Key evidence from clinical trials for pembrolizumab

Introduction

Pembrolizumab (Keytruda^®) is a highly selective humanized monoclonal antibody directed against programmed cell death 1 (PD-1) receiver in T cells. The drug blocks the PD-1 receptor, thus preventing the formation of programmed cell death ligand 1 (PD-L1) complexes. This mechanism causes the activation of T cell immune responses mediated against tumor cells.

On September 4, 2014, the United States Food and Drug Administration (FDA) approved pembrolizumab as an innovative therapy for the treatment of metastatic melanoma, based on response rates demonstrated in clinical trial data from 173 melanoma patients in a cohort from the KEYNOTE-001 study.

Since then, the results of two other 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 melanoma (metastatic or unresectable) in many countries around the world, including Europe, the United Kingdom, and New Zealand.

The KEYNOTE-001 Study

• the effectiveness pembrolizumab was investigated in a multicenter, open, randomized (1: 1), Phase 1b dose comparison study.
• The key eligibility criteria were unresectable or metastatic melanoma with disease progression and refractory to treatment with two or more doses of ipilimumab (3 mg / kg or more) and, if BRAF V600 mutation-positive, a BRAF or MEK inhibitorand disease progression within 24 weeks after the last dose of ipilimumab.
• Patients were randomized 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 tumor status was performed 12 weeks after the first dose of pembrolizumab and every 12 weeks thereafter.
• The main efficacy outcomes were duration of response and confirmed overall response rate (ORR) according to the Response Assessment 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.
• Duration of response in the remaining 18 patients (86%) ranged from 1.4 to 8.5 months and included eight patients with continuous responses of 6 months or longer.
• Similar ORR results were seen in the 10 mg / kg arm.
• The response rate did not differ significantly between patients who had previously received ipilimumab and those who had not.
• Table 1 presents Adverse reactions identified from analyzes of 89 patients with unresectable or metastatic melanoma who received 2 mg / kg of pembrolizumab every 3 weeks.
• The median duration of pembrolizumab exposure 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 due to adverse reactions.

Table 1. Drug-related adverse reactions occurred in> 10% of patients on KEYNOTE-001

AST: aspartate transaminase

The KEYNOTE-002 Study

Effectiveness

• KEYNOTE-002 was a phase II study evaluating the efficacy and safety of two doses of pembrolizumab compared to Investigator's Choice chemotherapy in patients with melanoma refractory to ipilimumab.
• The patients had histologically or cytologically confirmed unresectable stage III or stage IV melanoma that had progressed within 24 weeks after the last dose of ipilimumab (minimum two doses, 3 mg / kg once every 3 weeks) and / or had received prior treatment with inhibitors BRAF or MEK, or both (if mutant positive).
• Patients were randomized (1: 1: 1) to receive intravenous pembrolizumab 2 mg / kg or 10 mg / kg every 3 weeks or chemotherapy chosen by the investigator (paclitaxel plus carboplatin, paclitaxel, carboplatin, dacarbazine, or oral temozolomide).
• Tumor evaluations were performed prior to beginning study treatment (base), at week 12, every 6 weeks until week 48, and then every 12 weeks thereafter.
• the primary the end point was progression-free survival, the time from randomization first documented disease progression by RECIST v1.1 by independent central review, or death from any cause, whichever occurs first.
• The results are summarized in Table 2.

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

RECIST, Response Evaluation Criteria in Solid Tumors

Adverse events

• the incidence of KEYNOTE-002 grades 3-4 drug-related adverse events higher in chemotherapy-treated patients compared to pembrolizumab.
• The most common adverse events related to chemotherapy treatment were alopecia, anemia, decreased appetite, fatigue, nausea and vomiting.
• The treatment-related adverse events that were most common with pembrolizumab were rash, pruritus, and diarrhea.
• Table 3 is a summary of adverse events in KEYNOTE-002.

