KEYTRUDA + LENVIMA is the FIRST AND ONLY IO combination with data in both advanced clear cell and non-clear cell RCC in the FDA-approved labels^1-6

Studied in the first-line setting across MSKCC risk groups

A multicenter, randomized, open-label, phase 3 trial with 1,069 patients¹

North America vs Western Europe vs “Rest of the World.”

Randomization was stratified according to Memorial Sloan Kettering Cancer Center (MSKCC) prognostic risk groups: favorable vs intermediate vs poor.

Clinical data are presented from the KEYTRUDA + LENVIMA and sunitinib arms.

Administration of KEYTRUDA with LENVIMA was permitted beyond RECIST-defined disease progression, if the patient was clinically stable and considered by the investigator to be deriving clinical benefit.

1L = first-line; IRC = independent radiologic review committee; ORR = objective response rate; OS = overall survival; PD-L1 = programmed death ligand 1; PFS = progression-free survival; RCC = renal cell carcinoma; RECIST v1.1 = Response Evaluation Criteria In Solid Tumors v1.1.

KEYNOTE-581/CLEAR trial: Baseline characteristics (N=1,069)¹

Studied in the first-line setting across MSKCC risk groups

For the first-line treatment of adult patients with advanced RCC

KEYNOTE-581/CLEAR trial: Superior PFS with KEYTRUDA + LENVIMA vs sunitinib at protocol-specified interim analysis (HR^a=0.39; 95% CI, 0.32–0.49; P^b<0.0001)

• Number of events^c: 160/355 (45%) with KEYTRUDA + LENVIMA vs 205/357 (57%) with sunitinib; Progressive disease: 145/355 (41%) vs 196/357 (55%), respectively; Death: 15/355 (4%) vs 9/357 (3%), respectively
• Median PFS: 23.9 months (95% CI, 20.8–27.7) with KEYTRUDA + LENVIMA vs 9.2 months (95% CI, 6.0–11.0) with sunitinib

PFS and OS were major endpoints in the KEYNOTE-581/CLEAR trial.

Hazard ratio is based on a Cox Proportional Hazards Model. Stratified by geographic region and Memorial Sloan Kettering Cancer Center (MSKCC) prognostic groups.

Two-sided P value based on stratified log-rank test.

Tumor assessments were based on RECIST v1.1; data cutoff date = 28 Aug 2020.

CI = confidence interval; HR = hazard ratio.

KEYNOTE-581/CLEAR trial

Exploratory subgroup analysis of PFS for KEYTRUDA + LENVIMA vs sunitinib in patients with advanced RCC based on selected baseline features²

LIMITATION: The KEYNOTE-581/CLEAR trial was not powered to detect differences in the treatment effect in these subgroups. No statistical testing was planned for this exploratory analysis, and no adjustment for multiplicity was made, therefore, no conclusions can be drawn.

This exploratory analysis of the KEYNOTE-581/CLEAR trial evaluated PFS for KEYTRUDA + LENVIMA vs sunitinib in patients with advanced RCC with or without specific baseline features, including baseline lung metastases, baseline bone metastases, baseline liver metastases, prior nephrectomy, sarcomatoid component by histology, IMDC risk group, and MSKCC risk group.^a

PFS was assessed by IRC according to RECIST v1.1.

mPFS for the KEYTRUDA + LENVIMA and sunitinib arms was estimated using the Kaplan-Meier method; HR and 95% CIs comparing KEYTRUDA + LENVIMA with sunitinib were estimated by a stratified Cox model. If a stratification factor was itself a subgroup, this factor was removed from the stratified analysis.

IMDC = International Metastatic Renal Cell Carcinoma Database Consortium; ITT = intent to treat; mPFS = median progression-free survival.

Adapted from Grünwald V, Powles T, Eto M, et al. Front Oncol. 2023;13:1223282. doi:10.3389/fonc.2023.1223282, distributed under the terms of the Creative Commons Attribution License (CC BY).

