YERVOY

Ipilimumab is a fully humanized

IgG1 monoclonal antibody that blocks cytotoxic T lymphocyte antigen-4 (CTLA-4).

CTLA-4 removes an inhibitory signal from reducing the activity of T lymphocytes. 1, 2, 5 Ipilimumab was developed by Bristol-Myers Squibb and Medarex.

Ipilimumab was granted

FDA approval on 25 March 2011.

Ipilimumab is indicated in the following cancerous conditions: 8 Melanoma Treatment of unresectable or metastatic melanoma in adult and pediatric patients ≥12 years old, alone or in combination with nivolumab Adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of >1 mm who have undergone complete resection, including total lymphadenectomy Renal Cell Carcinoma (RCC) First-line treatment of patients with intermediate.

• or poor-risk advanced renal cell carcinoma in combination with nivolumab Colorectal Cancer In combination with nivolumab, treatment of patients ≥12 years old with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer Hepatocellular Carcinoma In combination with nivolumab, first-line treatment of adult patients with unresectable or metastatic hepatocellular carcinoma In combination with nivolumab, treatment of patients with hepatocellular carcinoma who have been previously treated with sorafenib Non-Small Cell Lung Cancer (NSCLC) Treatment of adult patients with metastatic non-small cell lung cancer expressing PD-L1, with no EFGR or ALK genomic tumor aberrations, as first-line treatment in combination with nivolumab Treatment of adult patients with metastatic or recurrent non-small cell lung cancer, with no EGFR or ALK genomic tumor aberrations, as first-line treatment in combination with nivolumab and 2 cycles of platinum-doublet chemotherapy Malignant Pleural Mesothelioma Treatment of adult patients with unresectable malignant pleural mesothelioma, as first-line treatment in combination with nivolumab Esophageal Cancer.

• Treatment of adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma, as first line treatment in combination with nivolumab

Ipilimumab is a human

IgG1 that binds CTLA-4, preventing 1 T-cell inhibition signal pathway.

It has a long duration of action as it is given every 3-4 weeks.

Patients should be counselled regarding the risk of immune-mediated adverse effects, infusion related reactions, and embryo-fetal toxicity.

C max was 65.8 µg/mL for 2-6 year olds, 70.1 µg/mL for 6-<12 year olds, and 73.3 µg/mL in patients 12 years and older.

Data regarding the AUC and

T max of ipilumumab are not readily available. 3, 5.

The volume of distribution at steady-state of ipilimumab is 7.21 L.

The metabolism of ipilimumab does not involve the cytochrome P450 enzyme system. 5, 6 Because ipilimumab is a protein, it is expected to be degraded into small peptides and amino acids by proteolytic enzymes.

Data regarding the route of elimination of ipilimumab is not readily available.

Ipilimumab has a half life of 14.7 days.

Ipilimumab has a clearance of 15.3 mL/hr.

Systemic clearance increases proportionally with body weight.

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Data regarding ipilumumab overdose is not readily available.

However, the most common adverse reactions to ipilumumab are fatigue, diarrhea, pruritus, rash, and colitis.

• Administer by intravenous infusion after dilution based upon recommended infusion rate for each indication.

• Unresectable or Metastatic Melanoma: ∘ YERVOY 3 mg/kg every 3 weeks for a maximum of 4 doses. ∘ YERVOY 3 mg/kg immediately following nivolumab 1 mg/kg on the same day, every 3 weeks for 4 doses.

After completing 4 doses of the combination, administer nivolumab as a single agent as recommended in the Full Prescribing Information for nivolumab.

• Adjuvant Treatment of Melanoma: YERVOY 3 mg/kg every 3 weeks for 4 doses, followed by 3 mg/kg every 12 weeks for up to 4 additional doses.

• Advanced Renal Cell Carcinoma: YERVOY 1 mg/kg immediately following nivolumab 3 mg/kg on the same day, every 3 weeks for 4 doses.

After completing 4 doses of the combination, administer nivolumab as a single agent as recommended in Full Prescribing Information for nivolumab.

