Clinical Challenges: When to Add Immunotherapy in Breast Cancer

For breast cancer patients, the current indications for immune checkpoint inhibitors (ICIs) are generally limited to triple-negative breast cancer (TNBC), both in high-risk early-stage disease or in the advanced setting for tumors with certain levels of PD-L1 expression.

Researchers, however, are looking to expand indications, particularly as an addition to other agents. “Combination therapies have been studied as a way to prime the tumor microenvironment to improve response rates and clinical benefit from these agents,” Evanthia Roussos Torres, MD, PhD, of the Norris Comprehensive Cancer Center in Los Angeles, told MedPage Today recently, in discussing her presentation from the European Society for Medical Oncology (ESMO) meeting.

“While the role of immunotherapy has been well established for other cancers such as lung and melanoma, it’s only in the last 3 years that ICI has made an impact in metastatic breast cancer treatment,” said Antoinette Tan, MD, MHSc, chief of Breast Medical Oncology at the Levine Cancer Institute in Charlotte.

Two recent FDA approvals spurred the shift.

In March 2019, atezolizumab (Tecentriq) became the first ICI to receive a breast cancer-specific approval. In combination with the chemotherapy nab-paclitaxel (Abraxane), atezolizumab was given the green light for patients whose triple-negative tumors express PD-L1. The move was based on a significant improvement in progression-free survival over nab-paclitaxel alone after an interim analysis of data from the IMpassion130 trial. The combination of atezolizumab and nab-paclitaxel was sanctioned for patients with unresectable locally advanced or metastatic TNBC. But efficacy concerns resulted in the withdrawal of its accelerated FDA approval status, a move some experts opposed.

In November 2020, the FDA granted accelerated approval to pembrolizumab (Keytruda) in combination with chemotherapy for patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1.

“The clinical indications for offering ICIs in metastatic breast cancer are in patients whose triple-negative tumors express PD-L1, which is about 40% of patients, and also those whose tumor genome has a high tumor mutational burden,” said Tan. “These subgroups have a greater likelihood of responding to immunotherapy.”

The national ASCO TAPUR basket study recently showed that about 21% of metastatic breast cancers with high tumor mutational burden responded to pembrolizumab.

Currently, ICIs combined with chemotherapy is a standard first-line treatment of patients with metastatic TNBC that can present as de novo or recurrent disease, Tan added.

Apart from their established role in TNBC, ICIs may have benefit in other breast cancer subtypes. Ongoing phase III trials, for example, are testing whether adding immunotherapy to standard anti-HER2 treatments may have a possible benefit in advanced HER2-positive disease, she said. Results are expected in 2 to 3 years.

“I believe there is a role for immunotherapy combined with chemotherapy, and it is currently integrated into our treatment pathway for metastatic TNBC,” Tan said. “Despite slower progress compared to other solid tumors, there’s real excitement about immunotherapy in breast cancer, and I look forward to seeing the field continue to evolve to expand the treatment options for our patients.”

According to Seattle Cancer Care Alliance oncologist Jennifer Specht, MD, an associate professor at the University of Washington School of Medicine and Fred Hutchinson Cancer Research Center, the biggest challenge facing clinicians is understanding the complexities of the immune system in order to identify patients who will benefit from ICIs and to make these treatments more effective. “Although we have some indications, many patients do not respond to ICIs and most who do develop resistance,” she told MedPage Today.

Beyond TNBC, the use of ICIs in breast cancer remains limited by modest or disappointing efficacy data in hormone receptor-positive, HER2-negative disease, Specht added. Her center currently has a portfolio of breast cancer oncology studies looking at new treatments that include immunotherapies beyond ICIs. “For example, we’re looking at cellular adoptive T-cell therapy in advanced breast cancer, and my colleagues have also done a lot of work in vaccine development.”

Future therapies may involve PARP inhibitors, cellular adoptive T-cell therapy, interventions in the vasculature to inhibit angiogenesis, and cell cycle inhibitors, Specht explained. Radiation and chemotherapy may be used to augment the tumor’s response to ICIs as well.

According to Torres, epigenetic modulation with entinostat, a histone deacetylase inhibitor, might prime the tumor microenvironment and improve response to ICIs. “And our preclinical data supported this growing body of work that found that there was improved survival in preclinical models that were treated with entinostat and anti-PD-1 and anti-CTLA-4,” she said.

She reported at ESMO on her group’s dose expansion cohort of 24 heavily pretreated patients with advanced HER2-negative breast cancer and no previous exposure to an ICI. They were treated with a recommended phase II dose, which included 5 mg of weekly entinostat for a 2-week run-in period, and then 3 mg/kg of nivolumab (Opdivo) every 2 weeks and 1 mg/kg of ipilimumab (Yervoy) every 6 weeks.

“So the exciting part of our presentation noted an objective response rate of 30%, with the response observed in both hormone-receptor positive and triple-negative subtypes, and the majority of these responses occurred in patients with triple-negative breast cancer,” Torres said. One patient had a complete response at the 6-month timepoint, and the duration of response ranged from less than 2 months to the longest response ongoing at greater than 24 months after initiation of treatment.

Data such as these will likely support an expanded role for ICIs and other immunotherapies in metastatic breast cancer treatment. “As we learn more about the immune system and the microenvironment in which tumors exist, these key components will help us to design more elegant and thoughtful trials of ways to augment the benefits already observed with ICIs and other immunotherapies,” Specht said.