUDA in cancer and the factors that may predict a patient's likelihood of benefiting from KEYTRUDA treatment, including examination of many different biomarkers.

Select Indications for KEYTRUDA® (pembrolizumab) in the US

Melanoma

KEYTRUDAindicated for the treatment of patients with unresectable or metastatic melanoma.

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

See additional selected indications for KEYTRUDA in the US. by selected important safety information

Selected Important Safety Information for KEYTRUDA

Severe and deadly immune system side effects

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to PD-1 or PD-L1 and block the PD-1/PD-L1 pathway, reversing inhibition of the immune response, potentially reducing peripheral tolerance and induction is nullified by immune-mediated side effects. Immune-related side effects, which can be serious or fatal, can occur in any organ or tissue, can affect more than one body system at the same time, and can occur any time after starting or stopping treatment. The important immune-related side effects listed here may not include all possible serious and fatal immune-related side effects.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early detection and treatment are essential to ensure the safe use of anti-PD-1/PD-L1 therapies. Assess liver enzymes, creatinine and thyroid function at baseline and periodically during treatment. In TNBC patients treated neoadjuvantly with KEYTRUDA, blood cortisol levels should be monitored at baseline, prior to surgery and as clinically indicated. If immune-related adverse reactions are suspected, an appropriate evaluation should be initiated to rule out alternative causes, including infection. Promptly initiate medical treatment, including specialist consultation, as needed.

Suspension or permanent discontinuation of KEYTRUDA, depending on the severity of the immunological adverse reaction. If KEYTRUDA is discontinued or discontinued, systemic corticosteroid therapy (1 to 2 mg/kg/day of prednisone or equivalent) should generally be continued until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, begin corticosteroid taper and continue taper for at least 1 month. Consider other systemic immunosuppressants in patients whose side effects are not controlled by corticosteroid therapy.

immune-mediated pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have previously received chest radiation. Immune-related 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%). Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and 0.9% (26) of patients. All discontinued patients resumed KEYTRUDA after symptom improvement. of these, 23% had a relapse. Pneumonitis was cured in 59% of the 94 patients.

Pneumonitis occurred in 8% (31/389) of adult patients with cHL who received KEYTRUDA as monotherapy, including Grade 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior chest irradiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% discontinued KEYTRUDA, 68% discontinued KEYTRUDA, and 77% were cured.

Pneumonitis occurred in 41 (7%) patients, including fatal adverse reactions (0.2%), Grade 4 (0.3%) and Grade 3 (1%). In adult patients receiving adjunctive therapy for NSCLC, patients received high-dose corticosteroids for a median of 10 days (range: 1 day to 2.3 months). Pneumonitis led to discontinuation of KEYTRUDA in 26 (4.5%) patients. Of the patients who developed pneumonitis, 54% discontinued KEYTRUDA, 63% discontinued KEYTRUDA, and 71% were cured.

immunocompromised colitis

KEYTRUDA can cause immune-mediated colitis, which may include diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-resistant immune-mediated colitis. In corticosteroid-resistant colitis, consideration should be given to repeat testing for infection to rule out alternative etiologies. Immune 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 immunosuppressive therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and 0.5% (13) of patients. All discontinued patients resumed KEYTRUDA after symptom improvement. of these, 23% had a relapse. Colitis healed in 85% of the 48 patients.

Hepatotoxicity and immune-mediated hepatitis

KEYTRUDA as sole 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%). Systemic corticosteroids were required in 68% (13/19) of patients. Additional immunosuppressive therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and 0.3% (9) of patients. All discontinued patients resumed KEYTRUDA after symptom improvement. none of them relapsed. Hepatitis was cured in 79% of the 19 patients.

