Immunotherapy Begins New Therapeutic Path in Metastatic TNBC

Jeremy M. Force, DO

Ever-expanding immunotherapeutic and other novel approaches could signal a change in treatment for patients with metastatic triple-negative breast cancer (TNBC), said Jeremy M. Force, DO.

For example, in March 2019, the FDA granted an accelerated approval to the frontline combination of atezolizumab (Tecentriq) plus nab-paclitaxel (Abraxane) for patients with unresectable locally advanced or metastatic PD-L1—positive TNBC. The decision was based on findings from the phase III IMpassion130 trial, in which the addition of atezolizumab to nab-paclitaxel reduced the risk of progression or death by 38% versus nab-paclitaxel alone in this patient population.

"We essentially have the first targeted treatment for what was un-targetable before, so trying to identify who would benefit the most or the least is of the utmost importance as we see the transition of these novel checkpoint blockades transition into the neoadjuvant setting."

Moreover, PARP inhibitors and antibody-drug conjugates (ADCs) are being explored in patients with TNBC, including in those with BRCA mutations.

In an interview during the 2019 OncLive State of the Science Summit on Breast Cancer, Force, a medical oncologist and assistant professor of medicine at Duke University School of Medicine, discussed current and emerging immunotherapy options in metastatic TNBC, as well as ongoing challenges in the space.

OncLive: Starting with frontline immunotherapy in metastatic TNBC, could you highlight the impact of the IMpassion130 trial?

Force: The IMpassion130 trial is a step in the right direction. Until now, there has not been targeted therapy for metastatic TNBC.

It is important to recognize that the PD-L1 positivity within the immune cell component is >1% [regarding which patients can receive the immunotherapy regimen]. As a positive phenotype, that provided an overall survival advantage for those patients.

IMpassion130 is quite a robust clinical trial that has positively impacted the lives of many of these patients to date. Certainly, it can be improved upon, but we are enthusiastic about it.

What other immunotherapy approaches are being investigated?

Other approaches being elucidated now include agents that stimulate some of the innate immune cell population, such as STING agonists, oncolytic viruses or toll-like receptor therapies that can be subsequently injected locally or into the tumor bed, and agents that stimulate immune cell trafficking, such as interleukin (IL)-12 or IL-2.

Inhibition of other pathways within the checkpoint blockade have been well recognized and are currently being studied as dual checkpoints or in combination with chemotherapy.

Could you elaborate on the KEYNOTE-522 findings?

The KEYNOTE-522 trial reported that there was increased pathologic complete response (pCR) in patients who received pembrolizumab combined with a chemotherapy backbone.

I hope it shows a robust (pCR) increase above that of chemotherapy. We need to see a follow-up of event-free survival, in order to know that a benefit will be determined long-term and not just the pCR we see.

That is important because we have trials of chemotherapy, which we know does improve pCR in patients receiving carboplatin; however, it did not turn into a long-term benefit for those patients.

This is a curable disease and this trial could, hopefully, [shed light on] a long-term, curable strategy for those patients.

Also, the biomarkers for KEYNOTE-522 will be important in terms of what, if anything, was looked at to identify which patients did or did not benefit from pembrolizumab. These are not without their adverse events, and it appears that the addition of pembrolizumab created increased pCR. [Even] if a patient has a PD-L1—negative tumor, there may still be increased pCR [with the immunotherapy regimen].

Is TNBC the most immunogenic of breast cancers subtypes?

It appears to be, but the caveat is that many of the immunogenicity components of breast cancer haven't been discovered yet.

Quite possibly, hormone receptor (HR)—positive or HER2-positive disease will be treated with an immunotherapeutic approach one day. Perhaps that will look something like inhibiting TGFß1, inhibiting the Wnt signaling pathway, or stimulating immune cell trafficking to tumor cells that were devoid of CD8-positive T cells.

Transitioning to PARP inhibitors, could you discuss their use in patients with germline BRCA mutations and the research being done in combination with immunotherapy?

PARP inhibitors should be readily available for all germline BRCA-mutated metastatic breast cancers. Olaparib (Lynparza) and talazoparib (Talzenna) are two FDA-approved agents available. They both show similar outcomes; however, there is a suggestion from the EMBRACA study that there is increased efficacy in patients with BRCA2 mutations and HR-positive metastatic breast cancer with talazoparib. Still, olaparib is an equally reasonable strategy in this disease.

The combination of PARP inhibitors with immunotherapy, specifically checkpoint blockade, makes biological sense. Recently, it has been shown that the STING pathway is upregulated in patients receiving PARP inhibition, which will lead to a robust, interferon response in T cell—mediated processes and lead to tumor cell death. Leverage with subsequent anti–PD-1 therapy makes a lot of sense.

What else is notable about PARP inhibitors?

[PARP inhibitors] can cause hematologic toxicity, so close clinical monitoring [is necessary]. With talazoparib or olaparib, we see that anemia starts to drop around 50 to 80 days [into treatment]. Hemoglobin can drop pretty low (5-6) from normal (above 14) in that time frame. Close monitoring and blood transfusion is certainly indicated in that situation.

These drugs are effective and are being looked at in the neoadjuvant setting in patients with germline BCRA-mutated breast cancers. We are seeing some increased pCRs equivalent to chemotherapy, which means a patient would be taking a pill once a day for about 5 months.

Those comparative results are a potential real win for those patients who have germline BRCA-mutated early-stage breast cancer.

What about ADCs? Are there any noteworthy developments being made in this space?

ADCs are certainly a novel [approach], especially with sacituzumab govitecan and the Trop2 [target]. In the heavily pretreated setting, where the anti-Trop2 therapy has been developed, I foresee an FDA approval.

There have been some manufacturing issues that has led to [sacituzumab govitecan’s] hindrance getting into the market, but it is fairly well tolerated. For patients going onto their third or fourth line of therapy, having that additional drug on your armamentarium makes sense.

What is the biggest challenge in TNBC management?

The biggest challenge is trying to leverage immunotherapy beyond the PD-L1 story. If you have your patient with curable breast cancer, a biomarker that could identify whether or not they would respond with the use of checkpoint blockade [would be invaluable].

The worst-case scenario would be that they develop hypothesitis or myocarditis. Many will develop thyroiditis, hypothyroidism, or an endocrinopathy similar to that, but that is a lifelong illness that now they have to deal with.

Is there anything else you would like to add about this evolving paradigm?

The Ventana PD-L1 (SP142) antibody is the compendium diagnostic utilized to identify PD-L1 status on the immune cell population. It can then indicate whether atezolizumab and nab-paclitaxel would be warranted. The cut-off is ≥1%—not 50%, or even 5%, like we see in other disease types. That is important to recognize.

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.