PEMBROLIZUMAB “Treatment of melanoma has never been this promising”

By: Patwant Dhillon

METASTATIC MELANOMA

•  10-year survival rate less than 10% •  Single-agent chemotherapy: •  Well-tolerated, but response rates of only 5-20%

•  Dacarbazine and Temozolomide: •  Equally effective; primarily for palliation

•  Phase II randomized trial studying dacarbazine vs temozolomide PFS 2.1 & 2.3 months; OS 9.3 & 9.1 months, respectively

•  Combination chemotherapy does not extend survival and is associated with greater toxicity

•  BRAF inhibitors for BRAF V600 mutation (+) melanoma: •  Vemurafenib in previously treated patients: 53% response rate, mean

duration of response 6.7 months

(Bhatia S., 2009); (NCI, 2014)

METASTATIC MELANOMA

•  Interleukin-2 •  In 270 patients, ORR was 16% and 60% of complete responders had

durable responses ranging from 42(+) to 122(+) months

•  Risk of multi-organ complications limits IL-2 to younger patients with excellent performance status and organ function

•  Ipilimumab: •  Anti-CTLA4 antibody that potentiates immune responses against

cancer cells

•  Phase 3 study, ipilimumab (10mg/kg) + dacarbazine (850mg/m2) vs dacarbazine + placebo •  OS 11.2 vs 9.1 months, respectively, with higher survival rates in

ipilimumab-dacarbazine at 1 year (47.3% vs 36.3%)

(Bhatia S., 2009); (Robert C., 2011)

WHAT IS PEMBROLIZUMAB?

•  A monoclonal IgG4 antibody that binds to programmed death receptor-1 (PD-1) receptors and blocks its interaction with PD-L1 and PD-L2 ligands

•  Also known as MK-3475, KEYTRUDA •  Previously known as Lambrolizumab

(FDA, 2014); (Merck & Co., Inc., 2014)

CLINICAL PHARMACOLOGY

•  Binding of PD-L1 and PD-L2 to PD-1 receptors on T cells inhibits T cell proliferation and cytokine production •  PD-L1 and/or PD-L2 expression by APCs or tumor cells down-

regulates the activity of PD-1–expressing T cells and other cells

•  Interruption of PD-1:PD-L1 and PD-1:PD-L2 binding by pembrolizumab prevents PD-1 pathway-mediated T-cell functional inhibition

(FDA, 2014); (Merck & Co., Inc., 2014); (Langer C., 2014)

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

of ipilimumab plus chemotherapy versus chemotherapy alonein squamous cell NSCLC (Table 3).

CLINICAL EXPERIENCE WITH PD-1 CHECKPOINTBLOCKADE IN NSCLC

Several agents that target the immune checkpoint PD-1pathway are undergoing clinical evaluation in patients withlung cancer. The agents differ in immunoglobulin G (IgG)isotype and binding specificity, and are fully human versushumanized, which may translate into differences in clinicalactivity and the safety profile. However, there are currently nohead-to-head trials comparing these agents.

Anti-PD-1 AgentsThe most clinically studied anti-PD-1 agent to date is

nivolumab (BMS-936558), a fully human monoclonal IgG4antibody against PD-1. Nivolumab yielded objective responsesin 17% of NSCLC patients (n = 129) who had received Z1prior chemotherapy regimen in a phase I study in patients withsolid tumors.47 These responses are notable as the patientswere heavily pretreated; 54% had received Z3 prior regimens.Many NSCLC patients showed ongoing, durable responses andsustained OS with single-agent nivolumab (1, 3, or 10 mg/kg)administered every other week. The median OS was 9.2 and10.1 months in patients with squamous or nonsquamousNSCLC, respectively (Table 2). Median OS across all patientswas 14.9 months at the 3 mg/kg dose, which was selected forfurther clinical development.

Treatment-related irAEs of any grade occurred in 41% ofpatients and included skin, gastrointestinal, pulmonary, andendocrine events. Grade 3/4 treatment-related irAEs occurredin 5% of patients. Two NSCLC patients died of pneumonitis;other early-grade pneumonitis was controlled by stoppingtreatment and/or administering corticosteroids.

Two phase III studies are comparing nivolumab withdocetaxel in patients with previously treated advanced/meta-static nonsquamous or squamous NSCLC (NCT01673867;NCT01642004). Nivolumab in combination with platinum-based doublet chemotherapy or with targeted agents is alsobeing investigated in stage IIIB/IV NSCLC (NCT01454102)(Fig. 2). These and other ongoing trials with immune check-point inhibitors in NSCLC are summarized in Table 3.

