KEYNOTE-054 & KEYNOTE-716 - Clinical Trial Results

Advanced Melanoma or Adjuvant Therapy for Melanoma

Adjuvant Therapy for Stage IIB, Stage IIC, or Stage III Melanoma

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

An anti–PD⁠-⁠1 adjuvant therapy approved for completely resected stage IIB and stage IIC melanoma.¹

Clinical Findings from KEYNOTE⁠-⁠716 (Stage IIB/IIC)

Significant Improvement in Recurrence-Free Survival (RFS) Demonstrated With KEYTRUDA vs Placebo

For adjuvant treatment in patients (12 years and older) with completely resected stage IIB or stage IIC melanoma

35%

Reduction in the risk of disease recurrence or death with KEYTRUDA compared with placebo

HR=0.65 (95% CI, 0.46–0.92; P=0.0132)

Initial analysis of RFS in KEYNOTE⁠-⁠716 for KEYTRUDA at a 14.4-Month Median Follow-Up vs 14.3 Months for Placebo²

KEYTRUDA (n=487)	Placebo (n=489)
HR^a,b=0.65 (95% CI, 0.46–0.92; P^b=0.0132^c)
Events observed 54 (11%)	Events observed 82 (17%)
Median in Months NR (95% CI, 22.6–NR)	Median in Months NR (95% CI, NR–NR)

a. Based on the stratified Cox proportional hazard model.

b. Based on log-rank test stratified by AJCC, 8th edition stage.

c. P-value is compared with 0.0202 of the allocated alpha for this interim analysis.

HR = hazard ratio; CI = confidence interval; AJCC = American Joint Committee on Cancer; NR = not reached.

Post hoc RFS Analysis from KEYNOTE⁠-⁠716 at a 52.8-Month Median Follow-Up^3,4

LIMITATION: No formal statistical testing was planned for the post hoc analysis for RFS that occurred at a median follow-up of 52.8 months and, therefore, no conclusions can be drawn.

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HR^d=0.62 (95% CI^d, 0.50–0.78)

Kaplan-Meier Estimates of Recurrence-Free Survival (RFS) With KEYTRUDA® (pembrolizumab) vs Placebo in KEYNOTE-716

Additional Information

Post hoc RFS analysis for KEYNOTE⁠-⁠716 at a 52.8-month median follow up:

The RFS hazard ratio^d was 0.62 (95% CI^d, 0.50–0.78).
134/487 (27.5%) of patients in the KEYTRUDA arm and 198/489 (40.5%) of patients in the placebo arm experienced RFS events.
Median RFS was not reached with KEYTRUDA (95% CI, NR–NR) and was 59.9 months with placebo.
According to Kaplan-Meier estimates, the 4-year RFS rates were 71% with KEYTRUDA and 58% with placebo.

d. Based on Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by melanoma T Stage (T3b vs T4a vs T4b).

KEYTRUDA Significantly Improved Distant Metastasis-Free Survival^e (DMFS) vs Placebo in Patients With Completely Resected Stage IIB or IIC Melanoma

KEYTRUDA significantly reduced the risk of completely resected stage IIB or IIC melanoma returning as stage IV disease^5,f by 36% vs placebo (HR^g,h=0.64; 95% CI, 0.47-0.88; P^g=0.0058ⁱ)

Initial Analysis of DMFS, an Additional Efficacy Outcome Measure, in KEYNOTE⁠-⁠716 at a 27.4-Month Median Follow-Up⁶

KEYTRUDA (n=487)	Placebo (n=489)
HR^g,h=0.64; (95% CI, 0.47–0.88; P^h=0.0058ⁱ)
Events observed 63 (13%)	Events observed 95 (19%)
Median in Months NR (95% CI, NR–NR)	Median in Months NR (95% CI, NR–NR)

e. DMFS was defined as the time from randomization to the first diagnosis of distant metastasis.⁷ Distant metastasis is defined as a spread of tumor to distant organs or distant lymph nodes.

f. As defined in American Joint Committee on Cancer (AJCC) 8th edition, the presence of distant metastases indicates stage IV disease.⁵

g. Based on the stratified Cox proportional hazard model.

h. Based on a a log-rank test stratified by AJCC 7th edition stage.

i. P-value is compared with 0.0256 of the allocated alpha for this interim analysis.

Post hoc Analysis: Kaplan-Meier Estimates of DMFS With KEYTRUDA and Placebo at a 52.8-Month Median Follow-Up in KEYNOTE⁠-⁠716^3,4

LIMITATION: No formal statistical testing was planned for the post hoc analysis for DMFS that occurred at a median follow-up of 52.8 months and, therefore, no conclusions can be drawn.

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HR^j=0.59 (95% CI, 0.45–0.77)

Kaplan-Meier Estimates of Distant Metastasis-Free Survival (DMFS) in KEYNOTE-716

Additional Information

Post hoc DMFS analysis for KEYNOTE⁠-⁠716 at a 52.8-month median follow up:

The DMFS hazard ratio was 0.59^j (95% CI, 0.45–0.77).
86/487 (17.7%) of patients in the KEYTRUDA arm and 137/489 (28.0%) of patients in the placebo arm experienced DMFS events.
Median DMFS was not reached in either arm.
According to Kaplan-Meier estimates, the 4-year DMFS rates were 81% with KEYTRUDA and 70% with placebo.

j. Based on Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by melanoma T Stage (T3b vs T4a vs T4b).⁴

Study Design for KEYNOTE⁠-⁠716 (Stage IIB/IIC)

Study Overview

Phase 3, multicenter, randomized, double-blind, placebo-controlled trial in 976 patients²

Select Eligibility Criteria Age ≥12 years Completely resected stage IIB or stage IIC melanoma No previous treatment for melanoma beyond complete surgical resection Randomization was stratified by AJCC 8th edition T stage (>2.0–4.0 mm with ulceration vs >4.0 mm without ulceration vs >4.0 mm with ulceration).

Randomized 1:1 (N=976)

Study Arms^2,7

KEYTRUDA

Treatment

Adults: KEYTRUDA 200 mg IV Q3W

Pediatric (≥12 years old): KEYTRUDA 2 mg/kg up to a maximum of 200 mg IV Q3W

Treatment continued for up to 1 year or until disease recurrence or unacceptable toxicity (n=487)

Recurrence >6 months: (after completion of 1 year of pembrolizumab)

Post Recurrence (Unblinded Treatment)

Adults: KEYTRUDA 200 mg IV Q3W

Pediatric (≥12 years old): KEYTRUDA 2 mg/kg up to a maximum of 200 mg IV Q3W

Treatment continued until disease progression, recurrence, unacceptable toxicity, or up to 2 years

Placebo

Treatment: Placebo IV Q3W for up to 1 year (n=489)

Recurrence: Crossover to KEYTRUDA

Post Recurrence (Unblinded Treatment)

Adults: KEYTRUDA 200 mg IV Q3W

Pediatric (≥12 years old): KEYTRUDA 2 mg/kg up to a maximum of 200 mg IV Q3W

Treatment continued until disease progression, recurrence, unacceptable toxicity, or up to 2 years

End Points

Major efficacy outcome measure (primary endpoint):

The major efficacy outcome measure was investigator-assessed RFS defined as the time between the date of randomization and the date of first recurrence [local, in-transit, or regional lymph nodes, or distant recurrence] or death, whichever occurred first).
New primary melanomas were excluded from the definition of RFS. Patients underwent imaging every 6 months for 1 year from randomization, every 6 months from years 2 to 4, and then once in year 5 from randomization or until recurrence, whichever came first.

