Merck has announced the Discontinuation of KeyVibe and KEYFORM Programs

Both programs have tested in fixed-dose combinations with pembrolizumab (KEYTRUDA®) in the KeyVibe and KEYFORM trials.

Merck (NYSE: MRK), known as MSD outside of the United States and Canada, announced the discontinuation of the clinical development programs for vibostolimab, an anti-TIGIT antibody, and favezelimab, an anti-LAG-3 antibody.

Vibostolimab is being evaluated as an investigational fixed-dose combination with pembrolizumab (KEYTRUDA®) in the KeyVibe program. Favezelimab is being evaluated as an investigational fixed-dose combination with pembrolizumab in the KEYFORM program.

Merck is discontinuing the Phase 3 KeyVibe-003 and KeyVibe-007 trials, which are evaluating the fixed-dose combination of vibostolimab and pembrolizumab in certain patients with non-small cell lung cancer (NSCLC), based on the recommendation of an independent Data Monitoring Committee (DMC).

In a pre-planned analysis, both trials met the pre-specified futility criteria for the primary endpoint of overall survival. In these studies, the safety profile of vibostolimab/pembrolizumab was consistent with that observed for vibostolimab and pembrolizumab in previously reported studies, with no new safety signals identified.

As expected with dual checkpoint inhibitor therapy, more immune-related adverse events were observed with the fixed-dose combination than with pembrolizumab. Considering the totality of data from the Phase 3 KeyVibe studies, including the efficacy outcomes from KeyVibe-003 and KeyVibe-007, the company has decided to discontinue the Phase 3 KeyVibe-006 trial and other vibostolimab studies.

Separately, Merck has decided to end the favezelimab clinical development program, and will stop enrollment in the Phase 3 KEYFORM-008 trial evaluating the fixed-dose combination of favezelimab and pembrolizumab in patients with relapsed or refractory classical Hodgkin lymphoma (cHL) whose disease has progressed following prior anti-PD-1 therapy. Patients currently in this trial may continue on therapy until study completion.

KEYFORM-008 is the only Phase 3 study in the KEYFORM clinical development program for which results are not available.

The company has made this decision after a thorough evaluation of data from the favezelimab clinical program and will prioritize the development of other candidates in its comprehensive and diversified oncology pipeline. This decision is not based on any concerns about the safety of this fixed-dose combination.

Merck is informing study investigators for these clinical trials and advises patients to speak to their study team and physician regarding next steps and treatment options. Data analyses for the Phase 3 trials are ongoing, and the results will be shared with the scientific community.

“Following a careful analysis of the data, the decision has been made to discontinue development of these candidates to prioritize other ongoing programs. We are grateful to all the patients, caregivers and investigators for their many contributions that made these studies possible.

We continue to pursue the most promising science with a focus on agents with the greatest potential to improve outcomes for more patients with cancer,” – said Dr. Marjorie Green, senior vice president and head of oncology, global clinical development, Merck Research Laboratories.

About KeyVibe-003

KeyVibe-003 is a randomized, double-blind Phase 3 trial evaluating the fixed-dose combination of vibostolimab and pembrolizumab (MK-7684A) versus pembrolizumab monotherapy, as a first-line treatment for patients with PD-L1 positive metastatic NSCLC.

The primary endpoint is overall survival (OS) in participants with PD-L1 TPS ≥50%. Secondary endpoints include OS in participants with PD-L1 TPS ≥1% and TPS 1-49%, progression-free survival (PFS), overall response rate (ORR), duration of response (DOR), safety and quality of life. The trial enrolled 1,264 patients who were randomized (1:1) to receive:

• Vibostolimab/pembrolizumab fixed-dose combination (pembrolizumab 200 mg and vibostolimab 200 mg intravenously [IV] every three weeks [Q3W] for up to 35 administrations); or
• Pembrolizumab (200 mg IV Q3W for up to 35 administrations)

About KeyVibe-007

KeyVibe-007 is a randomized, double-blind Phase 3 trial evaluating the fixed-dose combination of vibostolimab and pembrolizumab with chemotherapy in treatment-naïve patients with metastatic NSCLC.