• Treatment of microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer in combination with nivolumab: ∘ Adult and pediatric patients weighing 40 kg or greater: YERVOY 1 mg/kg immediately following nivolumab 240 mg on the same day every 3 weeks for a maximum of 4 doses.

After completing the combination, administer nivolumab as a single agent as recommended in Full Prescribing Information for nivolumab. ∘ Pediatric patients weighing less than 40 kg: YERVOY 1 mg/kg immediately following nivolumab 3 mg/kg on the same day every 3 weeks for a maximum of 4 doses.

After completing the combination, administer nivolumab as a single agent as recommended in Full Prescribing Information for nivolumab.

• Hepatocellular Carcinoma: YERVOY 3 mg/kg intravenously over 30 minutes immediately following nivolumab 1 mg/kg intravenously over 30 minutes on the same day, every 3 weeks for up to 4 doses.

After completing up to 4 doses of the combination, administer nivolumab as a single agent as recommended in Full Prescribing Information for nivolumab.

• Metastatic non-small cell lung cancer: ∘ YERVOY 1 mg/kg every 6 weeks with nivolumab 360 mg every 3 weeks. ∘ YERVOY 1 mg/kg every 6 weeks with nivolumab 360 mg every 3 weeks and 2 cycles of platinum-doublet chemotherapy.

• Malignant pleural mesothelioma: YERVOY 1 mg/kg every 6 weeks with nivolumab 360 mg every 3 weeks.

• Esophageal squamous cell carcinoma: YERVOY 1 mg/kg every 6 weeks with nivolumab 3 mg/kg every 2 weeks or 360 mg every 3 weeks.

• See full Prescribing Information for preparation and administration instructions and dosage modifications for adverse reactions. 2.1 Patient Selection Information on FDA-approved tests for patient selection is available at: Non-Small Cell Lung Cancer.

• Select patients with metastatic NSCLC for treatment with YERVOY in combination with nivolumab based on PD-L1 expression.

• Select patients with unresectable or advanced or metastatic ESCC for treatment with YERVOY in combination with nivolumab based on PD-L1 expression.

• An FDA-approved companion diagnostic for the detection of PD-L1 expression in patients with advanced or metastatic ESCC is not available. 2.2 Recommended Dosage The recommended dosages of YERVOY as a single agent are presented in Table 1.

YERVOY as a 30-minute intravenous infusion.

Table 1: Recommended Dosages for YERVOY as a Single Agent Indication Recommended YERVOY Dosage Duration of Therapy Unresectable or metastatic melanoma 3 mg/kg every 3 weeks Maximum of 4 doses Adjuvant treatment of melanoma 3 mg/kg every 3 weeks followed by 3 mg/kg every 12 weeks Every 3 weeks up to a maximum of 4 doses Every 12 weeks for up to 4 additional doses The recommended dosages of YERVOY in combination with other therapeutic agents are presented in Table 2.

YERVOY on the same day as other therapeutic agents.

Refer to the respective Prescribing

Information for each therapeutic agent administered in combination with YERVOY for recommended dosage information, as appropriate.

Table 2: Recommended Dosages of YERVOY in Combination with Other Therapeutic Agents Refer to the Prescribing Information for the agents administered in combination with YERVOY for recommended dosing information, as appropriate. † Refer to the Prescribing Information for nivolumab for dosage information after completing use in combination with YERVOY.

Indication Recommended YERVOY Dosage Duration of Therapy Unresectable or metastatic melanoma 3 mg/kg every 3 weeks with nivolumab 1 mg/kg In combination with nivolumab for a maximum of 4 doses or until unacceptable toxicity, whichever occurs earlier.

After completing 4 doses of combination therapy, administer nivolumab as a single agent until disease progression or unacceptable toxicity.† Advanced renal cell carcinoma 1 mg/kg every 3 weeks with nivolumab 3 mg/kg In combination with nivolumab for a maximum of 4 doses.

