Abstract PD11-11: PD11-11 Results from ALICE – Atezolizumab Combined with Immunogenic Chemotherapy in Patients with Metastatic Triple Negative Breast Cancer, a Randomized Phase IIb Trial

Abstract Background: Immune checkpoint inhibitors (CPI) have shown efficacy against metastatic triple negative breast cancer (mTNBC), but only for PD-L1 positive tumors. It is not known if so-called immunogenic chemotherapies may yield clinical relevant synergies with CPI. We addressed these issues, by conducting a trial evaluating atezolizumab (anti-PD-L1) in combination with doxorubicin, which has been reported to provoke immunogenic cell death, and low-dose metronomic cyclophosphamide, which has been reported to counter immunosuppressive cells. The pegylated liposomal form of doxorubicin (PLD) was selected to avoid steroids and allow for long term therapy in responders. To our knowledge, this is the first randomized trial reporting on the concomitant addition of CPI to antracyclines in mTNBC. Methods: The trial enrolled patients with mTNBC and maximum one previous line of chemotherapy in the metastatic setting. Patients were randomized 2:3 into arm A (n=28), receiving chemotherapy alone, or arm B (n=40), receiving chemotherapy in combination with atezolizumab (840 mg every 2nd week). The chemotherapy consisted of PLD (20mg/m2 every 2nd week) + oral cyclophosphamide (cyclo; 50mg/day, 2/4 weeks) in both arms. The per protocol (PP) population was defined as patients receiving > 3 doses of atezolizumab and >2 doses of PLD. The primary efficacy endpoint was progression-free survival (PFS) in the PP population. The protocol power analysis focused on durable response, as measured by 15 months PFS. Safety, a co-primary endpoint, was evaluated in all patients that started therapy (Full Analysis Set; FAS). Secondary endpoints included PFS in FAS, objective response rate (ORR), clinical benefit rate (CBR), durable response rate (>6 months; DRR), overall survival (OS) and biomarkers. PD-L1 status was determined retrospectively by the Ventana SP142 assay, as tumor-infiltrating immune cells with cut-off ≥ 1%. Efficacy data are given in the PP population unless stated otherwise. Hazard ratios (HR) are given with 95% confidence intervals (CI). Results: A total of 68 patients started therapy (FAS), of which 59 were in the PP population and 57% had not received previous chemotherapy in the metastatic setting. PFS was significantly improved in arm B compared to arm A in both the PP population (HR 0.57; CI 0.33-0.99; p=0.0477) and in the FAS (HR 0.56; CI 0.33-0.95; p=0.0326). Median PFS was 4.3 months in arm B versus 3.5 months in arm A. The progression-free proportion after 15 months was 14.7% (CI 6.4-30.1%) in arm B versus 0% in arm A. The ORR was 30.6%/21.7%, CBR was 52.8%/43.5% and DRR was 13.9%/4.3% in arm B/A. The PFS advantage was observed for both PD-L1+ (n=27; HR 0.58) and PD-L1- subjects (n=31; HR 0.66). All five patients without progression after 15 months belonged to arm B, and three out of these patients were PD-L1 negative. Serious adverse events occurred for 48% in arm B and 29% in arm A (FAS). The most common immune related adverse events of any grade in arm B/A were hypothyroidism (10.0%/7.1 %), pneumonitis (10.0%/3.6%), hyperthyroidism (5.0%/7.1%) and rash (7.5%/3.6%). Further biomarker analyses and assessments of immunological changes during therapy are ongoing. Conclusions: The addition of atezolizumab to PLD and low-dose metronomic cyclophosphamide significantly improved PFS. A benefit was indicated also in patients with PD-L1 negative disease. The combination regimen was well tolerated with no new safety signals. Results from the ongoing analyses of consecutive tumor and blood samples will be important to assess the hypothesized immunological effects of the chemotherapy and to investigate biomarkers associated with the response to the combined treatment. Citation Format: Jon Amund Kyte, Andreas H. Røssevold, Nikolai K. Andresen, Christina Annette Bjerre, Bjørnar Gilje, Erik Hugger Jakobsen, Sunil Xavier Raj, Ragnhild Sørum Falk, Elin Borgen, Thea Jahr, Øystein Garred, Jon Lømo, Randi Margit Mathiesen, Bjørn Naume. PD11-11 Results from ALICE – Atezolizumab Combined with Immunogenic Chemotherapy in Patients with Metastatic Triple Negative Breast Cancer, a Randomized Phase IIb Trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD11-11.