KEYTRUDA – Studied across a broad disease continuum in Melanoma1

a Staging according to AJCC 7th ed.1
AJCC = American Joint Committee on Cancer

Efficacy

KEYTRUDA (Pembrolizumab) as Adjuvant Therapy for Stage III Disease

KEYNOTE 054

Study Design

Multicenter, randomized, double-blind, placebo-controlled trial in patients with completely resected stage IIIA (>1 mm lymph node metastasis), IIIB, or IIIC melanoma as per AJCC 7th ed.2
• A total of 1,019 adult patients were randomized (1:1) to receive KEYTRUDA 200 mg every 3 weeks (n=514) or placebo (n=505), for up to 1 year or until disease recurrence or unacceptable toxicity.2
• Patients must have been at least 18 years of age, have complete resection of stage III melanoma within 13 weeks, no auto-immune disease, no systemic corticosteroids, no prior systemic therapy for Melanoma, ECOG 0-1, PD-L1 expression evaluation, have no mucosal or ocular melanoma, and if indicated have undergone complete lymph node dissection radiotherapy within 13 weeks prior to starting treatment.3,5
• The primary efficacy outcome measure was investigator-assessed recurrence-free survival (RFS) in the whole population and in the population with PD-L1 positive tumors.2

KEYNOTE-054 Study Design5

KEYNOTE-054 studied across stage IIIA (>1 mm lymph node metastasis), stage IIIB, and stage IIIC melanomaa1
KEYTRUDA was studied across a broad spectrum of nonmetastatic melanoma patients with nodal involvement regardless of ulceration status, PD-L1 expression, or BRAFmutation status.1,2
a Staging according to American Joint Committee on Cancer, 7th ed.1
IV = intravenous
PD-1 = programmed death receptor-1
PD-L1 = programmed death ligand 1
Q3W = every 3 weeks
BRAF = B-Raf proto-oncogene, serine/threonine kinase

Keynote 054 Patient Baseline Characteristics2, *

*    There were no significant between-group differences in the characteristics listed here. Percentages may not total 100 because of rounding.
AJCC denotes American Joint Committee on Cancer 2009 classification, 7th edition.
†   Data were from electronic case-report forms.
‡   One patient with in-transit metastases or satellites and without metastatic nodes was included in this subgroup.
§   This subgroup also included 11 patients with matted nodes as well as 5 patients with in-transit metastases or satellites and at least one positive lymph node.
¶ Membranous expression of programmed death ligand 1 (PD-L1) in tumor and tumor-associated immune cells was assessed by means of a 22C3 antibody assay and was scored on a scale of 0 to 5 (with higher scores reflecting a higher level of expression); a score 2 or higher (i.e., staining on >1% of cells) was considered to indicate PD-L1 positivity.

Efficacy

3.5 Year RFS in Keynote 054 in the overall population4,a

Events observed: 203/514 (39.5%) with KEYTRUDA vs 288/505 (57.0%) with placebo.4
The RFS rate at 12, 24, and 36 months was 75.3%, 68.0%, and 63.7%, respectively, for patients receiving KEYTRUDA vs 60.0%, 46.9%, and 43.5%, respectively, for patients receiving placebo.4
The RFS rate at 42 months was 59.8% for patients receiving KEYTRUDA vs 41.4% for patients receiving placebo.4
The median follow-up time was 42.3 months.4

Limitation:
No formal statistical testing was planned for the 3.5-year median follow-up analysis and, therefore, no statistical conclusions can be drawn.
a RFS was estimated by the Kaplan-Meier method.4
b The HR and its CI were estimated using the Cox proportional hazards model stratified by stage provided at randomization.4

