A Randomised Open-label Phase III Trial of REduced Frequency Pembrolizumab immuNothErapy for First-line Treatment of Patients With Advanced Non-small Cell Lung Cancer (NSCLC)

Study Overview
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Brief Summary
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REFINE-lung will test whether reduced pembrolizumab dose frequency after 6 months of standard treatment is safe and effective. Patients treated with 1st line pembrolizumab who are progression free and otherwise planning to continue therapy at 6 months will be initially randomised to control 6 weekly versus interventional 12 weekly therapy. If an interim analysis shows that the 12 weekly treatment is no less effective, subsequent patients will also be randomised to 9, 15 and 18 weekly treatment frequency arms. Patients who progress on a reduced frequency arm will be offered re-escalation to standard 6 weekly therapy.

Detailed Description
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Immunotherapy with pembrolizumab targeting the T cell inhibitory PD-1 receptor has significantly improved outcomes in advanced non-small cell lung cancer (NSCLC). Approximately 3600 new patients are treated in the 1st line setting per year in England alone and up to 25% remain on 6 weekly pembrolizumab for 2 years. However, pharmacological and clinical trial data suggest current frequent dosing for 2 years result in overtreatment. Indeed, pembrolizumab remains bound to its target receptor for up to 100 days following a single dose and studies in multiple tumour types have found no relationship between dose and patient outcome. Moreover, anti-PD1 treated patients who respond but discontinue therapy either as planned after 2 years, or earlier because of toxicity, can either remain in remission and/or be sensitive to re-challenge with pembrolizumab. REFINE-lung will test whether reduced pembrolizumab dose frequency (9, 12, 15, 18 weeks) after 6 months of standard treatment is safe and effective. This UK study represents a unique opportunity to determine whether pembrolizumab dose frequency can be safely reduced in NSCLC, resulting in significant cost benefits to the NHS and globally, in addition to enhanced patient QoL associated with fewer hospital attendances and reduced toxicity.

Official Title
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A Randomised Open-label Phase III Trial of REduced Frequency Pembrolizumab immuNothErapy for First-line Treatment of Patients With Advanced Non-small Cell Lung Cancer (NSCLC) Utilising a Novel Multi-arm Frequency-response Optimisation Design

Conditions
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Lung Cancer, Nonsmall Cell

Intervention / Treatment
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* Drug: Pembrolizumab 25 MG/ML [Keytruda]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent prior to initiation of any study procedures and willingness and ability to comply with the study schedule Any patient ≥18yrs who has received 6 months of pembrolizumab treatment with or without chemotherapy for advanced Non small cell lung cancer who is planned to continue immunotherapy treatment because of continued benefit. Exclusion Criteria: Disease progression or not tolerating treatment at 6 months into therapy Clinician does not intend to continue immunotherapy Any patient with a synchronous primary cancer. This includes any new cancer diagnoses or relapse of previously treated cancer since starting pembrolizumab treatment. Any patient currently receiving an investigational agent and/or using an investigational device or has participated in a study of an investigational agent and/or used an investigational device within 28 days of randomisation.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 6 weekly<br>6 weekly pembrolizumab, 400mg intravenous | Drug: Pembrolizumab 25 MG/ML [Keytruda]<br>* Pembrolizumab to be given at 400mg intravenous over 5 different frequencies<br>|
| Experimental: 9 weekly<br>9 weekly pembrolizumab, 400mg intravenous | Drug: Pembrolizumab 25 MG/ML [Keytruda]<br>* Pembrolizumab to be given at 400mg intravenous over 5 different frequencies<br>|
| Experimental: 12 weekly<br>12 weekly pembrolizumab, 400mg intravenous | Drug: Pembrolizumab 25 MG/ML [Keytruda]<br>* Pembrolizumab to be given at 400mg intravenous over 5 different frequencies<br>|
| Experimental: 15 weekly<br>15 weekly pembrolizumab, 400mg intravenous | Drug: Pembrolizumab 25 MG/ML [Keytruda]<br>* Pembrolizumab to be given at 400mg intravenous over 5 different frequencies<br>|
| Experimental: 18 weekly<br>18 weekly pembrolizumab, 400mg intravenous | Drug: Pembrolizumab 25 MG/ML [Keytruda]<br>* Pembrolizumab to be given at 400mg intravenous over 5 different frequencies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival at 2 years | Survival at 2 years, defined as from commencing pembrolizumab (18 months after randomisation) to death due to any cause or study termination | 18 months from randomisation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival from study entry | Survival, defined as from commencing pembrolizumab (18 months after randomisation) to death due to any cause or study termination | 2 years | 
| Progression free survival | Progression free survival as assessed by RECIST v1.1, defined as time from study entry to first evidence of disease progression or death due to any cause | 2 years | 
| Overall response rate | Overall response rate (ORR) as assessed by RECIST v1.1, defined as complete response (CR) or partial response (PR) | 2 years | 
| Duration of response | Duration of response (DoR) as assessed by RECIST v1.1, defined as time from study entry to change in response from CR or PR to stable disease (SD) or progressive disease (PD) | 2 years | 
| Incidence of adverse events | Safety and tolerability as assessed by adverse events according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 | 2 years |