After completing 4 doses of combination therapy, administer nivolumab as single agent until disease progression or unacceptable toxicity. † Microsatellite instability-high (MSI‑H) or mismatch repair deficient (dMMR) metastatic colorectal cancer Adult patients and pediatric patients age 12 years and older and weighing 40 kg or more: 1 mg/kg every 3 weeks with nivolumab 240 mg In combination with nivolumab for a maximum of 4 doses. † After completing 4 doses of combination therapy, administer nivolumab as single agent until disease progression, unacceptable toxicity, or up to 2 years. † Pediatric patients age 12 years and older and weighing less than 40 kg: 1 mg/kg every 3 weeks with nivolumab 3 mg/kg Hepatocellular carcinoma 3 mg/kg every 3 weeks with nivolumab 1 mg/kg In combination with nivolumab for a maximum of 4 doses.

After completing a maximum of 4 doses of combination therapy, administer nivolumab as single agent until disease progression or unacceptable toxicity. † Metastatic non-small cell lung cancer expressing PD‑L1 1 mg/kg every 6 weeks with nivolumab 360 mg every 3 weeks In combination with nivolumab until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression. † Metastatic or recurrent non-small cell lung cancer 1 mg/kg every 6 weeks with nivolumab 360 mg every 3 weeks and histology-based platinum‑doublet chemotherapy every 3 weeks In combination with nivolumab until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression. † 2 cycles of histology-based platinum-doublet chemotherapy Malignant pleural mesothelioma 1 mg/kg every 6 weeks with nivolumab 360 mg every 3 weeks In combination with nivolumab until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression. † Esophageal squamous cell carcinoma 1 mg/kg every 6 weeks with nivolumab 3 mg/kg every 2 weeks or 360 mg every 3 weeks In combination with nivolumab until disease progression, unacceptable toxicity, or up to 2 years. 2.3 Recommended Dosage Modifications for Adverse Reactions No dose reduction for YERVOY is recommended.

In general, withhold YERVOY for severe (Grade 3) immune-mediated adverse reactions.

Permanently discontinue

YERVOY for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, persistent moderate (Grade 2) or severe (Grade 3) reactions lasting 12 weeks or longer after last YERVOY dose (excluding endocrinopathy), or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating steroids.

Dosage modifications for YERVOY or

YERVOY in combination with nivolumab for adverse reactions that require management different from these general guidelines are summarized in Table 3.

YERVOY is administered in combination with nivolumab, withhold or permanently discontinue both YERVOY and nivolumab for toxicity.

Table 3: Recommended Dosage Modifications for Adverse Reactions ALT = alanine aminotransferase, AST = aspartate aminotransferase, DRESS = Drug Rash with Eosinophilia and Systemic Symptoms, SJS = Stevens Johnson Syndrome, TEN = toxic epidermal necrolysis, ULN = upper limit of normal * Based on Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 a Resume in patients with complete or partial resolution (Grade 0 or 1) after corticosteroid taper.

Permanently discontinue if no complete or partial resolution within 12 weeks of last dose or inability to reduce prednisone to 10 mg per day (or equivalent) or less within 12 weeks of initiating steroids. b If AST/ALT are less than or equal to ULN at baseline, withhold or permanently discontinue YERVOY based on recommendations for hepatitis with no liver involvement. c This guidance is only applicable to HCC patients who are being treated with YERVOY in combination with nivolumab. d Depending on clinical severity, consider withholding for Grade 2 endocrinopathy until symptom improvement with hormone replacement.

Resume once acute symptoms have resolved.

Severity* Dosage Modifications Immune-Mediated Adverse Reactions Colitis Grade 2 Withhold a Grade 3 or 4 Permanently discontinue Hepatitis with no tumor involvement of the liver or Hepatitis with tumor involvement of the liver/non-HCC AST or ALT increases to more than 3 times and up to 5 times the ULN or Total bilirubin increases to more than 1.5 times and up to 3 times the ULN Withhold a AST or ALT more than 5 times the ULN or Total bilirubin more than 3 times the ULN Permanently discontinue Hepatitis with tumor involvement of the liver b /HCC c Baseline AST/ALT is more than and up to 3 times ULN and increases to more than and up to 10 times ULN or Baseline AST/ALT is more than and up to 5 times ULN and increases to more than and up to 10 times ULN.

