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Home Topics A–Z Key clinical-trial evidence for pembrolizumab
Author: Anoma Ranaweera, Medical Writer, Auckland, New Zealand. DermNet NZ Editor in Chief: Adjunct A/Prof Amanda Oakley, Dermatologist, Hamilton, New Zealand. First published December 2014; updated March 2018. Copy edited by Gus Mitchell/Maria McGivern.
This article was updated with financial support from Merck Sharp & Dohme (New Zealand) Limited, distributors of Keytruda® in New Zealand. Sponsorship does not influence content.
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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.
Metastatic melanoma
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 | ||
Fatigue | 47 | 7 |
Peripheral oedema | 17 | 1 |
Chills | 14 | 0 |
Pyrexia | 11 | 0 |
Gastrointestinal disorders | ||
Diarrhoea | 20 | 0 |
Nausea | 30 | 0 |
Abdominal pain | 12 | 0 |
Respiratory disorders | ||
Cough | 30 | 1 |
Dyspnoea | 18 | 2 |
Skin disorders | ||
Rash | 29 | 0 |
Pruritus | 30 | 0 |
Vitiligo | 11 | 0 |
Musculoskeletal disorders | ||
Arthralgia | 20 | 0 |
Myalgia | 14 | 1 |
Back pain | 12 | 1 |
Nervous system disorders | ||
Headache | 16 | 0 |
Dizziness | 11 | 0 |
Liver function | ||
Increased AST | 24 | 2 |
AST: aspartate transaminase
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
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%) |
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 |
169 |
66.2 ± 22.1 |
120 |
66.3 ± 23.0 |
−2.6 (−6.2 to 1.0)a |
Pembrolizumab 10 mg/kg Q3W |
168 |
62.9 ± 23.6 |
132 |
64.3 ± 22.8 |
-2.6 (−6.0 to 0.9)a |
Chemotherapy |
155 |
64.0 ± 21.9 |
108 |
59.0 ± 23.2 |
−9.1 (−12.9 t −5.4) |
a P = 0.01 versus chemotherapy.
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
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