Pembrolizumab (Keytruda®) is a highly selective humanised monoclonal antibody directed against the programmed cell death 1 (PD-1) receptor on T cells. The drug blocks the PD-1 receptor, thereby preventing the formation of programmed cell death ligand 1 (PD-L1) complexes. This mechanism causes the activation of T-cell mediated immune responses against tumour cells.
On 4 September 2014, the US Food and Drug Administration (FDA) approved pembrolizumab as a breakthrough therapy for the treatment of metastatic melanoma, based on response rates demonstrated in clinical trial data from 173 patients with melanoma in a cohort of the KEYNOTE-001 study.
Since then results from two further clinical trials (KEYNOTE-002 and KEYNOTE-006) have continued to show the benefit of pembrolizumab for the treatment of advanced unresectable or metastatic melanoma.
Pembrolizumab is now registered for the treatment of advanced (metastatic or unresectable) melanoma in many countries worldwide, including Europe, the UK, and New Zealand.
The KEYNOTE-001 study
- The efficacy of pembrolizumab was investigated in a multicentre, open-label, randomised (1:1), dose-comparative Phase 1b study.
- The key eligibility criteria were unresectable or metastatic melanoma with progression of disease and refractory to treatment with two or more doses of ipilimumab (3 mg/kg or higher), and, if BRAF V600 mutation-positive, a BRAF or MEK inhibitor, and disease progression within 24 weeks following the last dose of ipilimumab.
- Patients were randomised to receive 2 mg/kg n = 89 or 10 mg/kg n = 84 of pembrolizumab every 3 weeks until unacceptable toxicity or disease progression that was symptomatic.
- Assessment of tumour status was performed 12 weeks after the first dose of pembrolizumab and every 12 weeks thereafter.
- The major efficacy outcome measures were duration of response and confirmed overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) as assessed by a blinded independent central review.
- The ORR was 24% (95% CI: 15–34) in the 2 mg/kg arm, consisting of one complete response and 20 partial responses.
- Among the 21 patients with an objective response, three (14%) had disease progression at 2.8, 2.9, and 8.2 months, respectively, after the initial response.
- The duration of response in the remaining 18 patients (86%) varied from 1.4 to 8.5 months and included eight patients with ongoing responses of 6 months or longer.
- Similar ORR results were observed in the 10 mg/kg arm.
- The response rate did not differ significantly between patients who had received prior ipilimumab treatment and those who had not.
- Table 1 presents adverse reactions identified from analyses of the 89 patients with unresectable or metastatic melanoma who received pembrolizumab 2 mg/kg every 3 weeks.
- The median duration of exposure to pembrolizumab was 6.2 months (range: 1 day to 15.3 months) with a median of nine doses (range: 1–23).
- Pembrolizumab was discontinued in 6% of the 89 patients because of adverse reactions.
Table 1. Drug-related adverse reactions occured in > 10% of patients in KEYNOTE-001
|Pembrolizumab 2 mg/kg every 3 weeks (n = 89)|
|Adverse reaction||All grades (%)||Grade 3 (%)|
|General disorders and administration site conditions|
|Nervous system disorders|
AST: aspartate transaminase
The KEYNOTE-002 study
- KEYNOTE-002 was a Phase II study that assessed the efficacy and safety of two pembrolizumab doses compared with investigator-choice chemotherapy in patients with ipilimumab-refractory melanoma.
- Patients had histologically or cytologically confirmed unresectable stage III or stage IV melanoma that had progressed within 24 weeks of the last ipilimumab dose (minimum two doses, 3 mg/kg once every 3 weeks) and/or had had previous BRAF or MEK inhibitor therapy, or both (if mutant-positive).
- Patients were randomised (1:1:1) to receive intravenous pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or investigator-choice chemotherapy (paclitaxel plus carboplatin, paclitaxel, carboplatin, dacarbazine, or oral temozolomide).
- Tumour assessments were done before starting study treatment (baseline), at Week 12, every 6 weeks through to Week 48, and then every 12 weeks thereafter.
- The primary endpoint was progression-free survival, the time from randomisation to first documented disease progression per RECIST v1.1 by an independent central review, or death from any cause, whichever occurred first.
- Results are summarised in Table 2.