CI = confidence interval
HR = hazard ratio

Safety Data

Adverse Events in KEYNOTE-0543,a

aThe safety analysis included all patients who underwent randomization and received at least 1 dose of trial agent (1,011 patients). Listed are the adverse events that were reported between the first dose and 30 days after the last dose; for all serious adverse events and serious immune-related adverse events, a time limit of 90 days after the last dose was used. All adverse events correspond to part 1 of the trial (the 1-year adjuvant therapy period) and not to part 2 (in which patients with disease recurrence were eligible to cross over or receive repeat treatment with pembrolizumab). The severity of adverse events was graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events, version 4.0.3
bThe investigators determined whether adverse events were related to a trial agent. Adverse events and immune-related adverse events that occurred in at least 10% of patients or those that were considered to be medically relevant are reported. Patients may have had more than 1 event.3
·       Adverse events of Grade 3, 4, or 5 that were related to the trial regimen occurred in 14.7% of patients in the pembrolizumab group and in 3.4% in the placebo group. There was one death due to myositis related to KEYTRUDA.3
Discontinuation due to treatment-related adverse events (TRAEs) was 13.0% with pembrolizumab compared to 1.6% with placebo.3

KEYTRUDA (Pembrolizumab) in Advanced Metastatic Disease

KEYNOTE 006

Study Design

KEYNOTE-006 was a randomised, controlled, international, multicentre Phase 3 trial of KEYTRUDA vs. ipilimumab in 834 patients with advanced melanoma, to assess the efficacy and safety of KEYTRUDA in advanced melanoma.6

• The primary endpoints were overall survival (OS) and progression-free survival (PFS), as assessed by Integrated Radiology and Oncology Assessment (IRO) review using Response Evaluation Criteria In Solid Tumors v1.1 (RECIST 1.1).6
• The secondary endpoints were overall response rate (ORR) and duration of response (DOR) and Safety.6

• Patients (N=834) must have been at least 18 years of age with histologically confirmed, unresectable Stage III or IV melanoma, no prior therapy with CTLA4, PD-1 or PD-L1 inhibitors and prior therapy with at most 1 other systemic treatment. ECOG performance status of 0 – 1. No ocular melanoma, active brain metastases or history of autoimmune disease. Known BRAF status. Patients with BRAF V600E–mutant melanoma were not required to have received prior BRAF inhibitor therapy. 6,7

• Patients were randomized (1:1:1) to receive KEYTRUDA at a dose of 10 mg/kg Q2W (n=279) or Q3W (n=277) or to receive ipilimumab 3 mg/kg Q3W for 4 cycles (n=278).6

Q2W = every 2 weeks

Q3W = every 3 weeks

BRAF = B-Raf proto-oncogene, serine/threonine kinase

Patients were followed up for a median of 57.7 months. Data cut-off was Dec 3rd, 2018.9
a Long GV, Schachter J, Ribas A, et al. 4-year survival and outcomes after cessation of pembrolizumab after 2 years in patients with ipilimumab-naive advanced melanoma in KEYNOTE-006. Presented at: American Society of Clinical Oncology Annual Meeting; 4 June 2018: Chicago, IL.7

Keynote 006 Patient Baseline Characteristics 8

ECOG PS=Eastern Cooperative Oncology Group performance status; LDH=lactate dehydrogenase; PDL1= programmed death ligand 1.
aOne additional patient had two lines of previous therapy.
bDefined as at least 1% staining in tumour and adjacent immune cells as assessed by immunohistochemistry (22C3 antibody).
cM0=no distant metastasis.
M1a=metastasis to skin, subcutaneous tissues, or distant lymph nodes.
M1b=metastasis to lung.
M1c=metastasis to all other visceral sites or distant metastases at any site associated with elevated serum concentrations of LDH.

