TNBC Paradigm Evolving With Intriguing Treatment Methods

Tiffany A. Traina, MD

Novel approaches, including immunotherapy, antibody-drug conjugates (ADCs), androgen receptor (AR)—targeting agents, AKT inhibitors, and PARP inhibitors, are rapidly shifting the treatment paradigm in metastatic triple-negative breast cancer (TNBC), said Tiffany A. Traina, MD.

“TNBC is a heterogeneous disease,” said Traina. “It is probably a composite of multiple subtypes of breast cancer, each defined by different relevant molecular drivers. I hope we do away with TNBC all together, and talk about the biology behind breast cancer. We have many promising drugs and I hope we continue to improve outcomes for women with this disease.”

In March 2019, the FDA approved atezolizumab (Tecentriq) in combination with nab-paclitaxel (Abraxane) for the treatment of patients with unresectable locally advanced or metastatic PD-L1—positive TNBC. The approval was based on data from the IMpassion130 trial showing an improvement in progression-free survival (PFS) demonstrated with the combination compared with nab-paclitaxel alone in this patient population.¹ Updated findings showed that, in the PD-L1—positive subgroup, the median overall survival (OS) was 25.0 months with atezolizumab/nab-paclitaxel and 18.0 months with nab-paclitaxel alone (HR, 0.71; 95% CI, 0.54-0.93).²

“The results of IMpassion130 have changed the standard of care for advanced TNBC,” said Traina. “It is essential for our patients to know the PD-L1 status of their tumor. That testing can be done on a primary or a metastatic site. This is mandatory information to know so that we can make the right treatment choices for our patients.”

Prior to the IMpassion130 readout, 2 PARP inhibitors, olaparib (Lynparza) and talazoparib (Talzenna), were approved by the FDA in January 2018 and October 2018, respectively, for select patients with BRCA-mutant breast cancer. Olaparib is specifically indicated for those with germline BRCA-positive, HER2-negative metastatic breast cancer who have previously received chemotherapy; talazoparib is approved for patients with deleterious or suspected deleterious germline BRCA-mutated, HER2-negative locally advanced or metastatic disease.

In an interview with OncLive^® during the 2019 State of the Science Summit™ on Breast Cancer, Traina, a medical oncologist at Memorial Sloan Kettering Cancer Center, discussed emerging therapies for the management of metastatic TNBC.

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

Traina: The IMpassion130 trial was presented about 1 year ago. The FDA approved the use of atezolizumab in patients with PD-L1—positive, metastatic TNBC based on the advantage seen in PFS for women who received atezolizumab in combination with nab-paclitaxel in the first-line setting.

The improvement in PFS was compelling, but what was most intriguing was the suggestion of an improvement in OS for the subset of women who had PD-L1—positive tumors. I should make a note that PD-L1 positivity was defined using the VENTANA PD-L1 (SP142) assay as ≥1% staining in the immune cells. That is a different definition and a unique assay compared with what we may be familiar with from other solid tumors.

How are ADCs being explored in this space?

We are familiar with the use of ADCs—more typically in the HER2-positive space. Agents such as ado-trastuzumab emtansine (T-DM1; Kadcyla) for example, have changed the landscape of the management of metastatic, and now even early-stage, HER2-positive breast cancer.

This construct is showing promise in TNBC; one such agent is sacituzumab govitecan. This is an ADC against Trop-2, which is highly expressed in epithelial cells in TNBC. There was an interesting phase II study that showed tremendous promise with this single-agent ADC with prolonged median PFS over what we would expect for heavily pretreated women with TNBC.

There is a randomized phase III trial of sacituzumab govitecan up against treatment of physician's choice that has fully completed. We are eagerly awaiting results.

In addition to sacituzumab govitecan, there are other interesting ADCs in development, such as [fam-] trastuzumab deruxtecan, which has shown some intriguing responses in patients with HER2-positive disease.

Another ADC in development for TNBC is ladiratuzumab vedotin (SGN-LIV1A), which is a LIV-1 ADC. This is a novel approach where we look at identifying a target differentially expressed in the cancer compared with normal cells. With a powerful linker, we are able to deliver cytotoxic chemotherapy in a high drug-to-antibody ratio directly to the cancer cell. We are seeing suggestion of benefit with less toxicity.

Moving to PARP inhibitors, what data have been reported with these agents for germline BRCA1/2-mutated TNBC? What does the future hold for them?

In the scenario of women who have hereditary BRCA1/2 mutations and metastatic breast cancer, we have 2 FDA-approved PARP inhibitors, olaparib and talazoparib, which are standard of care for these women.

These 2 drugs have been shown to improve PFS over treatment of physician's choice for women with germline BRCA mutations. They have tolerable side effect profiles, along with rather favorable time to response and improved overall response rates. The takeaway from the OlympiAD and EMBRACA trials are that we must know the germline BRCA status for women with TNBC.

An interesting avenue moving forward is looking at ways we can expand the benefits of PARP inhibition for women who do not have germline BRCA mutations, but perhaps have tumors that have BRCA1/2 mutations or other mutations that can cause homologous recombination deficiencies. Another interesting area is [combining] PARP inhibitors with chemotherapy or immunotherapy.

What research is ongoing regarding AKT inhibitors?

There have been 2 interesting trials of AKT inhibitors in women with metastatic TNBC. The IPATunity130 study looked at adding ipatasertib with paclitaxel compared with paclitaxel alone. In this randomized phase II trial, there appeared to be an advantage with the AKT inhibitor double in the subset of patients who had either a PIK3CA mutation or AKT alteration.

Similarly, another randomized phase II study with capivasertib in combination with paclitaxel also showed a benefit, particularly in women again who had AKT-altered PIK3CA mutations in their tumor. Both [ipatasertib and capivasertib] are now being studied in randomized phase III trials for women with TNBC.

AR-targeting agents are newer to this space. What updates are we seeing with them?

Yes, the role of the AR in TNBC is still being explored. We have now had several single-arm phase II trials, which have shown a suggested benefit to AR antagonism in this unique subset of luminal TNBC.

There has been some exploration in prognostic markers. We have been looking forward to the randomized trial of an AR antagonist up against standard chemotherapy. I’m happy to say we will be launching that trial shortly, so I would keep this in mind as another particularly important subset of TNBC.

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). Ann Oncol. 2018;29(suppl_8). doi: 10.1093/annonc/mdy424.008.
2. 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; abstr 1003). 10.1200/JCO.2019.37.15_suppl.1003