KEYNOTE-581/CLEAR trial

Updated PFS^a,b at final data cutoff³

LIMITATION: No statistical testing was planned for the updated PFS analysis, and therefore, no conclusions can be drawn.

• HR^c=0.47 (95% CI,^d 0.38–0.57)
• Number of events^b: 207/355 (58%) with KEYTRUDA + LENVIMA vs 214/357 (60%) with sunitinib
• Median PFS: 23.9 months (95% CI, 20.8–27.7) with KEYTRUDA + LENVIMA vs 9.2 months (95% CI, 6.0–11.0) with sunitinib

An updated PFS analysis was conducted when 304 deaths were observed based on the planned number of deaths for the prespecified final analysis.

Tumor assessments were based on independent imaging review per RECIST v1.1; updated OS cutoff date = 31 July 2022.

Hazard ratio is based on a Cox Proportional Hazards Model. Stratified by geographic region and Memorial Sloan Kettering Cancer Center (MSKCC) prognostic groups.

95% CI estimation method using a generalized Brookmeyer and Crowley method.

For the first-line treatment of adult patients with advanced RCC

KEYNOTE-581/CLEAR trial: Durable overall survival with KEYTRUDA + LENVIMA vs sunitinib

Superior OS demonstrated with KEYTRUDA + LENVIMA vs sunitinib at protocol-specified interim analysis

Updated OS^d,e at protocol-specified final analysis

This protocol-specified final analysis occurred after the interim analysis, which demonstrated the superiority of OS with KEYTRUDA + LENVIMA vs sunitinib. No statistical testing was planned for the protocol-specified final OS analysis.

• HR^a=0.79 (95% CI, 0.63–0.99)
• Number of deaths^e: 149/355 (42%) with KEYTRUDA + LENVIMA vs 159/357 (45%) with sunitinib
• Median OS: 53.7 months (95% CI, 48.7–NR) with KEYTRUDA + LENVIMA vs 54.3 months (95% CI, 40.9–NR) with sunitinib

Hazard ratio is based on a Cox Proportional Hazards Model. Stratified by geographic region and Memorial Sloan Kettering Cancer Center (MSKCC) prognostic groups.

Two-sided P value based on stratified log-rank test.

Data cutoff date = 28 Aug 2020.

An updated OS analysis was conducted when 304 deaths were observed based on the planned number of deaths for the prespecified final analysis.

Updated OS cutoff date = 31 July 2022.

For the first-line treatment of adult patients with advanced RCC

KEYNOTE-581/CLEAR trial: A greater ORR^a was demonstrated with KEYTRUDA + LENVIMA: 71% (95% CI, 66–76) vs 36% (95% CI, 31–41) with sunitinib (P^b<0.0001) at protocol-specified interim analysis

Tumor assessments were based on RECIST v1.1; only confirmed responses are included for ORR. Data cutoff date = 28 Aug 2020.

Two-sided P value based upon CMH test.

CMH = Cochran-Mantel-Haenszel; CR = complete response; ORR = objective response rate; PR = partial response.

KEYNOTE-581/CLEAR trial

Updated ORR^a at final data cutoff³

LIMITATION: No statistical testing was planned for the updated ORR analysis, and therefore, no conclusions can be drawn.

Tumor assessments were based on independent imaging review per RECIST v1.1; only confirmed responses are included for ORR. Updated OS cutoff date = 31 July 2022.

95% CI is constructed using the method of normal approximation.

Includes 59 patients receiving KEYTRUDA + LENVIMA with a “near CR,” defined as a PR with ≥75% change from baseline in sum of target lesion diameters.

Includes 25 patients receiving sunitinib with a “near CR,” defined as a PR with ≥75% change from baseline in sum of target lesion diameter.