The primary endpoint is OS in participants with PD-L1 TPS ≥1%. Secondary endpoints include OS in all participants, PFS, ORR and DOR in TPS ≥ 1% and all participants, safety and patient reported outcomes. The trial enrolled 739 patients who were randomized (1:1) to receive:

• Vibostolimab/pembrolizumab fixed-dose combination (pembrolizumab 200mg and vibostolimab 200 mg IV) plus platinum doublet chemotherapy (Q3W for 4 cycles ); then vibostolimab/pembrolizumab (200mg/200mg IV) for up to 31 cycles (plus pemetrexed 500mg/m2Q3W maintenance for nonsquamous histology)
• Pembrolizumab (200 mg IV) plus platinum doublet chemotherapy (Q3W for 4 cycles ); then pembrolizumab (200mg IV) for up to 31 cycles (plus pemetrexed 500mg/m2 Q3W maintenance for nonsquamous histology)

About KeyVibe-006

KeyVibe-006 is a randomized, open-label Phase 3 trial evaluating the fixed-dose combination of vibostolimab and pembrolizumab with concurrent chemoradiotherapy followed by vibostolimab and pembrolizumab versus concurrent chemoradiotherapy followed by durvalumab in patients with stage III NSCLC.

The primary endpoints are PFS and OS for all participants and for participants with TPS ≥ 1%. The secondary endpoints are ORR, DOR, safety and patient reported outcomes. The trial enrolled approximately 580 patients who were randomized (1:1) to receive:

• Vibostolimab/pembrolizumab (200mg/200mg IV) plus platinum doublet (1 cycle); then platinum doublet plus vibostolimab/pembrolizumab (2 cycles) plus thoracic radiotherapy; then vibostolimab/pembrolizumab (200mg/200mg IV Q3W for 17 cycles); or
• Platinum doublet (1 cycle); then platinum doublet (2 cycles) plus thoracic radiotherapy; then durvalumab (10 mg/kg Q2W for 26 cycles )

About KEYFORM-008

KEYFORM-008 is a randomized, open-label Phase 3 trial evaluating the fixed-dose combination of favezelimab and pembrolizumab (MK-4280A) versus physician’s choice chemotherapy for the treatment of patients with PD-1 relapsed or refractory classical Hodgkin lymphoma. The primary endpoint is PFS per Lugano Response Criteria as assessed by Blinded Independent Central Review (BICR). The secondary endpoints are OS, ORR, DOR and safety. The trial enrolled 169 patients who were randomized (1:1) to receive:

• Favezelimab/pembrolizumab (800 mg/200 mg IV on day 1, then Q3W for up to 35 infusions); or
• Physician’s choice of either bendamustine (between 90-120 mg/m2 IV on day 1 and day 2 of either a 3- or 4-week cycle for up to 6 cycles); or gemcitabine (between 800-1,200 mg/m2 IV on day 1 and day 8 of a Q3W cycle for up to 6 cycles)

About Vibostolimab

Vibostolimab (MK-7684) is an investigational humanized anti-TIGIT antibody discovered and developed by Merck. Vibostolimab restores antitumor activity by blocking the TIGIT receptor from binding to its ligands (CD112 and CD155), thereby activating T lymphocytes that help destroy tumor cells.

About Favezelimab

Favezelimab (MK-4280) is an investigational anti-lymphocyte activation gene-3 (LAG-3) antibody. LAG-3 is a cell surface immunomodulatory receptor expressed on various immune cells that down-regulates T cell proliferation and activation. Favezelimab aims to restore T cell effector function by preventing LAG-3 from binding to its primary ligand, major histocompatibility complex (MHC) class II molecules.

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.

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.

Classical Hodgkin Lymphoma (cHL)

– For adult patients with relapsed or refractory cHL.
– For pediatric patients with refractory cHL or relapsed cHL after ≥2 prior therapies.

Selected Important Safety Information for KEYTRUDA

Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA, an anti–PD-1 monoclonal antibody, may induce immune-mediated adverse reactions, potentially severe or fatal, in any organ system or tissue. These reactions can occur at any time during or after treatment.