Additional efficacy outcome measure (secondary endpoint):

The additional efficacy outcome measure was DMFS defined as the time from randomization to the first diagnosis of distant metastasis per RECIST v1.1. Distant metastasis refers to cancer that has spread from the original (primary) tumor and beyond local tissues and lymph nodes to distant organs or distant lymph nodes.⁷

Patient Characteristics

Baseline Characteristics of Patients (N=976)

All patients randomized at baseline:

Median age: 61 years (range: 16–87), 39% age 65 or older
Male: 60%
White: 98%
ECOG PS of 0: 93%; ECOG PS of 1: 7%
Stage IIB: 64%
Stage IIC: 35%

PD-1 = programmed death receptor-1; IV = intravenous; Q3W = every 3 weeks; RECIST v1.1 = Response Evaluation Criteria In Solid Tumors v1.1; ECOG PS = Eastern Cooperative Oncology Group performance status.

Stage IIB/IIC Melanoma: Risk of Recurrence from a Retrospective Study

Data from a Retrospective Study: Risk of Recurrence for Completely Resected Stage IIB and IIC Melanoma⁸

Study Design: This study was a retrospective chart review of 567 adult patients who were followed for a median of 38.8 months after complete resection of stage IIB or IIC cutaneous melanoma between 2008 and 2017. Patients in this study had at least 2 visits after diagnosis recorded within the US Oncology Network, a community-based network of over 480 cancer centers in 25 states. Eighty (14.1%) patients in the study received adjuvant treatment for stage IIB or IIC melanoma; of those who received adjuvant treatment, 77 (96.3%) received IFN-alpha. Recurrence in this study was captured as physician-documented recurrence or progression.

Rates of Recurrence⁸

Resected Stage IIB Melanoma	Resected Stage IIC Melanoma
Rate of Recurrence 37% (n=140/375)	Rate of Recurrence 43% (n=83/192)
Of the 140 patients with recurrence, distant metastasis was the first recurrence in 50% (n=70/140)	Of the 83 patients with recurrence, distant metastasis was the first recurrence in 58% (n=48/83)

Additional Information

Among these patients, sites of distant metastasis included lung, distant lymph nodes, brain, liver, bone, skin, peritoneum, muscle, and other.^8,k

k. Some sites of metastasis have been combined because of data privacy rules requiring masking of numbers ≤ 5.

IFN-alpha = interferon-alpha.

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): An NCCN Category 1 Option for Melanoma in Certain Adjuvant Treatment Settings⁹

Recommended by the National Comprehensive Cancer Network® (NCCN®) for Eligible Patients With Stages IIB/IIC or Stage III Melanoma⁹

Stage IIB and IIC melanoma: NCCN Guidelines® recommend pembrolizumab (KEYTRUDA) as an option for the adjuvant treatment of patients with pathological stage IIB or IIC cutaneous melanoma (category 1).^9,l-n

Stage III melanoma: NCCN Guidelines® recommend pembrolizumab (KEYTRUDA) as an option for the adjuvant treatment of select patients with stage III cutaneous melanoma with resectable clinically positive nodes (category 1 and preferred).^9,o

l. Adjuvant programmed cell death protein 1 (PD-1) therapy is approved for clinical or pathologic stage IIB and IIC melanoma. Pathologic staging (with SLNB) is strongly recommended prior to consideration of adjuvant pembrolizumab—to enhance risk/benefit patient discussions and optimize local/regional disease control.

m. For patients with stage IIB/IIC disease being considered for adjuvant therapy, baseline/pretreatment imaging is appropriate.

n. Adjuvant pembrolizumab reduces relapse events for resected pathologic stage IIB and IIC melanoma; longer follow up is needed to assess impact on OS. Clinicians considering adjuvant pembrolizumab therapy for stages IIB or IIC disease should have a detailed discussion with the patient (shared decision making) to weigh the pros and cons of treatment benefit versus toxicity. Factors to be considered include patient’s age, performance status, personal/family history of autoimmune disease, absolute risk of recurrence, and risk of long-term immunotoxicities including approximately 15% risk of lifelong endocrine dysfunction.²

o. Pembrolizumab has shown clinically significant improvement in RFS compared to placebo, but its impact on OS has not yet been reported.

NCCN makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

Category 1 = Based upon high-level evidence (≥1 randomized phase 3 trials or high-quality, robust meta-analyses), there is uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate.⁹

SLNB = sentinel lymph node biopsy; OS = overall survival.

9. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Cutaneous Melanoma V.2.2025. National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed January 29, 2025. To view the most recent and complete version of the guidelines, go online to NCCN.org.

Clinical Findings from KEYNOTE⁠-⁠054 (Stage III)

Significant Improvement in Recurrence-Free Survival (RFS) Demonstrated With KEYTRUDA vs Placebo

For adjuvant treatment in patients (12 years and older) with completely resected stage III melanoma

Initial Analysis of RFS in KEYNOTE⁠-⁠054 for KEYTRUDA vs Placebo at a 15.1-Month Median Follow-Up¹⁰

KEYTRUDA (n=514)	Placebo (n=505)
HR^p,q=0.57 (95% CI, 0.46–0.70; P^q<0.001^r)
Events observed 135 (26%)	Events observed 216 (43%)
Median in Months NR	Median in Months 20.4 (95% CI, 16.2–NR)

p. Based on the stratified Cox proportional hazard model.

q. Stratified by AJCC 7th edition stage.

r. P-value is compared with 0.016 of the allocated alpha for this interim analysis.

43%

Reduction in the risk of disease recurrence or death with KEYTRUDA compared with placebo

HR=0.57 (95% CI, 0.46–0.70; P<0.001)

5-Year RFS Analysis in KEYNOTE⁠-⁠054: Kaplan-Meier Estimates With KEYTRUDA and Placebo at a 4.9-Year Median Follow-Up^11,12

LIMITATION: No formal statistical testing was planned for the post hoc analysis of RFS that occurred at a median follow-up of 4.9 years and, therefore, no conclusions can be drawn.

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HR^s=0.61 (95% CI, 0.51–0.72)

5-Year Recurrence-Free Survival (RFS) Analysis in KEYNOTE⁠-⁠054

Additional Information

Updated RFS analysis from KEYNOTE⁠⁠-⁠054 at a 4.9-year median follow up:

The RFS hazard ratio^s,v was 0.61.
228/514 (44.4%) of patients in the KEYTRUDA arm and 304/505 (60.2%) of patients in the placebo arm experienced RFS events.
Median RFS was 67.4 months in the KEYTRUDA arm and 21.2 months in the placebo arm.

s. Based on Cox regression model with treatment as a covariate stratified by stage (IIIA [>1 mm metastasis] vs. IIIB vs. IIIC 1-3 nodes vs. IIIC = 4 nodes) as indicated at randomization.¹¹

Placebo = complete surgical resection followed by observation.

