Key clinical-trial evidence for pembrolizumab

Author: Anoma Ranaweera B.V. Sc; PhD (Clinical Biochemistry, University of Liverpool, UK). Chief Editor: Dr Amanda Oakley, Dermatologist, Hamilton, New Zealand, December 2014. Updated March 2018.

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.


Introduction

Pembrolizumab is a highly selective humanised monoclonal antibody directed against the PD-1 receptor on T-cells. The drug blocks the PD-1 receptor, thereby preventing the formation of PD-1/PD-L1 (programme death ligand one) complexes. This mechanism causes the activation of T-cell mediated immune responses against tumour cells.

On September 4, 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 2 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, UK and New Zealand.

Metastatic melanoma

KEYNOTE-001 study

  • The efficacy of pembrolizumab (KEYTRUDA®) was investigated in a multicenter, open-label, randomised (1:1), dose comparative phase 1b study.
  • 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 Tumours (RECIST 1.1) as assessed by 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, 3 (14%) had disease progression at 2.8, 2.9, and 8.2 months, respectively, after initial response.
  • The duration of response in the remaining 18 patients (86%) varied from 1.4 to 8.5 months and included 8 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 three 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 to 23).
  • Pembrolizumab was discontinued in 6% of the 89 patients because of adverse events.

Table 1. Drug-related adverse reactions in > 10% of patients

Pembrolizumab 2 mg/kg every 3 weeks (n = 89)
Adverse reactionAll 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

KEYNOTE-002 study

Efficacy

  • KEYNOTE-002 was a phase 2 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, Q3W) and/or 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 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 independent central review or death from any cause, whichever occurred first.
  • Results are summarised in Table 2.

Table 2. Summary of efficacy parameters – KEYNOTE-002.

 Pembrolizumab 2 mg/kg  (n = 180)Pembrolizumab 10 mg/kg (n = 181)Chemotherapy control (n = 179)
Progression free survival (% 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 (% 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. 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%)

 Adverse events

  • Incidence of grade 3–4 drug-related adverse events were higher in patients treated with chemotherapy compared to pembrolizumab.
  • The most common treatment-related adverse events with chemotherapy were alopecia, anaemia, decreased appetite, fatigue, nausea, and vomiting.
  • Those 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

 Pembrolizumab 2 mg/kg (n = 178)Pembrolizumab 10 mg/kg (n = 179)Chemotherapy control (n = 171)
 Grade 1–2Grade 3Grade 4Grade 1–2Grade 3Grade 4Grade 1–2Grade 3Grade 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 – KEYNOTE-002

  • Health-related quality of life (HRQoL) was assessed using the Global health status (GHS)/health-related quality-of-life 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 global health status score of the EORTC QLQ-C30 – KEYNOTE-002

Treatment armBaselineWeek 12Change from baseline least squares mean (95% CI)
nMean ± SD nMean ± SD

Pembrolizumab 2 mg/kg Q3W

169

66.2 ± 22.1

120

66.3 ± 23.0

           −2.6 (−6.2, 1.0)a

Pembrolizumab 10 mg/kg Q3W

168

62.9 ± 23.6

132

64.3 ± 22.8

           -2.6 (−6.0, 0.9)a

Chemotherapy

155

64.0 ± 21.9

108

59.0 ± 23.2

           −9.1 (−12.9, −5.4)

a P = 0.01 versus chemotherapy. 

KEYNOTE-006 study

Efficacy

  • The phase 3 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 (Q2W, n=279), intravenous or every 3 weeks (Q3W, 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 to 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; 95CI, 0.52 to 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 – KEYNOTE-006

  • The primary patient-related outcome assessment was the score change from baseline to week 12 in EORTC QLQ-C30 global health status (GHS)/HRQoL) score between treatment arms using 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 versus −10.0 for ipilimumab; p < 0.001 for each pembrolizumab arm versus ipilimumab; Table 5).
  • Fewer patients treated with pembrolizumab experienced deterioration in GHS at week 12 (31% for pembrolizumab Q2W; 29% for Q3W and 44% for ipilimumab), with similar trends observed for individual functioning and symptoms scales.

Table 5. Change from baseline to week 12 in the global health status score of the EORTC QLQ-C30 – KEYNOTE-006

Treatment  nBaseline Week 12 Change from baseline 
Mean (SD)nMean (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)

Adverse events – 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%).

Conclusions

  • The findings of KEYNOTE-001, 022 and 006 trials establish pembrolizumab as a new standard of care for melanoma and support the accelerated approval granted by the US Food and Drug Administration for the use of pembrolizumab in patients with unresectable or metastatic melanoma whose disease had progressed after ipilimumab and, if BRAFV600 mutant-positive, a BRAF inhibitor.
  • Health-related quality of life (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 and 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.

 

Related Information

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