Key Points:

– Monitor for symptoms of immune-mediated adverse reactions across body systems.
– Regularly evaluate liver enzymes, creatinine, and thyroid function.
– Early identification and management are critical for patient safety.

Immune-Mediated Adverse Reactions

Triple-Negative Breast Cancer (TNBC)

For TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. In suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative causes, including infection.

Start medical management promptly, including specialty consultation as needed. Withhold or permanently discontinue KEYTRUDA based on reaction severity.

If KEYTRUDA is interrupted or discontinued, administer systemic corticosteroids (1-2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less.

Upon improvement, taper corticosteroids over at least one month. Consider other systemic immunosuppressants if corticosteroids are insufficient.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis, with higher incidence in patients with prior thoracic radiation. Pneumonitis occurred in 3.4% of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), and Grade 3 (0.9%) cases. Systemic corticosteroids were required in 67% of cases, and pneumonitis led to permanent discontinuation in 1.3% of patients. Of those withheld, 23% had recurrence. Pneumonitis resolved in 59%.

In adult patients with classical Hodgkin lymphoma (cHL), pneumonitis occurred in 8%, with Grade 3-4 cases in 2.3%.

Corticosteroids were used for a median duration of 10 days. Pneumonitis led to discontinuation in 5.4% of patients, and 77% experienced resolution. For resected NSCLC, pneumonitis occurred in 7%, including fatal (0.2%) and Grade 3 (1%) reactions. High-dose corticosteroids were required for a median of 10 days. Discontinuation occurred in 4.5%, with 71% resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present as diarrhea. Cytomegalovirus infection/reactivation has been reported in corticosteroid-refractory cases.

Colitis occurred in 1.7% of patients, including Grade 4 (<0.1%) and Grade 3 (1.1%) reactions.

Systemic corticosteroids were required in 69%, with additional immunosuppressants needed in 4.2%. Colitis led to permanent discontinuation in 0.5% of patients. Colitis resolved in 85%.

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA as a Single Agent

Immune-mediated hepatitis occurred in 0.7% of patients, including Grade 4 (<0.1%) and Grade 3 (0.4%) cases. Systemic corticosteroids were required in 68%, with 11% needing additional immunosuppressants. Hepatitis led to permanent discontinuation in 0.2%, and 79% of cases resolved.

KEYTRUDA with Axitinib

KEYTRUDA with axitinib can cause hepatic toxicity. Monitor liver enzymes before and during treatment. For elevated liver enzymes, interrupt both drugs and consider corticosteroids. ALT ≥3 times ULN occurred in 20% of cases, with 59% receiving corticosteroids. ALT resolved to Grade 0-1 in 94%. Recurrence was observed in patients rechallenged with either KEYTRUDA, axitinib, or both. All patients recovered from the recurrence.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, provide symptomatic treatment, including hormone replacement as needed. Withhold KEYTRUDA based on severity. Adrenal insufficiency occurred in 0.8% of patients, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions.

Systemic corticosteroids were required in 77%, with most patients remaining on them. It led to permanent discontinuation in <0.1% and withholding in 0.3%. All withheld patients resumed KEYTRUDA after symptom improvement.

Hypophysitis

KEYTRUDA can cause immune-mediated hypophysitis, which may present with acute symptoms such as headache, photophobia, or visual field defects. It can lead to hypopituitarism. Initiate hormone replacement as needed. Withhold or permanently discontinue KEYTRUDA based on severity.

Hypophysitis occurred in 0.6% of patients, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions.

Systemic corticosteroids were required in 94%, with most patients remaining on them. It led to permanent discontinuation in 0.1% and withholding in 0.3%. All withheld patients resumed KEYTRUDA after symptom improvement.

Thyroid Disorders

KEYTRUDA can cause immune-mediated thyroid disorders, including thyroiditis, hyperthyroidism, and hypothyroidism.