KEYTRUDA Significantly Improved Distant Metastasis-Free Survival^t (DMFS) vs Placebo in Patients With Completely Resected Stage III Melanoma

KEYTRUDA significantly reduced the risk of completely resected stage III melanoma returning as stage IV disease^5,u or death vs placebo (HR^v,w=0.60; 95% CI, 0.49–0.73; P<0.0001^x,y)

Initial Analysis of DMFS, an Additional Efficacy Outcome Measure, in KEYNOTE⁠-⁠054 at a 42.3-Month Median Follow-Up¹³

KEYTRUDA (n=514)	Placebo (n=505)
HR^v,w=0.60 (95% CI, 0.49–0.73; P^w<0.0001^x,y)
Events observed 173 (34%)	Events observed 245 (49%)
Median in Months NR (95% CI, 49.6–NR)	Median in Months 40.0 (95% CI, 27.7–NR)

Initial Analysis (ITT Population): Kaplan-Meier Estimates of DMFS With KEYTRUDA vs Placebo at a 42.3-Month Median Follow-Up in KEYNOTE⁠-⁠054¹³

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HR^v,w=0.60 (95% CI, 0.49–0.73; P^w<0.0001^x,y)

Kaplan-Meier Estimates of Distant Metastasis-Free Survival (DMFS) With KEYTRUDA® (pembrolizumab) vs Placebo in KEYNOTE⁠-⁠054

t. DMFS was defined as the time from randomization to the first diagnosis of distant metastasis or date of death (whatever the cause), whichever occurred first.¹⁴ Distant metastasis is defined as a spread of tumor to distant organs or distant lymph nodes.

u. As defined in AJCC 7th edition, the presence of distant metastases indicates stage IV disease.

v. Based on the stratified Cox proportional hazard model.

w. Stratified by AJCC 7th edition stage.

x. P-value is compared with 0.028 of the allocated alpha for this analysis.

y. Based on a log-rank test stratified by AJCC 7th edition stage.

ITT = intent-to-treat.

Efficacy demonstrated regardless of PD⁠-⁠L1 status

For patients with PD⁠-⁠L1 positive tumors, the RFS HR was 0.54 (95% CI, 0.42–0.69); P<0.0001.

For patients with PD⁠-⁠L1 positive tumors, the DMFS HR was 0.61 (95% CI, 0.49–0.76); P<0.0001.

The RFS and DMFS benefit for KEYTRUDA compared with placebo was observed regardless of tumor PD⁠-⁠L1 expression.

PD⁠-⁠L1 = programmed death ligand 1; HR = hazard ratio; CI = confidence interval.

Study Design for KEYNOTE⁠-⁠054 (Stage III)

Study Overview^10,15

Phase 3, multicenter, randomized, double-blind, placebo-controlled trial conducted in collaboration with the European Organisation for Research and Treatment of Cancer (EORTC) to compare treatment with KEYTRUDA vs placebo following complete surgical resection of high risk, stage III melanoma, as well as an anti⁠–⁠PD⁠-1 rechallenge crossover design.

Select Eligibility Criteria^10,15 Age ≥18 years Completely resected stage IIIA (>1-mm lymph node metastasis), IIIB or IIIC melanoma (AJCC 7th ed.) PD⁠-⁠L1 expression evaluation Lymph node dissection within 13 weeks prior to starting treatment Randomization within 13 weeks of surgery Radiotherapy within 13 weeks post-surgery, if indicated, prior to starting treatment Randomization was stratified by AJCC 7th ed stage (IIIA vs IIIB vs IIIC 1-3 positive lymph nodes vs IIIC ≥4 positive lymph nodes) and geographic region (North America, European countries, Australia, and other countries as designated).

Randomized 1:1 (N=1019)

Study Arms¹⁵

KEYTRUDA

Treatment: KEYTRUDA 200 mg IV infusion Q3W for up to 1 year (n=514) until disease recurrence or unacceptable toxicity

Recurrence >6 months: (after completion of 1 year of pembrolizumab)

Post Recurrence (Unblinded Treatment): KEYTRUDA 200 mg IV Q3W until disease recurrence, or unacceptable toxicity, or up to 2 years

Placebo

Treatment: Placebo IV Q3W for up to 1 year (n=505)

Recurrence: Crossover to KEYTRUDA

Post Recurrence (Unblinded Treatment): KEYTRUDA 200 mg IV Q3W until disease recurrence, or unacceptable toxicity, or up to 2 years

End Points

Major efficacy outcome measure (primary endpoint):

Investigator assessed RFS in the whole population and in the population with PD⁠-⁠L1-positive tumors, where RFS was defined as the time between the date of randomization and the date of first recurrence (local, regional, or distant metastasis) or death, whichever occurs first.
New primary melanomas were excluded from the definition of RFS.

Additional efficacy outcome measure (secondary endpoint):

The additional efficacy outcome measure was DMFS, defined as the time from randomization to the first diagnosis of distant metastasis or date of death (whatever the cause), whichever occurs first.¹³

Study Design Details

Patients underwent imaging every 12 weeks after the first dose of KEYTRUDA for the first 2 years, then every 6 months from Year 3 to 5, and then annually.

Patient Characteristics

Baseline Characteristics of Patients (N=1019)

All patients randomized at baseline:

Median age: 54 years (range: 19–88), 25% age 65 or older
Male: 62%
ECOG PS of 0: 94%; ECOG PS of 1: 6%
Stage IIIA: 16%
Stage IIIB: 46%
Stage IIIC (1-3 positive lymph nodes): 18%
Stage IIIC (≥4 positive lymph nodes): 20%
BRAF V600 mutation positive: 50%
BRAF wild type: 44%
PD⁠-⁠L1 positive with TPS ≥1% according to an IUO assay: 84%

IV = intravenous; ECOG PS = Eastern Cooperative Oncology Group performance status; PD⁠-⁠L1 = programmed death ligand 1; TPS = tumor proportion score; IUO = investigational use only.

KEYNOTE⁠-⁠054 Recurrence Rates

Recurrence Rates at 3-Year Analysis in Patients With Stage III Melanoma Who Received Placebo in KEYNOTE⁠-⁠054¹⁶

Data shown are for patients with melanoma with involvement of lymph node(s) following complete resection.

LIMITATION: KEYNOTE⁠-⁠054 was not powered to measure rate of recurrence at the 3-year analysis for patients who received placebo or to detect differences in the treatment effect between substages. Therefore, no conclusions can be drawn.

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KEYNOTE-054 Recurrence Rates at 3-Year Analysis

Additional Information

Recurrence in the KEYNOTE⁠-⁠054 trial included local, regional, and distant recurrences, as well as death from any cause.

