Pelvic Pain

KEYTRUDA plus CRT is the first immunotherapy-based regimen to demonstrate a statistically significant improvement in OS in these patients RAHWAY, N.J.--(BUSINESS WIRE)-- Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced that the Phase 3 KEYNOTE-A18 trial, also known as ENGOT-cx11/GOG-3047, investigating KEYTRUDA, Merck’s anti-PD-1 therapy, in combination with chemoradiotherapy (CRT) met its primary endpoint of overall survival (OS) for the treatment of newly diagnosed patients with high-risk locally advanced cervical cancer. At a pre-specified interim analysis conducted by an independent Data Monitoring Committee, KEYTRUDA in combination with concurrent CRT showed a statistically significant and clinically meaningful improvement in OS versus concurrent CRT alone. The safety pro KEYTRUDA in this trial was consistent with that observed in previously reported studies; no new safety signals were identified. Results will be presented at an upcoming medical meeting and shared with regulatory authorities worldwide. As previously reported, KEYNOTE-A18 met its other primary endpoint of progression-free survival (PFS) in 2023. These PFS data were presented at the European Society for Medical Oncology (ESMO) Congress 2023 and supported the U.S. Food and Drug Administration's approval of KEYTRUDA in combination with CRT for the treatment of patients with FIGO (International Federation of Gynecology and Obstetrics) 2014 Stage III-IVA cervical cancer in January 2024. “This is the first Phase 3 trial in which an immunotherapy-based regimen has shown a statistically significant and clinically meaningful improvement in overall survival compared to chemoradiotherapy alone,” said Dr. Gursel Aktan, vice president, global clinical development, Merck Research Laboratories. “Building on the positive progression-free survival findings from this study, these results underscore our commitment to exploring the role of KEYTRUDA across different types of cancers in earlier stages of disease, where there is a greater potential for better outcomes.” “These findings are important for patients and the medical community alike and reinforce previous data from the KEYNOTE-A18 trial, now showing this regimen has the potential to extend the lives of patients with locally advanced cervical cancer,” said Prof. Domenica Lorusso, the study’s overall principal investigator, lead investigator for ENGOT, and professor of Obstetrics and Gynecology at Humanitas University. In the U.S., KEYTRUDA has two additional approved indications in cervical cancer: in combination with chemotherapy, with or without bevacizumab, for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test; and as a single agent, 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. About KEYNOTE-A18/ENGOT-cx11/GOG-3047 KEYNOTE-A18, also known as ENGOT-cx11/GOG-3047, is a randomized, double-blind Phase 3 trial (ClinicalTrials.gov, NCT04221945) sponsored by Merck and conducted in collaboration with the European Network for Gynecological Oncology Trial (ENGOT) groups and the GOG Foundation, Inc. (GOG) investigating KEYTRUDA in combination with CRT (cisplatin and external beam radiotherapy [EBRT] followed by brachytherapy [BT]) compared to placebo plus concurrent CRT for the treatment of newly diagnosed high-risk (stage IB2-IIB with lymph node-positive disease, and stage III-IVA with and without lymph node-positive disease) locally advanced cervical cancer where patients are treated with definitive intent. The primary endpoints are PFS and OS, and secondary endpoints include complete response rate, objective response rate and safety. The trial enrolled 1,060 patients with cervical cancer who had not previously received any definitive surgery, radiation, or systemic therapy for cervical cancer. Patients were randomized (1:1) to receive either: KEYTRUDA (200 mg intravenously [IV]) every three weeks (Q3W) for five cycles concurrent with cisplatin (40 mg/m2 IV) weekly for five cycles (an optional sixth infusion could be administered per local practice) and radiotherapy (EBRT followed by BT), followed by KEYTRUDA (400 mg IV) every six weeks (Q6W) for 15 cycles; Placebo IV Q3W for five cycles concurrent with cisplatin (40 mg/m2 IV) weekly for five cycles (an optional sixth infusion could be administered per local practice) and radiotherapy (EBRT followed by BT), followed by placebo IV Q6W for 15 cycles. About cervical cancer Cervical cancer forms in the cells lining the cervix, which is the lower part of the uterus. All women are at risk for cervical cancer, and it is most frequently diagnosed between the ages of 35 and 44. While screenings and prevention have resulted in declining cervical cancer rates, the disease continues to affect many people in the U.S. and around the world. Cervical cancer is the fourth most common cancer in women globally. In the U.S., it is estimated there will be approximately 13,820 new patients diagnosed with invasive cervical cancer and about 4,360 deaths from the disease in 2024. About Merck’s research in breast and gynecologic cancers Merck is advancing research aimed at improving outcomes for patients affected by breast and gynecologic (ovarian, cervical and endometrial) cancers. Merck has a comprehensive clinical development program across these cancers comprised of more than 20 Merck-sponsored Phase 3 studies evaluating KEYTRUDA as monotherapy and in combination with other medicines. In the U.S., KEYTRUDA currently has two approved indications for triple-negative breast cancer, including one for high-risk early-stage disease, and five approved indications across certain types of cervical and endometrial cancers (see indications below). Among Merck’s research efforts are trials focused on evaluating KEYTRUDA in earlier stages of these cancers, as well as identifying new combinations and coformulations with KEYTRUDA. About KEYTRUDA® (pembrolizumab) injection, 100 mg KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells. Merck has the industry’s largest immuno-oncology clinical research program. There are currently more than 1,600 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers. Selected KEYTRUDA® (pembrolizumab) Indications in the U.S. 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. See additional selected KEYTRUDA indications in the U.S. after the Selected Important Safety Information. Selected Important Safety Information for KEYTRUDA Severe and Fatal Immune-Mediated Adverse Reactions KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the PD-1 or the PD-L1, blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of anti–PD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. For patients with TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate. Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy. Immune-Mediated Pneumonitis KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients. Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution. 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. Infusion-Related Reactions KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA. Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after anti–PD-1/PD-L1 treatments. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between anti–PD-1/PD-L1 treatment and allogeneic HSCT. Follow patients closely for evidence of these complications and intervene promptly. Consider the benefit vs risks of using anti–PD-1/PD-L1 treatments prior to or after an allogeneic HSCT. Increased Mortality in Patients With Multiple Myeloma In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with an anti–PD-1/PD-L1 treatment in this combination is not recommended outside of controlled trials. Embryofetal Toxicity Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose. Adverse Reactions In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (≥20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%). In KEYNOTE-054, when KEYTRUDA was administered as a single agent to patients with stage III melanoma, KEYTRUDA was permanently discontinued due to adverse reactions in 14% of 509 patients; the most common (≥1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. The most common adverse reaction (≥20%) with KEYTRUDA was diarrhea (28%). In KEYNOTE-716, when KEYTRUDA was administered as a single agent to patients with stage IIB or IIC melanoma, adverse reactions occurring in patients with stage IIB or IIC melanoma were similar to those occurring in 1011 patients with stage III melanoma from KEYNOTE-054. In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (≥20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%). In KEYNOTE-407, when KEYTRUDA was administered with carboplatin and either paclitaxel or paclitaxel protein-bound in metastatic squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 15% of 101 patients. The most frequent serious adverse reactions reported in at least 2% of patients were febrile neutropenia, pneumonia, and urinary tract infection. Adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs 36%) and peripheral neuropathy (31% vs 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407. In KEYNOTE-042, KEYTRUDA was discontinued due to adverse reactions in 19% of 636 patients with advanced NSCLC; the most common were pneumonitis (3%), death due to unknown cause (1.6%), and pneumonia (1.4%). The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%). The most common adverse reaction (≥20%) was fatigue (25%). In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC; the most common was pneumonitis (1.8%). The most common adverse reactions (≥20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%). In KEYNOTE-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, and palmar-plantar erythrodysesthesia. 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 events 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 mUC. Serious adverse reactions occurred in 42% of patients; those ≥2% were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis. The most common adverse reactions (≥20%) were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%). In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in 8% of 266 patients with locally advanced or mUC. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients; those ≥2% were urinary tract infection, pneumonia, anemia, and pneumonitis. The most common adverse reactions (≥20%) in patients who received KEYTRUDA were fatigue (38%), musculoskeletal pain (32%), pruritus (23%), decreased appetite (21%), nausea (21%), and rash (20%). In KEYNOTE-057, KEYTRUDA was discontinued due to adverse reactions in 11% of 148 patients with high-risk NMIBC. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.4%). Serious adverse reactions occurred in 28% of patients; those ≥2% were pneumonia (3%), cardiac ischemia (2%), colitis (2%), pulmonary embolism (2%), sepsis (2%), and urinary tract infection (2%). The most common adverse reactions (≥20%) were fatigue (29%), diarrhea (24%), and rash (24%). Adverse reactions occurring in patients with MSI-H or dMMR CRC were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy. In KEYNOTE-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%). The most common adverse reactions (reported in ≥20%) of 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 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 discontinued due to adverse reactions in 15% of patients. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA (≥1%) were infections (1.8%) and diarrhea (1%). 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%). 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 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-564, when KEYTRUDA was administered as a single agent for the adjuvant treatment of renal cell carcinoma, serious adverse reactions occurred in 20% of patients receiving KEYTRUDA; the serious adverse reactions (≥1%) were acute kidney injury, adrenal insufficiency, pneumonia, colitis, and diabetic ketoacidosis (1% each). Fatal adverse reactions occurred in 0.2% including 1 case of pneumonia. Discontinuation of KEYTRUDA due to adverse reactions occurred in 21% of 488 patients; the most common (≥1%) were increased ALT (1.6%), colitis (1%), and adrenal insufficiency (1%). The most common adverse reactions (≥20%) were musculoskeletal pain (41%), fatigue (40%), rash (30%), diarrhea (27%), pruritus (23%), and hypothyroidism (21%). Adverse reactions occurring in patients with MSI-H or dMMR endometrial carcinoma who received KEYTRUDA as a single agent were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a single agent. Adverse reactions occurring in patients with TMB-H cancer were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent. Adverse reactions occurring in patients with recurrent or metastatic cSCC or locally advanced cSCC were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy. In KEYNOTE-522, when KEYTRUDA was administered with neoadjuvant chemotherapy (carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide) followed by surgery and continued adjuvant