Expert Discusses State of Immunotherapy in Breast Cancer Subtypes

Sylvia Adams, MD

The future of immunotherapy in the landscape of triple-negative breast cancer (TNBC) may lie in combinations, according to Sylvia Adams, MD.

Single-agent immunotherapy has demonstrated a modest clinical response in pretreated patients. The findings of the phase II KEYNOTE-086 trial showed that pembrolizumab (Keytruda) had antitumor activity in patients with heavily pretreated metastatic TNBC, with an overall response rate of 4.7% (95% CI, 2.3-9.2) as a single agent.¹

Additionally, atezolizumab (Tecentriq) monotherapy has been explored in women with metastatic TNBC in the frontline and pretreated setting. In a phase I trial, the 2-year overall survival rate of 47% in the frontline setting.²

Immunotherapy is also making an impact in metaplastic breast cancer, and the subtype is now included as an arm in the SWOG DART trial.

In an interview with OncLive during the PER^® 16th Annual International Congress on the Future of Breast Cancer^® (East), Adams, associate professor, Department of Medicine, director, Clinical Research, Breast Cancer Disease Management Group, NYU Langone Medical Center, discussed her presentation on immunotherapy updates in TNBC, as well as ongoing clinical trials that could change the treatment paradigm.

OncLive: What progress is being seen with combinations with immunotherapy in TNBC?

Adams: Combining immunotherapy with other targeted therapies, such as chemotherapies and radiation treatments, is probably going to be the future of breast cancer. [This is] because the response rate to single-agent immunotherapy remains low, especially in pretreated patients. Although in the frontline setting—the women who have been newly diagnosed with metastatic breast cancer—we see significant numbers of patients respond. The findings show that this response can be durable and can impact their outcome and survival. This is very, very important for TNBC because, currently, the standard of care is chemotherapy, which does not typically provide durable responses and comes with significant toxicities.

You spoke about a case of metaplastic breast cancer in your presentation. Could you discuss the work being done in that subtype?

In metaplastic breast cancer, we have seen an incredible response to immunotherapy in a woman who has recurrent disease with large-volume chest wall involvement and a lung metastasis. She had been refractory to several chemotherapies, so this is very exciting because it is one of the chemo-refractory, very poor prognosis subtypes of breast cancer.

After this observation, there have also been studies that specifically look at PD-1 and PD-L1 expression in these tumors. Due to that finding that most of those cancers express the target for immunotherapy, we are very excited to actually include an arm for metaplastic breast cancer in the ongoing National Cancer Institute-sponsored DART trial, which combines 2 immunotherapies—ipilimumab (Yervoy) and nivolumab (Opdivo)—for rare tumor types. This will be arm number 36, and this trial is open in 600 locations across the United States. We hope that this will provide access to patients with this rare subtype of breast cancer.

Are there any other ongoing trials that look particularly promising?

At NYU Langone Medical Center, we have an investigator-initiated study of pembrolizumab with nab-paclitaxel (Abraxane) for women who have TNBC but also [for women who have] hormone receptor—positive disease, for which there are very few immunotherapy trials.

There are also randomized phase III studies of neoadjuvant immunotherapy with chemotherapy. There is a large study that is looking at frontline treatment in women with metastatic TNBC.

Excitingly, we finished accrual to IMpassion130, which is a very large trial that was designed to get FDA registration, if positive. In this trial, women with metastatic TNBC are randomized to frontline backbone chemotherapy of nab-paclitaxel plus or minus atezolizumab (Tecentriq), to see if it affects responses to therapy, outcomes, and survival. There are multiple trials in this country and I would refer patients to clinical trials.

Would you say that immunotherapy has the biggest potential in TNBC of all breast cancer subtypes?

TNBC is the primary subtype in which it will be useful. Studies that were presented at the 2017 ASCO Annual Meeting showed significant improvement in achieving a response in the neoadjuvant setting. There will be many more studies coming in the next year that look at how to combine immunotherapy with standard therapy in this setting, and how to sequence it with the current chemotherapeutics.

What are the recent updates with pembrolizumab in the neoadjuvant setting?

The I-SPY trial was designed to look at new agents and to see whether there were any promising early signals so that they could graduate into larger randomized studies. The I-SPY 2 trial showed that the response is significantly improved if you add pembrolizumab to standard neoadjuvant chemotherapy.

What do you hope community oncologists took away from your presentation?

The take-home message is to consider immunotherapy trials early on in metastatic disease. We are still on the search for biomarkers to select the right patients for this treatment, especially if it is single-agent use. Single-agent activity is relatively low in patients with pretreated cancer, and women who had liver metastases showed no responses. It is important to select patients very carefully and to encourage enrollment into trials.

What do you believe is the most significant challenge for immunotherapy in breast cancer?

Increasing the response rate is the biggest challenge at this time. Single-agent activity in women who have been pretreated are in the single-digit range. Whereas, in the frontline setting, we have about 23% of patients achieve responses . Therefore, in the second-line and beyond settings, we need to find better combinations.

References

1. Adams S, Schmid P, Rugo HS, et al. Phase 2 study of pembrolizumab (pembro) monotherapy for previously treated metastatic triple-negative breast cancer (mTNBC): KEYNOTE-086 cohort A. J Clin Oncol. 2017;35 (suppl; abstr 1008).
2. Schmid P, Cruz C, Braiteh FS, et al. Atezolizumab in metastatic triple-negative breast cancer: long-term clinical outcomes and biomarker analyses. Abstract presented at: AACR Annual Meeting 2017; April 1-5, 2017; Washington DC. Abstract