Brufsky Highlights Novel Approaches for TNBC

Adam M. Brufsky, MD, PhD

As investigators increase their understanding of the biology of triple-negative breast cancer (TNBC), new approaches are emerging that could optimize patient outcomes.

“There are a lot of interesting data in triple-negative breast cancer, a field where we didn’t really have a lot, until recently,” said Adam M. Brufsky, MD, PhD.

For example, the FDA recently granted a priority review designation to a supplemental biologics license application (sBLA) for the frontline immunotherapy combination of atezolizumab (Tecentriq) plus nab-paclitaxel (Abraxane) for the treatment of patients with unresectable locally advanced or metastatic PD-L1—positive TNBC.

The sBLA is based on data from the phase III IMpassion130 trial, which found that the addition of atezolizumab to nab-paclitaxel reduced the risk of disease progression or death by 38% compared with nab-paclitaxel alone in this population.¹

Another therapy that is under investigation and showing promise is the antibody-drug conjugate (ADC) sacituzumab govitecan (IMMU-132), which was granted a priority review designation by the FDA in July 2018 for patients with metastatic TNBC who have undergone at least 2 previous therapies.

In a phase II trial, sacituzumab govitecan was associated with a 34% objective response rate (ORR) in patients with heavily pretreated metastatic TNBC. In the single-arm trial, which enrolled 110 patients, the ORR was accompanied by a stable disease rate for ≥6 months in 11% of patients, leading an overall disease control rate of 45%. Median progression-free survival (PFS) was 5.5 months (95% CI, 4.8-6.6), and the median OS was 12.7 months (95% CI, 10.8-13.6).²

Another area of interest in this space is the use of PARP inhibitors, such as talazoparib (Talzenna) and olaparib (Lynparza), which were recently approved by the FDA for the treatment of patients with BRCA-mutated disease.

OncLive: Could you provide an overview of your presentation on treatment approaches in TNBC?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Breast Cancer, Brufsky, professor of Medicine, associate chief, Division of Hematology/Oncology, co-director, Comprehensive Breast Cancer Center, associate director, Clinical Investigation, University of Pittsburgh, highlighted novel treatment approaches being explored in the TNBC space.Brufsky: What I talked about today had to do mostly with the genomic assays for breast cancer—in particular, the 21-Gene recurrence score assay, which is Oncotype DX, and the 70-gene signature test, which is MammaPrint. I compared and contrasted 2 of the large randomized clinical trials that have been done—TAILORx for Oncotype DX and MINDACT for MammaPrint.

What treatment approaches are being evaluated for patients with TNBC?

They both were interesting; it’s gratifying that they both measure the same thing; they identify a group of patients who do not require chemotherapy. In the case of TAILORx, it’s really for node-negative breast cancer, while with MammaPrint in the prospective trial, it was node-negative and node-positive disease. There will be node-positive data coming out from a trial called RxPONDER in the next few years as well.In TNBC, we are going to talk about the new data on checkpoint inhibitors, which are really exciting, especially for patients who are PD-L1 positive. Patients who are given these inhibitors have been shown to have a 2-year overall survival, which is double that of not having had the checkpoint inhibitor—that is really dramatic.

In my presentation, I spoke a bit about sacituzumab govitecan, which is an antibody-drug conjugate to the Trop-2 antigen; it also has a lot of exciting phase II data in the third-line setting and beyond in TNBC. A large randomized phase III trial is currently ongoing that is randomizing patients to receive either sacituzumab govitecan or the standard of care in TNBC, which is generally chemotherapy. This is exciting new research.

I also discussed the use of PI3K inhibitors in patients with TNBC. There’s a trial called PAKT, where women who had PI3K-, AKT-, or PTEN-mutated breast cancer were randomized to receive paclitaxel with or without the AKT inhibitor [AZD5363], and they had an overall survival benefit as well if they had a PI3K mutation.

The FDA recently approved talazoparib. Is this agent already being incorporated into your practice?

I discussed the use of PARP inhibitors—talazoparib and olaparib—which are generally used as first-and second-line therapy or beyond in patients who have BRCA-positive breast cancer.We participated in the EMBRACA trial, so we put patients on talazoparib and we know about that agent. Talazoparib adds another available PARP inhibitor to olaparib in the pipeline. There are certain patients who don’t tolerate olaparib well, so it’s nice that we have another drug. Also, talazoparib is 1 pill as opposed to 4 pills with olaparib.

Are there any immunotherapy combinations that have been examined in TNBC that stand out? How about immune agonists?

The really interesting thing though comes from the ovarian literature. Data that were presented at 2018 ESMO Congress suggests that maintenance therapy in the first-line setting [leads to] a 3- or 4-year progression-free survival. That changes everything, and I really wish we could do that in triple-negative breast cancer, where we treat women with triple-negative breast cancer with frontline chemotherapy and/or maybe checkpoint inhibitors. Then, if they’re BRCA-positive, you maintain them with a PARP inhibitor. I’d love to do that study; we don’t have any trials like that, but I suspect we will probably get the same benefit that we have seen in ovarian cancer.Right now, it’s nanoparticle paclitaxel and atezolizumab. That’s the only one that has the clinical trials data in a randomized fashion.

Which of the treatments you mentioned could become available in the near future?

What immune agonists do is increase the amount of neoantigens to make a “cold” tumor “hot.” There is ipatasertib, which is an AKT inhibitor, that people feel also may stimulate the immune system. We’re also participating in a trial examining cobimetinib (Cotellic). We’ve done a phase II trial, for which we’re going to present data on, that is combining atezolizumab, nanoparticle paclitaxel, and cobimetinib [at an upcoming meeting]. There are data coming out on these immune stimulants, which is what I would call them.Of all the drugs right now, within the first quarter of 2019, we’re probably going to have the checkpoint inhibitor atezolizumab likely available and probably sacituzumab govitecan as well.

References

1. Schmid P. IMpassion130: Results from a global, randomised, double-blind, phase 3 study of atezolizumab (atezo) + nab-paclitaxel (nab-P) vs placebo + nab-P in treatment-naive, locally advanced or metastatic triple-negative breast cancer (mTNBC). In: Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA1_PR.
2. Bardia A, Vahdat LT, Diamond J, et al. Sacituzumab govitecan (IMMU-132), an anti-Trop-2-SN-38 antibody-drug conjugate, as ≥3rd-line therapeutic option for patients with relapsed/refractory metastatic triple-negative breast cancer (mTNBC): efficacy results. In: Proceedings from the 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, Texas. Abstract GS1-07.