KEYTRUDA i Axitinibe

KEYTRUDA in combination with axitinib may cause liver toxicity. Monitor liver enzymes before starting treatment and periodically during treatment. Consider more frequent monitoring than when drugs are given as single agents. Discontinue KEYTRUDA and axitinib for elevated liver enzymes and consider corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grade 3 and 4 alanine aminotransferase (ALT) elevations (20%) and aspartate aminotransferase (AST) elevations (13%) occurred more frequently than with KEYTRUDA alone. Fifty-nine percent of patients with elevated ALT were receiving systemic corticosteroids. In patients with ALT ≥3 times the upper limit of normal (ULN) (Grades 2-4, n=116), ALT decreased to Grades 0-1 by 94%. Among 92 patients who were reintroduced with KEYTRUDA (n=3) or axitinib (n=34) alone or both (n=55), 1 patient who received KEYTRUDA had a relapse of ALT ≥ 3 times the ULN, in 16 patients who received axitinib and 24 patients who received both. All patients with ALT recurrence ≥3 ULN subsequently recovered from the event.

Immunvermittelte Endocrinopathien

Eat and Adrenaline

KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic therapy, including hormone replacement, as clinically indicated. Keep KEYTRUDA based on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients treated with 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 continued to use systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and 0.3% (8) of patients. All discontinued patients resumed KEYTRUDA after symptom improvement.

hypophysis

KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis may present with acute symptoms associated with masses such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Start hormone replacement as indicated. Suspension or permanent discontinuation of KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of KEYTRUDA-treated patients, including Grade 4 (<0.1%), Grade 3 (0.3%) and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients. of these, the majority continued to use systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and 0.3% (7) of patients. All discontinued patients resumed KEYTRUDA after symptom improvement.

thyroid disorders

KEYTRUDA can cause immune-mediated thyroid disease. Thyroiditis can occur with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement therapy for hypothyroidism or treat hyperthyroidism as clinically indicated. Suspension or permanent discontinuation of KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None were discontinued, but KEYTRUDA was discontinued in <0.1% (1) of patients.

Hyperthyroidism occurred in 3.4% (96/2799) of KEYTRUDA-treated patients, including Grade 3 (0.1%) and Grade 2 (0.8%). This led to permanent discontinuation of KEYTRUDA in <0.1% (2) and discontinuation in 0.3% (7) of patients. All discontinued patients resumed KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). This led to permanent discontinuation of KEYTRUDA in <0.1% (1) and discontinuation in 0.5% (14) of patients. All discontinued patients resumed KEYTRUDA after symptom improvement. Most patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new-onset or worsening hypothyroidism was highest in 1185 patients with HNSCC and occurred in 16% of patients receiving KEYTRUDA alone or in combination with platinum and FU, including grade 3 hypothyroidism (0.3%). The incidence of new-onset or worsening hypothyroidism was highest in 389 adult patients with cHL (17%) who received KEYTRUDA monotherapy, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism. The incidence of new or worsening hyperthyroidism was highest in 580 patients with resected NSCLC and occurred in 11% of patients receiving KEYTRUDA monotherapy as adjunctive therapy, including grade 3 hyperthyroidism (0.2%). The incidence of new or worsening hypothyroidism was highest in 580 patients with resected NSCLC and occurred in 22% of patients receiving KEYTRUDA monotherapy as adjunctive therapy (KEYNOTE-091), including grade 3 hypothyroidism (0.3%).

Type 1 diabetes mellitus (DM), which may be associated with diabetic ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate insulin therapy as clinically indicated. Keep KEYTRUDA based on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. This resulted in permanent discontinuation in <0.1%(1) and KEYTRUDA discontinuation in <0.1%(1) of patients. All discontinued patients resumed KEYTRUDA after symptom improvement.

Immune-mediated nephritis with renal dysfunction

KEYTRUDA can cause immune-mediated nephritis. Immune-related 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%). Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and 0.1% (3) of patients. All discontinued patients resumed KEYTRUDA after symptom improvement. none of them relapsed. Nephritis resolved in 56% of the 9 patients.

Immune-mediated dermatological side effects

KEYTRUDA may cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug eruption with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with anti-PD-1/PD-L1 therapies. Local emollients and/or topical corticosteroids may be sufficient to treat mild to moderate non-scaly eruptions. Suspension or permanent discontinuation of KEYTRUDA depending on severity. Immune-related dermatological adverse reactions occurred in 1.4% (38/2799) of patients treated with 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 of KEYTRUDA in 0.1% (2) and 0.6% (16) of patients. All discontinued patients resumed KEYTRUDA after symptom improvement. of these, 6% had a relapse. The reactions disappeared in 79% of the 38 patients.