treatment with KEYTRUDA as a single agent (n=778) to patients with newly diagnosed, previously untreated, high-risk early-stage TNBC, fatal adverse reactions occurred in 0.9% of patients, including 1 each of adrenal crisis, autoimmune encephalitis, hepatitis, pneumonia, pneumonitis, pulmonary embolism, and sepsis in association with multiple organ dysfunction syndrome and myocardial infarction. Serious adverse reactions occurred in 44% of patients receiving KEYTRUDA; those ≥2% were febrile neutropenia (15%), pyrexia (3.7%), anemia (2.6%), and neutropenia (2.2%). KEYTRUDA was discontinued in 20% of patients due to adverse reactions. The most common reactions (≥1%) resulting in permanent discontinuation were increased ALT (2.7%), increased AST (1.5%), and rash (1%). The most common adverse reactions (≥20%) in patients receiving KEYTRUDA were fatigue (70%), nausea (67%), alopecia (61%), rash (52%), constipation (42%), diarrhea and peripheral neuropathy (41% each), stomatitis (34%), vomiting (31%), headache (30%), arthralgia (29%), pyrexia (28%), cough (26%), abdominal pain (24%), decreased appetite (23%), insomnia (21%), and myalgia (20%). In KEYNOTE-355, when KEYTRUDA and chemotherapy (paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin) were administered to patients with locally recurrent unresectable or metastatic TNBC who had not been previously treated with chemotherapy in the metastatic setting (n=596), fatal adverse reactions occurred in 2.5% of patients, including cardio-respiratory arrest (0.7%) and septic shock (0.3%). Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA in combination with chemotherapy; the serious reactions in ≥2% were pneumonia (2.9%), anemia (2.2%), and thrombocytopenia (2%). KEYTRUDA was discontinued in 11% of patients due to adverse reactions. The most common reactions resulting in permanent discontinuation (≥1%) were increased ALT (2.2%), increased AST (1.5%), and pneumonitis (1.2%). The most common adverse reactions (≥20%) in patients receiving KEYTRUDA in combination with chemotherapy were fatigue (48%), nausea (44%), alopecia (34%), diarrhea and constipation (28% each), vomiting and rash (26% each), cough (23%), decreased appetite (21%), and headache (20%). Lactation Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 4 months after the 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 as 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 Carcinoma 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. 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 carcinoma (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). Renal Cell Carcinoma KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC). KEYTRUDA is indicated for the adjuvant treatment of patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions. Endometrial Carcinoma KEYTRUDA, as a single agent, is indicated for the treatment of patients with advanced endometrial carcinoma that is MSI-H or dMMR, as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. Tumor Mutational Burden-High Cancer KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase (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. Merck’s focus on cancer Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, the potential to bring new hope to people with cancer drives our purpose and supporting accessibility to our cancer medicines is our commitment. As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the largest development programs in the industry across more than 30 tumor types. We also continue to strengthen our portfolio through strategic acquisitions and are prioritizing the development of several promising oncology candidates with the potential to improve the treatment of advanced cancers. For more information about our oncology clinical trials, visit . About Merck At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information, visit and connect with us on X (formerly Twitter), Facebook, Instagram, YouTube and LinkedIn. Forward-Looking Statement of Merck & Co., Inc., Rahway, N.J., USA This news release of Merck & Co., Inc., Rahway, N.J., USA (the “company”) includes “forward-looking statements” within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of the company’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline candidates that the candidates will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements. Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; the company’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the company’s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions. The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in the company’s Annual Report on Form 10-K for the year ended December 31, 2023 and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site ( ). Please see Prescribing Information for KEYTRUDA (pembrolizumab) at and Medication Guide for KEYTRUDA at . View source version on businesswire.com: Contacts Media Contacts: Julie Cunningham (617) 519-6264 John Infanti (609) 500-4714 Investor Contacts: Peter Dannenbaum (732) 594-1579 Damini Chokshi (732) 594-1577 Source: Merck & Co., Inc. View this news release online at:

Mithra reports full year 2023 financial results Revenues were EUR 40.2 million, down from the 2022 result of EUR 67.0 million which was positively impacted by exceptional upfront cash payments from partnerships.Product sales were EUR 18.7 million, up +19.3% vs EUR 15.7 million in 2022.ESTELLE® product sales reached EUR 10.4 million in 2023 beating the September 2023 guidance of EUR 8.5 million and up from EUR 9.2 million in 2022.Cash position, at EUR 9.0 million at end of 2023, is down compared to previous year (EUR 28.3 million end 2022).In an effort to maximize value for all of Mithra’s stakeholders, the Company has initiated a Monetization Process to realize value from its assets involving the sale of various selected assets, particularly Estetra SRL (which includes the US DONESTA® out-licensing process), and/or the business as a whole.The delay in the DONESTA® US NDA filing negatively impacted the process to consummate a US licensing agreement, also negatively impacting expected revenues.Triggered by the monetization process, management recognized an impairment loss of EUR 74.1 million on two of those assets (namely the Mithra CDMO and ZORELINE®). This accounting conclusion does not affect the management’s commitment to continue to find the best possible outcome for those assets. Due to these impairments (non-cash items), among other factors, the net