Immunotherapy Continues to Show Promise in TNBC

Rita Nanda, MD

Nearly 1 year following the first checkpoint inhibitor approval in advanced triple-negative breast cancer, additional immunotherapeutic agents are poised to enter the field, according to Rita Nanda, MD.

“Historically, breast cancer was not believed to be an immunogenically active tumor [type],” said Nanda. “We have seen some emerging—likely practice-changing—data that may lead to approvals of new drugs [in breast cancer].”

In March 2019, the FDA granted accelerated approval to atezolizumab (Tecentriq) in combination with nab-paclitaxel (Abraxane) for the frontline treatment of patients with unresectable locally advanced or metastatic PD-L1—positive TNBC. The approval was based on results of the phase III IMpassion130 trial, which demonstrated a 40% reduction in the risk of disease progression or death with the combination of atezolizumab and nab-paclitaxel compared with nab-paclitaxel alone in this patient population.¹

"The IMpassion130 trial has certainly been practice changing," said Nanda. "It is the new standard of care for women with metastatic TNBC whose breast cancer expresses the PD-L1 protein. We are obviously looking to building on the promise that we have seen with this combination moving forward."

At the 2019 San Antonio Breast Cancer Symposium (SABCS), updated results from the phase III KEYNOTE-522 trial noted a greater rate of pathologic complete response (pCR) with the addition of pembrolizumab (Keytruda) to neoadjuvant and adjuvant chemotherapy for patients with newly diagnosed, operable TNBC. Regardless of PD-L1 expression, patients treated with pembrolizumab and chemotherapy had a pCR rate of 64.8% versus 51.2% for those treated with chemotherapy/placebo, leading to an absolute difference of 13.6% (95% CI, 5.4%-21.8%; P = .00055).²

In an interview with OncLive, Nanda, an associate professor of medicine and director of the Breast Oncology Program at the Duchossois Center for Advanced Medicine at the University of Chicago Medicine, discussed ongoing advances with immunotherapy in TNBC, as well as develops in the HER2-negative breast cancer paradigm.

OncLive: How has the addition of immunotherapy changed the TNBC treatment paradigm?

Nanda: Over the past year, we have seen some exciting data [regarding immunotherapy]. We had our first approval of an immunotherapeutic agent for advanced TNBC based on the IMpassion130 data.

In that large, randomized phase III trial, we saw a significant improvement in progression-free survival (PFS) and a trend toward improvement in overall survival (OS) for patients with PD-L1—positive TNBC when the combination of atezolizumab and nab-paclitaxel were given as opposed to nab-paclitaxel alone.

We also got our first peek at some data from the KEYNOTE-522 trial, in which we saw an improvement in pCR rates for pembrolizumab in combination with standard neoadjuvant chemotherapy for women with early-stage breast cancer.

Hopefully, more approvals are coming, particularly in the neoadjuvant setting for women with early-stage TNBC.

Also, there have been some interesting early-stage trials looking at MEK inhibitors and Akt inhibitors [in TNBC]. These agents have had promising preliminary results and are the subject of ongoing randomized phase III trials.

How have these trials shaped the way you treat patients with TNBC?

We do not yet have approval for pembrolizumab in the neoadjuvant setting, though I am hopeful it is coming. The event-free survival (EFS) [improvement demonstrated in KEYNOTE-522] is not yet significant; however, there is a very favorable trend toward improvement in EFS for women who receive pembrolizumab and standard neoadjuvant chemotherapy. Interestingly, the pCR benefit was seen regardless of PD-L1 status.

What role do novel agents, such as those used in the I-SPY 2 trial, have in future analyses of potential treatments for patients with TNBC?

I am very involved in the I-SPY 2 trial. It is an adaptively randomized phase II clinical trial that has been open since 2010. Additionally, it is a platform trial, so there are arms entering and exiting the trial throughout its course.

Most recently, pembrolizumab graduated for TNBC and high-risk hormone receptor (HR)—positive breast cancer. The results of the KEYNOTE-522 trial validated what we found in the pembrolizumab arm of I-SPY 2. It is exciting to see that with just 29 patients randomized to pembrolizumab, we are able to predict the outcome of a more than 1000-patient randomized phase III trial. It validates the I-SPY 2 trial design and concept.

Pembrolizumab also graduated for high-risk HR-positive, HER2-negative breast cancer. There was a doubling in pCR rate [for this patient population]. That is [being investigated] in an ongoing randomized phase III clinical trial.

Moving on to high-risk, HER2-negative breast cancer, what are the next steps in treatment development for these patients?

The 8-cycle pembrolizumab—arm of I-SPY 2—which removed [paclitaxel followed by doxorubicin and cyclophosphamide (AC)] from the last 4 cycles of therapy—did not graduate. The pembrolizumab 8-cycle regimen appeared to be as effective as paclitaxel followed by AC. Therefore, it did not graduate and will not be pursued further.

However, there is likely a subset of patients who do not need anthracycline-based chemotherapy. I've personally [treated] patients who did well on that arm of the trial.

In terms of those data, we need to look at the biomarker work. We are hoping to move toward a more precision medicine concept, where we can tailor our approaches to the individual patient needs.

For example, many patients may be able to de-escalate chemotherapy because they do not need as much chemotherapy as we are currently giving. [Conversely], some patients need chemotherapy and may not benefit from immune-based strategies. Looking at the biomarker data that will come from I-SPY 2 will be helpful in [starting to understand] how we want to plan the next generation of trials for women with early-stage, HER2-negative breast cancer.

What was the key takeaway from the 2019 SABCS?

We will be getting more data regarding immunotherapeutic agents in the neoadjuvant space. Data from the NeoTRIPaPDL1 trial will hint as to whether we can drop anthracyclines in the setting of platinum- and taxane-based therapy for patients with early-stage TNBC.

References

1. Schmid P, Adams S, Rugo HS, et al. IMpassion130: updated overall survival (OS) from a global, randomized, double-blind, placebo-controlled, phase III study of atezolizumab (atezo) + nab-paclitaxel (nP) in previously untreated locally advanced or metastatic triple-negative breast cancer (mTNBC). J Clin Oncol. 2019;37(suppl 15; abstr 1003). doi: 10.1200/JCO.2019.37.15_suppl.1003.
2. Schmid P, Park YH, Ferreira M, et al. KEYNOTE-522: phase 3 study of neoadjuvant pembrolizumab + chemotherapy versus placebo + chemotherapy, followed by adjuvant pembrolizumab versus placebo for early triple-negative breast cancer: pathologic complete response in key subgroups and by treatment exposure and residual cancer burden. Presented at: 2019 San Antonia Breast Cancer Symposium; December 10-14, 2019; San Antonio, Texas. bit.ly/36s817r.