Other immune-mediated side effects

The following clinically important immune-related adverse reactions have occurred with an incidence of < 1% (unless otherwise noted) in patients receiving KEYTRUDA or reported using other anti-PD-1/PD-L1 therapies. Severe or fatal cases of some of these side effects have been reported. Heart/vascular: myocarditis, pericarditis, vasculitis. Nervous system: meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve palsy, autoimmune neuropathy. Eyes: Uveitis, iritis, and other inflammatory ocular toxicities may occur. Some cases may be associated with retinal detachment. Varying degrees of visual impairment can occur, including blindness. If uveitis occurs in association with other immune-mediated adverse events, consider Vogt-Koyanagi-Harada type syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss. Gastrointestinal: pancreatitis, including increased serum amylase and lipase levels, gastritis, duodenitis. Musculoskeletal and Connective Tissues: Myositis/polymyositis, rhabdomyolysis (and related 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.

Infusion related reactions

KEYTRUDA can cause serious or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients treated with KEYTRUDA. Be alert for signs and symptoms of infusion-related reactions. Stop or decrease the infusion rate for Grade 1 or Grade 2 reactions. For Grade 3 or 4 reactions, stop the infusion and permanently stop KEYTRUDA.

Complications of allogeneic hematopoietic stem cell transplantation (HSCT)

Fatal and other serious complications can occur in patients receiving allogeneic HSCT before or after anti-PD-1/PD-L1 therapies. Transplantation-related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, reduced-grade post-conditioning hepatic veno-occlusive disease, and febrile syndrome requiring steroids (with no identified infectious cause). These complications can occur despite intermediate therapy between anti-PD-1/PD-L1 therapy and allogeneic HSCT. Monitor patients closely for signs of these complications and intervene promptly. Consider the benefits versus risks of using anti-PD-1/PD-L1 therapies before or after allogeneic HSCT.

Increased mortality in patients with multiple myeloma

In studies of patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with anti-PD-1/PD-L1 therapy in this combination is not recommended outside of controlled studies.

Fetal Toxicity

Due to its mechanism of action, KEYTRUDA can cause fetal harm if administered to a pregnant woman. Make women aware of this potential risk. In women of childbearing potential, assess pregnancy status before starting KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose.

Unwanted Actions

In KEYNOTE-006, 9% of 555 patients with advanced melanoma discontinued KEYTRUDA due to adverse events. Adverse reactions that led to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reactions (0.4%), polyneuropathy (0.4%) and heart failure. congestive (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 given as monotherapy in patients with stage III melanoma, KEYTRUDA was permanently discontinued in 14% of 509 patients due to adverse events. The most common (≥1%) were pneumonitis (1.4%), colitis (1.2%) and diarrhea (1%). Serious adverse events occurred in 25% of patients treated with KEYTRUDA. The most common adverse reaction (≥20%) with KEYTRUDA was diarrhea (28%). In KEYNOTE-716, when KEYTRUDA was given as monotherapy to patients with stage IIB or IIC melanoma, patients with stage IIB or IIC melanoma experienced adverse events similar to those seen in 1011 patients with stage III melanoma of KEYNOTE-054.

In KEYNOTE-189, when KEYTRUDA was co-administered with pemetrexed and platinum chemotherapy in non-squamous metastatic NSCLC, KEYTRUDA was discontinued in 20% of 405 patients due to adverse events. The most common adverse reactions leading to 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 fever (20%).

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

In KEYNOTE-042, KEYTRUDA was discontinued due to adverse events in 19% of 636 patients with advanced NSCLC. The most common were pneumonitis (3%), death from an unknown cause (1.6%) and pneumonia (1.4%). The most common serious adverse events 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 events 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%), dyspnoea (23%) and nausea (20%).

Adverse reactions seen in KEYNOTE-091 were generally similar to those seen in other NSCLC patients receiving KEYTRUDA monotherapy, with the exception of hypothyroidism (22%), hyperthyroidism (11%) and pneumonitis (7%). Two fatal myocarditis reactions occurred.