loss for the period was EUR 173.5 million.Post-closing events include the 06 February 2024 announcement of Mithra’s cash position of EUR 6.5 million, the 15 February 2024 sale of balance of shares held in Mayne Pharma for approximately EUR 12.8 million, the 05 March 2024 announcement of up to EUR 18.5 million bridge facility to initiate a monetization process of key Mithra assets, and the 05 March 2024 change of management announcement. Liege, Belgium, 08 March 2024 – 7:00 CET – Mithra (Euronext Brussels: MITRA), a company dedicated to Women’s Health, today announces its financial results for the year which ended on 31 December 2023, prepared in accordance with IFRS. Financial Highlights See "Note regarding basis of preparation" on page 5 below. FY 2023 revenues were EUR 40.2 million compared to EUR 67.0 million in 2022.Out-licencing revenues at EUR 19.0 million were mostly driven by ESTELLE® in 2023. On top of EUR 3.75 million invoiced to our partner Fuji, another EUR 12.5 million has been recognized as revenue according to our IFRS 15 accounting policy (respectively EUR 2.5 million with Gedeon Richter for China and EUR 10.0 million with Fuji). Balance of out-licencing was primarily for DONESTA® with EUR 1.5 million invoiced to our partner Searchlight and EUR 1.13 million recognized under IFRS for China and Israel.ESTELLE® product sales, at EUR 10.4 million, were above 2022 level (EUR 9.2 million) and above our latest guidance (EUR 8.5 million) given in September. This is due to, amongst other items, our first deliveries to our Japan partner Fuji Pharma.Total number of cycles of ESTELLE® (NEXTSTELLIS®) sold by our partner in the US Mayne Pharma increased +136% to 385k cycles. The increase in sales is expected to continue in 2024.ESTELLE® cycle sales in Europe (DROVELIS® and LYDISILKA® brand names) increased by 103% to 3.2 million cycles in 2023.Novalon sales of generic products, including MYRING®, TIBELIA® and DAPHNE®, were EUR 8.1 million in 2023, up by +28% compared to the previous year while R&D contracting revenue from our CDMO remained steady at EUR 2.4 million.Cash collection from out-licensing milestones totalled EUR 56.4 million in 2023; EUR 51.5 million from DONESTA® (EUR 50.0 million from Gedeon Richter, out of which EUR 39.7 million was recognized in 2022 according to IFRS 15 and EUR 1.5 million from Searchlight); EUR 4.8 million from ESTELLE® (EUR 3.8 million from Fuji Pharma and EUR 1.0 million from Gedeon Richter for two LATAM territories previously recognised under IFRS).R&D expenses (excluding depreciation) decreased slightly (EUR 52.9 million in 2023 versus EUR 53.7 million in 2022) coming in below the guidance of EUR 60 million given in May 2023. The stable level of spend is a product of the continued strategy to focus on core R&D projects (DONESTA® and ESTELLE®) and discontinuing or pausing other research activities outside Mithra’s core scope.REBITDA was EUR -48.2 million in 2023 compared to EUR -12.3 million in 2022 year mostly due to lower out-licencing revenue and, to a lesser extent, an increase in G&A expenses and lower other operating income.Share-based payments expenses include the one-time (non-cash) expense of EUR 4.1 million relating to the 20 million warrants issued to Armistice Capital, LLC; the remaining being the balance of costs relating to previously awarded plans.Impairment on non-current assets: due to current cash runway situation, focus for non-core assets has now shifted to short-term sale or disposal. Accordingly, an impairment loss of EUR 74.1 million for two such assets has been recorded in FY 2023 financial statements: EUR 47.7 million for Mithra CDMO and EUR 26.4 million for ZORELINE®. This accounting conclusion does not affect the management’s commitment to continue to find the best possible outcome for those assets.Deferred tax assets: Balance of deferred tax assets previously recognized within Mithra CDMO and Novalon have been reversed as essentially relating to expected future taxable profit of ZORELINE®, now most likely to be sold in the short term.Cash position, at EUR 9.0 million at end 2023, is down compared to previous year (EUR 28.3 million end 2022) as revenue cash collection, capital increases and draw-down on existing financing lines did not compensate for expenses as well as reimbursement of several credit lines with some of our lenders.Equity was EUR -103.2 million at the end of 2023, down EUR 136.9 million compared to end 2022 (EUR 33.7 million). The total comprehensive loss for the period (EUR 167.1 million) was only partially compensated by a capital increase of EUR 2.5 million with Highbridge and Whitebox, a loan conversion by a lender under the convertible loan facility (EUR 1.2 million) and several contributions in kind against the issuance of new shares for interest to the lenders for a total of EUR 3.5 million (net of transaction costs) and by the private placement in equity with Armistice Capital LLC for EUR 18.4 million (net of transaction costs of EUR 1.6 million). Operational highlights Mithra announced positive preclinical data from its CSF-1R inhibitor program following the earlier announcement of its initial pre-clinical study successes. This was achieved in partnership with BCI Pharma and focused on tyrosine kinases inhibitors, a new development axis in the treatment of many pathologies including endometriosis, oncology and inflammatory disorders. Mithra announced promising topline safety results from DONESTA® Phase 3 Study in North America positive topline safety results for its E4 COMFORT clinical trial in the United States and Canada aiming at evaluating the efficacy and safety of DONESTA® for the treatment of Vasomotor Symptoms (VMS) in post-menopausal women.Mithra and the University of Liège secure proof-of-concept for novel manufacturing process of E4 delivering an improved manufacturing methodology to boost robustness and productivity while ensuring a limited environmental footprint. The new metal-free process is based on the thermolysis of a key sulfoxide derivative of estrone.Mithra granted an additional patent for NEXTSTELLIS® (3 mg drospirenone and 14.2 mg estetrol (E4) tablets) in the United States by the United States Patent and Trademark Office. The new patent will provide NEXTSTELLIS® contraceptive with oral-dosage-unit protection in the US market until 2036. The patent is a continuation of U.S. Patent No. 11,147,771 and was listed in the FDA’s Orange Book.Mithra received guidance from the FDA for the DONESTA® NDA marketing