Clinical challenges: when to add immunotherapy in breast cancer

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

However, researchers are seeking to broaden the indications, particularly in addition to other agents. “Combination therapies have been studied as a way to prime the tumor microenvironment to improve response rates and clinical benefits of these agents,” said Evanthia Roussos Torres, MD, PhD, of the Norris Comprehensive Cancer Center in Los Angeles. MedPage today recently, discussing his presentation at the European Society for Medical Oncology (ESMO) meeting.

“Although the role of immunotherapy has been well established for other cancers such as lung and melanoma, it is only in the past 3 years that IBI has had an impact in the treatment of metastatic breast cancer, ”said Antoinette Tan, MD, MHSc, chief of medical breast oncology at the Levine Cancer Institute in Charlotte.

Two recent FDA approvals have spurred the change.

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 But efficacy concerns have resulted in its fast-track approval status being withdrawn from the FDA, a move some experts have objected to.

In November 2020, the FDA granted fast-track 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 proposing IBI in metastatic breast cancer are in patients whose triple negative tumors express PD-L1, or approximately 40% of patients, as well as in those whose tumor genome has a high tumor mutational burden” , Tan said. “These subgroups have a greater likelihood of responding to immunotherapy.”

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

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

In addition to their established role in TNBC, IBI may have beneficial effects on other subtypes of breast cancer. 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 2-3 years.

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

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

Beyond TNBC, the use of ICI in breast cancer remains limited by modest or disappointing efficacy data in HER2-negative hormone receptor disease, Specht added. Her center currently has a portfolio of breast cancer oncology studies focusing on new treatments that include immunotherapies beyond IBI. “For example, we are looking at adoptive T-cell cell therapy in advanced breast cancer, and my colleagues have also done a lot of work in vaccine development.”

Future therapies could involve PARP inhibitors, adoptive T-cell therapy, interventions in the vascular system to inhibit angiogenesis, and cell cycle inhibitors, Specht explained. Radiation therapy and chemotherapy can also be used to increase the tumor response to IBI.

According to Torres, epigenetic modulation with entinostat, a histone deacetylase inhibitor, could prime the tumor microenvironment and improve the response to ICI. “And our preclinical data supported this growing body of work which revealed that there was an improvement in survival in preclinical models treated with entinostat and anti-PD-1 and anti-CTLA-4”, she declared.

She reported to ESMO on the dose extension cohort of her group of 24 heavily pretreated patients with advanced HER2-negative breast cancer who had never been exposed to IBI. They were treated with a recommended phase II dose, which included 5 mg entinostat per week for a pre-inclusion period of 2 weeks, 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 seen in hormone receptor positive and triple negative subtypes, and the majority of those responses occurred in patients with the disease. triple negative breast cancer. Torres said. One patient had a complete response at the 6 month time point, and the duration of response ranged from less than 2 months at the longest ongoing response to more than 24 months after starting treatment.

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

  • Diana Swift is a Toronto-based freelance medical journalist.


Tan disclosed personal fees as well as funding for clinical trials for his institution from Genentech and Merck.

Specht had no competing interests to declare.

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