– Thyroiditis occurred in 0.6% of patients, including Grade 2 (0.3%). None discontinued, and <0.1% had KEYTRUDA withheld.
– Hyperthyroidism occurred in 3.4%, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation in <0.1% and withholding in 0.3%. All withheld patients resumed KEYTRUDA after symptom improvement.
– Hypothyroidism occurred in 8%, including Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent discontinuation in <0.1% and withholding in 0.5%. Most required long-term thyroid hormone replacement.

Higher rates of hypothyroidism were reported in:

– Head and Neck Squamous Cell Carcinoma (HNSCC): 16%, including Grade 3 (0.3%).
– Classical Hodgkin Lymphoma (cHL): 17%, including Grade 1 (6.2%) and Grade 2 (10.8%).
– Resected NSCLC (KEYNOTE-091): 22%, including Grade 3 (0.3%). Hyperthyroidism occurred in 11%, including Grade 3 (0.2%).

Type 1 Diabetes Mellitus (DM)

KEYTRUDA can cause Type 1 DM, which may present as diabetic ketoacidosis. Monitor for hyperglycemia and treat with insulin as needed. Withhold KEYTRUDA based on severity. Type 1 DM occurred in 0.2% of patients and led to permanent discontinuation in <0.1% and withholding in <0.1%. All withheld patients resumed KEYTRUDA after symptom improvement.

Immune-Mediated Nephritis With Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. It occurred in 0.3% of patients, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 89%. Nephritis led to permanent discontinuation in 0.1% and withholding in 0.1%. All withheld patients resumed KEYTRUDA after symptom improvement, with no recurrence. Nephritis resolved in 56% of cases.

Immune-Mediated Dermatologic Adverse Reactions

KEYTRUDA can cause immune-mediated rash or dermatitis, including exfoliative dermatitis, Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis. Mild to moderate nonexfoliative rashes may respond to topical treatments. Withhold or discontinue KEYTRUDA based on severity.

Dermatologic reactions occurred in 1.4% of patients, including Grade 3 (1%) and Grade 2 (0.1%).

Systemic corticosteroids were required in 40%. Reactions led to permanent discontinuation in 0.1% and withholding in 0.6%. All withheld patients resumed KEYTRUDA after symptom improvement, with 6% experiencing recurrence. These reactions resolved in 79% of cases.

Other Immune-Mediated Adverse Reactions

Incidence was <1% unless noted. Severe or fatal cases have occurred.
– Cardiac/Vascular: Myocarditis, pericarditis, vasculitis
– Nervous System: Meningitis, encephalitis, myelitis, demyelination, myasthenic syndrome, Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy
– Ocular: Uveitis, iritis, and inflammatory toxicities, possibly associated with retinal detachment or permanent vision loss. Vogt-Koyanagi-Harada-like syndrome may require systemic steroids
– Gastrointestinal: Pancreatitis, gastritis, duodenitis, increased amylase/lipase
– Musculoskeletal: Myositis, rhabdomyolysis, arthritis (1.5%), polymyalgia rheumatica
– Endocrine: Hypoparathyroidism
– Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, Kikuchi lymphadenitis, sarcoidosis, thrombocytopenic purpura, organ transplant rejection

Infusion-Related Reactions

Severe or life-threatening reactions, including hypersensitivity and anaphylaxis, occurred in 0.2% of patients. For Grade 1/2 reactions, interrupt or slow infusion rate. For Grade 3/4, stop infusion and discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)
Fatal and serious complications, including hyperacute GVHD, acute/chronic GVHD, hepatic veno-occlusive disease, and febrile syndrome, may occur with allogeneic HSCT. Monitor closely for these complications. Consider the risks of anti–PD-1/PD-L1 treatment before or after HSCT.

Increased Mortality in Patients With Multiple Myeloma
In trials, combining KEYTRUDA with a thalidomide analogue and dexamethasone increased mortality. This combination is not recommended outside 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

Adverse reactions in KEYNOTE-006 for advanced melanoma led to discontinuation in 9% of 555 patients. Reactions causing permanent discontinuation in more than one patient included colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).