Withhold a

AST/ALT increases to more than 10 times ULN or Total bilirubin increases to more than 3 times ULN.

Permanently discontinue Exfoliative Dermatologic Conditions Suspected

SJS, TEN, or DRESS Withhold Confirmed SJS, TEN, or DRESS Permanently discontinue Endocrinopathies d Grades 3 or 4 Withhold until clinically stable or permanently discontinue depending on severity Pneumonitis Grade 2 Withhold a Grade 3 or 4 Permanently discontinue Nephritis with Renal Dysfunction Grade 2 or 3 increased blood creatinine Withhold a Grade 4 increased blood creatinine Permanently discontinue Neurological Toxicities Grade 2 Withhold a Grade 3 or 4 Permanently discontinue Myocarditis Grade 2, 3 or 4 Permanently discontinue Ophthalmologic Grade 2, 3, or 4 that does not improve to Grade 1 within 2 weeks while receiving topical therapy or that requires systemic treatment Permanently discontinue Other Adverse Reactions Infusion-Related Reactions Grade 1 or 2 Interrupt or slow the rate of infusion Grade 3 or 4 Permanently discontinue 2.4 Preparation and Administration.

• Do not shake product.

• Visually inspect for particulate matter and discoloration prior to administration.

Discard vial if solution is cloudy, there is pronounced discoloration (solution may have pale-yellow color), or there is foreign particulate matter other than translucent-to-white, amorphous particles.

Preparation of

• Allow the vial(s) to stand at room temperature for approximately 5 minutes prior to preparation of infusion.

• Withdraw the required volume of YERVOY and transfer into an intravenous bag.

• Dilute with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to a final concentration ranging from 1 mg/mL to 2 mg/mL.

Mix diluted solution by gentle inversion.

• After preparation, store the diluted solution either refrigerated at 2°C to 8°C (36°F to 46°F) or at room te.

(ipilimumab) injection is a sterile, preservative-free, clear to slightly opalescent, colorless to pale-yellow solution.

YERVOY is available as follows

Carton Contents NDC One 50 mg/10 mL (5 mg/mL), single-dose vial NDC 0003-2327-11 One 200 mg/40 mL (5 mg/mL), single-dose vial NDC 0003-2328-22 Store YERVOY under refrigeration at 2°C to 8°C (36°F to 46°F).

YERVOY from light by storing in the original carton until time of use.

Do not freeze or shake.

Based on findings from animal studies and its mechanism of action, YERVOY can cause fetal harm when administered to a pregnant woman.

There is insufficient human data for

YERVOY exposure in pregnant women.

In animal reproduction studies, administration of ipilimumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in higher incidences of abortion, stillbirth, premature delivery (with corresponding lower birth weight), and higher incidences of infant mortality in a dose-related manner.

The effects of ipilimumab are likely to be greater during the second and third trimesters of pregnancy.

IgG1 is known to cross the placental barrier and ipilimumab is an IgG1; therefore, ipilimumab has the potential to be transmitted from the mother to the developing fetus.

Advise pregnant women of the potential risk to a fetus.

Report pregnancies to Bristol-Myers

Squibb at 1-844-593-7869.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

In a combined study of embryo-fetal and peri-postnatal development, pregnant cynomolgus monkeys received ipilimumab every 3 weeks from the onset of organogenesis in the first trimester through parturition.

No treatment-related adverse effects on reproduction were detected during the first two trimesters of pregnancy.

Beginning in the third trimester, administration of ipilimumab at doses resulting in exposures approximately 2.6 to 7.2 times the human exposure at a dose of 3 mg/kg resulted in dose-related increases in abortion, stillbirth, premature delivery (with corresponding lower birth weight), and an increased incidence of infant mortality.

In addition, developmental abnormalities were identified in the urogenital system of 2 infant monkeys exposed in utero to 30 mg/kg of ipilimumab (7.2 times the humans exposure based on area under the curve at a dose of 3 mg/kg).

