Positive Immunotherapy Signals in TNBC Need Further Study

Adam M. Brufsky, MD, PhD

Although there are some positive signals for immune checkpoint inhibitors in triple-negative breast cancer, the strategy still needs further research to determine whether these agents can make a difference in this challenging malignancy.

Pembrolizumab

“Unlike melanoma, lung cancer, and renal cell carcinoma, the feeling is that breast cancer is not as immunogenic, and that may or may not be true, but a lot of us are going to focus on whether we can make it more immunogenic,” said Adam M. Brufsky, MD, PhD, in an interview with OncologyLive^® in advance of his presentation on the subject at the 34th Annual Miami Breast Cancer Conference^®. Brufsky, a professor of medicine and co-director of the Comprehensive Breast Care Center at the University of Pittsburgh, reviewed recently completed and ongoing studies.Thus far, the most promising signs of efficacy of PD-1/PD-L1 inhibitors in TNBC have come from studies into pembrolizumab (Keytruda). In the phase Ib KEYNOTE-012 trial, single-agent pembrolizumab was given intravenously at 10 mg every 2 weeks to patients with advanced PD-L1— positive TNBC, head and neck cancer, urothelial cancer, or gastric cancer.

Thirty-two patients with PD-L1—positive TNBC were enrolled and assessed for safety and antitumor activity.¹ Of these patients, 28 (87.5%) were initially diagnosed with early-stage TNBC and had received neoadjuvant treatment. The remaining 4 patients (12.5%) had received at least 1 previous line of therapy in the metastatic setting. A median of 46.9% of patients in this study had received at least 3 lines of therapy for metastatic disease, and 25% had received at least 5 lines of therapy.

The median duration of treatment was 59.5 days, with 5 being the median number of pembrolizumab doses administered. Overall, 56.3% of patients experienced at least 1 adverse event (AE) due to treatment, with 15.6% experiencing at least 1 grade 3 to 5 AE. The most common AEs were arthralgia (18.8%), fatigue (18.8%), myalgia (18.8%), and nausea (15.6%).

Overall, 37.5% of patients experienced a decrease in tumor burden, and this was maintained over time. Of the 32 patients, 27 met the protocol-specified criteria for inclusion of the efficacy analysis population based on RECIST solid tumor assessment criteria (version 1.1). Of these 27 patients, the overall response rate (ORR) was 18.5%, with the best overall response being a complete response (CR) in 1 patient (3.7%). Partial response (PR) was observed in 4 patients (14.8%), stable disease was observed in 7 (25.9%), and progressive disease (PD) was observed in 13 (48.1%).

Atezolizumab

This trial was the first published report showing clinical activity for an immune checkpoint inhibitor in previously heavily treated mTNBC, according to the Journal of Clinical Oncology. One limitation to this study was the small sample size, which makes the results for efficacy less reliable, but this study did provide further understanding of how pembrolizumab performs in the treatment of mTNBC.¹The ongoing IMpassion130 trial is designed to test the effectiveness of a checkpoint inhibitor for patients with metastatic mTNBC. This phase III randomized trial involves the combination of PD-L1—inhibitor atezolizumab (Tecentriq) with nab-paclitaxel (Abraxane) in previously untreated patients with locally advanced TNBC or mTNBC. The trial will enroll 900 patients around the world (NCT02425891).

Avelumab

Patients will be randomized 1:1 to receive 840 mg of atezolizumab or placebo on days 1 and 15, plus 100 mg/m² of the widely used chemotherapy agent nab-paclitaxel on days 1, 8, and 15 of a 28-day cycle. The primary endpoints include progression-free survival (PFS) and overall survival (OS). Secondary endpoints include response rate, duration, and safety. Hazard ratios (HR) for progression or death will be estimated with a stratified Cox proportional hazards model. Results of this trial are not expected until 2020.Avelumab is an anti-PD-L1 antibody that was investigated in patients with locally advanced or metastatic breast cancer (MBC). In the phase Ib JAVELIN solid tumor study, the response rate was low for patients with MBC; however, a subset of patients with TNBC responded well, which researchers interpreted as promising.²

In the study, 168 patients with MBC received avelumab at 10 mg/kg every 2 weeks until confirmed progression, unacceptable toxicity, or withdrawal. Tumors were assessed every 6 weeks, with a median duration of treatment for 8 weeks. Treatment-related AEs were experienced in 120 patients, the most common being fatigue (19.6%) and nausea (14.3%).

There were 2 treatment-related deaths: 1 from acute liver failure and the other from respiratory disease.

Immunogenicity of Breast Cancer Tumors

The ORR in the entire patient cohort was 5.4%, with 1 patient with observed CR and 8 patients with observed PRs. Stable disease was observed in an additional 40 patients, making an overall disease control rate of 29.2%. Tumor reduction by more than 30% was observed in 15 patients.²The lack of strong immune system response in breast cancer relative to other types of cancer has led researchers to conclude that breast cancer is not an ideal target for immunotherapy, although TNBC as a subset of breast cancer is the exception because of the high levels of immune cells that tend to accumulate near TNBC tumors. “There are data that people have collected that have been circulating around, which have not been presented or published yet, that may suggest that not that many breast cancers when you look at them are immunogenic,” Brufsky said.

Based on recent studies, patients with breast cancer have some evidence of an adaptive immune response against their tumors, which can be detected in the peripheral blood or in the tumor. An immune response to breast cancer can begin as soon as the earliest stages of the disease. Recent evidence suggests that lymphocytes infiltrating breast cancers and the tumor stroma can be strong indications of a beneficial disease outcome. These observations help to add immunomodulation into standard-of-care therapy for the treatment of breast cancer.³

“I’d like to see the data. I’d like to know whether immunogenicity by the way we’re measuring it is actually important, and if it is, how can we make breast cancers more immunogenic. These are the things we need to think about,” Brufsky said.

References

1. Nanda R, Chow LQM, Dees EC, et al. Pembrolizumab in patients with advanced triple-negative breast cancer: phase Ib KEYNOTE-012 study. J Clin Oncol. 2016;34(21):2460-2467. doi:10.1200/jco.2015.64.8931.
2. Dirix LY, Takacs I, Nikolinakos P, et al. Avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: a phase Ib JAVELIN solid tumor trial. Cancer Res. 2016;76(suppl 4):abstr nr S1-04. doi: 10.1158/1538-7445.SABCS15-S1-04.
3. Disis ML, Stanton SE. Immunotherapy in breast cancer: an introduction. [Published online February 4, 2017] The Breast. doi: 10.1016/j.breast.2017.01.013.