In KEYNOTE-054, for stage III melanoma, KEYTRUDA was permanently discontinued in 14% of 509 patients due to adverse reactions. The most common reactions were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious adverse reactions occurred in 25% of patients. The most common adverse reaction was diarrhea (28%). In KEYNOTE-716, for stage IIB or IIC melanoma, adverse reactions were similar to those in KEYNOTE-054.

In KEYNOTE-189, for metastatic nonsquamous NSCLC, KEYTRUDA was discontinued in 20% of 405 patients due to adverse reactions. The most common causes of discontinuation were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions 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, for metastatic squamous NSCLC, KEYTRUDA was discontinued in 15% of 101 patients due to adverse reactions. Serious adverse reactions included febrile neutropenia, pneumonia, and urinary tract infection. Alopecia (47%) and peripheral neuropathy (31%) were more frequent in KEYNOTE-407 compared to KEYNOTE-189.

In KEYNOTE-042, for advanced NSCLC, KEYTRUDA was discontinued in 19% of 636 patients due to adverse reactions. The most common were pneumonitis (3%), death from unknown causes (1.6%), and pneumonia (1.4%). Serious adverse reactions included pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%). The most common adverse reaction was fatigue (25%). 

In KEYNOTE-010, for metastatic NSCLC, KEYTRUDA was discontinued in 8% of 682 patients due to adverse reactions, most commonly pneumonitis (1.8%). The most common adverse reactions were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%).

In KEYNOTE-671, for resectable NSCLC, adverse reactions were similar to other trials involving KEYTRUDA with chemotherapy. The most common adverse reactions were fatigue, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia, peripheral neuropathy, mucosal inflammation, stomatitis, headache, weight loss, abdominal pain, arthralgia, myalgia, insomnia, palmar-plantar erythrodysesthesia, urinary tract infection, and hypothyroidism.

In the neoadjuvant phase, serious adverse reactions occurred in 34% of 396 patients, including pneumonia (4.8%), venous thromboembolism (3.3%), and anemia (2%). Fatal reactions occurred in 1.3% of patients, including death from unknown causes (0.8%), sepsis (0.3%), and immune-mediated lung disease (0.3%). Adverse reactions led to permanent discontinuation in 18% of patients.

Surgery was canceled in 6% of patients due to adverse reactions, with interstitial lung disease as the most frequent cause.

In the adjuvant phase of KEYNOTE-671, serious adverse reactions occurred in 14% of 290 patients, with pneumonia being the most frequent. Fatal pulmonary hemorrhage occurred in one patient. KEYTRUDA was permanently discontinued in 12% of patients, with diarrhea, interstitial lung disease, increased aspartate aminotransferase, and musculoskeletal pain as the most frequent causes.

In KEYNOTE-091, adverse reactions were similar to those in other trials, but with higher incidences of hypothyroidism (22%), hyperthyroidism (11%), and pneumonitis (7%).

In KEYNOTE-048, for HNSCC, KEYTRUDA monotherapy was discontinued in 12% of 300 patients due to adverse events. The most common causes were sepsis (1.7%) and pneumonia (1.3%). The most common adverse reactions were fatigue (33%), constipation (20%), and rash (20%). In the combination arm with platinum and fluorouracil chemotherapy, KEYTRUDA was discontinued in 16% of 276 patients due to adverse reactions. The most common causes were pneumonia (2.5%), pneumonitis (1.8%), and septic shock (1.4%). The most common adverse reactions 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 (Head and Neck Squamous Cell Carcinoma)

– Discontinuation: 17% of 192 patients.
– Serious Adverse Reactions (ARs): 45% (≥2%: pneumonia, dyspnea, confusional state, vomiting, pleural effusion, respiratory failure).
– Common ARs (≥20%): Fatigue, decreased appetite, dyspnea.
– Notable Differences: Increased facial edema and hypothyroidism compared to melanoma or NSCLC.

In KEYNOTE-204, KEYTRUDA was discontinued due to adverse reactions in 14% of 148 patients with Classical Hodgkin Lymphoma (cHL).