In KEYNOTE-048, KEYTRUDA monotherapy was discontinued due to adverse events in 12% of 300 patients with HNSCC. The most common adverse events 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 given in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, KEYTRUDA was discontinued in 16% of 276 patients with HNSCC due to adverse events. The most common adverse reactions leading to 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 in 17% of 192 patients with HNSCC due to adverse events. Serious side effects occurred in 45% of patients. The most common serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnoea, confused state, vomiting, pleural effusion and respiratory failure. The most common adverse reactions (≥ 20%) were fatigue, decreased appetite and dyspnoea. Adverse reactions observed in patients with HNSCC were generally similar to those observed in patients with melanoma or NSCLC receiving KEYTRUDA monotherapy, with the exception of an increased incidence of facial edema and new or worsening hypothyroidism.

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

In KEYNOTE-087, KEYTRUDA was discontinued in 5% of 210 cHL patients due to adverse events. Serious side effects occurred in 16% of patients. these ≥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%), fever (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%) and rash (20%).

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

In KEYNOTE-869, when KEYTRUDA was given in combination with enfortumab vedotin in patients with mUC or locally advanced who were unsuitable for cisplatin-based chemotherapy (n=121), fatal adverse events, including sepsis, occurred in 5% of patients. patients (1.6%). , bullous dermatitis (0.8%), myasthenia gravis (0.8%) and pneumonitis (0.8%). Serious side effects occurred in 50% of patients receiving KEYTRUDA in combination with enfortumab vedotin. Serious adverse reactions in ≥ 2% of patients were acute kidney injury (7%), urinary tract infection (7%), urosepsis (5%), hematuria (3.3%), pneumonia (3.3%), pneumonitis (3.3%), sepsis (3.3%), anemia (2.5%), diarrhea (2.5%), hypotension (2.5%), myasthenia gravis (2.5%), myositis (2.5%) and urinary retention (2.5%). KEYTRUDA was permanently discontinued in 32% of patients. The most common adverse reactions (≥2%) leading to permanent discontinuation of KEYTRUDA were pneumonitis (5%), peripheral neuropathy (5%), rash (3.3%) and myasthenia gravis (2.5%). The most common adverse reactions (≥20%) reported in patients treated with KEYTRUDA in combination with enfortumab vedotin were rash (71%), peripheral neuropathy (65%), fatigue (60%), alopecia (52%), loss of weight (48%), diarrhea (45%), pruritus (40%), decreased appetite (38%), nausea (36%), dysgeusia (35%), urinary tract infection (30%), constipation (27 %), edema (26%), dry eyes (25%), dizziness (23%), arthralgia (23%) and dry skin (21%).

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

In KEYNOTE-045, KEYTRUDA was discontinued due to adverse events in 8% of 266 patients with mUC or locally advanced. The most common adverse reaction leading to permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Serious side effects occurred in 39% of patients treated with KEYTRUDA. these ≥2% were UTIs, pneumonia, anemia, and pneumonitis. The most common adverse reactions (≥20%) in patients receiving KEYTRUDA were fatigue (38%), musculoskeletal pain (32%), itching (23%), decreased appetite (21%), nausea (21%) and rash. (20%).

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

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

In KEYNOTE-158 and KEYNOTE-164, the adverse events seen in patients with MSI-H or dMMR cancers were similar to those seen in patients with other solid tumors who received KEYTRUDA as monotherapy.

In KEYNOTE-811, when KEYTRUDA was given in combination with trastuzumab, fluoropyrimidine, and platinum chemotherapy, KEYTRUDA was discontinued in 6% of 217 patients with locally advanced metastatic or unresectable HER2J+ disease due to adverse events. The most common adverse reaction leading to permanent discontinuation was pneumonitis (1.4%). In the KEYTRUDA versus placebo arm, there was a ≥5% difference in incidence between patients treated with KEYTRUDA and standard of care for diarrhea (53% vs 44%) and nausea (49% vs 44%).