Disclaimer: FDA approval was based on the KEYNOTE-581/CLEAR trial for advanced RCC

KEYNOTE-B61: The first clinical trial in advanced or metastatic non-clear cell RCC (N=158) with IO + TKI data included in the FDA-approved labels^4-7

A multicenter, single-arm trial that studied KEYTRUDA + LENVIMA in the first-line setting across IMDC risk groups and histologic subtypes, including papillary and chromophobe histologies

Administration of KEYTRUDA with LENVIMA was permitted beyond RECIST-defined disease progression if the patient was considered by the investigator to be deriving clinical benefit.

BICR = blinded independent central review; DOR = duration of response; IO = immunotherapy; TKI = tyrosine kinase inhibitor.

KEYNOTE-B61 trial: Baseline characteristics (N=158)

Studied in the first-line setting across IMDC risk groups and histologic subtypes

For the first-line treatment of adult patients with advanced RCC

In the single-arm KEYNOTE-B61 trial: Half of patients with advanced or metastatic non-clear cell RCC had a confirmed objective response with KEYTRUDA + LENVIMA

ORR was assessed by BICR using RECIST 1.1.

For the first-line treatment of adult patients with advanced RCC

In the single-arm KEYNOTE-B61 trial: Confirmed objective response was observed with KEYTRUDA + LENVIMA across multiple histologic subtypes

LIMITATION: No statistical testing was conducted to compare histologic subtypes in this single-arm study. This descriptive analysis is limited by the small sample sizes of each histologic subtype. Therefore, no conclusions can be drawn.

Assessed by BICR using RECIST 1.1.

Includes other non-clear cell histologic subtypes.

For the first-line treatment of adult patients with advanced RCC

In the single-arm KEYNOTE-B61 trial: A median DOR^a,b of 19.5 months (range: 1.5+ to 23.5+) was observed with KEYTRUDA + LENVIMA

Based on Kaplan-Meier estimates.

“+” denotes ongoing response.

For the first-line treatment of adult patients with advanced RCC

Adverse reactions (ARs) in the KEYNOTE-581/CLEAR trial

The safety of KEYTRUDA + LENVIMA was investigated in the KEYNOTE-581/CLEAR trial in patients treated with KEYTRUDA + LENVIMA (n=352) compared to sunitinib (n=340) at the protocol-specified interim analysis.

The median duration of exposure to KEYTRUDA + LENVIMA was 17 months (range: 0.1 to 39).

Permanent discontinuation, dose interruption, and dose reduction due to an adverse reaction in the KEYNOTE-581/CLEAR trial

	Permanent Discontinuation (%)	Dose Interruption (%)	Dose Reduction (%)
KEYTRUDA, LENVIMA, or both	37	78	—
KEYTRUDA + LENVIMA	13	39	—
KEYTRUDA only	29	55	—
LENVIMA only	26	73	69
KEYTRUDA, LENVIMA, or both	Permanent Discontinuation (%)37	Dose Interruption (%)78	Dose Reduction (%)—
KEYTRUDA + LENVIMA	Permanent Discontinuation (%)13	Dose Interruption (%)39	Dose Reduction (%)—
KEYTRUDA only	Permanent Discontinuation (%)29	Dose Interruption (%)55	Dose Reduction (%)—
LENVIMA only	Permanent Discontinuation (%)26	Dose Interruption (%)73	Dose Reduction (%)69

• No dose reduction for KEYTRUDA is recommended.