– Discontinuation: 14% of 148 patients.
– Serious ARs: 30% (≥1%: pneumonitis, pneumonia, pyrexia, myocarditis, acute kidney injury, febrile neutropenia, sepsis).
– Deaths: 2 post-allogeneic HSCT, 1 unknown cause.
– Common ARs (≥20%): Upper respiratory infection (41%), musculoskeletal pain (32%), diarrhea (22%), pyrexia, fatigue, rash, cough (20% each).

In KEYNOTE-087, KEYTRUDA was discontinued due to adverse reactions in 5% of 210 patients with cHL.

– Discontinuation: 5% of 210 patients.
– Serious ARs: 16% (≥1%: pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, herpes zoster).
– Deaths: 1 due to GVHD post-HSCT, 1 due to septic shock.
– Common ARs (≥20%): Fatigue (26%), pyrexia and cough (24%), musculoskeletal pain (21%), diarrhea, rash (20% each).

In KEYNOTE-170, KEYTRUDA was discontinued due to adverse reactions in 8% of 53 patients with PMBCL.

– Discontinuation: 8% of 53 patients.
– Serious ARs: 26% (arrhythmia, cardiac tamponade, myocardial infarction, pericardial effusion, pericarditis; each 2%-4%).
– Deaths: 11% within 30 days.
– Common ARs (≥20%): Musculoskeletal pain (30%), upper respiratory infection and pyrexia (28% each), cough (26%), fatigue (23%), dyspnea (21%).

In KEYNOTE-A39 KEYTRUDA was administered in combination with enfortumab vedotin to patients with locally advanced or metastatic urothelial cancer (n=440).

– Fatal ARs: 3.9% (acute respiratory failure, pneumonia, pneumonitis/ILD).
– Serious ARs: 50% (≥2%: rash, acute kidney injury, pneumonitis/ILD, UTI, diarrhea, pneumonia, pyrexia, hyperglycemia).
– Discontinuation: 27% due to ARs (notably pneumonitis/ILD: 4.8%; rash: 3.4%).
– Common ARs (≥20%): Rash (68%), peripheral neuropathy (67%), fatigue (51%), pruritus, diarrhea, alopecia, weight loss, decreased appetite, nausea, constipation, dry eye, dysgeusia, UTI.

In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in 11% of 370 patients with locally advanced or metastatic urothelial carcinoma.

– Discontinuation: 11% of 370 patients.
– Serious ARs: 42% (≥2%: UTI, hematuria, acute kidney injury, pneumonia, urosepsis).
– Common ARs (≥20%): Fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation, rash (21%), diarrhea (20%).

In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in 8% of 266 patients with locally advanced or metastatic urothelial carcinoma. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%).

– Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients; those ≥2% were urinary tract infection, pneumonia, anemia, and pneumonitis.
– 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.

– Serious adverse reactions occurred in 28% of 148 patients, including pneumonia, cardiac ischemia, colitis, pulmonary embolism, sepsis, and UTI (≥2%). KEYTRUDA was discontinued in 11% of patients, with pneumonitis being the most common cause (1.4%).
– 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 (KEYTRUDA 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.

In combination with trastuzumab and chemotherapy, serious adverse reactions occurred in 45% of 785 patients. Fatal adverse reactions occurred in 8%, including infection and thromboembolism. Discontinuation due to adverse reactions occurred in 15% of patients, most commonly due to infections and diarrhea (≥1%). The most common adverse reactions (≥20%) included peripheral neuropathy, nausea, fatigue, diarrhea, vomiting, decreased appetite, abdominal pain, and weight loss.

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 occurred in 30% of 370 patients treated with cisplatin and fluorouracil. KEYTRUDA was discontinued in 15% of patients, with pneumonitis, acute kidney injury, and pneumonia (≥1%) as common causes.
– The most common adverse reactions (≥20%) were nausea, fatigue, decreased appetite, constipation, diarrhea, vomiting, stomatitis, and weight loss.

