Researchers have evaluated the efficacy of atezolizumab in combination with carboplatin in patients with triple-negative breast cancer, according to a recent study published by Lehmann et al in JAMA Oncology. The new findings may help researchers better understand biomarkers of immunotherapy response.
Background
Immunotherapy plus chemotherapy has become an important therapeutic option for some patients with metastatic breast cancer. Nonetheless, researchers are still uncertain of which patients may benefit the most from it. Current biomarkers used to predict response, such as PD-L1, are not always accurate.
Atezolizumab became the first immunotherapy agent approved for breast cancer following its accelerated approval by the U.S. Food and Drug Administration in 2019. Atezolizumab had been approved for metastatic PD-L1–positive triple-negative breast cancer in combination with the chemotherapy nab-paclitaxel. However, 2 years later, its manufacturer voluntarily withdrew the indication after additional data from a follow-up clinical trial failed to corroborate its efficacy.
“Triple-negative breast cancer is difficult to treat because we don’t have a clear target, and understanding the underlying factors that affect response to a treatment is key. This study is … important because we were able to collect biopsies in all of the participants and really understand factors that affect response,” highlighted co–study author Vandana Abramson, MD, the Donna S. Hall Professor of Cancer Research and Co-Leader of the Breast Cancer Research Program at the Vanderbilt-Ingram Cancer Center.
Study Methods and Results
In the recent phase II clinical trial, the researchers assigned 106 patients with metastatic triple-negative to receive either atezolizumab plus carboplatin or carboplatin alone. The trial was conducted at six cancer centers through the Translational Breast Cancer Research Consortium.
The researchers hypothesized that atezolizumab might have better efficacy with carboplatin because the platinum chemotherapy agent causes structural DNA changes and generates neoantigens that may stimulate an immune response. Conversely, nab-paclitaxel, a microtubule-stabilizing agent, works by preventing cancer cells from dividing into new cells.
The researchers found that the treatment combination was effective at improving progression-free survival from a median of 2.2 months to 4.1 months and overall survival from a median of 8.6 months for controls to 12.6 months for those who received both atezolizumab and carboplatin. Of note, patients with a higher body mass index and uncontrolled blood glucose levels at prediabetic and diabetic levels experienced greater benefit from atezolizumab plus carboplatin. The researchers suggested these patients may have more immune cells upon which anti–PD-1 or anti–PD-L1 therapies can act.
“Both obesity and diabetes are linked to systemic inflammation, and the increased benefit may be attributed to higher adipose tissue composition in the breast and augmented by metabolic syndrome conditions such as type 2 diabetes. Further studies are necessary to validate these findings and delineate the effects of blood glucose and obesity on immunotherapy,” indicated lead study author Brian Lehmann, PhD, Research Associate Professor of Medicine at the Vanderbilt University Medical Center.
A lower risk of disease progression was also associated with high tumor mutational burden and increased tumor-infiltrating lymphocytes.
“The tremendous knowledge gained from our multidisciplinary analyses of the patients and their tumors will continue to be important for clinical decision-making. After our first description of the triple-negative breast cancer subtypes over 10 years ago, more recently, we refined the subtypes further into four, which were analyzed in this study: two basal-like subtypes, a mesenchymal subtype, and a lumen androgen receptor–expressing subtype. When we refined the triple-negative breast cancer subtypes, we revealed an immune-modulatory descriptor or correlation,” explained senior study author Jennifer Pietenpol, PhD, Chief Scientific and Strategy Officer, Executive Vice President for Research, and Professor of Cancer Research at the Vanderbilt University Medical Center.
The researchers reported that the combination therapy was generally well tolerated, and its toxic effects were consistent with previous reports for atezolizumab. The most common side effects in the patients who received both atezolizumab and carboplatin were nausea, fatigue, low blood platelet counts, anemia, lymphocytopenia, and increased liver enzymes.
Conclusions
“In this study, we observed that patients received benefit with atezolizumab, even if the tumors were PD-L1–negative. We also showed that, like prior clinical trials in melanoma and renal and lung cancers, tumors with high mutational burdens and the presence of immune cells within or around the tumors received greater benefit from immunotherapy. This makes sense because each mutation has the potential to be recognized as non-self by the immune system, increasing the probability of immune cells already positioned around the tumor to recognize and target the cancer,” emphasized Dr. Lehmann.
“This … study and others continue to confirm that lymphocytes, as measured by the immune-modulatory correlation, have predictive value for better relapse-free survival for [patients with] triple-negative [breast cancer]. Further, this study provides evidence that the luminal androgen receptor–[expressing] subtype is more like estrogen receptor–positive disease. Prior studies investigating immunotherapy in breast cancers have shown that patients with [estrogen receptor–positive] disease have less benefit from immunotherapy, and we found that to be the case with patients with luminal androgen–positive tumors in this trial,” underscored Dr. Pietenpol. “It is important to highlight that these discoveries would not have been possible without the contributions of [patients with] breast cancer and their willingness to contribute their time and numerous biospecimens to this study. These patients … partnered with oncologists, pathologists, radiologists, basic and translational scientists, and biostatisticians to complete this trial,” concluded Dr. Pietenpol.
Disclosure: The research in this trial was supported by the National Cancer Institute, Susan G. Komen, Genentech, and the Translational Breast Cancer Research Consortium. For full disclosures of the study authors, visit jamanetwork.com.