Patients enrolled in KEYNOTE⁠-⁠054 had stage IIIA (>1mm lymph node metastasis), stage IIIB, or stage IIIC melanoma according to AJCC, 7th ed.

Median follow-up time for 3-year analysis was 36.6 months.

z. Staging according to AJCC 7th ed.

aa. Staging according to AJCC 8th ed.

Hypothetical Patient Cases

Based on Those Studied in KEYNOTE-716 and KEYNOTE-054

FRANK

Diagnosis

STAGE IIB (T4aN0M0) MELANOMA¹⁷

Presentation

• Presented with an asymmetric lesion on his left shoulder.
• Punch biopsy results:
4.7-mm-thick superficial spreading melanoma; non-ulcerated

Sentinel Lymph Node Biopsy Results

Negative

Wide Local Excision Results

Margins clear

ECOG PS

0

Age62

GenderMale

MARIEL

Diagnosis

STAGE IIIA (T2aN1aM0) MELANOMA¹⁷

Presentation

• Noticed 2 new small skin lesions during her regular self-examination.
• Punch biopsy results:
–1.2-mm-thick superficial spreading melanoma; non-ulcerated
–1.3-mm-thick superficial spreading melanoma; non-ulcerated

Sentinel Lymph Node Biopsy Results

Node positive (1/2 nodes; >1-mm metastatic focus within node)

Wide Local Excision

Margins clear

Biomarker Testing Results

BRAF wild type; PD-L1 not tested

PET/CT Results

No additional local or distant metastasis

ECOG PS

0

Age39

GenderFemale

PET/CT = positron emission tomography/computed tomography.

You Might Also Be Interested In

Resources

Mechanism of Action

Resources

Access & Reimbursement Support

1. Opdivo. Package Insert. Bristol-Myers Squbb Company; 2024.

2. Luke JJ, Rutkowski P, Queirolo P, et al. Pembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716): a randomised, double-blind, phase 3 trial. Lancet. 2022;399(10336):1718–1729. doi:10.1016/S0140-6736(22)00562-1

3. Data available on request from the Merck National Service Center via email at daprequests@merck.com. Please specify information package US-OOC-02729.

4. Luke JJ, Ascierto PA, Khattak MA, et al. Pembrolizumab versus placebo as adjuvant therapy in resected stage IIB or IIC melanoma: Final analysis of distant metastasis-free survival in the phase III KEYNOTE-716 study. J Clin Oncol. 2024;42(14):1619–1624. doi:10.1200/JCO.23.02355

5. Keung E, Gershenwald J. The eighth edition American Joint Committee on Cancer (AJCC) melanoma staging system: implications for melanoma treatment and care. Expert Rev Anticancer Ther. 2018;18(8):775–784. doi:10.1080/14737140.2018.1489246

6. Long GV, Luke JJ, Khattak MA, et al. Pembrolizumab versus placebo as adjuvant therapy in resected stage IIB or IIC melanoma (KEYNOTE-716): distant metastasis-free survival results of a multicentre, double-blind, randomised, phase 3 trial. Lancet Oncol. 2022;23(11):1378-1388. doi: 10.1016/S1470-2045(22)00559-9

7. Luke JJ, Rutkowski P, Queirolo P, et al. Supplementary Appendix to: Pembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716): a randomised, double-blind, phase 3 trial. Lancet. 2022;399(10336):1718–1729. doi:10.1016/S0140-6736(22)00562-1

8. Samlowski W, Silver MA, Hohlbauch A, et al. Real-world clinical outcomes of patients with stage IIB or IIC cutaneous melanoma treated at US community oncology clinics. Future Oncol. 2022;18(33):3755-3767. doi:10.2217/fon-2022-0508

10. Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med. 2018;378(19):1789–1801.

11. Data available on request from the Merck National Service Center via email at daprequests@merck.com. Please specify information package US-OOC-02442.

12. Eggermont AMM, Kicinski M, Blank CU, et al. Five-Year analysis of adjuvant pembrolizumab or placebo in stage iii melanoma. NEJM Evid. 2022;1(1):1-12. doi:10.1056/EVIDe2100015

13. Eggermont AMM, Blank CU, Mandalà M, et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. 2021;22(5):643-654. doi:10.1016/S1470-2045(21)00065-6

14. Study of pembrolizumab (MK-3475) versus placebo after complete resection of high-risk stage III melanoma (MK-3475-054/1325-MG/KEYNOTE-054). Clinical Trials.gov. Updated August 21, 2023. Accessed November 11, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT02362594?term=Nct02362594&draw=2&rank=1

15. Eggermont AMM, Blank CU, Mandala M, et al. Supplementary Appendix to: Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med. 2018;378(19):1789-1801. doi:10.1056/NEJMoa1802357.

16. Eggermont AMM, Blank CU, Mandala M, et al. Longer follow-up confirms recurrence-free survival benefit of adjuvant pembrolizumab in high-risk stage III melanoma: updated results from the EORTC 1325-MG/KEYNOTE⁠-⁠054 trial. J Clin Oncol. 2020;38(33):3925–3936.

17. Gershenwald JE, Scolyer RA, Hess KR, et al. Melanoma of the skin. In: AJCC Cancer Staging Manual. 8th ed. American Joint Committee on Cancer; 2017:563–585.

Adverse Reactions

In KEYNOTE⁠-⁠006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (≥20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).

In KEYNOTE⁠-⁠054, when KEYTRUDA was administered as a single agent to patients with stage III melanoma, KEYTRUDA was permanently discontinued due to adverse reactions in 14% of 509 patients; the most common (≥1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. The most common adverse reaction (≥20%) with KEYTRUDA was diarrhea (28%). In KEYNOTE⁠-⁠716, when KEYTRUDA was administered as a single agent to patients with stage IIB or IIC melanoma, adverse reactions occurring in patients with stage IIB or IIC melanoma were similar to those occurring in 1011 patients with stage III melanoma from KEYNOTE⁠-⁠054.

In KEYNOTE⁠-⁠189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (≥20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%).

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

In KEYNOTE⁠-⁠042, KEYTRUDA was discontinued due to adverse reactions in 19% of 636 patients with advanced NSCLC; the most common were pneumonitis (3%), death due to unknown cause (1.6%), and pneumonia (1.4%). The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%). The most common adverse reaction (≥20%) was fatigue (25%).

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

In KEYNOTE⁠-⁠671, adverse reactions occurring in patients with resectable NSCLC receiving KEYTRUDA in combination with platinum-containing chemotherapy, given as neoadjuvant treatment and continued as single-agent adjuvant treatment, were generally similar to those occurring in patients in other clinical trials across tumor types receiving KEYTRUDA in combination with chemotherapy.

The most common adverse reactions (reported in ≥20%) in patients receiving KEYTRUDA in combination with chemotherapy or chemoradiotherapy were fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia, peripheral neuropathy, mucosal inflammation, stomatitis, headache, weight loss, abdominal pain, arthralgia, myalgia, insomnia, palmar-plantar erythrodysesthesia, urinary tract infection, hypothyroidism, radiation skin injury, dysphagia, dry mouth, and musculoskeletal pain.

