Immune checkpoint inhibitors have not been extensively explored in estrogen receptor-positive breast cancer (ER+ BC). This BC entity is considered to be immunologically “cold”. Therefore, we tested nivolumab (nivo; anti-PD1) and ipilimumab (ipi; anti-CTLA-4) in combination with anthracyclines and low-dose cyclophosphamide, which are reported to provoke immunogenic cell death and to counter immunosuppressive cells.
The trial enrolled patients with ER+ HER-2- metastatic BC and maximum one previous line of chemotherapy after metastasis. Patients were randomized 2:3 into two arms (A:B). Arm A patients received only chemotherapy, i.e. pegylated liposomal doxorubicin (PLD; 20mg/m2 every 2nd week) + cyclophosphamide (cyclo; 50mg/day, 2/4 weeks). Arm B patients received PLD + cyclo + ipi (1mg/kg every 6th week) + nivo (240mg every 2nd week). Descriptive assessments of safety and progression-free survival (PFS) were the primary endpoints. Secondary endpoints included overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR) and biomarkers (PD-L1, immune gene expression, mutation burden). Hazard ratios (HR) are presented with confidence intervals (CI).
82 patients were randomized to arm A (n=33) or arm B (n=49). 46% had not received previous chemotherapy in the metastatic setting. Serious adverse events occurred in 63% of the patients in arm B, versus 39% in arm A. The most common immune related adverse events in arm B were hypothyroidism (45%), hyperthyroidism (22%), hypophysitis (10%) and pneumonitis (8%). Median PFS was 5.1 months in arm B versus 3.7 months in arm A; PFS HR [95% CI] 0.94 [0.59-1.5]. Median OS was 20.9 months versus 19.9 months in arm B and arm A, respectively; OS HR 1.13 [0.65-1.98]. ORR was 32% in arm B versus 29% in arm A. CBR was 55% in arm B versus 48% in arm A. Biomarker analyses and assessments of immunological changes during therapy are ongoing.
The concomitant addition of ipi/nivo to chemotherapy did not show any clear benefit. Patients receiving ipi/nivo had more adverse events, but the toxicity was manageable. Biomarker analyses will be important to determine if further studies on selected subgroups are warranted.
Clinical trial identification
Legal entity responsible for the study
Oslo University Hospital.
Norwegian Health Region South-East, Bristol Myers Squibb.
J.A. Kyte: Other, Institutional, Research Grant: Bristol Myers Squibb, Roche. B. Gilje: Financial Interests, Personal and Institutional, Advisory Board: Daiichi Sankyo, Novartis, Eli Lilly. All other authors have declared no conflicts of interest.