authorization filing in the US and received positive DSMB opinion on the DONESTA® European Phase 3 trial. Mithra received feedback regarding its new drug application (NDA) marketing authorization filing for DONESTA® in the United States. This follows an agreement in principle with the FDA for Mithra to conduct additional endometrial data analyses with a formal NDA submission now planned for Q4 2024 to allow for the time required to perform these additional analyses pursuant to FDA guidance. Pending regulatory approval, DONESTA® is expected to target a US market of nearly 63 million women between the ages of 45 and 65 years-old and experiencing vasomotor symptoms of menopause (VMS). Mithra also received a positive review from the independent Data and Safety Monitoring Board (DSMB) on its phase 3 program for DONESTA®.Mithra completed its pediatric study of ESTELLE® in adolescent patients, evaluating the safety, compliance, and pharmacokinetic profile of ESTELLE® in more than 100 participants aged 12 to 17 years old. The primary endpoint of the study, which was conducted in Estonia, Finland, Georgia, Latvia, Poland and Sweden, was to evaluate the safety of ESTELLE® in post-menarchal subjects.Mayne Pharma and Mithra announced the US launch of HALOETTE®, a vaginal hormonal contraceptive ring, resulting in a EUR 1.6 million milestone payment. HALOETTE® is a generic version of NUVARING®. According to IQVIA, NUVARING® US brand and generic sales were approximately USD 564 million for the 12 months ended November 2022.Mithra signs license agreement for the commercialization of DONESTA® with Gedeon Richter, Searchlight and Rafa Laboratories expanding its potential reach to Canada, Israel, Europe, the CIS countries, Latin America, Australia and New Zealand.Mithra received EUR 3.75 million milestone payments from Fuji Pharma under its ESTELLE® licensing agreement in Japan. A payment of EUR 1.25 million was triggered by completion of the interim clinical study reports of Phase 3 trials investigating ESTELLE® for the treatment of patients with dysmenorrhea or endometriosis. An additional EUR 2.5 million payment was made in October following the submission of an application for marketing approval in Japan in a drive to help combat dysmenorrhea.Mithra and Gedeon Richter signed a supply agreement for production of API for ESTELLE® and DONESTA® in August. The agreement specifies that Gedeon Richter will manufacture and supply the Estetrol (E4) native estrogen for Mithra’s leading products.Mithra and Gedeon Richter signed a binding Head of Terms to commercialize ESTELLE® and DONESTA® in China. Upon the finalization of the license agreements, Gedeon Richter will have the exclusive commercial rights for both products in China. Under the head of terms, Gedeon Richter to perform and fund the clinical studies required to obtain marketing approvals in China; upon the closing of the two licencing agreements, Mithra to receive a combined milestone payment of EUR 4.5 million. Events beyond the reporting period Mithra provided an update on its current cash position and its plans to address its runway and creating and optimizing value for all its stakeholders on 06 February, 2024. Announced the sale of all 4,221,815 shares it held in Mayne Pharma Group Limited on 15 February 2024. The shares were sold at a price of A$ 5.03 per share for aggregate net proceeds of A$ 21,129,551 (approx. EUR 12.8 million).Reported the last patient-out in the DONESTA® C301 Endometrial Safety Study. was reached on 8 February 2024. This marks the completion of patient treatments and the initiation of the data management/reporting phase.On 05 March 2024, Mithra announced the initiation of a monetization process and signing of a new secured bridge loan facility expected to fund that process through 30 April. The monetization process and Facility are further to Mithra’s 06 February 2024 announcement on its cash position. In an effort to maximize value for all of Mithra’s stakeholders, the Company has initiated a monetization process to realize value from its assets involving the sale of various selected assets, particularly Estetra SRL, and/or the business as a whole. The Company is finalizing negotiations with an internationally recognized investment bank to help conduct the Monetization Process in collaboration with DC Advisory and Alvarez & Marsal, who are advising on liquidity management and advising on monetization, among other things. Parties interested in participating in the Monetization Process should contact Ed Kulik of DC Advisory (Ed.Kulik@dcadvisory.com) and Thomas Dillenseger of Alvarez & Marsal (TDillenseger@alvarezandmarsal.com).Management Changes: Appointment of Christophe Maréchal1 and Xavier Paoli as co-CEOs following, 05 March 2024 termination of the management agreement of former CEO. Financial results Note regarding basis of preparation: The consolidated financial results of Mithra Pharmaceuticals SA and its subsidiaries (“Mithra”) included in this release have been prepared in accordance with International Financial Reporting Standards as adopted by the European Union. These include International Financial Reporting Standards (IFRS) and the related interpretations issued by the International Accounting Standards Board (IASB), and the IFRS Interpretations Committee (IFRIC), effective at the reporting date and adopted by the European Union. These consolidated financial results have been prepared on the basis of a going concern. However, as announced on 06 February 2024 and 05 March 2024, there are material uncertainties about Mithra's ability to continue in operation beyond 30 April 2024. As of 07 March 2024, Mithra has approximately EUR 9.0 million in cash and cash equivalents including the first drawdown under the bridge facility. Its lenders have provided a committed bridge facility of up to EUR 13.5 million, plus an uncommitted "accordion" facility for a further EUR 5 million, in each case subject to milestones, as described in that 05 March 2024 press release, in order to fund a monetization process. However, as noted in that release there is a risk that Mithra will not be able to draw the full amount, for instance if it is not able to initiate a Monetization Process. Even if a Monetization Process is initiated, there is a material risk that that process will not be successful, in whole or in part, or may not significantly reduce Mithra's existing indebtedness. If Mithra is not able to draw funds under the new bridge facility or is otherwise not able to raise or generate sufficient cash, this will adversely affect Mithra's continued operations and ability to operate as a going concern. 