Pembrolizumab (MK-3475), a humanized monoclonalIgG4 antibody against PD-1, contains sequences of a very–high-affinity mouse anti-human PD-1 antibody grafted on to ahuman IgG4 with engineered Fc region pembrolizumab hasshown preclinical antitumor activity in multiple tumor types,and evidence of antitumor activity has been observed clin-ically.52 Pembrolizumab was administered at 10 mg/kg every 3weeks to 38 previously treated patients with NSCLC.46 Theobjective response rate using RECIST v1.1 was 21% overall,and most responses were observed by 9 weeks. The prelim-inary median OS was 51 weeks, and median PFS was 9.7weeks. Responses were observed in patients with squamous(33%) and nonsquamous (16%) histology. Fifty-three percentof patients experienced drug-related AEs; the most commonincluded rash (21%), pruritus (18%), fatigue (16%), and diar-rhea (13%). One case of grade 3 pulmonary edema occurred.Ongoing clinical trials are evaluating pembrolizumab in lungcancer, either as monotherapy or in combination with cisplatin/pemetrexed or carboplatin/paclitaxel or compared with doce-taxel in previously-treated patients (Table 3). The early phase Itrials included patients with PD-L1-negative tumors, but cur-rent development is focused on those with PD-L1-positivedisease.

Anti-PD-L1 AgentsThe anti-PD-L1 antibody BMS-936559 is a high-affinity,

fully human, PD-L1-specific, IgG4 monoclonal antibody thathas shown activity in NSCLC patients.50 In a phase II clinicalstudy, 5 of 49 NSCLC patients had an objective response, andthe response lasted Z24 weeks in 3 of the patients. Sixpatients had stable disease lasting Z24 weeks. In this study,irAEs were mainly grade 1 or 2 and included rash, hypo-thyroidism, and hepatitis.

MPDL3280A is a human anti-PD-L1 monoclonal antibodyengineered to prevent antibody-dependent cell-mediated cyto-toxicity.53,54 MPDLA3280A is being assessed in a dose-ranging

A

B

FIGURE 1. Antibody blockade of the CTLA-4 and PD-1 immunecheckpoint pathways. Immune checkpoint blockade can restoreantitumor T-cell responses. A, Anti–CTLA-4 antibodies preventCTLA-4 from binding its ligands (B7-1 and B7-2) on APCs andinterrupt negative signaling to the T cell. B, PD-L1 and/or PD-L2expression by APCs or tumor cells downregulates the activity ofPD-1–expressing T cells and other cells. Interruption of PD-1:PD-L1 and PD-1:PD-L2 binding by anti–PD-1 antibodies or inter-ruption of PD-1:PD-L1 binding by anti–PD-L1 antibodies preventsPD-1 pathway-mediated T-cell functional inhibition. APC indi-cates antigen-presenting cell; CTLA-4, cytotoxic T-lymphocyte–associated antigen 4; PD-1, programmed cell death protein 1;PD-L1, programmed cell death 1 ligand 1; PD-L2, programmedcell death 2 ligand 1;T, T cell.

American Journal of Clinical Oncology ! Volume 00, Number 00, ’’ 2014 Emerging Immunotherapies in the Treatment of NSCLC

r 2014 Lippincott Williams & Wilkins www.amjclinicaloncology.com | 3

(Langer C., 2014)

Many cancers suppress cytotoxic T cell activity by expressing PD-L1/PD-L2 on cell surfaces

FDA APPROVAL

•  FDA approved pembrolizumab under the Accelerated Approval Program based on tumor response rate and durability of response

•  Based on the results of a multi-centre, open-label, randomized (1:1), expansion cohort of phase 1 KEYNOTE-001 study

(FDA, 2014); (Robert C., et al., 2014)

KEYNOTE-001

•  Ongoing multi-centre, single arm, open-label study evaluating pembrolizumab monotherapy in more than 1000 patients with diverse late-stage cancers, predominantly melanoma and lung

•  3 dosing regimens evaluated: 10mg/kg every 2 weeks, 10mg/kg every 3 weeks, 2mg/kg every 3 weeks

•  Tumour response assessed every 12 weeks by independent, central, blinded radiographic review per RECIST1.1

(ClinicalTrials.gov, 2014)

KEYNOTE-001

Part A: Safety, tolerability, PK, PD, maximum tolerated doses

Part B: Safety, tolerability, efficacy in metastatic melanoma

Expansion cohort

Part D: Low and high doses (2 mg/kg or 10 mg/kg every 3 weeks) in metastatic melanoma

Part F: Low and high doses in NSCLC

(ClinicalTrials.gov, 2014)

FDA APPROVAL

•  Eligibility Criteria: •  Age 18 years or older

•  Progressive, measurable, unresectable melanoma previously treated with at least 2 doses of ipilimumab 3mg/kg or higher every 3 weeks

•  Confirmed disease progression using immune-related response criteria within 24 weeks of last dose of ipilimumab

•  Adequate performance status and organ function

•  Resolution of all ipilimumab-related adverse effects to grade 0 or 1

•  Previous treatment with BRAF inhibitor required if BRAF-mutant melanoma

(FDA, 2014); (Robert C., et al., 2014)

FDA APPROVAL

•  Exclusion Criteria: •  Previous treatment with PD-1 or PD-L1 blocking agent

•  Current systemic immunosuppressive therapy

•  Active infection or autoimmune disease

•  History of severe immune-mediated adverse events from ipilimumab •  Defined as any grade 4 toxicity requiring treatment with corticosteroids,

or

•  Grade 3 toxicity requiring corticosteroid treatment (greater than 10 mg/day prednisone or equivalent) for more than 12 weeks