Most common adverse reactions that resulted in dose reduction or interruption in the KEYNOTE-581/CLEAR trial

Adverse reactions that occurred in ≥20% of patients receiving KEYTRUDA + LENVIMA in the KEYNOTE-581/CLEAR trial

• Fifteen percent (15%) of patients treated with KEYTRUDA + LENVIMA received an oral prednisone equivalent to ≥40 mg daily for an immune-mediated adverse reaction.
• Clinically relevant adverse reactions (<20%) that occurred in patients receiving KEYTRUDA + LENVIMA were myocardial infarction (3%) and angina pectoris (1%).
• Grade 3 and 4 increased ALT or AST was seen in 9% of patients. Grade ≥2 increased ALT or AST was reported in 64 (18%) patients, of whom 20 (31%) received ≥40 mg daily oral prednisone equivalent. Recurrence of Grade ≥2 increased ALT or AST was observed on rechallenge in 3 patients receiving LENVIMA, in 10 patients receiving both KEYTRUDA and LENVIMA (n=38), and was not observed on rechallenge with KEYTRUDA alone (n=3).

Includes asthenia, fatigue, lethargy, malaise.

Includes diarrhea, gastroenteritis.

Includes arthralgia, arthritis, back pain, bone pain, breast pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, pain in extremity, pain in jaw.

Includes hypothyroidism, increased blood thyroid stimulating hormone, secondary hypothyroidism.

Includes essential hypertension, increased blood pressure, increased diastolic blood pressure, hypertension, hypertensive crisis, hypertensive retinopathy, labile blood pressure.

Includes aphthous ulcer, gingival pain, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral discomfort, oral mucosal blistering, oral pain, oropharyngeal pain, pharyngeal inflammation, stomatitis.

Includes decreased appetite, early satiety.

Includes genital rash, infusion site rash, penile rash, perineal rash, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular.

Includes hemoglobinuria, nephrotic syndrome, proteinuria.

Includes palmar erythema, palmar-plantar erythrodysesthesia syndrome, plantar erythema.

Includes all hemorrhage terms. Hemorrhage terms that occurred in 1 or more subjects in either treatment group include anal hemorrhage, aneurysm ruptured, blood blister, blood loss anemia, blood urine present, catheter site hematoma, cerebral microhemorrhage, conjunctival hemorrhage, contusion, diarrhea hemorrhagic, disseminated intravascular coagulation, ecchymosis, epistaxis, eye hemorrhage, gastric hemorrhage, gastritis hemorrhagic, gingival bleeding, hemorrhage urinary tract, hemothorax, hematemesis, hematoma, hematochezia, hematuria, hemoptysis, hemorrhoidal hemorrhage, increased tendency to bruise, injection site hematoma, injection site hemorrhage, intra-abdominal hemorrhage, lower gastrointestinal hemorrhage, Mallory-Weiss syndrome, melaena, petechiae, rectal hemorrhage, renal hemorrhage, retroperitoneal hemorrhage, small intestinal hemorrhage, splinter hemorrhages, subcutaneous hematoma, subdural hematoma, subarachnoid hemorrhage, thrombotic thrombocytopenic purpura, tumor hemorrhage, traumatic hematoma, upper gastrointestinal hemorrhage.

Includes abdominal discomfort, abdominal pain, abdominal rigidity, abdominal tenderness, epigastric discomfort, lower abdominal pain, upper abdominal pain.

Includes alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, drug-induced liver injury, hepatic enzyme increased, hepatic failure, hepatic function abnormal, hepatocellular injury, hepatotoxicity, hyperbilirubinemia, hypertransaminasemia, immune-mediated hepatitis, liver function test increased, liver injury, transaminases increased, gammaglutamyltransferase increased.

Includes acute kidney injury, azotemia, blood creatinine increased, creatinine renal clearance decreased, hypercreatininemia, renal failure, renal impairment, oliguria, glomerular filtration rate decreased, nephropathy toxic.

ALT = alanine aminotransferase; AST = aspartate aminotransferase.

Post hoc analysis: Median time to first onset of select adverse reactions with KEYTRUDA + LENVIMA in KEYNOTE-581/CLEAR (n=352)⁸

LIMITATION: This is a post hoc analysis based on data from KEYNOTE-581/CLEAR. No formal statistical testing was planned and, therefore, no conclusions can be drawn.