Table 2. Summary of efficacy parameters in KEYNOTE-002.
|Pembrolizumab 2 mg/kg (n = 180)||Pembrolizumab 10 mg/kg (n = 181)||Chemotherapy control (n = 179)|
|Progression free survival (% of patients) assessed by RECIST v1.1 by investigator review|
|Progression free at 6 months||3326||45% (37–52)||15% (10–21)|
|Progression free at 9 months||32% (25–40)||36% (29–44)||10% (6–15)|
|Progression free survival (% of patients) assessed by modified RECIST v1.1 by independent central review|
|Progression free at 6 months||43% (35–50)||48% (40–55)||17% (12–23)|
|Progression free at 9 months||35% (27–43)||38% (30–46)||10% (6–16)|
|Best overall response (no. of patients) assessed per RECIST v1.1 by independent central review|
|Complete response||4 (2%)||5 (3%)||0|
|Partial response||34 (19%)||41 (23%)||8 (4%)|
|Progressive disease||84 (47%)||86 (48%)||111 (62%)|
RECIST, Response Evaluation Criteria in Solid Tumors
- The incidence of Grades 3–4 drug-related adverse events in KEYNOTE-002 higher in patients treated with chemotherapy compared to those treated with pembrolizumab.
- The most common treatment-related adverse events with chemotherapy were alopecia, anaemia, decreased appetite, fatigue, nausea, and vomiting.
- The treatment-related adverse events that were more frequent with pembrolizumab were rash, pruritus, and diarrhoea.
- Table 3 is a summary of adverse events in KEYNOTE-002.
Table 3. Summary of adverse events — KEYNOTE-002
|Adverse event||Pembrolizumab 2 mg/kg (n = 178)||Pembrolizumab 10 mg/kg (n = 179)||Chemotherapy control (n = 171)|
|Grades 1–2||Grade 3||Grade 4||Grades 1–2||Grade 3||Grade 4||Grades 1–2||Grade 3||Grade 4|
|Fatigue||38 (21%)||2 (1%)||0||51 (28%||1 (< 1%)||0||54 (32%)||8 (5%)||0|
|Pruritus||37 (21%)||0||0||42 (23%)||0||0||6 (4%)||0||0|
|Nausea||8 (4%)||0||0||15 (8%)||1 (< 1%)||0||52 (30%)||3 (2%)||1 (< 1%)|
|Decreased appetite||8 (4%)||0||0||15 (8%)||2 (1%)||0||26 (15%)||0||0|
|Anaemia||4 (2%)||1 (< 1%)||0||7 (4%)||0||0||26 (15%)||9 (5%)||0|
|Rash||21 (12%)||0||0||18 (10%)||0||0||8 (5%)||0||0|
|Alopecia||5 (3%)||0||0||1 (< 1%)||0||0||24 (20%)||1 (< 1%)||0|
|Vomiting||1 (< 1%)||1 (< 1%)||0||9 (5%)||1 (< 1%)||0||22 (13%)||3 (2%)||1 (< 1%)|
|Arthralgia||12 (7%)||1 (< 1%)||0||10 (6%)||1 (< 1%)||0||8 (5%)||1 (< 1%)||0|
|Myalgia||7 (4%)||2 (1%)||0||7||0||0||9 (5%)||1 (< 1%)||0|
|Diarrhoea||15 (8%)||0||0||17 (9%)||2 (1%)||0||11 (6%)||3 (2%)||0|
|Neutropenia||1 (< 1%)||0||0||1 (< 1%)||0||0||8 (5%)||4 (2%)||2 (1%)|
|Leucopenia||0||0||0||0||0||0||8 (5%)||4 (2%)||2 (1%)|
Health-related quality of life
- Health-related quality of life (HRQoL) was assessed using the Global Health Status (GHS)/HRQoL scores of the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30 (EORTC QLQ-C30) at baseline, Weeks 3, 6, 12, 24, and 36, at treatment discontinuation, and during safety follow-up.
- HRQoL was maintained to a greater degree with pembrolizumab versus chemotherapy, with fewer patients treated with pembrolizumab experiencing deterioration in GHS at Week 12 (31.8% patients with pembrolizumab 2 mg/kg, 26.6% for 10 mg/kg, and 38.3% for chemotherapy).
- Results are summarised in Table 4.
- In addition to the GHS/HRQoL score, patients in the two pembrolizumab arms had consistently smaller longitudinal score changes from baseline to Week 12 across functional scales, including physical, cognitive, social, and emotional functions, and across symptoms scales including fatigue, nausea/vomiting, pain, dyspnoea, insomnia, appetite loss, constipation, and diarrhoea.
Table 4. Change from baseline to Week 12 in the GHS score of the EORTC QLQ-C30 in KEYNOTE-002
|Treatment arm||Baseline||Week 12||Change from baseline least squares mean (95% CI)|
|n||Mean ± SD||n||Mean ± SD|
Pembrolizumab 2 mg/kg Q3W
66.2 ± 22.1
66.3 ± 23.0
−2.6 (−6.2 to 1.0)a
Pembrolizumab 10 mg/kg Q3W
62.9 ± 23.6
64.3 ± 22.8
-2.6 (−6.0 to 0.9)a
64.0 ± 21.9
59.0 ± 23.2
−9.1 (−12.9 t −5.4)
a P = 0.01 versus chemotherapy.