(FDA, 2014); (Robert C., et al., 2014)

FDA APROVAL

•  Open-label study •  178 patients were randomly assigned to receive one of 2

dosing regimens: 2 mg/kg every 3 weeks or 10 mg/kg every 3 weeks administered by IV over 30 minutes •  First 60 patients randomly assigned in 2:1 ratio to 2mg/kg every 3

weeks or 10mg/kg every 3 weeks

•  Sample size was later increased by 100 patients, randomized in a 2:3 ratio •  Median age 61

•  40% female; 97% White

•  BRAF V600 mutation (+) 17%

•  Brain metastases 9%

•  2 or more prior treatments for advanced/metastatic disease 73%

(FDA, 2014); (Robert C., et al., 2014)

FDA APPROVAL

•  Primary endpoint: •  Overall response rate according to RECIST v.1.1 as assessed by

independent central review

•  Secondary endpoint: •  Response duration, progression-free survival, & overall survival

•  Tumor response assessed every 12 weeks

(FDA, 2014); (Robert C., et al., 2014)

FDA APPROVAL

•  178 patients randomized; 173 received treatment

•  Overall response rate 26% in both arms •  2 mg/kg arm: •  1 complete and 20 partial

responses •  Among 21 with objective

response, 3 had disease progression at 2.8, 2.9, 8.2 months after initial response

•  Remaining 18 had ongoing responses ranging 1.4(+) to 8.5(+) months

•  Similar ORR results observed in 10 mg/kg arm

•  Progression free survival: 22 and 14 weeks with 2mg/kg and 10mg/kg, respectively

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1112 www.thelancet.com Vol 384 September 20, 2014

overall survival were calculated in accordance with Greenwood’s formula.25 The hazard ratio (HR) and its 95% CI were calculated for between-dose comparisons of PFS with the Cox proportional hazards model with Efron’s tie handling.26 A population pharmacokinetic analysis was done with NONMEM.27 Individual post-hoc estimates of the pembrolizumab area under the curve at steady state were summarised descriptively. Analysis was done on the population of patients who provided at least one post-baseline blood sample.

Role of the funding sourceThis study was funded by Merck Sharp and Dohme, Whitehouse Station, NJ, a subsidiary of Merck, which provided the study drug and worked jointly with the senior academic authors to design the study and gather, analyse, and interpret the results. CR, AR, and AD had full access to the study data and worked with employees of the funder to analyse the results. All authors approved the decision to submit the manuscript for publication, affi rm the accuracy and completeness of the data, and attest that the study was done in accordance with the protocol and all amendments. All drafts of the manuscript were written by the corresponding author and AD with input from the other authors. The funder provided assistance with manuscript preparation and funded medical writing support. Aside from the authors and those listed in the acknowledgments, no one else contributed to the preparation of the manuscript.

ResultsBetween Aug 28, 2012, and April 5, 2013, 178 patients with ipilimumab-refractory advanced melanoma who were enrolled at 15 sites in four countries were randomly assigned to the pembrolizumab 2 mg/kg (n=91) or pembrolizumab 10 mg/kg group (n=87), and 173 received treatment (89 and 84 patients, respectively; fi gure 1). At baseline, 110 (64%) of 173 patients were stage M1c, 68 (39%) had elevated lactate dehydrogenase concentrations, 31 (18%) had BRAF mutations, and 15 (9%) had a history of brain metastases (table 1). The patients were heavily pretreated, with 125 (72%) receiving at least two and 60 (35%) receiving at least three previous treatments including ipilimumab (table 1). Baseline characteristics were generally well balanced between treatment groups, although there were some minor imbalances (eg, a higher percentage of patients with BRAF-mutant melanoma and a lower percentage with increases in lactate dehydrogenase concentrations in the pembrolizumab 10 mg/kg group; table 1). Ten (6%) of 170 patients with available data had an objective response and 35 (21%) had stable disease as their best overall response to previous ipilimumab treatment. The mean interval between the last dose of ipilimumab and the fi rst dose of pembrolizumab was 33·4 weeks (range 4·0–173·0) in the pembrolizumab 2 mg/kg group and 34·1 weeks (6·0–248·0) in the pembrolizumab 10 mg/kg group.