Table 3. Summary of adverse events - KEYNOTE-002

Quality of life related to health

• Health-related quality of life (HRQoL) was assessed using the Global Health Status (GHS) / HRQoL scores from the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) at the start of the study, weeks 3, 6, 12, 24 and 36, at treatment interruption and during safety follow-up.
• HRQL was more maintained with pembrolizumab versus chemotherapy, with fewer pembrolizumab-treated patients experiencing deterioration in SGA at week 12 (31.8% patients on pembrolizumab 2 mg / kg, 26.6% for 10 mg / kg, and 38.3% for chemotherapy).
• The results are summarized in Table 4.
• In addition to the GHS / HRQoL score, patients in the two pembrolizumab arms had consistently smaller longitudinal score changes from baseline through week 12 on all functional scales, including physical, cognitive, social, and emotional functions, and on scales symptoms including fatigue, nausea / vomiting, pain, dyspnea, insomnia, loss of appetite, constipation and diarrhea.

Table 4. Change from baseline to week 12 in EORTC QLQ-C30 GHS score in KEYNOTE-002

a P = 0.01 versus chemotherapy.

The KEYNOTE-006 Study

Effectiveness

• The KEYNOTE-006 Phase III study showed higher Overall and progression-free survival of pembrolizumab versus ipilimumab in patients with advanced melanoma.
• 834 patients with advanced melanoma were enrolled and randomized to receive intravenous pembrolizumab every 2 weeks (n = 279), intravenous or every 3 weeks (n = 277), or intravenous ipilimumab every 3 weeks (n = 278).
• The 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.
• Estimates of one-year overall survival were 74.1% for patients receiving pembrolizumab every 2 weeks (hazard ratio of death compared to ipilimumab group 0.63; 95% CI 0.47-0, 83; p <0.0005), 68.4% for those receiving pembrolizumab every 3 weeks (hazard ratio of death compared to ipilimumab group 0.69, 951 CITP1T 0.52 to 0.90; p = 0.0036) and 58.2% for those who received ipilimumab.
• The overall survival rate at 24 months was 55% in the 2-week group, 55% in the 3-week group, and 43% in the ipilimumab group.

Quality of life related to health

• The primary patient-related outcome assessment in KEYNOTE-006 was score change from baseline to week 12 in the EORTC QLQ-C30 GHS / HRQoL score between treatment arms, using restricted 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 arm of pembrolizumab vs ipilimumab; see Table 5).
• Fewer pembrolizumab-treated patients 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 seen for individual functioning and symptom scales.

Table 5. Change from baseline to week 12 in EORTC QLQ-C30 GHS score - KEYNOTE-006

CI, confidence interval; EORTC QLQ-C30, European Organization 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

Adverse events

• In KEYNOTE-006, the most common treatment-related adverse events of any grade that occurred in the pembrolizumab groups were fatigue (20.9% in the 2-week group and 19.1% in the 3-week group), diarrhea (16.9% and 14.4%, respectively), skin rash (14.7% and 13.4%, respectively), and pruritus (14.4% and 14.1%, respectively).
• For ipilimumab, the most common adverse events were pruritus (25.4%), diarrhea (22.7%), fatigue (15.2%), and rash (14.5%).

Conclusions

• Results from the KEYNOTE-001, KEYSTONE-002 and KEYSTONE-006 Trials Establish Pembrolizumab as a New Standard of Care for Melanoma and Support Accelerated US FDA Approval for Pembrolizumab in Patients with unresectable or metastatic melanoma whose disease had progressed after ipilimumab and, if BRAF V600 positive mutant, a BRAF inhibitor.
• HRQoL was better maintained with pembrolizumab than chemotherapy (KEYNOTE-002) or ipilimumab (KEYNOTE-006), further supporting the use of pembrolizumab in patients with melanoma refractory to ipilimumab.
• Overall, the combination of long progression-free survival and overall survival, a lower incidence of high-grade toxicity, and a better HRQoL provided by pembrolizumab compared to ipilimumab or chemotherapy, supports the use of this drug as a standard of care for patients with advanced melanoma