TNBC Data Encouraging, But Unmet Needs Remain

Jane L. Meisel, MD

A better understanding of the biology of triple-negative breast cancer (TNBC) has led to the development of novel treatment approaches in a space where chemotherapy had been the sole option, said Jane L. Meisel, MD, but researchers are only just scratching the surface and more work needs to be done to further progress.

“Up until recently, all we had was chemotherapy; this approach works for some patients, but it doesn't work well for others,” said Meisel. “TNBC is probably not just 1 disease—some may be driven by BRCA status or by an immune-mediated environment. Some patients may have other targets that we don't even know about yet.”

Immunotherapy, which has had a dramatic impact in other solid tumors, is now making headway in TNBC in the form of checkpoint inhibitors. In results from the phase III IMpassion130 study, the addition of atezolizumab (Tecentriq) to nab-paclitaxel (Abraxane) reduced the risk of disease progression or death by 38% versus nab-paclitaxel alone in patients with unresectable locally advanced or metastatic PD-L1—positive TNBC.¹

In addition, antibody-drug conjugates (ADC), such as sacituzumab govitecan, have shown potential for later lines of therapy. In a phase II study presented at the 2017 San Antonio Breast Cancer Symposium, sacituzumab govitecan demonstrated an objective response rate of 34% in patients with heavily pretreated TNBC. In these patients, the median progression-free survival was 5.5 months and the median overall survival was 12.7 months.²

These positive results led to the FDA’s decision to grant a priority review designation to a biologics license application (BLA) for sacituzumab govitecan in July 2018. However, in January 2019, the regulatory agency issued a complete response letter to Immunomedics, the manufacturer of the ADC, regarding its BLA for the drug, citing chemistry, manufacturing, and control matters.

OncLive: What is the state of TNBC treatment?

What are your thoughts on this?

If eventually approved by the FDA, what would the clinical implications be?

Could you discuss the recent research being done with the ADC ladiratuzumab vedotin?

What has been the impact of the IMpassion130 trial findings?

In an interview during the 2019 OncLive^® State of the Science Summit™ on Breast Cancer, Meisel, an assistant professor in the Department of Gynecology & Obstetrics at Emory School of Medicine, Winship Cancer Institute, discussed recent breakthroughs in the previously stagnant field of TNBC and what these advances mean for patients.Meisel: TNBC is not estrogen-driven or HER2 targetable, so it is really a disease that, until recently, all we had [to treat these patients with] was chemotherapy. [In my presentation at the meeting,] I set the stage for the fact that this [approach] is not enough because not enough patients are being cured upfront. Metastatic TNBC outcomes are pretty dismal; this is a disease that tends to affect some of our youngest women and has a very aggressive nature. [In my presentation], I spent most of the time talking about some different areas of TNBC that have come up recently, such as [the research exploring] PARP inhibitors as treatment for patients with BRCA mutations. Immunotherapy is now playing a role in first-line metastatic disease. I also discussed some of the ADCs that should be coming to market soon. The FDA recently issued a complete response letter to Immunomedics regarding their BLA for the ADC sacituzumab govitecan.My understanding is that it [was due to] a manufacturing [concern]; it was not really about the data we have seen with the drug. Many of us in practice were eagerly awaiting that January 19, 2019 [action], date. It is definitely a slight disappointment we didn't get the result we wanted, but it is just a slight bump in the road.When the approval comes, the agent will be [indicated] for [use] after second-line therapy. In my mind, particularly for patients who progress quickly on 2 lines of chemotherapy, I feel less excited about a third line of chemotherapy being the miraculous thing that helps them. The idea of having a drug with a different mechanism of action in that setting, particularly with good response rates, is very exciting. As that drug gets studied more in the upfront setting, we could expand its reach.At Emory University, we are part of the study evaluating this drug in combination with pembrolizumab (Keytruda) in the first-line setting. It is an interesting idea to have this ADC with immunotherapy and maybe increase response rates. We are probably still a little too early on [in the research] to decide the kind of impact it will have, but it is an up-and-coming thing to look out for.There is a lot of potential. From the data presented at the 2017 ASCO Annual Meeting, we are already seeing some potential for the upfront combination of neoadjuvant chemotherapy with immunotherapy. We will have KEYNOTE-355 results eventually, in which investigators are looking at the use of pembrolizumab (Keytruda) in the frontline metastatic setting. [IMpassion130] is definitely the first study to come out with these data and have an impact. But I don't think it is the end of immunotherapy—it is just the beginning.

Are there any other emerging treatment strategies that you are excited about?

The KEYNOTE-355 trial is also looking at frontline metastatic disease; it is evaluating the use of pembrolizumab or placebo combined with physician's choice of chemotherapy.The idea of combining PARP inhibitors with immunotherapy is really exciting. I treat patients with ovarian and breast cancers, and we have already seen exciting phase I data in the platinum-resistant ovarian cancer population. I consider those patients to be similar to those with TNBC, particularly the ones with BRCA mutations.

Another area of interest is the androgen receptor (AR)-positive group. There are some interesting data out there with enzalutamide (Xtandi) in these patients. The key, overall, with treating these patients is that we don't have a specific biomarker of treatment response, but we can continue to identify these targets.

References

1. Schmid P, Adams S, Rugo HS, et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379(22):2108-2121. doi: 10.1056/NEJMoa1809615.
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. Cancer Research. 2018;78(4). doi: 10.1158/1538-7445.SABCS17-GS1-07.