One female infant monkey had unilateral renal agenesis of the left kidney and ureter, and 1 male infant monkey had an imperforate urethra with associated urinary obstruction and subcutaneous scrotal edema.

Genetically engineered mice heterozygous for

CTLA-4 (CTLA-4+/−), the target for ipilimumab, appeared healthy and gave birth to healthy CTLA-4+/− heterozygous offspring.

CTLA-4+/− heterozygous mice also produced offspring deficient in CTLA-4 (homozygous negative, CTLA-4−/−).

CTLA-4−/− homozygous negative offspring appeared healthy at birth, exhibited signs of multiorgan lymphoproliferative disease by 2 weeks of age, and all died by to 4 weeks of age with massive lymphoproliferation and multiorgan tissue destruction.

The safety and effectiveness of

YERVOY have been established in pediatric patients aged 12 years and older for the following indications: as a single agent and in combination with nivolumab for unresectable or metastatic melanoma, in combination with nivolumab for the treatment of MSI-H or dMMR unresectable and metastatic CRC, and in combination with nivolumab for MSI-H or dMMR mCRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

Use of

YERVOY for these indications is supported by evidence from adequate and well-controlled studies in adults with melanoma or MSI-H or dMMR mCRC and additional pharmacokinetic data in pediatric patients.

Ipilimumab exposures in pediatric patients 12 years and older are comparable to that of adults, and the courses of melanoma and MSI-H or dMMR mCRC are similar in pediatric patients aged 12 years and older to that of adults to allow extrapolation of safety and efficacy.

YERVOY have not been established in pediatric patients younger than 12 years old with unresectable or metastatic melanoma or MSI-H or dMMR mCRC.

YERVOY have not been established in pediatric patients for the adjuvant treatment of melanoma or for the treatment of advanced renal cell carcinoma, hepatocellular carcinoma, metastatic non-small cell lung cancer, malignant pleural mesothelioma and esophageal cancer.

In a dose-finding trial (NCT01445379), 33 patients aged to 21 years (median 13 years) with relapsed or refractory solid tumors were evaluated including unresectable stage IIIc or stage IV melanoma, progressive or refractory sarcomas, renal or bladder carcinoma, and neuroblastoma.

No responses in the patients with non-melanoma solid tumors and no new safety signals were observed in pediatric patients in this study.

Of the 511 patients treated with YERVOY in Study MDX010-20 (unresectable or metastatic melanoma), 28% were 65 years and over.

No overall differences in safety or effectiveness were observed between these patients and younger patients.

Of the 314 patients randomized to YERVOY administered with nivolumab in CHECKMATE-067, 41% were 65 years or older and 11% were 75 years or older.

No overall differences in safety or effectiveness were reported between elderly patients and younger patients.

Of the 576 patients randomized to YERVOY 1 mg/kg every 6 weeks with nivolumab 3 mg/kg every 2 weeks in CHECKMATE-227 (NSCLC), 48% were 65 years or older and 10% were 75 years or older.

No overall difference in safety was reported between older patients and younger patients; however, there was a higher discontinuation rate due to adverse reactions in patients aged 75 years or older (29%) relative to all patients who received YERVOY with nivolumab (18%).

Of the 396 patients in the primary efficacy population (PD-L1 ≥1%) randomized to YERVOY 1 mg/kg every 6 weeks with nivolumab 3 mg/kg every 2 weeks in CHECKMATE-227, the hazard ratio for overall survival was 0.70 (95% CI: 0.55, 0.89) in the 199 patients younger than 65 years compared to 0.91 (95% CI: 0.72, 1.15) in the 197 patients 65 years or older.

Of the 303 patients randomized to YERVOY 1 mg/kg every 6 weeks in combination with nivolumab 3 mg/kg every 2 weeks in CHECKMATE-743 (malignant pleural mesothelioma), 77% were 65 years old or older and 26% were 75 years or older.

No overall difference in safety was reported between older patients and younger patients; however, there were higher rates of serious adverse reactions and discontinuation rate due to adverse reactions in patients aged 75 years or older (68% and 35%, respectively) relative to all patients who received YERVOY with nivolumab (54% and 28%, respectively).

For patients aged 75 years or older who received chemotherapy, the rate of serious adverse reactions was 34% and discontinuation due to adverse reactions was 26% relative to 28% and 19% respectively for all patients.

The hazard ratio for overall survival was 0.76 (95% CI: 0.52, 1.11) in the 71 patients younger than 65 years compared to 0.74 (95% CI: 0.59, 0.93) in the 232 patients 65 years or older randomized to YERVOY in combination with nivolumab.

Of the 550 patients randomized to YERVOY 1 mg/kg with nivolumab in CHECKMATE-214 (renal cell carcinoma), 38% were 65 years or older and 8% were 75 years or older.

No overall difference in safety was observed between these patients and younger patients.

In geriatric patients with intermediate or poor risk, no overall difference in effectiveness was observed.

Of the 354 patients with dMMR or MSI-H metastatic CRC (mCRC) who were randomized to YERVOY in combination with nivolumab, 44% were 65 years or older and 14% were 75 years or older.

Of the 353 patients randomized to nivolumab, as a single agent, 45% were 65 years or older and 13% were 75 years or older.

There was a higher incidence of any Grade 3 or 4 adverse reactions (55%) in patients aged 65 years or older receiving YERVOY in combination with nivolumab compared to those younger than 65 receiving the combination (42%).

There was a higher incidence of adverse reactions leading to discontinuation in patients aged 65 years or older receiving YERVOY in combination with nivolumab (23%) compared to those younger than 65 receiving the combination (15%).

No overall differences in effectiveness were reported between elderly patients and younger patients receiving YERVOY in combination with nivolumab.

Of the 335 patients with unresectable hepatocellular carcinoma who were randomized to YERVOY in combination with nivolumab, 52% were 65 years or older and 14% were 75 years or older.

No overall difference in safety was reported between elderly patients and younger patients.

Of the 49 patients who received YERVOY 3 mg/kg with nivolumab in Cohort of CHECKMATE-040 (previously treated hepatocellular carcinoma), 29% were between 65 years and 74 years of age and 8% were 75 years or older.

Clinical studies of

YERVOY in combination with nivolumab did not include sufficient numbers of patients with hepatocellular carcinoma aged and over to determine whether they respond differently from younger patients.

Of the 325 patients who received YERVOY 1 mg/kg every 6 weeks in combination with nivolumab 3 mg/kg every 2 weeks in CHECKMATE-648 (ESCC), 43% were 65 years old or older and 7% were 75 years or older.

No overall difference in safety was reported between older patients and younger patients; however, there was a higher discontinuation rate due to adverse reactions in patients aged 75 years or older (38%) relative to all patients who received YERVOY with nivolumab (23%).

For patients aged 75 years or older who received chemotherapy, the discontinuation rate due to adverse reactions was 33% relative to 23% for all patients.

CA184-029 (adjuvant treatment of melanoma) and CHECKMATE-142 (metastatic colorectal cancer) did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients.

In Combination with Nivolumab and Platinum-Doublet Chemotherapy Of the 361 patients randomized to YERVOY 1 mg/kg every 6 weeks in combination with nivolumab 360 mg every 3 weeks and platinum-doublet chemotherapy every 3 weeks (for 2 cycles) in CHECKMATE-9LA (NSCLC), 51% were 65 years or older and 10% were 75 years or older.

No overall difference in safety was reported between older patients and younger patients; however, there was a higher discontinuation rate due to adverse reactions in patients aged 75 years or older (43%) relative to all patients who received YERVOY with nivolumab and chemotherapy (24%).

For patients aged 75 years or older who received chemotherapy only, the discontinuation rate due to adverse reactions was 16% relative to all patients who had a discontinuation rate of 13%.

Based on an updated analysis for overall survival, of the 361 patients randomized to YERVOY in combination with nivolumab and platinum-doublet chemotherapy in CHECKMATE-9LA, the hazard ratio for overall survival was 0.61 (95% CI: 0.47, 0.80) in the 176 patients younger than 65 years compared to 0.73 (95% CI: 0.56, 0.95) in the 185 patients 65 years or older.