CRUK/22/014: KETO-Lung: assessing the impact of the adoption of a continuous ketogenic diet on the efficacy of combination chemo-immunotherapy using paclitaxel/carboplatin/pembrolizumab in advanced squamous cell cancer of the lung

Background Lung cancer is the commonest cause of cancer death in the UK. Squamous cell lung cancer (LUSC) accounts for 9000 deaths/annum.

Whilst targeted therapy has significantly improved outcomes in non-squamous lung cancer, stratification by genomic aberration has had no impact in LUSC.

In PS0/1 patients receiving first-line chemo-immunotherapy median OS remains below 18 months with little more than 1/3 surviving beyond 2-years.

Aims • To develop a novel therapy approach in LUSC through targeting the unique metabolic vulnerability of LUSC in order to improve outcomes in this disease. • To assess whether the addition of a ketogenic diet (KD) to chemo-immunotherapy to target the glycolytic dependency in LUSC is acceptable/tolerated by people with LUSC. • To assess whether KD leads to the induction of ketosis and beneficial changes in cancer metabolism. • To assess effects of KD plus chemo-immunotherapy in LUSC on quality of life, clinical efficacy and adverse events.

Methods We propose a single-arm phase II trial of KD added to standard of care chemo-immunotherapy, namely paclitaxel/carboplatin/pembrolizumab. Implementation of 12 weeks of KD will cover all 4 cycles of chemotherapy plus anti-PD-1.

Key outcomes are compliance to maintain KD for 6 and 12 weeks, ketosis at 6 and 12 weeks, quality of life, objective response, durable clinical benefit, progression-free survival time, overall survival time and adverse events.

We will analyse the metabolism of glucose and 3HB to assess appropriate target engagement and how it affects tumour metabolism using either 13C-enriched glucose (13C-[U]-glucose) or 13C-enriched BHB (13C-[U]-3-hydroxybutyrate). 13C incorporation into blood and tumour metabolites will allow monitoring of the change in tumour metabolism elicited by KD and whether it has altered ‘addiction’ to glucose in LUSC.

How this research will be used These results will provide unique insights into the acceptability, metabolic and clinical efficacy of dietary manipulation to target a metabolically vulnerable cancer. They will inform the feasibility and likely success of transitioning this concept into the randomised setting.