82P - Cyclic fasting-mimicking diet as a strategy to improve the efficacy of standard antitumor therapies in cancer patients

Background

Preclinical studies showed that nutrient starvation, in the form of cyclic fasting or fasting-mimicking diet (FMD), sensitizes cancer cells to the antitumor effect of cytotoxic agents and boosts antitumor immunity. These effects are in part mediated by the reduction of blood glucose, insulin and IGF-1 concentration, and by the inhibition of the IGF1-IGF1R axis in tumor cells.

Methods

We conducted a prospective phase Ib clinical trial (NCT03340935) to assess the safety, feasibility and biological effects of a cyclic, 5-day, calorie-restricted, low-carbohydrate, low-protein FMD regimen in a heterogeneous population of cancer patients (pts), and a window-of-opportunity trial (DigesT trial, NCT03454282), in pts with early-stage breast cancer (BC) or melanoma to investigate the immunological effects of a single FMD cycle before surgery.

Results

In 101 pts enrolled in the NCT03340935 trial, and in 22 BC pts included in an interim analysis of the DigesT trial, cyclic FMD was safe, and feasible, and patient compliance was excellent. In addition, the FMD reduced plasma glucose, insulin and IGF-1 concentration and lowered expression/activation of IGF1R in tumor cells. These changes were paralleld by desirable immunologic modifications, including a reduction of circulating immunosuppressive myeloid cells and an increase in activated/cytotoxic T cells and memory T cells at both peripheral blood and tumor levels. Five complete and long-lasting tumor responses were observed in pts with extensive-stage small cell lung cancer (ES-SCLC), advanced pancreatic cancer, metastatic triple-negative BC (TNBC) and metastatic colorectal cancer.

Conclusions

Cyclic FMD may increase the efficacy of standard anticancer therapies. Based on these results we are going to present our next 2 prospective studies: 1) a monocentric, single-arm, phase 2 trial “FASTIMMUNE” to investigate the antitumor efficacy of maintenance atezolizumab plus cyclic FMD in pts with ES-SCLC after 4 cycles of induction chemo-immunotherapy, and 2) the multicentric, open-label, randomized, phase 2 trial “BREAKFAST-2” to investigate if cyclic FMD improves the antitumor activity of neoadjuvant chemoimmunotherapy in patients with stage II/III TNBC.

Clinical trial identification

NCT03340935; NCT03454282.

Editorial acknowledgement

Legal entity responsible for the study

F.G.M. De Braud.

Funding

Associazione Italiana per la Ricerca sul Cancro (AIRC); European Union Framework Program Horizon 2020.

Disclosure

F.G.M. De Braud: Financial Interests, Personal, Invited Speaker: BMS, Healthcare Research & Pharmacoepidemiology, Merck Group, MSD, Pfizer, Servier, Sanofi, Roche, Amgen, Incyte, Dephaforum, Seagen, Novartis, F.Hoffmann-LaRoche Ltd, BMS, Ignyta Operating INC, Merck Sharp & Dohme Spa, Kymab, Pfizer, Tesaro, MSD, MedImmune LCC, Exelixis Inc, Loxo Oncology Incorporated, Daiichi Sankio Dev. Limited, Basilea Pharmaceutica International AG, Janssen-Cilag International NV, Merck KGAA; Financial Interests, Personal, Other, Consultant Advisory Board: Roche, EMD Serono, NMS Nerviano Medical Science, Sanofi, MSD, Novartis, Incyte, BMS, Menarini, AstraZeneca, Pierre Fabre. G. Pruneri: Financial Interests, Personal, Invited Speaker: Roche, Lilly, Exact Sciences, Novartis; Financial Interests, Personal, Advisory Board: Exact Sciences, ADS Biotec; Financial Interests, Institutional, Research Grant: Roche. L. Rivoltini: Financial Interests, Personal, Invited Speaker, Teaching in educational events: BMS; Non-Financial Interests, Personal, Advisory Role: DKTK. All other authors have declared no conflicts of interest.