1472P - Circulating tumor DNA in unresectable pancreatic cancer is a strong predictor of response to first-line therapy: The KRASCIPANC study

Background

Prognosis of unresectable pancreatic cancer (uPC) remains poor with short overall survival (OS) and no robust predictive marker of response. KRAS mutation is observed in 90% of PCs and GNAS mutation in about 60% still poorly studied. KRAS-mutated circulating tumor DNA (KRAS-mut ctDNA) emerges as prognostic marker but whether ctDNA kinetics is a reliable predictor of response to chemotherapy (CT) remains uncertain. KRASCIPANC study evaluated KRAS-mut ctDNA kinetic as early predictor of response to 1^st line CT in uPCs.

Methods

Sixty-nine patients with uPC, treated with 1^st line CT treatment were included. Blood samples were taken before CT (D0) and at 28 days (D28). Level of circulating-free DNA (cfDNA), KRAS-mut and GNAS-mut ctDNA were determined by digital droplet PCR. Primary endpoint was KRAS-mut ctDNA kinetics between D0 and D28 as predictor of disease control rate (DCR) according to RECIST 1.1 criteria. OS and progression-free survival (PFS) were calculated using the Kaplan Meier method.

Results

Median OS was 11.1 months, median PFS was 6.3 months and DCR was 56.5%. KRAS-mut ctDNA at D0 was detectable in 62.9% of patients with KRAS-mutated tumors. Median allelic frequency (AF) of KRAS-mut ctDNA and GNAS-mut ctDNA was 2.4% (0.1%-63.9%) and 0.12% (0.03%-0.51%) respectively. High AF of KRAS-mut ctDNA at D0 was associated with lower DCR (p<0.001), shorter PFS (p=0.008) and OS (p=0.005). Among the 80.6% GNAS-mutated tumors, 34.0% had GNAS-mut ctDNA (3 patients had GNAS-mut ctDNA without KRAS-mut ctDNA). High AF of GNAS-mut ctDNA was associated with lower DCR (p=0.016) and tended to be associated with shorter PFS (p=0.220) and OS (p=0.260). KRAS-mut ctDNA kinetics between D0 and D28 was associated with DCR (p=0.012), PFS (p=0.016) and OS (p=0.005) but not cfDNA kinetics. In multivariate analysis only KRAS-mut ctDNA remained an independent predictive factor of DCR (p=0.048) and OS (p=0.005).

Conclusions

KRAS-mutated ctDNA kinetics between D0 and D28 was strongly associated with 1^st line CT efficacy in uPC. These promising results need to be confirmed in larger series and especially in a prospective trial using ctDNA kinetic as early marker to start 2^nd line CT before radiological progression.

Clinical trial identification

NCT04560270; 15th november 2019.

Editorial acknowledgement

Legal entity responsible for the study

Pr Tougeron David.

Funding

Has not received any funding.

Disclosure

C. Evrard: Non-Financial Interests, Personal, Other, Congress: Pfizer; Non-Financial Interests, Personal, Other, Congres: Amgen; Financial Interests, Personal, Invited Speaker: Merck. G. Tachon: Financial Interests, Personal, Invited Speaker: Astrazeneca; Financial Interests, Personal, Training: Astrazeneca; Financial Interests, Personal, Training: Roche; Financial Interests, Personal, Training: Glaxosmithline; Financial Interests, Personal, Training: Pfizer. V. Randrian: Financial Interests, Personal, Invited Speaker: Amgen. N. Isambert: Financial Interests, Personal, Invited Speaker: Ipsen; Financial Interests, Personal, Invited Speaker: Transgene; Non-Financial Interests, Personal, Other, Congress: Pfizer; Non-Financial Interests, Personal, Other, Congress: Astrazeneca; Financial Interests, Personal, Expert Testimony: Daichi; Financial Interests, Personal, Expert Testimony: Amgen. L. Karayan Tapon: Financial Interests, Personal, Invited Speaker: Astrazeneca. D. Tougeron: Financial Interests, Personal, Expert Testimony: Amgen; Financial Interests, Personal, Expert Testimony: MSD; Financial Interests, Personal, Expert Testimony: Pierre Fabre; Non-Financial Interests, Personal, Other, Congress: Merck; Non-Financial Interests, Personal, Other, Congress: Roche; Financial Interests, Personal, Sponsor/Funding: Bayer; Financial Interests, Personal, Sponsor/Funding: Ipsen. All other authors have declared no conflicts of interest.