In the neoadjuvant phase of KEYNOTE⁠-⁠671, when KEYTRUDA was administered in combination with platinum-containing chemotherapy as neoadjuvant treatment, serious adverse reactions occurred in 34% of 396 patients. The most frequent (≥2%) serious adverse reactions were pneumonia (4.8%), venous thromboembolism (3.3%), and anemia (2%). Fatal adverse reactions occurred in 1.3% of patients, including death due to unknown cause (0.8%), sepsis (0.3%), and immune-mediated lung disease (0.3%). Permanent discontinuation of any study drug due to an adverse reaction occurred in 18% of patients who received KEYTRUDA in combination with platinum-containing chemotherapy; the most frequent adverse reactions (≥1%) that led to permanent discontinuation of any study drug were acute kidney injury (1.8%), interstitial lung disease (1.8%), anemia (1.5%), neutropenia (1.5%), and pneumonia (1.3%).

Of the KEYTRUDA-treated patients who received neoadjuvant treatment, 6% of 396 patients did not receive surgery due to adverse reactions. The most frequent (≥1%) adverse reaction that led to cancellation of surgery in the KEYTRUDA arm was interstitial lung disease (1%).

In the adjuvant phase of KEYNOTE⁠-⁠671, when KEYTRUDA was administered as a single agent as adjuvant treatment, serious adverse reactions occurred in 14% of 290 patients. The most frequent serious adverse reaction was pneumonia (3.4%). One fatal adverse reaction of pulmonary hemorrhage occurred. Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 12% of patients who received KEYTRUDA as a single agent, given as adjuvant treatment; the most frequent adverse reactions (≥1%) that led to permanent discontinuation of KEYTRUDA were diarrhea (1.7%), interstitial lung disease (1.4%), increased aspartate aminotransferase (1%), and musculoskeletal pain (1%).

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

In KEYNOTE⁠-⁠689, the most common adverse reactions (≥20%) in patients receiving KEYTRUDA were stomatitis (48%), radiation skin injury (40%), weight loss (36%), fatigue (33%), dysphagia (29%), constipation (27%), hypothyroidism (26%), nausea (24%), rash (22%), dry mouth (22%), diarrhea (22%), and musculoskeletal pain (22%).

In the neoadjuvant phase of KEYNOTE-689, of the 361 patients who received at least one dose of single agent KEYTRUDA, 11% experienced serious adverse reactions. Serious adverse reactions that occurred in more than one patient were pneumonia (1.4%), tumor hemorrhage (0.8%), dysphagia (0.6%), immune-mediated hepatitis (0.6%), cellulitis (0.6%), and dyspnea (0.6%). Fatal adverse reactions occurred in 1.1% of patients, including respiratory failure, clostridium infection, septic shock, and myocardial infarction (one patient each). Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 2.8% of patients who received KEYTRUDA as neoadjuvant treatment. The most frequent adverse reaction which resulted in permanent discontinuation of neoadjuvant KEYTRUDA in more than one patient was arthralgia (0.6%).

Of the 361 patients who received KEYTRUDA as neoadjuvant treatment, 11% did not receive surgery. Surgical cancellation on the KEYTRUDA arm was due to disease progression in 4%, patient decision in 3%, adverse reactions in 1.4%, physician’s decision in 1.1%, unresectable tumor in 0.6%, loss of follow-up in 0.3%, and use of non-study anti-cancer therapy in 0.3%.

Of the 323 KEYTRUDA-treated patients who received surgery following the neoadjuvant phase, 1.2% experienced delay of surgery (defined as on-study surgery occurring ≥9 weeks after initiation of neoadjuvant KEYTRUDA) due to adverse reactions, and 2.8% did not receive adjuvant treatment due to adverse reactions.

In the adjuvant phase of KEYNOTE-689, of the 255 patients who received at least one dose of KEYTRUDA, 38% experienced serious adverse reactions. The most frequent serious adverse reactions reported in ≥1% of KEYTRUDA-treated patients were pneumonia (2.7%), pyrexia (2.4%), stomatitis (2.4%), acute kidney injury (2.0%), pneumonitis (1.6%), COVID-19 (1.2%), death not otherwise specified (1.2%), diarrhea (1.2%), dysphagia (1.2%), gastrostomy tube site complication (1.2%), and immune-mediated hepatitis (1.2%). Fatal adverse reactions occurred in 5% of patients, including death not otherwise specified (1.2%), acute renal failure (0.4%), hypercalcemia (0.4%), pulmonary hemorrhage (0.4%), dysphagia/malnutrition (0.4%), mesenteric thrombosis (0.4%), sepsis (0.4%), pneumonia (0.4%), COVID-19 (0.4%), respiratory failure (0.4%), cardiovascular disorder (0.4%), and gastrointestinal hemorrhage (0.4%). Permanent discontinuation of adjuvant KEYTRUDA due to an adverse reaction occurred in 17% of patients. The most frequent (≥1%) adverse reactions that led to permanent discontinuation of adjuvant KEYTRUDA were pneumonitis, colitis, immune-mediated hepatitis, and death not otherwise specified.

In KEYNOTE⁠-⁠048, KEYTRUDA monotherapy was discontinued due to adverse events in 12% of 300 patients with HNSCC; the most common adverse reactions leading to permanent discontinuation were sepsis (1.7%) and pneumonia (1.3%). The most common adverse reactions (≥20%) were fatigue (33%), constipation (20%), and rash (20%).

In KEYNOTE⁠-⁠048, when KEYTRUDA was administered in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, KEYTRUDA was discontinued due to adverse reactions in 16% of 276 patients with HNSCC. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonia (2.5%), pneumonitis (1.8%), and septic shock (1.4%). The most common adverse reactions (≥20%) were nausea (51%), fatigue (49%), constipation (37%), vomiting (32%), mucosal inflammation (31%), diarrhea (29%), decreased appetite (29%), stomatitis (26%), and cough (22%).

In KEYNOTE⁠-⁠012, KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (≥20%) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of facial edema and new or worsening hypothyroidism.

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

In KEYNOTE⁠-⁠087, KEYTRUDA was discontinued due to adverse reactions in 5% of 210 patients with cHL. Serious adverse reactions occurred in 16% of patients; those ≥1% were pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from causes other than disease progression: 1 from GVHD after subsequent allogeneic HSCT and 1 from septic shock. The most common adverse reactions (≥20%) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%).