At the time of analysis (Oct 18, 2013), median follow-up was 8 months (IQR 7–10), with all patients having at

RECIST, independent central review Immune-related response criteria, investigator review

Pembrolizumab 2 mg/kg

Pembrolizumab 10 mg/kg

Estimated di! erence(95% CI)

Pembrolizumab 2 mg/kg

Pembrolizumab10 mg/kg

Estimated di! erence(95% CI)

Best overall response* n=81 n=76 n=89 n=84

Complete response 1 (1%) 1 (1%) ·· 3 (3%) 0 (0%) ··

Partial response 20 (25%) 19 (25%) ·· 21 (24%) 27 (32%) ··

Stable disease 20 (25%) 18 (24%) ·· 31 (35%) 27 (32%) ··

Progressive disease 27 (33%) 31 (41%) ·· 24 (27%) 19 (23%) ··

Not evaluable† 13 (16%) 7 (9%) ·· ·· ·· ··

No assessment‡ ·· ·· ·· 10 (11%) 11 (13%) ··

Overall response rate (95% CI) 26% (17 to 37) 26% (17 to 38) 0%§ (–14 to 13); p=0·96 27% (18 to 37) 32% (22 to 43) –5%§ (–19 to 8); p=0·46

Disease control rate (95% CI) 51% (39 to 62) 50% (38 to 62) 1%§ (–15 to 16); p=0·94 62% (51 to 72) 64% (53 to 74) –2%§ (–17 to 12); p=0·75

Patients with response n=21 n=20 ·· n=24 n=27 ··

Time to response(weeks; median, range)

12 (11 to 36) 12 (7 to 17) ·· 12 (11 to 24) 12 (7 to 39) ··

Response duration(weeks; median, range)

NR (6–37¶) NR (8–37¶) ·· NR (12–42¶) NR (4–37¶) ··

Progression-free survival n=89 n=84 ·· n=89 n=84 ··

Median (weeks; 95% CI) 22 (12 to 36) 14 (12 to 24) 0·84|| (0·57–1·23) 31 (22 to 48) 35 (24 to NR) 1·12|| (0·73–1·72)

At 24 weeks (95% CI) 45% (34 to 55) 37% (27 to 48) ·· 57% (46 to 67) 57% (45 to 67) ··

RECIST=Response Evaluation Criteria In Solid Tumors (version 1.1). NR=not reached. *Eight patients in each treatment group did not have measurable disease as per independent central review at baseline and were excluded from the analysis of best overall response as per RECIST by independent central review. †Patients who had no scans for response assessment or who had radiological images of non-diagnostic quality. ‡Patients who exited the study without post-baseline response assessment by the investigator. §Di! erence. ¶Non-progressive disease or ongoing response at the last assessment. ||Hazard ratio. Two-sided p values are provided for testing the null hypothesis that there is no di! erence in the response between groups versus there is a response di! erence.

Table !: Antitumour activity of pembrolizumab at 2mg/kg and 10 mg/kg

(FDA, 2014); (Robert C., et al., 2014)

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least 6 months of follow-up. Median number of days from fi rst to last pembrolizumab dose was 188·0 days in the pembrolizumab 2 mg/kg group and 185·5 days in the pembrolizumab 10 mg/kg group (appendix). At analysis, 73 (42%) of 173 patients were still on treatment (fi gure 1). The most common reason for discontinuation of treatment was disease progression (59 [34%] of 173).

The ORR was 26% in the pembrolizumab 2 mg/kg (21 of 81 patients) and 10 mg/kg groups (20 of 76

patients; p=0·96; table 2). 59 (73%) patients in the pembrolizumab 2 mg/kg group and 52 (68%) in the 10 mg/kg group had a reduction from baseline in target lesion size (fi gure 2A). Change from baseline in index lesion size by immune-related response criteria was also assessed (appendix). Median response duration was not reached in either dose group at the time of analysis (range >6 weeks to >37 weeks), with 36 (88%) of 41 responders alive with no other anticancer

Figure !: E! cacy of pembrolizumab at 2 mg/kg and 10 mg/kg(A) Waterfall plot of maximum percentage change from baseline in the sum of the longest diameter of each target lesion as assessed per RECIST by independent central review for patients with measurable disease by independent central review at baseline who had at least one post-baseline tumour assessment. (B) Time to and duration of response in responders as assessed per RECIST by independent central review. RECIST=Response Evaluation Criteria In Solid Tumors (version 1.1).

–100

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Pembrolizumab 2 mg/kgPembrolizumab 10 mg/kgComplete responsePartial responseProgressionOn treatment

59 (73%) patients in 2 mg/kg group and 52 (68%) patients in 10 mg/kg group had reduction from baseline in target lesion size

(FDA, 2014); (Robert C., et al., 2014)

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least 6 months of follow-up. Median number of days from fi rst to last pembrolizumab dose was 188·0 days in the pembrolizumab 2 mg/kg group and 185·5 days in the pembrolizumab 10 mg/kg group (appendix). At analysis, 73 (42%) of 173 patients were still on treatment (fi gure 1). The most common reason for discontinuation of treatment was disease progression (59 [34%] of 173).

