Translational analysis and final efficacy of the AVETUX trial - Avelumab, cetuximab and FOLFOX in metastatic colorectal cancer

TY - JOUR

T1 - Translational analysis and final efficacy of the AVETUX trial - Avelumab, cetuximab and FOLFOX in metastatic colorectal cancer

AU - Tintelnot, Joseph

AU - Ristow, Inka

AU - Sauer, Markus

AU - Simnica, Donjete

AU - Schultheiß, Christoph

AU - Scholz, Rebekka

AU - Goekkurt, Eray

AU - von Wenserski, Lisa

AU - Willscher, Edith

AU - Paschold, Lisa

AU - Lorenzen, Sylvie

AU - Riera-Knorrenschild, Jorge

AU - Depenbusch, Reinhard

AU - Ettrich, Thomas J

AU - Dörfel, Steffen

AU - Al-Batran, Salah-Eddin

AU - Karthaus, Meinolf

AU - Pelzer, Uwe

AU - Hinke, Axel

AU - Bauer, Marcus

AU - Massa, Chiara

AU - Seliger, Barbara

AU - Wickenhauser, Claudia

AU - Bokemeyer, Carsten

AU - Hegewisch-Becker, Susanna

AU - Binder, Mascha

AU - Stein, Alexander

N1 - Copyright © 2022 Tintelnot, Ristow, Sauer, Simnica, Schultheiß, Scholz, Goekkurt, von Wenserski, Willscher, Paschold, Lorenzen, Riera-Knorrenschild, Depenbusch, Ettrich, Dörfel, Al-Batran, Karthaus, Pelzer, Hinke, Bauer, Massa, Seliger, Wickenhauser, Bokemeyer, Hegewisch-Becker, Binder and Stein.

PY - 2022

Y1 - 2022

N2 - INTRODUCTION: In metastatic colorectal cancer (mCRC), the efficacy of immune checkpoint blockade (ICB) has so far been limited to patients with microsatellite instability high tumors (MSI-H). Unfortunately, most mCRC patients suffer from non-immunogenic microsatellite stable (MSS) tumors. Therefore, new combinatorial strategies are urgently needed to enhance the immunogenicity of MSS tumors to finally increase the number of patients benefiting from ICB.METHODS: The AVETUX trial aimed to combine the PD-L1 antibody avelumab with the standard of care chemotherapy combination FOLFOX and the anti-EGFR antibody cetuximab. Furthermore, we performed a central radiological review of the pre- and on-treatment computed tomography scans to better define the individual response to treatment.RESULTS AND DISCUSSION: In total, 43 patients were treated of which 39 patients were confirmed as RAS/BRAF wildtype in central tissue review and finally response evaluated. A final progression-free survival (PFS) of 11.1 (range: 0.8 to 22.3 months) and a herein updated final overall survival (OS) of 32.9 months (range: 0.8 to 47.1 months) was reached. We observed a strong median depth of response of 67.5% tumor shrinkage and deepness of response correlated significantly with survival. On the other hand, early tumor shrinkage was not an indicator of better outcome at a cut-off of 20% (median values). In a next step, we correlated the individual best radiological response with potential ICB response biomarkers and found that the clonality and diversity, but not frequency of tumor infiltrating lymphocytes (TiLs) and peripheral blood mononuclear cells (PBMCs), strongly correlated with response. In summary, we report the final overall survival of the AVETUX trial and propose T cell clonality and diversity as a potential marker to predict response to chemo-immunotherapy combinations in MSS mCRC by performing a central radiological review.CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier (NCT03174405).

AB - INTRODUCTION: In metastatic colorectal cancer (mCRC), the efficacy of immune checkpoint blockade (ICB) has so far been limited to patients with microsatellite instability high tumors (MSI-H). Unfortunately, most mCRC patients suffer from non-immunogenic microsatellite stable (MSS) tumors. Therefore, new combinatorial strategies are urgently needed to enhance the immunogenicity of MSS tumors to finally increase the number of patients benefiting from ICB.METHODS: The AVETUX trial aimed to combine the PD-L1 antibody avelumab with the standard of care chemotherapy combination FOLFOX and the anti-EGFR antibody cetuximab. Furthermore, we performed a central radiological review of the pre- and on-treatment computed tomography scans to better define the individual response to treatment.RESULTS AND DISCUSSION: In total, 43 patients were treated of which 39 patients were confirmed as RAS/BRAF wildtype in central tissue review and finally response evaluated. A final progression-free survival (PFS) of 11.1 (range: 0.8 to 22.3 months) and a herein updated final overall survival (OS) of 32.9 months (range: 0.8 to 47.1 months) was reached. We observed a strong median depth of response of 67.5% tumor shrinkage and deepness of response correlated significantly with survival. On the other hand, early tumor shrinkage was not an indicator of better outcome at a cut-off of 20% (median values). In a next step, we correlated the individual best radiological response with potential ICB response biomarkers and found that the clonality and diversity, but not frequency of tumor infiltrating lymphocytes (TiLs) and peripheral blood mononuclear cells (PBMCs), strongly correlated with response. In summary, we report the final overall survival of the AVETUX trial and propose T cell clonality and diversity as a potential marker to predict response to chemo-immunotherapy combinations in MSS mCRC by performing a central radiological review.CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier (NCT03174405).

U2 - 10.3389/fonc.2022.993611

DO - 10.3389/fonc.2022.993611

M3 - SCORING: Journal article

C2 - 36605436

VL - 12

JO - FRONT ONCOL

JF - FRONT ONCOL

SN - 2234-943X

M1 - 993611

ER -