• As this information is descriptive only, it may not be reflective of clinical practice; it should not replace physician judgement and evaluation of a potential adverse reaction should it occur.
• Health care professionals should monitor and evaluate patients for the presence of potential adverse reactions throughout treatment with KEYTRUDA, in combination with LENVIMA, and following discontinuation.
• Immune-mediated adverse reactions can occur at any time after starting treatment with a PD-1/PD-L1 blocking antibody. While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies.
• Data does not represent a complete list of each adverse reaction that occurred during the CLEAR trial.
• The interquartile range (Q1:Q3) represents the time to onset (the earliest treatment-emergent adverse reaction [AR] start date) for the AR for the middle 50% of patients who experienced that AR from quartile 1 to quartile 3.
• ARs were chosen based on frequency of occurrence (in ≥30% of patients). ARs could have occurred while receiving LENVIMA and/or KEYTRUDA or within the protocol-defined follow-up period of 30 days after the patient’s last dose. ARs were recorded until the end of the follow-up period or until resolution, whichever came first. Grading of ARs was performed according to Common Terminology Criteria for Adverse Events v4.03.

Chart adapted with permission from Motzer R, George S, Merchan JR, et al. Characterization and management of adverse reactions from the CLEAR study in advanced renal cell carcinoma treated with lenvatinib plus pembrolizumab. Oncologist. 2023;28(6):501–509. doi:10.1093/oncolo/oyac269

Median time to first onset in patients who experienced the adverse reaction. Gray boxes represent Q1–Q3. Lines represent the range.

Any grade.

Percentages are based on the safety population of the KEYTRUDA + LENVIMA group (n=352). The safety population included all patients who received at least 1 dose of any study drug.

Includes essential hypertension, increased blood pressure, increased diastolic blood pressure, hypertension, hypertensive crisis, hypertensive retinopathy, and labile blood pressure.

Includes fatigue, asthenia, malaise, and lethargy.

Includes hemoglobinuria, nephrotic syndrome, and proteinuria.

Includes arthralgia, arthritis, back pain, bone pain, breast pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, noncardiac chest pain, pain in extremity, and pain in jaw.

Aphthous ulcer, gingival pain, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral discomfort, oral mucosal blistering, oral pain, oropharyngeal pain, pharyngeal inflammation, and stomatitis.

Includes genital rash, infusion site rash, penile rash, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular.

Includes hypothyroidism, increased blood thyroid-stimulating hormone, and secondary hypothyroidism.

Includes decreased appetite and early satiety.

Includes diarrhea and gastroenteritis.

MAX = maximum; MIN = minimum; PD-1 = programmed death receptor-1; PD-L1 = programmed death ligand 1; Q1 = first quartile; Q3 = third quartile.

KEYTRUDA + LENVIMA: Recommended dosage and administration

When administering KEYTRUDA + LENVIMA for the first-line treatment of adult patients with advanced renal cell carcinoma, modify the dosage of one or both drugs as appropriate. Withhold or discontinue KEYTRUDA as shown in this resource. Withhold, dose reduce, or discontinue LENVIMA as shown in this resource. No dose reductions are recommended for KEYTRUDA.

Dosage and administration for KEYTRUDA

• Continue treatment with KEYTRUDA until disease progression, unacceptable toxicity, or up to 24 months.
• See full Prescribing Information for preparation and administration instructions and dosage modifications for adverse reactions.

IV = intravenous; RCC = renal cell carcinoma.

Managing adverse reactions to KEYTRUDA

Help manage your patients’ adverse reactions to KEYTRUDA

• When administering KEYTRUDA in combination with LENVIMA, modify the dosage of one or both drugs as appropriate. Withhold or discontinue KEYTRUDA as shown in this resource.
• No dose reductions of KEYTRUDA are recommended.
• In general, withhold KEYTRUDA for severe (Grade 3) immune-mediated adverse reactions.
• Permanently discontinue KEYTRUDA for:
  • Life-threatening (Grade 4) immune-mediated adverse reactions.
  • Recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment.
  • An inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating steroids.