In KEYNOTE-590, 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, fatal adverse reactions occurred in 1.4% of 292 patients treated with CRT, including sepsis, large intestinal perforation, and vaginal hemorrhage. Serious adverse reactions occurred in 30%, including UTI, urosepsis, and sepsis (≥1%). KEYTRUDA was discontinued in 7% of patients, with diarrhea being the most common cause (1%). The most common adverse reactions (≥10%) included nausea, diarrhea, vomiting, UTI, fatigue, and hypothyroidism.

In KEYNOTE-826, fatal adverse reactions occurred in 4.6% of 307 patients treated with chemotherapy with or without bevacizumab, including sepsis, hemorrhage, and unknown causes. Serious adverse reactions occurred in 50%, most commonly febrile neutropenia, UTI, and anemia. KEYTRUDA was discontinued in 15% of patients, with colitis being the most common cause (1%).

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.

– Serious adverse reactions occurred in 13% of 299 patients, with ascites being the most common cause of discontinuation (2.3%).
– The most common adverse reactions (≥10%) included pyrexia, rash, diarrhea, decreased appetite, and pruritus.

In KEYNOTE-966, KEYTRUDA was discontinued for adverse reactions in 15% of 529 patients with locally advanced unresectable or metastatic biliary tract cancer.

In combination with gemcitabine and cisplatin, serious adverse reactions occurred in 15% of 529 patients. KEYTRUDA was discontinued in 15%, with pneumonitis being the most common cause (1.3%). The most frequent adverse reactions or lab abnormalities leading to treatment interruption (≥2%) included decreased neutrophil and platelet counts, anemia, and cholangitis.

In KEYNOTE-426, fatal adverse reactions occurred in 3.3% of 429 patients treated with axitinib, with hepatotoxicity, diarrhea, and acute kidney injury (≥1%) being the most frequent serious adverse reactions. KEYTRUDA was discontinued in 31% of patients due to hepatotoxicity, diarrhea, or colitis. The most common adverse reactions (≥20%) included diarrhea, fatigue, hypertension, and hepatotoxicity.

In KEYNOTE-564, serious adverse reactions occurred in 20% of patients, with acute kidney injury, pneumonia, and colitis (1%) being the most frequent. Discontinuation occurred in 21%, with increased ALT and colitis being the most common causes.

In KEYNOTE-868, In combination with paclitaxel and carboplatin, serious adverse reactions occurred in 35% of 382 patients, with fatal adverse reactions in 1.6%, including COVID-19 and cardiac arrest. Adverse reactions were generally consistent with those observed with KEYTRUDA or chemotherapy alone, except for a higher incidence of rash.

In KEYNOTE-522, In patients with high-risk early-stage TNBC treated with neoadjuvant chemotherapy and adjuvant KEYTRUDA, fatal adverse reactions occurred in 0.9%, including adrenal crisis, encephalitis, and sepsis. Serious adverse reactions occurred in 50% of patients.

– Serious adverse reactions occurred in 44% of KEYTRUDA patients; those ≥2% included febrile neutropenia (15%), pyrexia (3.7%), anemia (2.6%), and neutropenia (2.2%).

KEYTRUDA was discontinued in 20% of patients due to adverse reactions. Common reactions (≥1%) leading to permanent discontinuation included increased ALT (2.7%), increased AST (1.5%), and rash (1%).

-The most common adverse reactions (≥20%) were fatigue (70%), nausea (67%), alopecia (61%), rash (52%), constipation (42%), diarrhea and peripheral neuropathy (41%), 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, fatal adverse reactions occurred in 2.5% of patients receiving KEYTRUDA with chemotherapy, including cardio-respiratory arrest (0.7%) and septic shock (0.3%). Serious adverse reactions (≥2%) included pneumonia (2.9%), anemia (2.2%), and thrombocytopenia (2%). KEYTRUDA was discontinued in 11% due to adverse reactions.

The most common reactions leading to permanent discontinuation were increased ALT (2.2%), increased AST (1.5%), and pneumonitis (1.2%). Common adverse reactions (≥20%) included fatigue (48%), nausea (44%), alopecia (34%), diarrhea and constipation (28%), vomiting and rash (26%), cough (23%), decreased appetite (21%), and headache (20%).