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

In KEYNOTE-590, when KEYTRUDA was administered with cisplatin and fluorouracil in patients with metastatic or locally advanced esophageal carcinoma or GEJ (tumors centered 1 to 5 cm above the GEJ) and who were not candidates for surgical discectomy or discectomy. due to side effects in 15% of the 370 patients. The most common adverse reactions leading to permanent discontinuation of KEYTRUDA (≥1%) were pneumonitis (1.6%), acute renal failure (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 seen in patients with esophageal cancer who received KEYTRUDA as monotherapy were similar to those seen in patients with melanoma or NSCLC who received KEYTRUDA as monotherapy.

In KEYNOTE-826, when KEYTRUDA was administered in combination with paclitaxel and cisplatin or paclitaxel and carboplatin, with or without bevacizumab (n=307), in patients with first-line persistent, recurrent, or metastatic cervical cancer, regardless of PD-L1 Tumor of expression that did not undergo chemotherapy, 4.6% of patients, unless used concomitantly as a radiosensitizer, experienced fatal adverse reactions, including 3 cases of bleeding, 2 cases of sepsis of unknown cause and 1 case of acute infarction myocardium, autoimmune encephalitis, cardiac arrest, stroke, femoral fracture with perioperative pulmonary embolism, intestinal perforation and pelvic infection. Serious side effects occurred in 50% of patients who received KEYTRUDA in combination with chemotherapy with or without bevacizumab. these ≥3% were febrile neutropenia (6.8%), urinary tract infection (5.2%), anemia (4.6%), and acute kidney injury and sepsis (3.3% each).

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

In patients treated with KEYTRUDA, chemotherapy, and bevacizumab (n=196), the most common adverse reactions (≥20%) were peripheral neuropathy (62%), alopecia (58%), anemia (55%), fatigue/illness (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%).

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

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

Adverse reactions that occurred in patients with HCC were generally similar to those in patients with melanoma or NSCLC receiving KEYTRUDA monotherapy, with the exception of increased rates of ascites (8% Grades 3-4) and immune hepatitis (2.9%). . The most common laboratory abnormalities (Grade 3-4) were increased AST (20%), ALT (9%) and hyperbilirubinemia (10%).

In the 50 patients with MCC enrolled in the KEYNOTE-017 study, adverse reactions in patients with MCC were generally similar to those in patients with melanoma or NSCLC receiving KEYTRUDA as monotherapy. The most common laboratory abnormalities (Grade 3-4) were AST elevation (11%) and hyperglycemia (19%).

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

In KEYNOTE-564, when KEYTRUDA was given as monotherapy for the adjunctive treatment of renal cell carcinoma, serious adverse events occurred in 20% of patients receiving KEYTRUDA. Serious adverse reactions (≥1%) were acute kidney injury, adrenal insufficiency, pneumonia, colitis, and diabetic ketoacidosis (1% each). Fatal side effects occurred in 0.2%, including 1 case of pneumonia. KEYTRUDA was discontinued in 21% of 488 patients due to adverse events. The most common (≥1%) were elevated ALT (1.6%), colitis (1%) and adrenal insufficiency (1%). The most common adverse events (≥20%) were musculoskeletal pain (41%), fatigue (40%), rash (30%), diarrhea (27%), pruritus (23%), and hypothyroidism (21%).

Adverse reactions seen in patients with MSI-H or dMMR endometrial cancer who received KEYTRUDA as monotherapy were similar to those seen in patients with melanoma or NSCLC who received KEYTRUDA as monotherapy.

Side effects seen in patients with TMB-H cancer were similar to those seen in patients with other solid tumors who received KEYTRUDA as monotherapy.

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

In KEYNOTE-522, when KEYTRUDA was given with neoadjuvant chemotherapy (carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide) followed by surgery and continuous adjuvant monotherapy with KEYTRUDA (n=778) in previously undiagnosed patients, high- risk , fatal adverse events including 1 of each adrenal crisis, autoimmune encephalitis, hepatitis, pneumonia, pneumonitis, pulmonary embolism and sepsis associated with multiple organ dysfunction syndrome and myocardial infarction occurred in 0.9% of patients. Serious side effects occurred in 44% of patients treated with KEYTRUDA. these ≥2% were febrile neutropenia (15%), pyrexia (3.7%), anemia (2.6%), and neutropenia (2.2%). KEYTRUDA was discontinued in 20% of patients due to adverse events. The most common reactions (≥1%) leading to permanent discontinuation were ALT rise (2.7%), AST rise (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%), fever (28%), cough (26%), abdominal pain (24%) , decreased appetite (23%), insomnia (21%) and myalgia (20%).