1. Consolidated statement of profit or loss Thousands of euro (€)20232022 Revenue40,15566,997Cost of sales(21,950)(19,623)Gross profit18,20547,374Research and development expenses(63,170)(64,041)General and administrative expenses(22,085)(14,675)Selling expenses(2,271)(2,100)Impairment on non-current assets(74,147)-Other operating income4,3367,196Loss from operations(139,132)(26,245)Change in fair value of contingent consideration payable(1,510)28,335Net fair value gains/(losses) on financial assets at fair value through profit or loss--Financial income1,7459,852Financial expenses(22,899)(23,422)Loss before taxes(161,795)(11,480)Income taxes(11,707)(48,139)NET LOSS FOR THE PERIOD(173,502)(59,620) 2. Consolidated statement of financial position As at 31 DecemberThousands of euro (€)20232022ASSETS Property, plant and equipment13,40540,717Right-of-use assets38,08365,534Goodwill5,2335,233Other intangible assets108,713134,905Deferred income tax assets1,28916,354Contract assets1792.828Derivatives financial assets349-Investment in equity securities16,01521,437Other non-current assets9,8749,544Non-current assets193,139296,552 Inventories48,28950,312Contract assets19,53644,988Derivatives financial assets47-Trade and other receivables16,55622,277Other short-term deposits--Cash and cash equivalents8,98028,285Current assets93,408145,863 TOTAL ASSETS286,546442,414 As at 31 DecemberThousands of euro (€)20232022EQUITY AND LIABILITIES Share capital50,59441,228Additional paid-in-capital424,858408,647Other reserves10,586(19,934)Accumulated deficit(589,294)(396,254)Equity attributable to equity holders(103,255)33,687 Subordinated loans9,79110,710Other loans137,739127,052Lease liabilities31,63138,253Refundable government advances7,6478,127Other financial liabilities73,73174,210Derivatives financial liabilities13,63615,261Contract liabilities10,300-Provisions266266Deferred tax liabilities1,0814,420Non-current liabilities285,822278,298 Current portion of subordinated loans1,2521,252Current portion of other loans19,00145,980Current portion of lease liabilities6,4505,179Current portion of refundable government advances2,5071,417Current portion of other financial liabilities15,69815,959Derivatives financial liabilities-2,561Trade and other payables59,07258,082Current liabilities103,981130,431 TOTAL EQUITY AND LIABILITIES286,546442,414 3. Consolidated statement of cash flows As at 31 DecemberThousands of euro (€)20232022Cash and cash equivalents at beginning of year28,28532,872Net cash (used in)/ provided by operating activities(2,184)(56,819)Net cash (used in)/ provided by investing activities3,452(25,490)Net cash (used in)/provided by financing activities(20,538)77,869Net increase/(decrease) in cash and cash equivalents(19,270)(4,440)Effects of exchange rate changes on cash and cash equivalents(35)(147)Cash and cash equivalents at end of period8,98028,285 Statement of profit and loss The Group reported a net loss of EUR 173.5 million in 2023, compared to a net loss of EUR 59.6 million in 2022. The main contributor to this difference was an impairment loss of EUR 74.1 million registered on the value of Mithra CDMO and ZORELINE® assets. Revenues were EUR 40.2 million compared with EUR 67.0 million in 2022. The revenues breakdown as follows: Overall product sales of EUR 18.7 million were largely driven by ESTELLE® (EUR 10.4 million), which are higher than in 2022 (EUR 9.2 million) and MYRING® (EUR 6.0 million) that improves the revenue on our generic portfolio to EUR 8.3 million compared to EUR 6.5 million in 2022.Out-licensing revenue for the year was EUR 19 million from ESTELLE® and DONESTA® milestones (EUR 16.3 million and EUR 2.6 million, respectively). For ESTELLE®, on top of EUR 3.75 million invoiced to our Partner Fuji, another EUR 12.5 million has been recognized as revenue according to our IFRS 15 accounting policy (respectively EUR 2.5 million with Gedeon Richter for China and EUR 10.0 million with Fuji). Balance of out-licencing was primarily for DONESTA® with EUR 1.5 million invoiced to our partner Searchlight and EUR 1.13 million recognised under IFRS for China and Israel.Revenues from the R&D contracting activities of the CDMO were stable at EUR 2.4 million compared to EUR 2.3 million in 2022. R&D expenses (including depreciation) decreased slightly to EUR 63.2 million. The stable level of research expenses is due to the continued focus on our core R&D projects, namely the DONESTA® Phase II and III clinical studies and the ESTELLE® post-approval safety study (PASS). G&A and selling expenses increased +44% to EUR 24.4 million due to a higher impact of share-based payments accounting entries (charge of EUR 4.5 million compared to charge of EUR 2.0 million in 2022); increase in professional services to assist us in our attempt to strengthen our balance sheet and refocus on innovative R&D, but also relating to administration of our financial liabilities and uncomfortable cash position; and, to a lesser extent, an increase in insurance costs and salaries indexation. Impairment on non-current assets: as focus for non-core assets has now shifted to short-term sale or disposal of those assets, an impairment loss of EUR 74.1 million for two such assets has been recorded in FY 2023 financial statements: EUR 47.7 million for Mithra CDMO and EUR 26.4 million for ZORELINE®. Other operating income of EUR 4.3 million (compared to EUR 7.2 million in 2022) mostly consists of an R&D tax credit for EUR 1.3 million which is directly related to R&D expenses level and of EUR 1.4 million exemption from the withholding tax on professional income for R&D staff. Main reason for lower other operating income is that last year included a reinvoicing of costs of EUR 2.2 million that did not repeat in 2023. The negative impact of approximately EUR -1.5 million for change in fair value related to contingent consideration payable ESTELLE® is the consequence of the update of both the discount rate and the timing effect. The decrease in financial income to EUR 1.7 million from EUR 9.9 million in 2022 is explained by the lower impact of the remeasurement of refundable government advances measured at amortized cost following the update of forecasts (EUR 0.5 million in 2023 vs EUR 3.6 million last year). Last year also included EUR 3.0 million of dividend from Mayne Pharma as well as a realized gain of EUR 2.5 million following the