Dose Tapering and Early Discontinuation to InCreAse cosT-effectIveness Of Immunotherapy for Non-small Cell Lung Carcinoma

1. INTRODUCTION AND RATIONALE

1.1 General introduction The recent introduction of immune checkpoint inhibitors (ICI) has dramatically changed treatment and prognosis of metastasized non-small cell lung carcinoma (NSCLC). Depending on the type of treatment, the line of treatment and tumour characteristics, response rates of 20 to over 60% are shown, and durable responses are seen. However, the accessibility to novel cancer treatments in The Netherlands is at serious risk due to the rising incidence of cancer as well as the exponentially increasing costs of these new and effective drugs. As an example, the yearly costs for treatment of metastasized NSCLC with Pembrolizumab single agent therapy in the Netherlands was estimated to be 27 million euro in 2018. With the recent new indications in the first line treatment in lung cancer alone this sum is surpassed by at least a four-fold. With ever increasing strains on healthcare budgets, we have a societal responsibility to decrease treatment costs wherever possible. Furthermore, for the individual patient it is very relevant to offer a treatment only if it is effective. By investing in a more tailored treatment we intend to personalize treatment, thereby allowing significant cost-reduction, without reducing the promise that all these new treatment options hold for the individual patients. For the individual patient we have the responsibility to expose patients to no more drug than strictly necessary and to limit the number of hospital visits.

1.2 Immune checkpoint inhibitors ICI have revolutionized systemic treatment of many malignancies. By targeting the programmed death (ligand)-1 (PD-1/PD-L-1) axis with specific ICI's, T-cell tolerance can be overcome and cellular immune response to tumour cells is boosted. In contrast to previous treatment modalities, ICI are able to induce durable responses thereby improving overall survival in NSCLC. In 2015, nivolumab was the first PD1 monoclonal antibody that showed a clinically relevant efficacy in patients with metastasized disease. Since then, many phase III trials have shown positive results thereby improving both progression free and overall survival in patients with advanced and or metastasized disease. ICI's have been introduced rapidly in The Netherlands and the efficacy results of real-life data are comparable to those from phase 3 trials. Both PD1 and PDL1 monoclonal antibodies are currently approved for the treatment of NSCLC and, at present, the vast majority of patients fit for systemic treatment will receive a form of ICI.Currently, pembrolizumab forms the mainstay first line therapy for metastasized NSCLC. We expect that in the Netherlands approximately 2500-3000 NSCLC patients will be treated with an immune checkpoint inhibitor on a yearly basis, with pembrolizumab as the cornerstone in treatment.

1.3 Dose tapering of immune checkpoint inhibitors There are no known exposure-toxicity relationships for pembrolizumab and usually dosing regimens are usually developed for prescriber's convenience, i.e. as a one-dose-fits-all regimen. During clinical phase development a dose is selected that will result in therapeutic exposure in all patients, indicating that in the majority of patients pembrolizumab is overdosed.

1.4 Pembrolizumab dose tapering rationale As pembrolizumab will be the main ICI for NSCLC in the upcoming years, we focus on pembrolizumab in the current study. We postulate that the approved dose of pembrolizumab (200 mg every three weeks [Q3W] or 400 mg every 6 weeks [Q6W]) can be decreased to a 300 mg dose Q6W or 100 mg dose Q3W without compromising efficacy.