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

In KEYNOTE⁠-⁠A39, when KEYTRUDA was administered in combination with enfortumab vedotin to patients with locally advanced or metastatic urothelial cancer (n=440), fatal adverse reactions occurred in 3.9% of patients, including acute respiratory failure (0.7%), pneumonia (0.5%), and pneumonitis/ILD (0.2%). Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA in combination with enfortumab vedotin; the serious adverse reactions in ≥2% of patients were rash (6%), acute kidney injury (5%), pneumonitis/ILD (4.5%), urinary tract infection (3.6%), diarrhea (3.2%), pneumonia (2.3%), pyrexia (2%), and hyperglycemia (2%). Permanent discontinuation of KEYTRUDA occurred in 27% of patients. The most common adverse reactions (≥2%) resulting in permanent discontinuation of KEYTRUDA were pneumonitis/ILD (4.8%) and rash (3.4%). The most common adverse reactions (≥20%) occurring in patients treated with KEYTRUDA in combination with enfortumab vedotin were rash (68%), peripheral neuropathy (67%), fatigue (51%), pruritus (41%), diarrhea (38%), alopecia (35%), weight loss (33%), decreased appetite (33%), nausea (26%), constipation (26%), dry eye (24%), dysgeusia (21%), and urinary tract infection (21%).

In KEYNOTE⁠-⁠052, KEYTRUDA was discontinued due to adverse reactions in 11% of 370 patients with locally advanced or metastatic urothelial carcinoma. Serious adverse reactions occurred in 42% of patients; those ≥2% were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis. The most common adverse reactions (≥20%) were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%).

In KEYNOTE⁠-⁠045, KEYTRUDA was discontinued due to adverse reactions in 8% of 266 patients with locally advanced or 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. The most common adverse reactions (≥20%) in patients who received KEYTRUDA were fatigue (38%), musculoskeletal pain (32%), pruritus (23%), decreased appetite (21%), nausea (21%), and rash (20%).

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

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

In KEYNOTE⁠-⁠158 and KEYNOTE⁠-⁠164, adverse reactions occurring in patients with MSI⁠-⁠H or dMMR cancer were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent.

In KEYNOTE⁠-⁠859, when KEYTRUDA was administered in combination with fluoropyrimidine- and platinum-containing chemotherapy, serious adverse reactions occurred in 45% of 785 patients. Serious adverse reactions in >2% of patients included pneumonia (4.1%), diarrhea (3.9%), hemorrhage (3.9%), and vomiting (2.4%). Fatal adverse reactions occurred in 8% of patients who received KEYTRUDA, including infection (2.3%) and thromboembolism (1.3%). KEYTRUDA was permanently discontinued due to adverse reactions in 15% of patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (≥1%) were infections (1.8%) and diarrhea (1.0%). The most common adverse reactions (reported in ≥20%) in patients receiving KEYTRUDA in combination with chemotherapy were peripheral neuropathy (47%), nausea (46%), fatigue (40%), diarrhea (36%), vomiting (34%), decreased appetite (29%), abdominal pain (26%), palmar-plantar erythrodysesthesia syndrome (25%), constipation (22%), and weight loss (20%).

In KEYNOTE⁠-⁠590, when KEYTRUDA was administered with cisplatin and fluorouracil to patients with metastatic or locally advanced esophageal or GEJ (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma who were not candidates for surgical resection or definitive chemoradiation, KEYTRUDA was discontinued due to adverse reactions in 15% of 370 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (≥1%) were pneumonitis (1.6%), acute kidney injury (1.1%), and pneumonia (1.1%). The most common adverse reactions (≥20%) with KEYTRUDA in combination with chemotherapy were nausea (67%), fatigue (57%), decreased appetite (44%), constipation (40%), diarrhea (36%), vomiting (34%), stomatitis (27%), and weight loss (24%).

Adverse reactions occurring in patients with esophageal cancer who received KEYTRUDA as a monotherapy were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

In KEYNOTE⁠-⁠A18, when KEYTRUDA was administered with CRT (cisplatin plus external beam radiation therapy [EBRT] followed by brachytherapy [BT]) to patients with FIGO 2014 Stage III-IVA cervical cancer, fatal adverse reactions occurred in 1.4% of 292 patients, including 1 case each (0.3%) of large intestinal perforation, urosepsis, sepsis, and vaginal hemorrhage. Serious adverse reactions occurred in 30% of patients; those ≥1% included urinary tract infection (2.7%), urosepsis (1.4%), and sepsis (1%). KEYTRUDA was discontinued for adverse reactions in 7% of patients. The most common adverse reaction (≥1%) resulting in permanent discontinuation was diarrhea (1%). For patients treated with KEYTRUDA in combination with CRT, the most common adverse reactions (≥10%) were nausea (56%), diarrhea (50%), vomiting (33%), urinary tract infection (32%), fatigue (26%), hypothyroidism (20%), constipation (18%), decreased appetite and weight loss (17% each), abdominal pain and pyrexia (12% each), hyperthyroidism, dysuria, rash (11% each), and pelvic pain (10%).

In KEYNOTE⁠-⁠826, when KEYTRUDA was administered in combination with paclitaxel and cisplatin or paclitaxel and carboplatin, with or without bevacizumab (n=307), to patients with persistent, recurrent, or first-line metastatic cervical cancer regardless of tumor PD⁠-⁠L1 expression who had not been treated with chemotherapy except when used concurrently as a radio-sensitizing agent, fatal adverse reactions occurred in 4.6% of patients, including 3 cases of hemorrhage, 2 cases each of sepsis and due to unknown causes, and 1 case each of acute myocardial infarction, autoimmune encephalitis, cardiac arrest, cerebrovascular accident, femur fracture with perioperative pulmonary embolus, intestinal perforation, and pelvic infection. Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA in combination with chemotherapy with or without bevacizumab; those ≥3% were febrile neutropenia (6.8%), urinary tract infection (5.2%), anemia (4.6%), and acute kidney injury and sepsis (3.3% each).

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

For patients treated with KEYTRUDA, chemotherapy, and bevacizumab (n=196), the most common adverse reactions (≥20%) were peripheral neuropathy (62%), alopecia (58%), anemia (55%), fatigue/asthenia (53%), nausea and neutropenia (41% each), diarrhea (39%), hypertension and thrombocytopenia (35% each), constipation and arthralgia (31% each), vomiting (30%), urinary tract infection (27%), rash (26%), leukopenia (24%), hypothyroidism (22%), and decreased appetite (21%).

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

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

In KEYNOTE⁠-⁠966, when KEYTRUDA was administered in combination with gemcitabine and cisplatin, KEYTRUDA was discontinued for adverse reactions in 15% of 529 patients with locally advanced unresectable or metastatic biliary tract cancer. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA (≥1%) was pneumonitis (1.3%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 55% of patients. The most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were decreased neutrophil count (18%), decreased platelet count (10%), anemia (6%), decreased white blood cell count (4%), pyrexia (3.8%), fatigue (3.0%), cholangitis (2.8%), increased ALT (2.6%), increased AST (2.5%), and biliary obstruction (2.3%).

In KEYNOTE⁠-⁠017 and KEYNOTE⁠-⁠913, adverse reactions occurring in patients with MCC (n=105) were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a single agent.