early repurchase of EUR 34.1 million tranche of our convertible bonds due in 2025 at a discount to par, via the convertible loan signed with Highbridge Capital Management, LLC (“Highbridge“) and funds managed by Whitebox Advisors, LLC (“Whitebox”). Financial expenses remained stable compared to last year, albeit at a high level. The group recorded a tax loss of EUR -11.7 million for 2023 as the balance of deferred tax assets previously recognised within Mithra CDMO and Novalon have been reversed as essentially relating to expected future taxable profit of ZORELINE® now most likely to be sold in the short term. Statement of financial position Assets As of 31 December 2023, the statement of financial position shows a total of EUR 193.1 million in non-current assets-- the majority of which are other intangible assets (EUR 108.7 million); right-of-use assets (EUR 38.1 million); investments in equity securities (EUR 16.0 million); property, plant and equipment (EUR 13.4 million) and deferred tax assets (EUR 1.3 million). In 2023, new additions to the other intangible assets have been limited to a total of EUR 4.2 million (EUR 33.3 million in 2022) and almost offset by EUR 3.5 million of depreciation. Main change of 2023 was the result of the impairment testing of our CDMO and ZORELINE® that led to a one-time depreciation of EUR 27.0 million (EUR 0.6 million and EUR 26.4 million respectively for the CDMO and ZORELINE®). The same impairment testing also led to a one-time depreciation of EUR -47.2 million on our CDMO Tangible fixed assets (Property, plant and equipment and the right-of-use assets). Otherwise, limited additions during the year (EUR 1.2 million) were more than offset by depreciation of the period (EUR 8.2 million). Deferred tax assets decreased to EUR 1.3 million as balance of deferred tax assets previously recognised within Mithra CDMO and Novalon have been reversed as essentially relating to expected future taxable profit of our complex therapeutics products now most likely to be sold in the short term. Contract assets amount decreased to EUR 19.7 million (non-current and current) versus EUR 47.8 million in 2022. New contract assets recognized (essentially EUR 10 million for Fuji and EUR 3.5 million relating to ESTELLE® & DONESTA® in China) were more than offset by unbilled revenues recognised in prior year(s) and invoiced in 2023 (EUR 40.7 million for Gedeon Richter). Current assets at the end of 2023 are about EUR 93.4 million and include, besides contract assets explained here above, Cash and cash equivalents of EUR 9.0 million, Trade & other receivables of EUR 16.6 million, and Inventories of EUR 48.3 million. Equity and liabilities Total equity at year-end is negative at EUR -103.3 million as the total comprehensive loss for the period (EUR 167.1 million) was only partially compensated by several capital increases for a total amount of EUR 25.6 million (net of transaction costs). Non-current liabilities increased to EUR 285.8 million at the end of 2023, compared to EUR 278.3 million end of 2022. The main changes during the period relate to the access in June 2023 to a new tranche of the amended loan facility concluded with funds managed by Highbridge and Whitebox (“Convertible loans” in the above table) for an amount of EUR 12.5 million and the recognition of a contract liability of EUR 10.3 million with Gedeon Richter for DONESTA®. Current liabilities decreased to EUR 104.0 million at the end of 2023, compared to EUR 130.4 million in 2022. The decrease of the Current liabilities is mainly explained by the reimbursement of straight loans at maturity for an amount of EUR 26.8 million. Alternative performance measures Mithra uses some alternative performance measures (APMs) that are not defined in IFRS but that provide helpful additional information to better assess how the business has performed over the period. Mithra decided to use REBITDA and EBITDA in order to provide information on recurring items, but those measures should not be viewed in isolation or as an alternative to the measures presented in accordance with IFRS. REBITDA is an alternative performance measure calculated by excluding the non-recurring items and the depreciation & amortization from EBIT (loss from operations) from the consolidated statement of profit or loss prepared in accordance with IFRS. The Group considers share-based payments as non-recurring item above EBITDA. EBITDA is an alternative performance measure calculated by excluding the depreciation and amortization from EBIT (loss from operations) from the consolidated statement of profit or loss prepared in accordance with IFRS. Financial highlights are presented as follows in the first section of this press release (management figures): Year ended 31 DecemberThousands of euro (€)20232022 Revenue40,15566,997Cost of sales(21,189)(19,112)Gross profit18,96647,886Research and development expenses(52,869)(53,668)General and administrative expenses(16,450)(11,707)Selling expenses(2,213)(2,029)Other operating income4,3367,196REBITDA(48,231)(12,322)Share-based payments expenses(4,540)(1,983)EBITDA(52,771)(14,305)Depreciation(12,214)(11,940)Non-recurring items(74,147)-Loss from operations(139,132)(26,245)Change in fair value of contingent consideration payable(1,510)28,335Net fair value gains/(losses) on financial assets at fair value through profit or loss--Financial income1,7459,852Financial expenses(22,899)(23,422)Loss before taxes(161,795)(11,480)Income taxes(11,707)(48,139)NET LOSS FOR THE PERIOD(173,502)(59,620) Please refer to the table below for the reconciliation to loss from operations as presented within consolidated statement of profit or loss: Year ended 31 DecemberThousands of euro (€)20232022Loss from operations(139,132)(26,245)Depreciation12,21411,940Non-recurring items – impairment charges on non-current assets74,147-Share-based payments expenses4,5401,983REBITDA(48,231)(12,322)Share-based payments expenses(4,540)(1,983)EBITDA(52,771)(14,305) Annual report 2023The auditor, BDO Réviseurs d’Entreprises SRL, has stated that the statutory audit is still ongoing as of the date of this press release. Based on the unfinished status of the audit procedures and the uncertainty about the evolution of the group in the coming weeks, the auditor is not yet able to provide information on the audit opinion he intends to issue on the consolidated financial statements. Financial CalendarThe following are anticipated dates in the Company's 2024 financial calendar and subject to change: 