Low TMB as predictor for additional benefit from neoadjuvant immune checkpoint inhibition in triple-negative breast cancer.

Journal of Clinical Oncology, vol. 40, pp. 581

Abstract

581 Background: It is commonly anticipated that a high tumor mutational burden (TMB) is a predictor of response to immune checkpoint blockade (ICB). We previously showed that triple-negative breast cancer (TNBC) from the GeparNuevo study with high TMB displayed increased response both to neoadjuvant chemo-ICB with durvalumab but also to chemotherapy alone, with no significant interaction with treatment arm (Karn et al. Ann Oncol 2020). In contrast, we also observed that cases with very low TMB more often displayed a pCR after treatment with chemo-ICB than with chemotherapy alone. This may in fact suggest a benefit of ICB to those TNBC with rather low TMB. Methods: We have analyzed the distant disease-free survival (DDFS) of GeparNuevo patients according to TMB and treatment arm (neoadjuvant chemotherapy plus durvalumab or chemotherapy plus placebo). For TMB (mut/Mb) we applied the identical cutoff of the upper tertile as in our previous analysis. Results: The median follow-up of the time-to-event data was 43.7 months. Data of TMB was available in 149 of 174 patients. We found that within the high-TMB tumors (durvalumab: n=27; placebo: n=23), DDFS was similar between both arms of the trial (durvalumab vs. placebo: HR (hazard ratio) 0.95 [95%CI 0.19-4.69], p=0.95). Strikingly however, within the low-TMB group (durvalumab: n=47; placebo: n=52) we observed a significantly better DDFS in the durvalumab-chemotherapy combination arm, in contrast to the arm treated only with chemotherapy (durvalumab vs. placebo: HR 0.23 [95%CI 0.06-0.79], p=0.02; interaction test for TMB and treatment arm p=0.17). The observation was also robust to alternative TMB cutoffs. Similar results were obtained for invasive disease-free survival. Conclusions: Our results show, in contrast to other published data, that patients with early TNBC and low TMB/neoantigen counts may benefit from short-term neoadjuvant durvalumab treatment, while for those with high TMB, durvalumab plus chemotherapy does not improve efficacy over chemotherapy alone.

Authors 18

1. Thomas Karn

   Goethe University Frankfurt

   Affiliation as printed

   Goethe-Universität Frankfurt, UCT-Frankfurt-Marburg, Frankfurt, Germany;

2. Carsten Denkert

   Philipps University of Marburg

   Affiliation as printed

   Institute of Pathology, Philipps-University Marburg and University Hospital Marburg, Marburg, Germany;

3. Julia Rey

   German Breast Group

   Affiliation as printed

   German Breast Group (GBG), Neu-Isenburg, Germany;

4. Karsten Ernst Weber

   German Breast Group

   Affiliation as printed

   German Breast Group (GBG), Neu-Isenburg, Germany;

5. Uwe Holtrich

   Goethe University Frankfurt

   Affiliation as printed

   Goethe-Universität Frankfurt, UCT-Frankfurt-Marburg, Frankfurt, Germany;

6. Claus Alexander Hanusch

   Rotkreuzklinikum München

   Affiliation as printed

   Gynäkologie, Rotkreuzklinikum München, München, Germany;

7. Bruno Valentin Sinn

   Charité - Universitätsmedizin Berlin

   Affiliation as printed

   Institute of Pathology, Charité-Universitätsmedizin Berlin, Berlin, Germany;

8. Paul Jank

   Philipps University of Marburg · Universitätsklinikum Gießen und Marburg

   Affiliation as printed

   Institute of Pathology, Philipps University Marburg and Marburg University Hospital (UKGM),, Marburg, Germany;

9. Jens Huober

   Kantonsspital St. Gallen

   Affiliation as printed

   Kantonsspital St.Gallen, Brustzentrum, Departement Interdisziplinäre medizinische Dienste, St.Gallen, Switzerland;

10. Jens‐Uwe Blohmer

    Charité - Universitätsmedizin Berlin

    Affiliation as printed

    Gynäkologie mit Brustzentrum, Charité-Universitätsmedizin Berlin, Berlin, Germany;

11. Wolfgang Schmitt

    Charité - Universitätsmedizin Berlin

    Affiliation as printed

    Institute of Pathology, Charité-Universitätsmedizin Berlin, Berlin, Germany;

12. Marion van Mackelenbergh

    University Hospital Schleswig-Holstein

    Affiliation as printed

    Universitätsklinikum Schleswig-Holstein, Klinik für Gynäkologie und Geburtshilfe, Schleswig-Holstein, Germany;

13. Christian Schem

    Mammazentrum Hamburg · Krankenhaus Jerusalem

    Affiliation as printed

    Krankenhaus Jerusalem, Mammazentrum Hamburg, Hamburg, Germany;

14. Elmar Stickeler Aachen Klinik für Gynäkologie und Geburtsmedizin

    Universitätsklinikum Aachen

    Affiliation as printed

    Klinik für Gynäkologie und Geburtsmedizin, Uniklinik Aachen, Aachen, Germany;

15. Christian Jackisch

    Sana Klinikum Offenbach

    Affiliation as printed

    Sana Klinikum Offenbach, Offenbach, Germany;

16. Michael Untch

    Helios Hospital Berlin-Buch

    Affiliation as printed

    Department of Gynecology and Obstetrics, Helios Klinikum Berlin-Buch, Berlin, Germany;

17. Andreas Schneeweiß

    German Cancer Research Center · National Center for Tumor Diseases

    Affiliation as printed

    Nationales Centrum für Tumorerkrankungen, Universitätsklinikum und Deutsches Krebsforschungszentrum, Heidelberg, Germany;

18. Sibylle Loibl

    German Breast Group

    Affiliation as printed

    German Breast Group, Neu-Isenburg, Germany;