The ORR was 26% in the pembrolizumab 2 mg/kg (21 of 81 patients) and 10 mg/kg groups (20 of 76

patients; p=0·96; table 2). 59 (73%) patients in the pembrolizumab 2 mg/kg group and 52 (68%) in the 10 mg/kg group had a reduction from baseline in target lesion size (fi gure 2A). Change from baseline in index lesion size by immune-related response criteria was also assessed (appendix). Median response duration was not reached in either dose group at the time of analysis (range >6 weeks to >37 weeks), with 36 (88%) of 41 responders alive with no other anticancer

Figure !: E! cacy of pembrolizumab at 2 mg/kg and 10 mg/kg(A) Waterfall plot of maximum percentage change from baseline in the sum of the longest diameter of each target lesion as assessed per RECIST by independent central review for patients with measurable disease by independent central review at baseline who had at least one post-baseline tumour assessment. (B) Time to and duration of response in responders as assessed per RECIST by independent central review. RECIST=Response Evaluation Criteria In Solid Tumors (version 1.1).

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Pembrolizumab 2 mg/kgPembrolizumab 10 mg/kgComplete responsePartial responseProgressionOn treatment

Analysis of time to response: although most responses occurred by week 12, responses might also occur late in the course of treatment, some as late as 36 weeks

(FDA, 2014); (Robert C., et al., 2014)

FDA APPROVAL

•  Adverse effects identified in 89 patients who received pembrolizumab 2mg/kg every 3 weeks

•  Pembrolizumab was discontinued for adverse reactions in 7% of 89 patients

•  Most common adverse reactions (reported in at least 20% of patients) were: •  Fatigue, cough, nausea, pruritus, rash, decreased appetite,

constipation, arthralgia, and diarrhea

•  Most frequent (>20%) serious adverse reactions included: •  Renal failure, dyspnea, pneumonia, and cellulitis

(FDA, 2014); (Robert C., et al., 2014)

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DiscussionThe anti-PD-1 antibody pembrolizumab at doses of 2 mg/kg and 10 mg/kg every 3 weeks had similar and substantial anticancer activity and an acceptable safety profi le in patients with advanced melanoma whose disease had progressed on ipilimumab, and in those with BRAF-mutant disease, who were previously treated with BRAF or MEK inhibitors, or both. This study is the largest reported of anti-PD-1 therapy in patients with melanoma and the fi rst reported randomised comparison of an anti-PD-1 agent (panel).

Similar to other immunotherapies,14,28 the clinical benefi t provided by pembrolizumab is long lasting. With a median follow-up of 8 months (minimum of 6 months), 88% of responses were ongoing at the time of analysis. This response duration is consistent with data previously reported for patients with pembrolizumab-treated melanoma, whereby after a median follow-up of 15 months, 88% of responses were ongoing and the median duration of response was not reached.16 A high percentage of patients were progression free at 24 weeks. The fi nding that 19% of patients with progressive disease as per RECIST were progression free at 6 months as per immune-related response criteria suggests that conventional use of RECIST might underestimate the therapeutic benefi t of pembrolizumab. The fi nding of delayed response also suggests that additional objective responses will occur with longer follow-up. According to previously reported data for a mixed population of ipilimumab-treated and ipilimumab-naive patients, initial responses occurred as late as 11 months after initiation of pembrolizumab, with complete responses occurring as late as 16 months.16 This prolonged time to complete response might partly explain why the percentage of patients with complete response in this study after a median follow-up of 8 months was only 1%. With additional follow-up, it is possible that there will be more complete responses. Overall, and as was previously suggested for ipilimumab,21,29 these data suggest that traditional response criteria might need to be revised for the overall therapeutic benefi ts of pembrolizumab to be fully appreciated.

Of note, there were a small number of patients with BRAF-mutant melanoma enrolled in this study relative to the frequency of BRAF mutation generally noted in patients with advanced melanoma. In our study, previous BRAF or MEK inhibitor therapy, or both, was required for patients with BRAF-mutant melanoma. Thus, it is possible that the small BRAF-mutant population enrolled is a result of a more aggressive disease that occurs after progression on a BRAF inhibitor,30,31 which could have led to patients not having suffi cient performance status to permit their enrolment in this study. Generally, the response rate associated with immunotherapy in patients with melanoma does not diff er by BRAF mutation status.32 In our study, there was

a trend towards a lower response in the BRAF-mutant population. However, the small number of patients with BRAF mutation and BRAF or MEK inhibitor, or both, pretreatment makes it diffi cult to identify the various factors that might have contributed to response in this important patient group. In view of the small sample size, exploratory analysis, and over lapping 95% CIs compared with the overall and BRAF-wild type populations, our fi ndings should be interpreted with caution. Data from the ongoing, randomised, controlled KEYNOTE-002 study (ClinicalTrials.gov, number NCT01704287), which is in progress in a similarly defi ned population but with a larger sample size (n=540), are expected to be more defi nitive about the activity of

Pembrolizumab 2 mg/kg (n=89)

Pembrolizumab 10 mg/kg (n=84)

Total (n=173)

Drug-related adverse events

Total 73 (82%) 69 (82%) 142 (82%)

Grade 3 or 4 13 (15%) 7 (8%) 20 (12%)

Serious 7 (8%) 1 (1%) 8 (5%)

Immune-related adverse events

Grade 3 or 4 1 (1%) 2 (2%) 3 (2%)

Serious 3 (3%) 1 (1%) 4 (2%)