Efficacy

With five years of data, KEYTRUDA offers longer overall survival vs. ipilimumab8,9

• Superior OS vs ipilimumab at 2 years: 32% reduction in the risk of death with KEYTRUDA 10 mg/kg every 3 weeks vs ipilimumab (HR=0.68; 95% CI, 0.53–0.86; P<0.001).1

• Long-term OS through 5 years in a controlled, phase 3 trial: According to Kaplan-Meier estimates, OS at 5 years was 38.7% (95% CI, 34.2–43.1) with KEYTRUDA vs 31.0% (95% CI, 25.3–36.9) with ipilimumab.8,9

  • Median follow-up time of surviving patients was 57.7 months (IQR: 56.7–59.2 months).9

• Long-term OS through 5 years in a subgroup analysis of treatment-naïve patients: According to Kaplan Meier estimates, OS at 5 years was 43.2% with KEYTRUDA vs 33.0% with ipilimumab.8,9

  • Median OS for treatment-naïve patients was 38.7 months (95% CI, 27.3–50.7) with KEYTRUDA vs 17.1 months (95% CI, 13.8–26.2) with ipilimumab.9
  • 58.6 % of patients received pembrolizumab in the first line.9

Updated Treatment-Naïve OS Data From 5-Year Extension Analysis of KEYNOTE-006
(Data Cutoff: 3 December 2018)8,9,a,b,c

aFrom product-limit (Kaplan-Meier) method for censored data.9
bBased on Cox regression model with treatment as a covariate stratified by line of therapy (first vs second), PDL1
status (positive vs negative), and ECOG PS (0 vs 1).9
cThis was a subgroup analysis of an extension analysis, neither of which was powered to demonstrate
statistical significance or powered to detect differences in the treatment effect in these subgroups.
Therefore, results from exploratory analyses should be interpreted with caution.
 
According to Kaplan-Meier estimates, the probability of a patient being alive at 5 years was 43% with
KEYTRUDA vs 33% with ipilimumab in a subgroup analysis of treatment-naïve patients.9
Median OS was 38.7 months (95% CI 27.3-50.7) with KEYTRUDA and 17.1 months (95% CI 0.57-0.92) with
ipilimumab in a subgroup analysis of treatment-naïve patients.9

BRAF = B-Raf proto-oncogene, serine/threonine kinase CI = confidence interval ECOG PS = Eastern Cooperative Oncology Group performance status HR = hazard ratio IQR = interquartile range PD-L1 = programmed death ligand 1 Q2W = every 2 weeks Q3W = every 3 weeks

Safety Data

Treatment related Adverse Events in KEYNOTE-006 8,9

Data are n (%). Treatment-related adverse events are designed by the investigator. Grade 1-2 events that occurred in at least 10% of patients. Grade 3-5 events are listed for only those grade 1-2 treatment-related adverse events that occurred in at least 10% of patients. A given patient may be counted in more than one toxicity grade category.
  1. Summary of product Characteristics. Available from www.medicines.ie. Last accessed March 2022
  2. 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
  3. Eggermont AMM, Blank CU, Mandala M, et al. Protocol for: adjuvant pembrolizumab versus placebo in resected stage III melanoma. (N Engl J Med. 2018;378(19):1789–1801.) doi:10.1056/NEJMoa1802357
  4. Eggermont AMM, Blank CU, Mandala 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. Epub 2021. doi:10.1016/S1470-2045(21)00065-6
  5. Eggermont AMM, Blank CU, Mandala M, et al. Supplementary Appendix to: 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. Epub 2020.) doi:10.1200/JCO.20.02110
  6. Robert C, et al. N Eng J Med 2015;372(26):2521-2531
  7. Long GV, Schachter J, Ribas A, et al. 4-year survival and outcomes after cessation of pembrolizumab after 2 years in patients with ipilimumab-naive advanced melanoma in KEYNOTE-006. Presented at: American Society of Clinical Oncology Annual Meeting; 4 June 2018: Chicago, IL
  8. C.Robert, A. Ribas, J. Schacter et al. Pembrolizumab versus ipilimubab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol.2019;20: 1239-1251, suppl.
  9. Robert C, Ribas A, Schachter J, et al. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE 006): post-hoc 5-year results from an open label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol. 2019;20(9):1239–1251.