In KEYNOTE-355, when KEYTRUDA and chemotherapy (paclitaxel, protein-bound paclitaxel, or gemcitabine and carboplatin) were administered to patients with recurrent locally unresectable or metastatic TNBC who had not received prior chemotherapy in the metastatic setting (=596n), fatal adverse events occurred in 2.5% of patients, including cardiac arrest (0.7%) and septic shock (0.3%). Serious side effects occurred in 30% of patients who received KEYTRUDA in combination with chemotherapy. Severe reactions in ≥2% were pneumonia (2.9%), anemia (2.2%), and thrombocytopenia (2%). KEYTRUDA was discontinued in 11% of patients due to adverse events. The most common reactions leading to permanent discontinuation (≥1%) were ALT elevation (2.2%), AST elevation (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), and vomiting Rash ( 26% each), cough (23%), decreased appetite (21%) and headache (20%).

lactation

Due to the potential for serious side effects in breast-fed infants, women should be advised not to breast-feed during treatment and for 4 months after the last dose.

Use in pediatrics

In KEYNOTE-051, 173 pediatric patients (65 pediatric patients 6 months to less than 12 years of age and 108 pediatric patients 12 to 17 years of age) received 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 ≥10% more frequently in pediatric patients compared to adults were pyrexia (33%), leukopenia (31%), vomiting (29%), neutropenia (28%), headache (25%) , abdominal pain (23%), thrombocytopenia (22%), anemia (17%), decreased lymphocyte count (13%) and decreased white blood cell count (11%).

Additional US indications for KEYTRUDA

Non-small cell lung cancer

KEYTRUDA, in combination with pemetrexed and platinum-based chemotherapy, is indicated for the first-line treatment of patients with metastatic non-squamous non-small cell lung cancer (NSCLC) without EGFR or ALK tumor genome changes.

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

KEYTRUDA is indicated as a single agent for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) ≥ 1%] as determined by an FDA-approved test, without EGFR or ALK genomic tumor abnormalities and is:

• Stage III, when patients are not candidates for surgical resection or definitive chemoradiotherapy, or
• metastatic.

KEYTRUDA is indicated as a single agent for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as identified in an FDA-approved study and whose disease progression is occurring during or after platinum-based chemotherapy . Patients with EGFR or ALK tumor genomic aberrations must have disease progression on an FDA-approved therapy for these aberrations before receiving KEYTRUDA.

KEYTRUDA as a single agent is indicated for adjunctive therapy following resection and platinum-based chemotherapy in adult patients with stage IB (T2a ≥ 4 cm), II or IIIA NSCLC.

Head and Neck Squamous Cell Carcinoma

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

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

KEYTRUDA is indicated as monotherapy for the treatment of patients with recurrent or metastatic HNSCC with disease progression before or after platinum-based chemotherapy.

Classic Hodgkin's Lymphoma

KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin's lymphoma (HLc).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory or relapsed HLc 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 mediastinal large B-cell lymphoma (PMBCL) or patients who have relapsed after 2 or more previous lines of therapy. KEYTRUDA is not recommended for the treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urotelkarzinom

KEYTRUDA, in combination with enfortumab vedotin, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma (mUC) refractory to cisplatin-based chemotherapy.

This indication will be approved with accelerated approval based on tumor response rate and durability of response. Further approval of this indication may depend on verification and characterization of the clinical benefit in confirmatory studies.

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

• who are not suitable for platinum-based chemotherapy, or
• who have disease progression during or after platinum-based chemotherapy or within 12 months of platinum-based neoadjuvant or adjuvant chemotherapy.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with high-risk Bacillus Calmette-Guerin (BCG) refractory non-invasive bladder cancer (NMBC) with carcinoma in situ (CIS) with or without papillary tumors that are or are unsuitable decided against a cystectomy.

Microsatellite Instability - High or discordant repair of insufficient cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic solid microsatellite tumors, highly unstable (MSI-H) or with incompatible repair deficiency (dMMR) identified by an FDA-approved test and who have progressed after previous therapy who do not have satisfactory alternative treatment options.