Adverse events of special interest

Grade 3 or 4 4 (4%) 7 (8%) 11 (6%)

Drug-related, grade 3 or 4 3 (3%) 4 (5%) 7 (4%)

Serious 4 (4%) 4 (5%) 8 (5%)

Adverse events leading to discontinuation of drug*

Total 6 (7%) 9 (11%) 15 (9%)

Drug-related, any grade 5 (6%) 1 (1%) 6 (3%)

Drug-related, grade 3 or 4 2 (2%) 1 (1%) 3 (2%)

Immune-related 3 (3%) 1 (1%) 4 (2%)

Of special interest 3 (3%) 1 (1%) 4 (2%)

Grade 3 or 4 drug-related adverse events occurring in one or more patients

Fatigue 5 (6%) 0 5 (3%)

Amylase increased 1 (1%) 0 1 (<1%)

Anaemia 1 (1%) 0 1 (<1%)

Autoimmune hepatitis 1 (1%) 0 1 (<1%)

Confusion 1 (1%) 0 1 (<1%)

Diarrhoea 0 1 (1%) 1 (<1%)

Dyspnoea 0 1 (1%) 1 (<1%)

Encephalopathy 1 (1%) 0 1 (<1%)

Hypophysitis 1 (1%) 0 1 (<1%)

Hypoxia 0 1 (1%) 1 (<1%)

Muscular weakness 1 (1%) 0 1 (<1%)

Muscoloskeletal pain 0 1 (1%) 1 (<1%)

Pancreatitis 0 1 (1%) 1 (<1%)

Peripheral motor neuropathy 1 (1%) 0 1 (<1%)

Pneumonitis 1 (1%) 0 1 (<1%)

Rash 0 1 (1%) 1 (<1%)

Rash maculopapular 0 1 (1%) 1 (<1%)

Data are number (%), unless otherwise indicated. *Medical Dictionary for Regulatory Activities preferred terms “progressive disease” and “malignant neoplasm progression” not related to study drug are excluded.

Table !: Summary of adverse events in the pembrolizumab 2mg/kg and 10 mg/kg groups

•  Adverse events in 73 & 69 patients

•  8 patients had drug-related serious AE •  7% & 11% patients discontinued

treatment in 2mg/kg and 10mg/kg arms, respectively

•  No drug-related deaths were reported

•  Grade 3 or 4 AE occurred in 20 patients •  Only fatigue occurred in more than 1

patient (5)

•  Grade 3 or 4 AE of special interest occurred in 11 patients, 7 classified as drug-related: •  Autoimmune hepatitis, diarrhea, hypo-

physitis, maculopapular rash, pancreatitis, pneumonitis

•  Immune-mediated AE manageable with treatment interruptions and corticosteroids

(FDA, 2014); (Robert C., et al., 2014)

FDA APPROVAL

•  Doses of 2mg/kg and 10mg/kg every 3 weeks had similar and substantial anticancer activity and acceptable safety profiles

•  Estimated progression-free survival at 24 weeks was 45% in 2mg/kg group and 37% in 10mg/kg group •  Estimated 1 year overall survival was 58% and 63%, respectively

•  88% of responders were alive and progression-free at time of analysis, with at least 6 months of follow-up

•  Finding of delayed response suggests additional objective responses will occur with longer follow-up •  As late as 11 months for initial responses and 16 months for complete responses

•  Trend towards a lower response in BRAF-mutant population (ORR 19%) •  Small number of patients with BRAF mutation and BRAF inhibitor pretreatment

makes it difficult to identify factors contributing to the response

(Bhatia S., 2014); (FDA, 2014); (Robert C., et al., 2014)

WHY WAS IT GRANTED ACCELERATED APPROVAL?

•  10 year survival for patients with metastatic melanoma is less than 10%

•  Recent successes with ipilimumab and inhibitors of BRAF (vemurafenib, dabrafenib, trametinib) •  Ipilimumab is current standard of therapy, but patients who do not

respond or progress while receiving ipilimumab have very few options remaining

•  Pembrolizumab confirmed to be an active agent against melanoma in patients having previously received ipilimumab and/or BRAF inhibitors

(Bhatia S., 2014); (FDA, 2014); (Robert C., et al., 2014)

HOW DO WE GET IT IN CANADA?

•  Pembrolizumab is available via Special Access Program in Canada

•  Supplier: Idis pharma

•  Patient’s health care providers must fill out the Health Canada Special Access Form A •  Patient’s medical history, severity of condition, prognosis

•  Treatments failed/considered/unsuitable

•  Why the patient is a candidate for pembrolizumab therapy •  Why pembrolizumab is the best choice for the patient

•  Specific data/references with respect to safety and efficacy of pembrolizumab that supports practitioner’s decision

(Health Canada, 2014)

NSCLC

•  Pembrolizumab studied in phase 1 study as initial therapy in previously untreated patients with PD-L1 positive, Stage IV NSCLC

•  Preliminary data presented at ASCO 2014 annual meeting: •  Objective response rate was 47% by irRC