16 April 2024: 2023 Annual Report16 May 2024: Annual General Shareholders’ Meeting26 September 2024: Half Year Report 2024 For more information, please contact: Mithra Pharmaceuticals SAAlex Sokolowski, PhDHead of IR & Communicationsinvestorrelations@mithra.com +32 (0)4 349 28 22Frédérique Depraetere Communications Directorinfo@mithra.com+32 (0)4 349 28 22 About Mithra Mithra Pharmaceuticals SA (Euronext: MITRA) is a Belgian biopharmaceutical company dedicated to transforming women’s health by offering new choices through innovation, with a particular focus on contraception and menopause. Mithra’s goal is to develop products offering better efficacy, safety and convenience, meeting women’s needs throughout their life span. Mithra explores the potential of the unique native estrogen estetrol in a wide range of applications in women health and beyond. After having successfully launched the first estetrol-based product in 2021, the contraceptive pill ESTELLE®, Mithra is now focusing on its second product DONESTA®, the next-generation hormone therapy. Mithra also offers partners a complete spectrum of solutions from early drug development, clinical batches and commercial manufacturing of complex polymeric products (vaginal ring, implants) and complex liquid injectables and biologicals (vials, pre-filled syringes or cartridges) at its technological platform Mithra CDMO. Active in more than 100 countries around the world, is headquartered in Liège, Belgium. www.mithra.com ESTELLE®, NEXTSTELLIS®, LYDISILKA®, MYRING®, HALOETTE®, ZORELINE®, TIBELIA® and DONESTA® are registered trademarks of Mithra Pharmaceuticals or one of its affiliates. DROVELIS® is a registered trademark of Richter Gedeon Nyrt. DAPHNE® is a registered trademark of Ceres Pharma. NUVARING® is a registered trademark of Organon NV. Important informationThe contents of this announcement include statements that are, or may be deemed to be, "forward-looking statements". These forward-looking statements can be identified by the use of forward-looking terminology, including the words "believes", "estimates," "anticipates", "expects", "intends", "may", "will", "plans", "continue", "ongoing", "potential", "predict", "project", "target", "seek" or "should", and include statements the Company makes concerning the intended results of its strategy. By their nature, forward-looking statements involve risks and uncertainties, and readers are cautioned that any such forward-looking statements are not guarantees of future performance. The Company's actual results may differ materially from those predicted by the forward-looking statements. The Company undertakes no obligation to publicly update or revise forward-looking statements, except as may be required by law. Subscribe to our mailing list on investors.mithra.com to receive press releases by email or follow us on social media:LinkedIn • X • Facebook 1 Acting through CMM&C SRL. Attachment 2024-03-08_Mithra_Press-release_FY2023-Results_FR

A perplexing problem for people with recurring urinary tract infections (UTIs) is persistent pain, even after antibiotics have successfully cleared the bacteria. Now researchers have identified the likely cause -- an overgrowth of nerve cells in the bladder. A perplexing problem for people with recurring urinary tract infections (UTIs) is persistent pain, even after antibiotics have successfully cleared the bacteria. Now Duke Health researchers have identified the likely cause -- an overgrowth of nerve cells in the bladder. The finding, appearing March 1 in the journal Science Immunology, provides a potential new approach to managing symptoms of recurring UTIs that would more effectively target the problem and reduce unnecessary antibiotic usage. "Urinary tract infections account for almost 25% of infections in women," said senior author Soman Abraham, Ph.D., professor in the departments of Pathology, Molecular Genetics and Microbiology, Integrative Immunobiology, and Cell Biology at Duke University School of Medicine. "Many are recurrent UTIs, with patients frequently complaining of chronic pelvic pain and urinary frequency, even after a round of antibiotics," Abraham said. "Our study, for the first time, describes an underlying cause and identifies a potential new treatment strategy." Abraham and colleagues collected bladder biopsies from recurrent UTI patients who were experiencing pain despite no culturable bacteria in their urine. Using biopsies from people without UTIs as a comparison, they found evidence that sensory nerves were highly activated in the UTI patients, explaining the persistent sense of pain and urinary frequency. Further studies in mice revealed the underlying events, with unique conditions in the bladder that prompt activated nerves in the lining to bloom and grow with each infection. "Typically, during every bout of UTI, epithelial cells laden with bacteria are sloughed off, and significant destruction of nearby nerve tissue occurs," said Byron Hayes, lead author of the study and previously a postdoctoral fellow in Duke's Department of Pathology. "These events trigger a rapid repair program in the damaged bladder involving massive regrowth of destroyed nerve cells." This immune response, including repair activities, is led by mast cells -- which are immune cells that fight infection and allergens. Mast cells release chemicals called nerve growth factor, which drive overgrowth and increase sensitivity of nerves. The result is pain and urgency. The researchers were able to address these symptoms by treating study mice with molecules that suppress production of the mast-cell generated nerve growth factor. "This work helps illuminate a puzzling clinical condition that drives medical costs and affects the quality of life of millions of people, primarily women," Abraham said. "Understanding the crosstalk between mast cells and nerves is an essential step toward effective treatments for people suffering repeat urinary tract infections." In addition to Abraham and Hayes, study authors include Hae Woong Choi, Abhay PS Rathore,Chunjing Bao, Jianling Shi, Yul Huh, Michael W Kim, Andrea Mencarelli, Pradeep Bist, Lai Guan Ng, Changming Shi, Joo Hwan Nho, Aram Kim, Hana Yoon, Donghoon Lim, Johanna L Hannan, J Todd Purves, Francis M Hughes Jr, and Ru-Rong Ji. The study received funding support from the National Institutes of Health (K12-DK100024, R01-DK121969, R01-DK121032, R01-GM144606), the National Research Foundation of Korea (2020R1C1C1003257), and a Korea University grant.