Title: REFINE-Lung (formerly known as CONVOLUTE): 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.
Funder: Department of Health and Social Care

Abstract: Lung cancer is the most common cause of cancer related death. Over 85% of cases are due to non small cell lung cancer (NSCLC). Most patients present with inoperable advanced disease that is incurable with chemotherapy and/or radiotherapy. Recently, more effective medicines have been found that work by activating the body’s immune cells to attack the cancer. These include medicines such as pembrolizumab (pembro)._x000D_ _x000D_ For patients who benefit from pembro, an effect is usually seen within 3-6 months of starting treatment._x000D_ However, treatment is usually continued every 3 weeks and more recently every 6 weeks (standard_x000D_ treatment) for two years or until it stops working. There are several reasons to think 2 years of_x000D_ standard treatment may be unnecessary. For example, many people who respond to treatment and_x000D_ stop early because of side-effects or when the course finishes at 2 years, continue to benefit from_x000D_ pembro long afterwards, i.e. their disease does not grow back. This may be because pembro_x000D_ continues to work on immune cells long after it can’t be detected in the blood. Taken together, we think_x000D_ that pembro can be given less frequently after patients have achieved benefit. If pembro can be given_x000D_ less frequently, it would result in fewer hospital visits and potentially reduced side effects resulting in_x000D_ improved quality of life. Reducing the cost of therapy would free up resources to support other new_x000D_ treatments._x000D_ _x000D_ To find if treatment can be given less often without reducing how well it works, we propose to carry out_x000D_ a study of patients treated with the same dose of pembro but less frequently than standard._x000D_ In this study, we plan to take patients who have been on standard treatment with pembro for 6 months_x000D_ and then randomise them to either continuing standard treatment or have treatment at a reduced_x000D_ frequency of every 12 weeks. If 12 weekly is as effective as 6 weekly treatment, we will then assign_x000D_ participants to have pembro every 9, 15 or 18 weeks. This is needed to enable us to enrol the least_x000D_ number of patients necessary to tell which reduced frequency is best._x000D_ Although we’ll be giving pembro less often than normal to some patients, everyone will have the_x000D_ normal 3 monthly scans. If the cancer is found to be growing, patients receiving less frequent_x000D_ treatment will be returned to the standard treatment. If the cancer is found to be growing for people_x000D_ receiving the standard treatment, study treatment would be stopped and next steps discussed with the_x000D_ local medical team. No other trial in the world is currently testing this important hypothesis for any_x000D_ cancer type. Our results could be ground-breaking and lead to similar trials in multiple other cancer_x000D_ types where pembro has become the standard of care._x000D_ _x000D_ Both trial design and plain English summary have been developed along with patient groups. Patient_x000D_ representatives will also contribute to: (i) management of the trial to ensure patients’ perspectives are_x000D_ considered throughout the study; (ii) developing and participant information resources, e.g. patient_x000D_ information sheets, to ensure ease of understanding and (iii) publication of research findings, e.g. easy_x000D_ to understand reports and lay summaries for use on relevant web pages, e.g. Cancer Research UK,_x000D_ Macmillan and NHS.

Lay abstract: RESEARCH QUESTION: Can pembrolizumab (pembro) dose frequency be reduced without compromising efficacy in advanced non-small cell lung cancer (NSCLC)?_x000D_ _x000D_ BACKGROUND: The anti-PD1 directed monoclonal antibody pembro is now given to ~3600 patients/year with advanced NSCLC in England alone. Treatment continues 6 weekly (wkly) for 2 years (yrs) or until disease progression/unmanageable toxicity. Up to 25% of patients remain on therapy at 2 yrs. However, pharmacodynamics and clinical studies suggest 6 wkly therapy results in overtreatment. Indeed, pembro remains bound to its target on T cells 100 days after a single dose [12], multiple trials have found no relationship between immunotherapy dose and efficacy [13–16] and long lasting anti-tumour and autoimmune effects are observed long after discontinuation [8,9,17,18]. Six wkly administration may therefore be unnecessarily costly, toxic and negatively impact patient quality of life. _x000D_ _x000D_ AIMS AND OBJECTIVES: Our primary goal is to determine the longest dose frequency of pembro with non-inferior survival compared to control 6 wkly therapy. Our secondary goals are to determine the cost, toxicity and quality of life benefits of reduced frequency therapy._x000D_ _x000D_ METHODS: We propose a multicentre, randomised, phase III trial. We will recruit patients from 27-35 UK centres, with advanced NSCLC receiving first line pembro with or without chemotherapy, who are progression free at 6 months and planning to continue treatment. _x000D_ _x000D_ Using a novel DURATIONS design developed for this trial [21], patients will be recruited to control 6 wkly and experimental 9, 12, 15 and 18 weekly pembro arms. The frequency-response relationship will be modelled to determine the longest dose frequency that is non-inferior to control. Patients progressing on an experimental arm will be allowed to re-escalate to 6 wkly therapy. _x000D_ _x000D_ To assess the safety of this intervention, we will initially randomise patients 1:1 to 6 wkly (control) and 12 wkly arms. Once 150 patients are enrolled, an interim safety analysis will be performed. If the 12 wkly arm is not significantly less effective in terms of PFS, the remaining 9, 15 and 18 wkly reduced frequency arms will be opened. Simulation based sample size calculations indicate a requirement for 1750 patients (equally distributed across 5 arms) to identify whether the 18 weekly arm is non-inferior to control with 80% power at an alpha of 5%._x000D_ _x000D_ Our primary outcome measure is landmark survival at 2 yrs post-initiation of pembro. Key secondary outcomes include time-to-event overall survival, progression free survival, quality of life (QoL) and cost savings. Collection of toxicity and quality of life data (using cancer EORTC QLQ C30, lung cancer EORTC QLQ LC13 and EQ-5D-5L questionnaires translated into QALYs) will enable a refined health-economic evaluation._x000D_ _x000D_ TIMELINES: Total duration from setup to closure and publication will be 78 months._x000D_ _x000D_ IMPACT AND DISSEMINATION: Our findings will potentially alter the landscape of NSCLC therapy, translate into significant cost savings for the NHS and health care systems worldwide and positively impact patient QoL. Our unique trial design will serve as a model for future immunotherapy studies a REFINE basket of trials across indications is in setup. Dissemination will be through a range of media including high impact peer-reviewed publication, national and international conference presentation, news media, NHS and departmental social media accounts.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS