180P - FIRE-6: Longitudinal immune profiling identified disturbed NK cell functionality in RAS/BRAF wild-type metastatic colorectal cancer patients and during combined treatment with FOLFIRI, cetuximab followed by avelumab maintenance

Background

The multi-centre, single-arm FIRE-6 study tested the efficacy of avelumab maintenance after induction therapy with FOLFIRI plus cetuximab (FOLFIRI/Cet) in the 1st-line treatment of RAS/BRAF wild-type metastatic colorectal cancer (mCRC) patients. Here, we aimed to assess longitudinal immune dynamics in order to identify dysregulations and potential biomarkers of response.

Methods

Blood samples and isolated PBMCs from 52 patients prior to therapy initiation, after one or four cycles of FOLFIRI/Cet or after one additional cycle of combination therapy also containing avelumab and 10 age-matched healthy donors underwent multi-parameter flow cytometry and in vitro stimulation for comprehensive immune profiling and assessment of NK cell functionality.

Results

Longitudinal assessment of 172 immune parameters revealed that the FIRE-6 regime mainly induced changes in populations, which resemble an enhanced activation of T- and NK cells. However, in vitro co-culture assays identified disturbed NK cell mediated ADCC, induction of activation markers and degranulation of NK cells from mCRC patients and during the course of the FIRE-6 therapy. Increased levels of PD1+ NK cells and diminished lysis of PDL1-expressing CRC cells by NK cells from mCRC patients suggest the involvement of the PD1-PDL1 axis in reduced NK functionality. Despite hampered NK cell functionality, a high baseline frequency of cytotoxic CD56dim NK cells was still associated with improved progression-free survival.

Conclusions

The FIRE-6 regime induced profound immune alterations accompanied by impaired NK cell functionality. While presence of cytotoxic NK cells correlated with improved response, reversal of cancer- and therapy-induced NK cell dysfunctions might serve as a strategy to improve anti-cancer immunotherapies.

Clinical trial identification

Protocol code: FIRE-6, EudraCT 2018-002010-12.

Editorial acknowledgement

Legal entity responsible for the study

Klinikum der Universität München.

Funding

Merck KGaA, Darmstadt.

Disclosure

S. Stintzing: Financial Interests, Personal, Advisory Board: Amgen, Bayer, BMS, Eisai, Lilly, Merck KGaA, MSD, Pierre Fabre, Roche, Sanofi, Servier, Taiho, Takeda; Financial Interests, Personal, Invited Speaker: Amgen, Bayer, BMS, Eisai, Leo Pharma, Lilly, Merck KGaA, MSD, Pierre Fabre, Roche, Sanofi, Servier, Taiho, Takeda; Financial Interests, Institutional, Research Grant: Merck KGaA, Pierre Fabre, Servier, Roche. J. von Einem: Financial Interests, Personal, Expert Testimony: AstraZeneca; Financial Interests, Personal, Advisory Board: BMS, Eisai, Lilly, Bayer, Merck KGaA, Pierre Fabre, Roche, Sanofi, Servier, Taiho. D.P. Modest: Financial Interests, Personal, Invited Speaker: Merck Serono, Amgen, Servier, BMS, Taiho, Merck Sharp & Dohme, Pierre Fabre, Takeda, Onkowissen, Sanofi, Lilly, AstraZeneca, Incyte; Financial Interests, Personal, Advisory Role: Merck Serono, Amgen, Merck Sharp & Dohme, Roche, Servier, Incyte, BMS, Pierre Fabre, Lilly, Cor2Ed, IQVIA, Onkowissen; Financial Interests, Institutional, Research Funding: Amgen, Servier. V. Heinemann: Financial Interests, Personal, Expert Testimony: Merck, Amgen, Roche, Sanofi, Sirtex, Servier, Pfizer, Pierre Fabre, AstraZeneca; Financial Interests, Invited Speaker: Merck, Amgen, Roche, Sanofi, Sirtex, BMS, MSD, Novartis, Boehringer Ingelheim, Servier, Pierre Fabre, Celgene, Terumo; Financial Interests, Institutional, Research Grant: Merck, Amgen, Roche, Sanofi, Pfizer, Boehringer Ingelheim, Sirtex, Bayer, Servier. I. Na: Financial Interests, Institutional, Research Funding: BMS, Shire/Takeda, Novartis, Octapharma. All other authors have declared no conflicts of interest.