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

In KEYNOTE⁠-⁠564, when KEYTRUDA was administered as a single agent for the adjuvant treatment of renal cell carcinoma, serious adverse reactions occurred in 20% of patients receiving KEYTRUDA; the serious adverse reactions (≥1%) were acute kidney injury, adrenal insufficiency, pneumonia, colitis, and diabetic ketoacidosis (1% each). Fatal adverse reactions occurred in 0.2% including 1 case of pneumonia. Discontinuation of KEYTRUDA due to adverse reactions occurred in 21% of 488 patients; the most common (≥1%) were increased ALT (1.6%), colitis (1%), and adrenal insufficiency (1%). The most common adverse reactions (≥20%) were musculoskeletal pain (41%), fatigue (40%), rash (30%), diarrhea (27%), pruritus (23%), and hypothyroidism (21%).

In KEYNOTE⁠-⁠868, when KEYTRUDA was administered in combination with chemotherapy (paclitaxel and carboplatin) to patients with advanced or recurrent endometrial carcinoma (n=382), serious adverse reactions occurred in 35% of patients receiving KEYTRUDA in combination with chemotherapy, compared to 19% of patients receiving placebo in combination with chemotherapy (n=377). Fatal adverse reactions occurred in 1.6% of patients receiving KEYTRUDA in combination with chemotherapy, including COVID-19 (0.5%) and cardiac arrest (0.3%). KEYTRUDA was discontinued for an adverse reaction in 14% of patients. Adverse reactions occurring in patients treated with KEYTRUDA and chemotherapy were generally similar to those observed with KEYTRUDA alone or chemotherapy alone, with the exception of rash (33% all Grades; 2.9% Grades 3-4).

Adverse reactions occurring in patients with MSI⁠-⁠H or dMMR endometrial carcinoma who received KEYTRUDA as a single agent were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a single agent.

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

In KEYNOTE⁠-⁠522, when KEYTRUDA was administered with neoadjuvant chemotherapy (carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide) followed by surgery and continued adjuvant treatment with KEYTRUDA as a single agent (n=778) to patients with newly diagnosed, previously untreated, high-risk early-stage TNBC, fatal adverse reactions occurred in 0.9% of patients, including 1 each of adrenal crisis, autoimmune encephalitis, hepatitis, pneumonia, pneumonitis, pulmonary embolism, and sepsis in association with multiple organ dysfunction syndrome and myocardial infarction. Serious adverse reactions occurred in 44% of patients receiving KEYTRUDA; those ≥2% were febrile neutropenia (15%), pyrexia (3.7%), anemia (2.6%), and neutropenia (2.2%). KEYTRUDA was discontinued in 20% of patients due to adverse reactions. The most common reactions (≥1%) resulting in permanent discontinuation were increased ALT (2.7%), increased AST (1.5%), and rash (1%). The most common adverse reactions (≥20%) in patients receiving KEYTRUDA were fatigue (70%), nausea (67%), alopecia (61%), rash (52%), constipation (42%), diarrhea and peripheral neuropathy (41% each), stomatitis (34%), vomiting (31%), headache (30%), arthralgia (29%), pyrexia (28%), cough (26%), abdominal pain (24%), decreased appetite (23%), insomnia (21%), and myalgia (20%).

In KEYNOTE⁠-⁠355, when KEYTRUDA and chemotherapy (paclitaxel, paclitaxel protein⁠-⁠bound, or gemcitabine and carboplatin) were administered to patients with locally recurrent unresectable or metastatic TNBC who had not been previously treated with chemotherapy in the metastatic setting (n=596), fatal adverse reactions occurred in 2.5% of patients, including cardio-respiratory arrest (0.7%) and septic shock (0.3%). Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA in combination with chemotherapy; the serious reactions in ≥2% were pneumonia (2.9%), anemia (2.2%), and thrombocytopenia (2%). KEYTRUDA was discontinued in 11% of patients due to adverse reactions. The most common reactions resulting in permanent discontinuation (≥1%) were increased ALT (2.2%), increased AST (1.5%), and pneumonitis (1.2%). The most common adverse reactions (≥20%) in patients receiving KEYTRUDA in combination with chemotherapy were fatigue (48%), nausea (44%), alopecia (34%), diarrhea and constipation (28% each), vomiting and rash (26% each), cough (23%), decreased appetite (21%), and headache (20%).

Clinical Trial Results

Adjuvant Therapy for Stage IIB, Stage IIC, or Stage III Melanoma

On this page

An anti–PD⁠-⁠1 adjuvant therapy approved for completely resected stage IIB and stage IIC melanoma.1

Clinical Findings from KEYNOTE⁠-⁠716 (Stage IIB/IIC)

Significant Improvement in Recurrence-Free Survival (RFS) Demonstrated With KEYTRUDA vs Placebo

For adjuvant treatment in patients (12 years and older) with completely resected stage IIB or stage IIC melanoma

Reduction in the risk of disease recurrence or death with KEYTRUDA compared with placeboHR=0.65 (95% CI, 0.46–0.92; P=0.0132)

Initial analysis of RFS in KEYNOTE⁠-⁠716 for KEYTRUDA at a 14.4-Month Median Follow-Up vs 14.3 Months for Placebo2

HRa,b=0.65 (95% CI, 0.46–0.92; Pb=0.0132c)

54 (11%)

82 (17%)

NR

NR

Post hoc RFS Analysis from KEYNOTE⁠-⁠716 at a 52.8-Month Median Follow-Up3,4

HRd=0.62 (95% CId, 0.50–0.78)

Additional Information

KEYTRUDA Significantly Improved Distant Metastasis-Free Survivale (DMFS) vs Placebo in Patients With Completely Resected Stage IIB or IIC Melanoma

KEYTRUDA significantly reduced the risk of completely resected stage IIB or IIC melanoma returning as stage IV disease5,f by 36% vs placebo (HRg,h=0.64; 95% CI, 0.47-0.88; Pg=0.0058i)

Initial Analysis of DMFS, an Additional Efficacy Outcome Measure, in KEYNOTE⁠-⁠716 at a 27.4-Month Median Follow-Up6

HRg,h=0.64; (95% CI, 0.47–0.88; Ph=0.0058i)

63 (13%)

95 (19%)

NR

NR

Post hoc Analysis: Kaplan-Meier Estimates of DMFS With KEYTRUDA and Placebo at a 52.8-Month Median Follow-Up in KEYNOTE⁠-⁠7163,4

HRj=0.59 (95% CI, 0.45–0.77)

Additional Information

Study Design for KEYNOTE⁠-⁠716 (Stage IIB/IIC)

Study Overview

Study Arms2,7

End Points

Patient Characteristics

Stage IIB/IIC Melanoma: Risk of Recurrence from a Retrospective Study

Data from a Retrospective Study: Risk of Recurrence for Completely Resected Stage IIB and IIC Melanoma8

Rates of Recurrence8

37%

43%

50%

58%

Additional Information

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): An NCCN Category 1 Option for Melanoma in Certain Adjuvant Treatment Settings9

Recommended by the National Comprehensive Cancer Network® (NCCN®) for Eligible Patients With Stages IIB/IIC or Stage III Melanoma9

Clinical Findings from KEYNOTE⁠-⁠054 (Stage III)