•  80% demonstrated tumor shrinkage

•  Interim progression-free survival was 37 weeks

•  Most common AE: fatigue, pruritus, hypothyroidism, rash, diarrhea, dyspnea •  AE resulting in discontinuation: pneumonitis (1 grade 3) and acute

kidney injury (1 grade 2)

(Johnson D. et al., 2014)

BLADDER CANCER

•  Studied as monotherapy in patients with PD- L1 positive, advanced urothelial cancer

•  Ongoing KEYNOTE-012 trial

•  Results from early findings presented at ESMO 2014

Congress: •  Confirmed overall response rate 24% (n = 7/29) •  Pembrolizumab used as monotherapy measured by RECIST1.1, central

review

•  Complete response rate 10% (n = 3/29)

•  Response durations spanned 16(+) to 40(+) weeks

(Halse, K., 2014)

GASTRIC CANCER

•  Phase 1b study assessing safety, tolerability, and antitumor activity in patients with recurrent/metastatic adenocarcinoma of stomach or gastroesophageal junction

•  Treated with pembrolizumab 10 mg/kg every 2 weeks up to 24 months

•  Overall response rate 31% •  Responses were ongoing, ranging 8(+) to 20(+) weeks

•  Common AE treatment-related: hypothyroidism & fatigue •  Grade 3 or greater AE deemed treatment-related occurred in 3

patients •  1 hypoxia, 1 peripheral neuropathy, 1 pneumonitis

(ESMO, 2014)

KEYNOTE-028 (PMH)

Patients with PD-L1 (+) advanced solid tumors who failed standard therapy, for which no standard therapy exists, or standard therapy is not appropriate 20 advanced solid tumors: colon/rectal, pancreas, esophageal, ovarian, fallopian tube, cervical …

Phase 1B Pembrolizumab 10 mg/kg every 2 week

KEYNOTE-023 (PMH)

Patients with multiple myeloma who have failed at least 2 lines of prior therapy

Phase 1 Pembrolizumab + lenalidomide + dexamethasone

ONGOING STUDIES

(ClinicalTrials.gov, 2014)

KEYNOTE-013 (PMH)

Hematologic malignancies: Hodgkin’s lymphoma, mediastinal large B cell lymphoma, non-Hodgkin’s lymphoma, myelodysplastic syndrome

Phase 1B Pembrolizumab:10 mg/kg every 2 weeks for 24 months

KEYNOTE-031

Renal cell cancer in 36 patients

Phase 1 Pembrolizumab: up to 3 doses of 200 mg every 3 weeks + Surgical Resection vs. Surgical Resection (Standard of care)

ONGOING STUDIES

(ClinicalTrials.gov, 2014)

KEYNOTE-010 (PMH)

NSCLC PD-L1(+) tumors who have disease progression after platinum-containing therapy

Phase 2/3 Pembrolizumab: 2 mg/kg every 3 weeks or 10 mg/kg every 3 weeks vs. Docetaxel 75 mg/m2 every 3 weeks

KEYNOTE-006 (PMH)

Advanced melanoma

Phase 3 Pembrolizumab: 10 mg/kg every 2 weeks or 10 mg/kg every 3 weeks vs. Ipilimumab 3 mg/kg every 3 weeks for 4 doses

ONGOING STUDIES

(ClinicalTrials.gov, 2014)

CONCERNS

•  Improvement in survival or disease-related symptoms was not established with the expansion cohort

•  Conditions for approval: •  MERCK is required to conduct a multi-centre, randomized trial

establishing superiority of pembrolizumab against standard therapy to verify and describe clinical benefit

•  Very expensive: $150,000 per year in US

(Bhatia S., 2014); (FDA, 2014); (Robert C., et al., 2014)

PRESCRIBING INFORMATION

•  Indication: •  Treatment of patients with unresectable or metastatic melanoma and

disease progression following ipilimumab, and if BRAF V600 mutation positive, a BRAF inhibitor

•  Dosage and Administration: •  2 mg/kg as IV infusion over 30 minutes every 3 weeks until disease

progression or unacceptable toxicity

(Merck & Co., Inc., 2014)

PREPARATION

•  Dosage form: 50 mg, lyophilized powder in single-use vial for reconstitution

•  Preparation: •  Add 2.3 mL Sterile Water for Injection by injecting water along walls

of vial and not directly into powder

•  Swirl vial slowly. Allow 5 minutes for bubbles to clear

•  Visually inspect reconstituted solution for particulate matter and discoloration •  Reconstituted pembrolizumab is clear to slightly opalescent, colourless to

slightly yellow solution

•  Withdraw required volume and inject into 50mL 0.9% Sodium Chloride IV bag and mix by gentle inversion

(Merck & Co., Inc., 2014)

STORAGE AND ADMINISTRATION

•  Product does not contain preservative •  Store reconstituted solutions either: •  Room temperature for no more than 4 hours from time of

reconstitution •  Includes: room temperature storage of reconstituted vials, storage of

infusion solution in IV bag, and duration of infusion

•  At 2-8oC for no more than 24 hours

•  Administer IV over 30 minutes through IV line containing a sterile, non-pyrogenic, low-protein binding 0.2-5 micron in-line or add-on filter