Microsatellite instability - high or discrepancy repairs insufficient colon cancer

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic MSI-H colorectal cancer (CRC) or dMMR, as determined by an FDA-approved test.

Stomach cancer

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

This indication will be approved with accelerated approval based on tumor response rate and durability of response. Further approval of this indication may depend on verification and characterization of the clinical benefit in confirmatory studies.

esophageal cancer

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic carcinoma of the esophagus or gastroesophageal junction (GEJ) (tumors with a center 1 to 5 cm above the GEJ) amenable to surgical resection or definitive chemoradiotherapy, or:

• 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 PD-L1 expressing squamous cell tumors (CPS ≥10) as determined by an FDA-approved test.

cervical cancer

KEYTRUDA, in combination with chemotherapy with or without bevacizumab, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥ 1) as determined by an FDA-approved test.

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

hepatocellular carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have previously been treated with sorafenib. This indication will be approved with accelerated approval based on tumor response rate and durability of response. Further approval of this indication may depend on verification and characterization of the clinical benefit in confirmatory studies.

Merkel cell carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with locally advanced or metastatic Merkel cell carcinoma (MCC). This indication will be approved with accelerated approval based on tumor response rate and durability of response. Further approval of this indication may depend on verification and characterization of the clinical benefit in confirmatory studies.

renal cell carcinoma

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

KEYTRUDA is indicated for the adjunctive treatment of patients with RCC at moderate or high risk of recurrence after nephrectomy or after nephrectomy and resection of metastases.

carcinoma endometrial

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

Tumor mutation burden - high cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors (TMB-H) [≥ 10 mutations/megabase], as identified in an FDA-approved study, who have progressed after prior therapy with no treatment options satisfactory alternatives. This indication will be approved with accelerated approval based on tumor response rate and durability of response. Further approval of this indication may depend on verification and characterization of the clinical benefit in confirmatory studies. The safety and efficacy of KEYTRUDA in pediatric patients with TMB-H CNS cancer 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 unresectable by surgery or radiation.

triple negative breast cancer

KEYTRUDA is indicated for the treatment of patients with high-risk, triple-negative, early-stage breast cancer (TNBC) in combination with chemotherapy as neoadjuvant therapy and then continued as monotherapy as adjuvant therapy after surgery.

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

Merck's focus on cancer

Our goal is to translate cutting-edge research into innovative cancer medicines to help people living with cancer around the world. At Merck, our goal is to bring new hope to people living with cancer, and supporting access to our cancer medicines is our commitment. As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the industry's largest development programs in more than 30 tumor types. We continue to strengthen our portfolio through strategic acquisitions and prioritize the development of several promising oncology candidates with the potential to improve the treatment of advanced cancers. For more information about our oncology clinical trials, visitwww.merck.com/clinicaltrials.

About Merck

At Merck, known as MSD outside the US and Canada, we are united in our purpose: harnessing the power of cutting-edge science to save and improve lives around the world. For over 130 years, we have brought hope to humanity through the development of essential medicines and vaccines. We aspire to be the world's leading research-intensive biopharmaceutical company - and today we are at the forefront of research to provide innovative healthcare solutions that advance the prevention and treatment of disease in humans and animals. We foster a diverse and inclusive global workforce and act responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information visitwww.merck.comand connect with usTwitter,Facebook,Instagram,YouTubeELinkedIn.

About Moderna

In the more than 10 years since its inception, Moderna has grown from a research-stage company advancing messenger RNA (mRNA) programs to a company with a diverse clinical portfolio of vaccines and therapeutics across seven areas, a broad portfolio of intellectual property in areas such as mRNA and lipid nanoparticle synthesis, and an integrated manufacturing facility that enables rapid production at clinical and commercial scale. Moderna maintains alliances with several government and commercial partners in the country and abroad, which has allowed the pursuit of cutting-edge research and the rapid expansion of production. More recently, Moderna's resources were pooled to enable the authorized use and approval of one of the first and most effective vaccines against the COVID-19 pandemic.

