Data from the ALICE trial published in Nature Medicine

The randomized, placebo-controlled ALICE trial investigated the effect of treating metastatic triple-negative breast cancer patients with a combination of the immune checkpoint inhibitor atezolizumab and chemotherapy. Conclusions from this trial, led by Jon Amund Kyte at Oslo University Hospital (OUH), have now been published in Nature Medicine in an article titled “Atezolizumab plus anthracyclin-based chemotherapy in metastatic triple-negative breast cancer: the randomized, double-blind phase IIb ALICE trial”.

Patients with metastatic triple-negative breast cancer have a poor prognosis with a median survival of approximately one year. The current treatment options are limited, and there is a need to find new treatment options. In the ALICE trial, altogether 70 patients were enrolled at three university hospitals in Norway (OUH, Stavanger University Hospital and St. Olavs Hospital) as well as at two Centres in Denmark (Rigshospitalet, Vejle Hospital).

Whereas immune checkpoint inhibitors (ICIs) targeting PD1 / PD-L1 are effective drugs against metastatic disease in many cancers, they have limited efficacy against metastatic triple-negative breast cancer when given as a monotherapy. Previous studies using immune checkpoint inhibitors in combination with chemotherapy have resulted in conflicting findings, and there is a need to better understand how the activity of immune checkpoint inhibitors is affected by chemotherapy. Furthermore, no effect of combining immune checkpoint inhibitors and chemotherapy has so far been reported for PD-L1 negative metastatic triple-negative breast cancer, which make up a large proportion of the patients.

The ALICE trial investigated the safety and efficacy of adding atezolizumab (anti PD-L1) to pegylated liposomal doxorubicin (PLD) combined with low-dose metronomic cyclophophamide. The chemotherapy was selected based on an assumption that it may trigger sensitivity of immune checkpoint inhibitors in patients that are otherwise non-responsive, while also being adequate as standard treatment. The study allowed inclusion of patients both with and without PD-L1 expression in their tumors to investigate both population’s response to PD-L1 blockade in the described setup. Primary endpoints in ALICE were descriptive assessment of progressive-free survival and safety.

ALICE is the first randomized trial in metastatic triple-negative breast cancer investigating the addition of an immune checkpoint inhibitor to anthracyclines, although anthracyclines are widely used for this disease. Jon Amund Kyte explains that the aim was to explore the selected combination due to the perceived immunogenic properties of anthracyclines, the avoidance of steroids by using PLD as well as the reported effects on regulatory T cells from low-dose cyclophosphamide.  

The study indicates that adding atezolizumab to PLD and low-dose cyclophosphamide improved the progression-free survival in patients with metastatic triple-negative breast cancer. The progression-free proportion after 15 months was 15% in the atezolizumab-chemo arm versus 0% in the placebo-chemo arm. Importantly, a benefit was also indicated in patients with PD-L1 negative disease, with a hazard ratio of 0.57. Moreover, the combination therapy was tolerable and no new safety signals were identified. Patient-reported outcomes indicated that the patients in the atezolizumab-chemo arm had a better quality of life. The study also investigated biomarkers for personalized therapy and identified immune signatures in tumor biopsies and in blood samples that if validated in independent studies, may be used for selecting patients likely to benefit fromatezolizumab.  

Kyte says that the findings from ALICE are consistent with the concept that immune checkpoint inhibitors may synergize with selected immune-stimulating chemotherapy.

“This trial was a small, randomized study, but the results provide a basis for future investigations in larger metastatic triple-negative breast cancer cohorts. The findings also suggest that similar immunomodulatory chemotherapies may be considered in combination with immune checkpoint inhibitors in other cancer forms”, says Kyte.

“We are grateful to all the patients who agreed to enroll in the trial, and of course delighted that our efforts and findings from this study are now acknowledged by Nature Medicine. We look forward to continuing our work within this field”, says Jon Amund Kyte.

The sponsor of the ALICE trial was Oslo University Hospital, and Sigbjørn Smeland, head of the Cancer Clinic at OUH, says that this is a very important study for several reasons.

“Firstly, the results are promising for a patient group that we currently have too little to offer. Secondly, the study points to a principle about the usefulness of combining immunotherapy with chemotherapy, which should also be tested for other forms of cancer. Finally, it demonstrates the strength of a well-designed randomized trial with associated laboratory projects”, says Sigbjørn Smeland.

The trial was supported with free drug and a funding contribution from Roche, and by grants from the Norwegian Cancer Society, the Norwegian Breast Cancer Society and the South-Eastern Norway Regional Health Authority.

Jon Amund Kyte is an oncologist and has broad expertise in clinical studies. In addition to heading the Department of Clinical Cancer Research and his own research group, Jon Amund Kyte is also in the management team of MATRIX, the Norwegian Centre for Clinical Cancer Research.

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