(Merck & Co., Inc., 2014)

PHARMACOKINETICS

•  Studied in 479 patients receiving doses of 1-10 mg/kg every 2 weeks or 2-10 mg/kg every 3 weeks

•  Mean clearance: 0.22 L/day

•  Mean elimination half-life: 26 days •  Clearance increased with increasing body weight •  Adequately addressed by administration of weight-based dosing

•  No important effect on clearance: age, gender, renal impairment, mild hepatic impairment, tumor burden

•  Steady-state concentration reached by 18 weeks of repeated dosing with an every 3-week regimen

(Merck & Co., Inc., 2014)

ADVERSE REACTIONS

Immune-Mediated Pneumonitis

-  Evaluate patients with radiographic imagining and administer corticosteroids for grade 2 or greater pneumonitis

-  Withhold for grade 2 pneumonitis and permanently discontinue for grade 3-4 pneumonitis

Immune-Mediated Colitis

-  Administer corticosteroids for grade 2 or greater -  Withhold for grade 2 or severe colitis, permanently

discontinue for life-threatening (grade 4) colitis.

Immune-Mediated Hepatitis

-  Monitor for changes in liver function. Administer corticosteroids for grade 2 or greater hepatitis

-  Withhold: AST/ALT 3-5 times ULN -  Discontinue: AST/ALT >5 times ULN or total bilirubin >3

times ULN

(Merck & Co., Inc., 2014)

ADVERSE REACTIONS

Renal Failure & Immune-Mediated Nephritis

-  Including: autoimmune nephritis & interstitial nephritis -  Monitor changes in renal function. Administer corticosteroids

for grade 2 or greater nephritis -  Withhold for grade 2 and discontinue for grade 3-4

Immune-Mediated Adverse Reactions

-  Exfoliative dermatitis, uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, partial seizures, adrenal insufficiency

-  Withhold for grade 3; discontinue for persistent grade 2 or 3 adverse reactions that do not recover to grade 0-1 within 12 weeks

Immune-Mediated Hyperthyroidism & Hypothyroidism

-  Monitor for changes in thyroid function. Administer corticosteroids for grade 3 or greater hyperthyroidism

-  Withhold for grade 3 hyperthyroidism, discontinue for grade 4. Isolated hypothyroidism may be managed with replacement therapy without interruptions

(Merck & Co., Inc., 2014)

REFERENCES

Bhatia S., Tykodi S., Thompson J. Treatment of Metastatic Melanoma: An Overview. Oncology (Williston Park). 2009 May;23(6):488-496. Bhatia S. & Thompson J. Melanoma: immune checkpoint blockade story gets better. Lancet. 2014 Sep 20;384(9948):1078-9. doi: 10.1016/S0140-6736(14)61140-5. ClinicalTrials.gov. A service of the U.S. National Institutes of Health. Obtained from: http://clinicaltrials.gov/ct2/results?term=pembrolizumab&Search=Search European Society for Medical Oncology. ESMO 2014: Pembrolizumab shows promise in several solid tumours. 2014 Sept 30. Obtained from: http://www.esmo.org/Conferences/ESMO-2014-Congress/News-Articles/Pembrolizumab-Shows-Promise-in-Several-Solid-Tumours Halse K. Merck drug shows promise in bladder cancer. Daily Digest News 2014 Sept 29. Obtained from: http://dailydigestnews.com/2014/09/merck-drug-shows-promise-in-bladder-cancer/ Health Canada. Special Access to Drugs & Health Products. 2013 Dec 20. Obtained from: http://www.hc-sc.gc.ca/dhp-mps/acces/drugs-drogues/index-eng.php Johnson D., Rioth M., Horn L. Immune Checkpoint Inhibitors in NSCLC. Current Treatment Options Oncology. 2014 Aug 6. doi: 10.1007/s11864-014-0305-5.

REFERENCES

Langer C. Emerging Immunotherapies in the Treatment of Non-Small Cell Lung Cancer (NSCLC). Am J Clin Oncol 2014 March 28:00:000-0000. doi: 10.1097/COC. 0000000000000059. National Cancer Institute. Unresectable Stage III, Stage IV, and Recurrent Melanoma Treatment. 2014 Sept 19. Obtained from: http://www.cancer.gov/cancertopics/pdq/treatment/melanoma/HealthProfessional/page9 Merck & Co. Inc. Highlights of Prescribing Information KEYTRUDA. 2014 September. Obtained from: http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf Robert C. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet 2014;384(9948):1109-17. doi: 10.1016/S0140-6736(14)60958-2 Robert C. et al. Ipilimumab plus Dacarbazine for Previously Untreated Metastatic Melanoma. N Engl J Med 2011;364:2517-2526. doi: 10.1056/NEJMoa1104621 U.S. Food and Drug Administration. Pembrolizumab. 2014 September 5. Obtained from: http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm412861.htm