Significant Improvement in Recurrence-Free Survival (RFS) Demonstrated With KEYTRUDA vs Placebo

For adjuvant treatment in patients (12 years and older) with completely resected stage III melanoma

Initial Analysis of RFS in KEYNOTE⁠-⁠054 for KEYTRUDA vs Placebo at a 15.1-Month Median Follow-Up10

HRp,q=0.57 (95% CI, 0.46–0.70; Pq<0.001r)

135 (26%)

216 (43%)

NR

20.4

Reduction in the risk of disease recurrence or death with KEYTRUDA compared with placeboHR=0.57 (95% CI, 0.46–0.70; P<0.001)

5-Year RFS Analysis in KEYNOTE⁠-⁠054: Kaplan-Meier Estimates With KEYTRUDA and Placebo at a 4.9-Year Median Follow-Up11,12

HRs=0.61 (95% CI, 0.51–0.72)

Additional Information

KEYTRUDA Significantly Improved Distant Metastasis-Free Survivalt (DMFS) vs Placebo in Patients With Completely Resected Stage III Melanoma

KEYTRUDA significantly reduced the risk of completely resected stage III melanoma returning as stage IV disease5,u or death vs placebo (HRv,w=0.60; 95% CI, 0.49–0.73; P<0.0001x,y)

Initial Analysis of DMFS, an Additional Efficacy Outcome Measure, in KEYNOTE⁠-⁠054 at a 42.3-Month Median Follow-Up13

HRv,w=0.60 (95% CI, 0.49–0.73; Pw<0.0001x,y)

173 (34%)

245 (49%)

NR

40.0

Initial Analysis (ITT Population): Kaplan-Meier Estimates of DMFS With KEYTRUDA vs Placebo at a 42.3-Month Median Follow-Up in KEYNOTE⁠-⁠05413

HRv,w=0.60 (95% CI, 0.49–0.73; Pw<0.0001x,y)

Efficacy demonstrated regardless of PD⁠-⁠L1 status

Study Design for KEYNOTE⁠-⁠054 (Stage III)

Study Overview10,15

Study Arms15

End Points

Study Design Details

Patient Characteristics

KEYNOTE⁠-⁠054 Recurrence Rates

Recurrence Rates at 3-Year Analysis in Patients With Stage III Melanoma Who Received Placebo in KEYNOTE⁠-⁠05416

Additional Information

Hypothetical Patient Cases

Based on Those Studied in KEYNOTE-716 and KEYNOTE-054

STAGE IIB (T4aN0M0) MELANOMA17

An anti–PD⁠-⁠1 adjuvant therapy approved for completely resected stage IIB and stage IIC melanoma.¹

Reduction in the risk of disease recurrence or death with KEYTRUDA compared with placebo

HR=0.65 (95% CI, 0.46–0.92; P=0.0132)

Initial analysis of RFS in KEYNOTE⁠-⁠716 for KEYTRUDA at a 14.4-Month Median Follow-Up vs 14.3 Months for Placebo²

HR^a,b=0.65 (95% CI, 0.46–0.92; P^b=0.0132^c)

Post hoc RFS Analysis from KEYNOTE⁠-⁠716 at a 52.8-Month Median Follow-Up^3,4

HR^d=0.62 (95% CI^d, 0.50–0.78)

KEYTRUDA Significantly Improved Distant Metastasis-Free Survival^e (DMFS) vs Placebo in Patients With Completely Resected Stage IIB or IIC Melanoma

KEYTRUDA significantly reduced the risk of completely resected stage IIB or IIC melanoma returning as stage IV disease^5,f by 36% vs placebo (HR^g,h=0.64; 95% CI, 0.47-0.88; P^g=0.0058ⁱ)

Initial Analysis of DMFS, an Additional Efficacy Outcome Measure, in KEYNOTE⁠-⁠716 at a 27.4-Month Median Follow-Up⁶

HR^g,h=0.64; (95% CI, 0.47–0.88; P^h=0.0058ⁱ)

Post hoc Analysis: Kaplan-Meier Estimates of DMFS With KEYTRUDA and Placebo at a 52.8-Month Median Follow-Up in KEYNOTE⁠-⁠716^3,4

HR^j=0.59 (95% CI, 0.45–0.77)

Study Arms^2,7

Data from a Retrospective Study: Risk of Recurrence for Completely Resected Stage IIB and IIC Melanoma⁸

Rates of Recurrence⁸

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): An NCCN Category 1 Option for Melanoma in Certain Adjuvant Treatment Settings⁹

Recommended by the National Comprehensive Cancer Network® (NCCN®) for Eligible Patients With Stages IIB/IIC or Stage III Melanoma⁹

Initial Analysis of RFS in KEYNOTE⁠-⁠054 for KEYTRUDA vs Placebo at a 15.1-Month Median Follow-Up¹⁰

HR^p,q=0.57 (95% CI, 0.46–0.70; P^q<0.001^r)

Reduction in the risk of disease recurrence or death with KEYTRUDA compared with placebo

HR=0.57 (95% CI, 0.46–0.70; P<0.001)

5-Year RFS Analysis in KEYNOTE⁠-⁠054: Kaplan-Meier Estimates With KEYTRUDA and Placebo at a 4.9-Year Median Follow-Up^11,12

HR^s=0.61 (95% CI, 0.51–0.72)

KEYTRUDA Significantly Improved Distant Metastasis-Free Survival^t (DMFS) vs Placebo in Patients With Completely Resected Stage III Melanoma

KEYTRUDA significantly reduced the risk of completely resected stage III melanoma returning as stage IV disease^5,u or death vs placebo (HR^v,w=0.60; 95% CI, 0.49–0.73; P<0.0001^x,y)

Initial Analysis of DMFS, an Additional Efficacy Outcome Measure, in KEYNOTE⁠-⁠054 at a 42.3-Month Median Follow-Up¹³

HR^v,w=0.60 (95% CI, 0.49–0.73; P^w<0.0001^x,y)

Initial Analysis (ITT Population): Kaplan-Meier Estimates of DMFS With KEYTRUDA vs Placebo at a 42.3-Month Median Follow-Up in KEYNOTE⁠-⁠054¹³

HR^v,w=0.60 (95% CI, 0.49–0.73; P^w<0.0001^x,y)

Study Overview^10,15

Study Arms¹⁵

Recurrence Rates at 3-Year Analysis in Patients With Stage III Melanoma Who Received Placebo in KEYNOTE⁠-⁠054¹⁶

STAGE IIB (T4aN0M0) MELANOMA¹⁷

• Presented with an asymmetric lesion on his left shoulder.
• Punch biopsy results:
4.7-mm-thick superficial spreading melanoma; non-ulcerated

STAGE IIIA (T2aN1aM0) MELANOMA¹⁷

• Noticed 2 new small skin lesions during her regular self-examination.
• Punch biopsy results:
–1.2-mm-thick superficial spreading melanoma; non-ulcerated
–1.3-mm-thick superficial spreading melanoma; non-ulcerated