The KEYNOTE-006 study
- The Phase III KEYNOTE-006 study showed superior overall and progression-free survival of pembrolizumab versus ipilimumab in patients with advanced melanoma.
- 834 patients with advanced melanoma were enrolled and randomly assigned to receive intravenous pembrolizumab every 2 weeks (n = 279), intravenous or every 3 weeks (n = 277), or intravenous ipilimumab every 3 weeks (n = 278).
- Median follow-up was 22.9 months.
- The estimated 6-month progression-free survival rates were 47.3% for patients receiving pembrolizumab every 2 weeks, 46.4% for those receiving pembrolizumab every 3 weeks, and 26.5% for those receiving ipilimumab.
- One-year estimates of overall survival were 74.1% for patients receiving pembrolizumab every 2 weeks (hazard ratio for death as compared with the ipilimumab group, 0.63; 95% CI: 0.47–0.83; p < 0.0005), 68.4% for those receiving pembrolizumab every 3 weeks (hazard ratio for death as compared with the ipilimumab group, 0.69; 95% CI: 0.52–0.90; p = 0.0036), and 58.2% for those receiving ipilimumab.
- 24-month overall survival rate was 55% in the 2-week group, 55% in the 3-week group, and 43% in the ipilimumab group.
Health-related quality of life
- The primary patient-related outcome assessment in KEYNOTE-006 was the score change from baseline to Week 12 in EORTC QLQ-C30 GHS/HRQoL score between treatment arms, using a constrained longitudinal data analysis.
- From baseline to Week 12, GHS/HRQoL scores were better maintained with pembrolizumab than with ipilimumab (decrease of −1.9 and −2.5 for pembrolizumab vs −10.0 for ipilimumab; p < 0.001 for each pembrolizumab arm vs ipilimumab; see Table 5).
- Fewer patients treated with pembrolizumab experienced deterioration in GHS at Week 12 (31% for pembrolizumab every 2 weeks; 29% for pembrolizumab every 3 weeks, and 44% for ipilimumab), with similar trends being observed for individual functioning and symptoms scales.
Table 5. Change from baseline to Week 12 in the GHS score of the EORTC QLQ-C30 — KEYNOTE-006
|Treatment||n||Baseline||Week 12||Change from baseline|
|Mean (SD)||n||Mean (SD)||LS mean (95% CI)|
|Pembrolizumab 10 mg/kg Q2W||239||71.4 (20.4)||172||71.1(19.3)||−1.9 (−4.86 to 1.01)|
|Pembrolizumab 10 mg/kg Q3W||230||70.5 (21.9)||188||69.5 (22.3)||−2.5 (−5.32 to 0.37)|
|Ipilimumab||213||67.4 (24.0)||149||64.3 (25.8)||−10.0 (−13.16 to −6.85)|
CI, confidence interval; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30; GHS, Global Health Status; LS, least squares; Q2W, every 2 weeks; Q3W, every 3 weeks; SD, standard deviation
- In KEYNOTE-006, the most common treatment-related adverse events of any grade occurring in the pembrolizumab groups were fatigue (20.9% in the 2-week group and 19.1% in the 3-week group), diarrhoea (16.9% and 14.4%, respectively), rash (14.7% and 13.4%, respectively), and pruritus (14.4% and 14.1%, respectively).
- For ipilimumab, the most frequent adverse events were pruritus (25.4%), diarrhoea (22.7%), fatigue (15.2%), and rash (14.5%).
- The findings of the KEYNOTE-001, KEYSTONE-002 and KEYSTONE-006 trials establish pembrolizumab as a new standard of care for melanoma and support the accelerated approval granted by the US FDA for the use of pembrolizumab in patients with unresectable or metastatic melanoma whose disease had progressed after ipilimumab and, if BRAF V600 mutant-positive, a BRAF inhibitor.
- HRQoL was better maintained with pembrolizumab than with chemotherapy (KEYNOTE-002) or ipilimumab (KEYNOTE-006), further supporting the use of pembrolizumab in patients with ipilimumab-refractory melanoma.
- Overall, the combination of prolonged progression-free survival and overall survival, a decreased incidence of high-grade toxicity, and a better HRQoL provided by pembrolizumab compared with ipilimumab or chemotherapy, supports the use of this drug as a standard of care for patients with advanced melanoma.
We suggest you refer to your national drug approval agency such as the Australian Therapeutic Goods Administration (TGA), US Food and Drug Administration (FDA), UK Medicines and Healthcare products regulatory agency (MHRA) / emc, and NZ Medsafe, or a national or state-approved formulary eg, the New Zealand Formulary (NZF) and New Zealand Formulary for Children (NZFC) and the British National Formulary (BNF) and British National Formulary for Children (BNFC).