Abstract P1-07-30: Phase II adaptive TONIC2 trial to dissect immunomodulatory capacity of doxorubicin or cisplatin induction followed by anti-PD1 in mTNBC

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Abstract Introduction: Anti-PD1 in metastatic triple negative breast cancer (mTNBC) results in modest response rates but can lead to durable responses. Immunomodulatory strategies inducing a more inflamed tumor microenvironment (TME) could enhance response to anti-PD1. The TONIC1 trial explored immune induction strategies in relation to likelihood of response to PD1 blockade. Translational data of TONIC1 and the clinical data according to a pick-the-winner design identified low-dose doxorubicin and cisplatin as promising immune induction strategies [Voorwerk et al, Nat Med 2019]. Here, we present the randomized phase II TONIC2 study independently validating the benefit of using low-dose doxorubicin or cisplatin as induction therapy before the start of anti-PD1 (NCT04159818). Methods: The non-comparative, phase II TONIC2 trial, using Simon’s two-stage design, randomized patients with mTNBC to nivolumab (nivo) with either 2-week low-dose doxorubicin induction (15mg, weekly) or no induction. After completing recruitment of these cohorts, next cohorts randomized to nivo without induction or with 2-week cisplatin induction (40mg/m2, weekly). Primary endpoint was progression-free survival (PFS). Metastatic lesion biopsies were taken at baseline, after induction and on nivo for bulk RNA-Seq, single-cell RNA-Seq and tissue imaging (MIBI, 37 markers), to assess the induction effects on the TME. Results: Among 97 randomized patients, 92 were evaluable for efficacy analyses (n=22 received doxorubicin followed by nivo, n=35 cisplatin followed by nivo, n=35 started directly with nivo without induction). The ORR was 20% in the control arm, 9% in the arm with doxorubicin induction and 9% in the arm with cisplatin induction. Median PFS (iRECIST) was 5.29 weeks (5.00 - 18.71) for patients in the doxorubicin arm, 5.86 weeks (5.14 - 17.00) in the cisplatin arm and 8.71 weeks (5.57 – 12.57) in the control arm. Median OS was similar across arms. The immunomodulatory effects of induction treatments on the TME were studied among all patients included in cisplatin, doxorubicin or control arms in TONIC1 and 2 (doxorubicin n=39, cisplatin n=48, no induction n=47). The control arm for postinduction comparisons consisted of patients who had a 2-week waiting period instead of induction treatment in TONIC1. The immunosuppressive Myc pathway decreased upon nivo compared to baseline in the doxorubicin induction arm (FDR<0.25). Immune checkpoints TIGIT and 4-1BB increased upon nivo after doxorubicin induction. Upon doxorubicin induction, deltas in PD-L1 CD8+ T cells, GLUT1+ CD8 T cells and HLADR+ CD4+ T cells were higher than in the control arm based on tissue imaging using MIBI. In addition, the delta of granulocyte to cancer cell ratio was lower in the doxorubicin arm. Upon induction with cisplatin, we observed an increase in IFNα response (FDR<0.25). The differential gene expression profile of postinduction biopsies showed increased levels of immune checkpoint molecules, MHCI and MHCII, cytokines and T cell markers compared to baseline. Upon nivo after cisplatin induction, we observed an increase in IFNγ, inflammatory response pathways and IL6 signaling compared to baseline (FDR<0.25). Detailed translational analyses, including single-cell RNA-Seq, and outcomes in relation to PDL1 expression will be presented at the meeting. Conclusion: Although exploratory results in the TONIC1 trial suggested a more favorable response rate upon nivo after induction with low-dose doxorubicin or cisplatin, these immune inductions did not result in significantly higher ORR/longer PFS in the independent and larger TONIC2 trial. In-depth translational analyses revealed modest but some favorable changes in the TME after induction with doxorubicin and cisplatin that could be important for future trial design. Citation Format: Marleen Kok, Veerle Geurts, Olga Isaeva, Manon de Graaf, Sara Balduzzi, Leonie Voorwerk, Ferry Lalezari, Michiel de Maaker, Nina Abbott, Iris Nederlof, Noah Greenwald, Thomas van Brussel, Mi He, Elisa Champanhet, Maksim Chelushkin, Ingrid Mandjes, Martine Heuver-Mes, Koen van de Vijver, Inge Kemper, Roberto Salgado, Hugo Horlings, Ton Schumacher, Lodewyk Wessels, Diether Lambrechts, Michael Angelo, Marleen Kok. Phase II adaptive TONIC2 trial to dissect immunomodulatory capacity of doxorubicin or cisplatin induction followed by anti-PD1 in mTNBC [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-07-30.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.