Moderna's mRNA platform is based on continuing advances in fundamental and applied mRNA science, delivery and manufacturing technology and has enabled the development of therapies and vaccines for infectious diseases, immuno-oncology, orphan diseases, cardiovascular and autoimmune diseases. Moderna has been recognized by Science as a top biopharmaceutical employer for the past eight years. To learn more, visit www.modernatx.com.

Moderna's focus on cancer

At Moderna, we are fulfilling the promise of mRNA science to create a new generation of life-changing medicines for patients. We are working tirelessly to improve our cancer care, discovering mRNA drugs that use the body's immune system to identify and kill cancer cells in the same way the immune system recognizes and fights infection. An example of a promising candidate in oncology is the development of personalized mRNA-based cancer therapies. We continue to strengthen our portfolio through strategic partnerships that enhance our ability to improve treatment options for cancer patients.

Forward-looking statement by Merck & Co., Inc., Rahway, N.J., USA.

This press release from Merck & Co., Inc., Rahway, N.J., USA. (the "Company") contains "forward-looking statements" within the meaning of the safe harbor provisions of the US Private Securities Reform Act of 1995. The statements are based on management's current beliefs and expectations and are subject to risks and uncertainties. With respect to any pipeline candidate, there is no guarantee that the candidate will receive the necessary regulatory approvals or be commercially successful. Should underlying assumptions prove to be inaccurate, or risks or uncertainties materialize, actual results could vary materially from those projected in the forward-looking statements.

Risks and uncertainties include, among other things, general industry and competitive conditions. general economic factors, including interest rates and exchange rate fluctuations; the impact of the global outbreak of the novel coronavirus disease (COVID-19); the impact of the pharmaceutical industry and health legislation in the US and internationally; global trends for health care cost containment; technological developments, new products and patents acquired from competitors; challenges associated with new product development, including obtaining regulatory approvals; the Company's ability to accurately predict future conditions, difficulties or delays in manufacturing; financial instability of international economies and sovereign risks; Confidence in the effectiveness of the company's patent and other protections for innovative products and vulnerability to litigation, including patent litigation and/or regulatory action.

The Company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. See the Company's Annual Report on Form 10-K for the year ended December 31, 2022 and the Company's other filings with the Securities for additional factors that could cause results to differ materially from those described in the forward-looking statements and the Exchange Commission (SEC) available on the SEC website (www.sec.gov).

Moderna's forward-looking statements

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including: the development by Moderna and Merck of a personalized cancer vaccine (mRNA-4157/V940); the ability and potential of mRNA-4157/V940 to improve recurrence-free survival (RFS) rates in patients with stage III/IV melanoma. the tolerability and safety profile for mRNA-4157/V940. the potential of mRNA, including mRNA-4157, to effectively treat various cancers, including melanoma, and plans to investigate the treatment of other cancers, including lung cancer. the potential development of personalized cancer vaccines and therapies, plans to conduct a Phase 3 study of mRNA-4157/V940; the ability of a personalized cancer vaccine to elicit a personalized anti-tumor response specific to a patient's tumor mutation signature. and the potential for rapid regulatory approval and commercialization of mRNA-4157/V940. The forward-looking statements contained in this press release are not promises or guarantees, and you should not place undue reliance on these forward-looking statements because they involve known and unknown risks, uncertainties and other factors, many of which are beyond Moderna's control and could lead to the results Actual figures may differ materially from those expressed or implied by these forward-looking statements. These risks, uncertainties and other factors include the other risks and uncertainties described under the heading "Risk Factors" in Moderna's most recent Annual Report on Form 10-K for the year ended December 31, 2022, filed with the Securities and Exchange Commission (SEC) and Moderna's subsequent filings with the SEC, which are available on the SEC's website at www.sec.gov. Except as required by law, Moderna disclaims any intent or responsibility to update or revise any forward-looking statements contained in this press release, whether as a result of new information, future developments or otherwise. These forward-looking statements are based on Moderna's current expectations and speak only as of the date of this press release.

See KEYTRUDA (pembrolizumab) prescribing information below http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf and Medication Guide for KEYTRUDA at http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_mg.pdf .

¹Personalized therapy with neoantigens was formerly known as personalized cancer vaccine or PCV.