Ipilimumab and nivolumab combined with anthracycline-based chemotherapy in metastatic hormone receptor-positive breast cancer: a randomized phase 2b trial

Abstract

Background: Immune checkpoint inhibitors have shown minimal clinical activity in hormone receptor-positive metastatic breast cancer (HR⁺mBC). Doxorubicin and low-dose cyclophosphamide are reported to induce immune responses and counter regulatory T cells (Tregs). Here, we report the efficacy and safety of combined programmed cell death protein-1/cytotoxic T-lymphocyte-associated protein 4 blockade concomitant with or after immunomodulatory chemotherapy for HR⁺mBC.

Methods: Patients with HR⁺mBC starting first-/second- line chemotherapy (chemo) were randomized 2:3 to chemotherapy (pegylated liposomal doxorubicin 20 mg/m² every second week plus cyclophosphamide 50 mg by mouth/day in every other 2-week cycle) with or without concomitant ipilimumab (ipi; 1 mg/kg every sixth week) and nivolumab (nivo; 240 mg every second week). Patients in the chemo-only arm were offered cross-over to ipi/nivo without chemotherapy. Co-primary endpoints were safety in all patients starting therapy and progression-free survival (PFS) in the per-protocol (PP) population, defined as all patients evaluated for response and receiving at least two treatment cycles. Secondary endpoints included objective response rate, clinical benefit rate, Treg changes during therapy and assessment of programmed death-ligand 1 (PD-L1), mutational burden and immune gene signatures as biomarkers.

Results: Eighty-two patients were randomized and received immune-chemo (N=49) or chemo-only (N=33), 16 patients continued to the ipi/nivo-only cross-over arm. Median follow-up was 41.4 months. Serious adverse events occurred in 63% in the immune-chemo arm, 39% in the chemo-only arm and 31% in the cross-over-arm. In the PP population (N=78) median PFS in the immune-chemo arm was 5.1 months, compared with 3.6 months in the chemo-only arm, with HR 0.94 (95% CI 0.59 to 1.51). Clinical benefit rates were 55% (26/47) and 48% (15/31) in the immune-chemo and chemo-only arms, respectively. In the cross-over-arm (ipi/nivo-only), objective responses were observed in 19% of patients (3/16) and clinical benefit in 25% (4/16). Treg levels in blood decreased after study chemotherapy. High-grade immune-related adverse events were associated with prolonged PFS. PD-L1 status and mutational burden were not associated with ipi/nivo benefit, whereas a numerical PFS advantage was observed for patients with a high Treg gene signature in tumor.

Conclusion: The addition of ipi/nivo to chemotherapy increased toxicity without improving efficacy. Ipi/nivo administered sequentially to chemotherapy was tolerable and induced clinical responses.

Trial registration number: ClinicalTrials.gov Identifier: NCT03409198.

Keywords: Breast Neoplasms; Immune Checkpoint Inhibitors; Ipilimumab; Nivolumab; T-Lymphocytes, Regulatory.

Figure 1

Consolidated Standards of Reporting Trials diagram. The FAS (full analysis set) is a modified intention-to-treat population including all patients starting allocated therapy. The PP (per-protocol) population includes all patients that received the equivalent of at least two treatment cycles and were evaluated for tumor response.CNS, central nervous system

Figure 2

Clinical outcome. Kaplan-Meier plots of (A) PFS and (B) OS in the PP population. HRs are presented with a 95% CI. (C) Swimmer plot of the ipi/nivo-only cross-over arm. (D) Waterfall plot of best change in target lesions in ipi/nivo-only cross-over patients evaluated for response. Dashed lines represent 20% increase and 30% reduction in target lesions. ipi, ipilimumab; iRECIST, immune Response Evaluation Criteria In Solid Tumors; mo, months; nivo, nivolumab; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PP, per-protocol.

Figure 3

Progression-free survival in subgroups. Forest plot of PFS in subgroups of the PP population. PD-L1 expression was assessed by IHC in prestudy biopsies using the SP142 assay. PAM50 subtype, tumor inflammation signature, PD-L1 gene expression and Treg gene signature were obtained from bulk RNA isolation from prestudy biopsies (nCounter BC360 assay). Tumor-infiltrating lymphocytes (TILs) were scored from 0 to 3 on H&E stained slides and categorized as low (0–1) or high (2-3) infiltration. TILs were assessed in pretreatment screening biopsies (N=55) or if not sufficient material the most recent prestudy biopsy available (N=19). HER2 status was based on pathology reports from prestudy biopsies (primary tumors N=31, metastases N=42). HER2 zero defined as IHC 0 and HER2 low defined as either IHC 1+ or IHC 2+ with a negative in situ hybridization assay. HRs are presented with 95% CIs. HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; ipi, ipilimumab; nivo, nivolumab; PD-L1, programmed death-ligand 1; PFS, progression-free survival; PP, per-protocol; Treg, regulatory T cell.

Figure 4

Impact of therapy on the phenotype and frequency of circulating T cells. PBMC from screening and week 8 were assessed for T-cell subsets by flow cytometry in 52 patients (chemo-only N=21, immune-chemo N=31, ipi/nivo cross-over N=11). Absolute cell counts were available from a subset of 41 patients (chemo only N=17, immune-chemo N=24, ipi/nivo cross-over N=10). Fold changes from screening to week 8 were calculated and log2 transformed. Data are presented as mean±SEM. CD4+ and CD8+ T-cell subsets are shown as a percentage of total lymphocytes and regulatory T cells are shown as a percentage of CD4+ T cells. (A) Percentage of T-cell subsets. (B) Absolute cell counts. P values were calculated using the Wilcoxon matched-pairs signed-rank test. Treg, regulatory T cell; ipi, ipilimumab; nivo, nivolumab; PBMC, peripheral blood mononuclear cell.