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.
• 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 immune-mediated adverse reactions are not controlled with corticosteroid therapy.
• Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (eg, endocrinopathies and dermatologic reactions) are discussed below.
• Additional monitoring and management considerations for selected immune-mediated adverse reactions are also discussed.

When administering KEYTRUDA + LENVIMA for the first-line treatment of adult patients with advanced renal cell carcinoma, modify the dosage of one or both drugs as appropriate. Withhold or discontinue KEYTRUDA as shown in this resource. Withhold, dose reduce, or discontinue LENVIMA as shown in this resource. No dose reductions are recommended for KEYTRUDA.

PD-1 = programmed death receptor-1; PD-L1 = programmed death ligand 1.

Dosage and administration for LENVIMA^a

• If a dose is missed and cannot be taken within 12 hours, skip that dose and take the next dose at the usual time of administration.
• Continue treatment with LENVIMA in combination with KEYTRUDA until disease progression or unacceptable toxicity or up to 2 years.
• After completing 2 years of combination therapy, LENVIMA may be administered as a single agent until disease progression or until unacceptable toxicity.
• The recommended dosage of LENVIMA for patients with advanced RCC and severe renal impairment (creatinine clearance less than 30 mL/min calculated by Cockcroft-Gault equation using actual body weight) is 10 mg orally once daily.
• The recommended dosage of LENVIMA for patients with advanced RCC and severe hepatic impairment (Child-Pugh C) is 10 mg orally once daily.

When administered with KEYTRUDA.

LENVIMA: Preparation of suspension

• Place the required number of capsules, up to a maximum of 5, in a small container (approximately 20 mL capacity) or syringe (20 mL).
  Do not break or crush capsules.
• Add 3 mL of liquid to the container or syringe. Wait 10 minutes for the capsule shell (outer surface) to disintegrate, then stir or shake the mixture for 3 minutes until capsules are fully disintegrated and administer the entire contents.
• Next, add an additional 2 mL of liquid to the container or syringe using a second syringe or dropper, swirl or shake and administer. Repeat this step at least once and until there is no visible residue to ensure all of the medication is taken.
• If 6 capsules are required for a dose, follow these instructions using 3 capsules at a time.

If LENVIMA suspension is not used at the time of preparation, LENVIMA suspension may be stored in a refrigerator at 36 ºF to 46 ºF (2 ºC to 8 ºC) for a maximum of 24 hours in a covered container. If not administered within 24 hours, the suspension should be discarded.

Note: Compatibility has been confirmed for polypropylene syringes and for feeding tubes of at least 5 French diameter (polyvinyl chloride or polyurethane tube) and at least 6 French diameter (silicone tube).

Managing adverse reactions to LENVIMA

Help manage your patients’ adverse reactions to LENVIMA

• Withhold, dose reduce, or discontinue LENVIMA based on the type and/or severity (grade) of the adverse reaction.
• Recommendations for adverse reaction management, including dose modifications, are included in the Prescribing Information for LENVIMA and outlined below and on the following pages.

Recommended dosage reductions for LENVIMA for patients with advanced renal cell carcinoma^a

• When administering LENVIMA in combination with KEYTRUDA for the treatment of adult patients with advanced renal cell carcinoma, modify the dosage of one or both drugs, as appropriate, or withhold, dose reduce, or discontinue LENVIMA as shown in this resource.
• The recommended dosage of LENVIMA for patients with advanced renal cell carcinoma and severe renal impairment (creatinine clearance less than 30 mL/min calculated by Cockcroft-Gault equation using actual body weight) is 10 mg orally once daily.
• The recommended dosage of LENVIMA for patients with advanced renal cell carcinoma and severe hepatic impairment (Child-Pugh C) is 10 mg orally once daily.

When administered with KEYTRUDA.