Lactation

Advise women not to breastfeed during treatment and for 4 months after the last dose due to potential serious reactions in breastfed children.

Pediatric Use

In KEYNOTE-051, adverse reactions in pediatric patients (aged 6 months to 17 years) occurred at a ≥10% higher rate compared to adults. These included pyrexia (33%), leukopenia (30%), 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 564 patients treated with KEYTRUDA and enfortumab vedotin for urothelial cancer, 44% were aged 65-74 years and 26% were aged 75 years or older. There were no significant safety or effectiveness differences between patients aged ≥65 years and younger patients. However, patients aged ≥75 experienced a higher incidence of fatal adverse reactions (7% vs. 4%).

Additional Selected KEYTRUDA Indications

– Melanoma: For unresectable or metastatic melanoma and adjuvant treatment following complete resection in adults and pediatric patients aged 12 years and older.

– Malignant Pleural Mesothelioma: In combination with pemetrexed and platinum chemotherapy for unresectable advanced or metastatic MPM.

– Head and Neck Squamous Cell Cancer: In combination with platinum and fluorouracil (FU) for first-line treatment, or as a single agent for PD-L1 positive cases.

– Primary Mediastinal Large B-Cell Lymphoma: For refractory or relapsed patients after 2 or more prior therapies.

– Urothelial Cancer: In combination with enfortumab vedotin or as a single agent for advanced or metastatic urothelial carcinoma.

– Microsatellite Instability-High or Mismatch Repair Deficient Cancer: For unresectable or metastatic MSI-H or dMMR solid tumors.

– Colorectal Cancer: For unresectable or metastatic MSI-H or dMMR CRC.

– Gastric and Esophageal Cancer: In combination with chemotherapy for first-line treatment of advanced gastric, gastroesophageal junction (GEJ), or esophageal cancers.

– Cervical Cancer: In combination with chemoradiotherapy or chemotherapy for persistent, recurrent, or metastatic cervical cancer.

– Hepatocellular Carcinoma: For patients with HCC secondary to hepatitis B who have received prior systemic therapy.

– Biliary Tract Cancer: In combination with gemcitabine and cisplatin for advanced BTC.

– Merkel Cell Carcinoma: For recurrent locally advanced or metastatic MCC.

– Renal Cell Carcinoma: In combination with axitinib for advanced RCC, and adjuvant treatment for intermediate-high or high-risk RCC after nephrectomy.

– Endometrial Carcinoma: In combination with chemotherapy for advanced or recurrent cases, and as a single agent for MSI-H or dMMR endometrial carcinoma.

– Tumor Mutational Burden-High Cancer: For unresectable or metastatic TMB-H solid tumors.

– Cutaneous Squamous Cell Carcinoma: For recurrent or metastatic cSCC or locally advanced cSCC not curable by surgery or radiation.

– Triple-Negative Breast Cancer: For high-risk early-stage TNBC in combination with chemotherapy as neoadjuvant and adjuvant treatment, or with chemotherapy for locally recurrent unresectable or metastatic cases.

Merck’s focus on cancer

Every day, Merck follows the science to discover innovations that can help patients, no matter what stage of cancer they face. As a leading oncology company, Merck pursues research where scientific opportunity and medical need converge, underpinned by its diverse pipeline of more than 25 novel mechanisms.

With one of the largest clinical development programs across more than 30 tumor types, Merck strives to advance breakthrough science that will shape the future of oncology. By addressing barriers to clinical trial participation, screening, and treatment, the company works with urgency to reduce disparities and help ensure patients have access to high-quality cancer care. Its unwavering commitment is what will bring the company closer to its goal of bringing life to more patients with cancer.

About Merck 

At Merck, known as MSD outside of the United States and Canada, the company is unified around its purpose: using the power of leading-edge science to save and improve lives around the world. For more than 130 years, Merck has brought hope to humanity through the development of important medicines and vaccines.

Merck aspires to be the premier research-intensive biopharmaceutical company in the world—and today, it remains at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. It fosters a diverse and inclusive global workforce and operates responsibly every day to enable a safe, sustainable, and healthy future for all people and communities.