Greater Genomic Understanding Is Gateway to Drug Development in TNBC

Roberto A. Leon Ferre, MD

The use of PARP inhibitors, antibody-drug conjugates, and immunotherapies have all shown significant activity in select subgroups of patients with triple-negative breast cancer (TNBC), but greater insight into the genomics and proteomics responsible for driving tumor growth are needed to inform development of novel therapeutics, explained Roberto A. Leon Ferre, MD.

“The more we understand the biology of both the tumor and the surrounding stroma, the better equipped we'll be to develop novel agents,” said Leon Ferre.

Encouraging findings from the phase III IMpassion130 trial showed that the addition of the PD-L1 inhibitor atezolizumab (Tecentriq) to nab-paclitaxel (Abraxane) reduced the risk of progression or death by 38% (HR, 0.62; 95% CI, 0.49-0.78; P <.0001) compared with nab-paclitaxel alone in patients with unresectable locally advanced or metastatic PD-L1—positive TNBC. Based on these data, the FDA is reviewing an application for atezolizumab in this setting, with an action date set for March 12, 2019.

Regarding driver mutations, patients who harbor aberrations amenable to the available targeted therapies account for a small percentage of the TNBC population, said Leon Ferre, with cytotoxic chemotherapy remaining the predominant therapeutic approach for the 60% to 70% of patients who do not express a specific target.

OncLive: How has the biology of TNBC informed its management?

In a presentation during the 2018 OncLive State of the Science Summit™ on Breast Cancer, Leon Ferre, oncologist, Mayo Clinic, discussed new insights into the biology of TNBC that may lead to the emergence of novel therapies for these patients.Ferre: For a long time, TNBC has been sort of a “black box” in breast cancer. It starts with the name. We're really talking about a disease that is defined by what it doesn't have. Until we really understand what drives the growth of these tumors, we're not going to make a big dent on the outcomes of patients who have this disease. The vast majority of patients who get diagnosed with this disease will be exposed to cytotoxic chemotherapy, which is a broad spectrum-type of treatment; it’s not targeted to attack certain vulnerabilities of the cancer.

What are the main takeaways on the biology of TNBC?

In patients who have early-stage disease, the standard of care in the majority of patients is neoadjuvant chemotherapy followed by surgery and radiation, if indicated. Depending on the type of response in the surgical specimen, some patients may need additional treatment after that. I would argue that this treatment [approach] continues to be suboptimal. The standard of care should be, and continues to be, clinical trials [investigating] novel agents.It is an incredibly exciting time to be an oncologist who treats patients with TNBC. We are starting to see a lot of the preclinical work and laboratory research being translated to the clinic. We just saw the results of a clinical trial incorporating immunotherapy with traditional chemotherapy in patients with metastatic TNBC. For the first time, we saw an OS improvement with a novel regimen in this disease. It is the first immunotherapy to prove beneficial in the clinic, so this regimen is likely to be approved by the FDA soon.

In the last couple of years, we’ve seen the first targeted therapies approved for TNBC, including that of the PARP inhibitors for patients who have germline BRCA mutations. That [approval] set a really significant milestone in TNBC, as it was the first nonchemotherapy drug that was approved for this patient population. We're also seeing a great deal of activity with new classes of drugs, including antibody-drug conjugates; there are several of them that are in different phases of development, some of which have been granted breakthrough therapy designations by the FDA.

How has this insight impacted the treatment landscape?

There's also a lot of activity in trying to understand some of the molecular drivers of TNBC. We will see the development of more targeted therapies, and we may repurpose the endocrine therapies that may have some activity in TNBC.We are going to start thinking about TNBC as a multitude of diseases rather than one subtype. Biologically and clinically meaningful subtypes are emerging, so we're going to start categorizing TNBC according to the driver. That is going to impact how we select treatments for these patients in a more precise way.

What is the biggest challenge in achieving this?

What are the next steps for research in this space?

Are there any data you want to highlight?

What is your main message to other clinicians?

For example, we will be able to identify the subtypes of TNBC that are more enriched by immune system responses and select immunotherapy for those patients. We may be able to identify patients who have germline BRCA mutations and potentially other [mutations] that may make them eligible to receive this targeted therapy. Hopefully, there’s going to be a move away from cytotoxic chemotherapy towards a more personalized treatment approach that will lead to a longer life and a better quality of life for our patients.We still do not have a good understanding of the drivers behind the growth of TNBC cells. We're seeing development in certain areas, but those patients are still a minority of patients with TNBC. The patients who have PD-L1 expression may account for up to 20% of patients. Germline BRCA mutations continue to account for a minority of patients with TNBC, and that’s where the biggest developments have been made. There's a large proportion of patients—60% to 70%—with TNBC for which we don't yet have a defined strategy other than chemotherapy. The next frontier is to try to identify additional targets for those patients who do not fit into those already defined categories.The next steps will be exploring the genomics and proteomics of TNBC at a deeper level; this will inform the development of new drugs. For a long time, we focused on the tumor, but we're starting to focus a lot more on the microenvironment, which is where that tumor cell resides. That [approach] may potentially unlock many secrets we are not yet aware of that may help us direct treatment towards a tumor cell, and also towards the microenvironment that supports that tumor cell. I have a lot of enthusiasm for the research that is being done on the microenvironment. We'll have a great deal of data coming up that we may have a hard time interpreting.For clinicians, the main data set that has come is from the IMpassion130 trial, which combined atezolizumab with nab-paclitaxel. That study showed that the addition of immunotherapy to chemotherapy in patients who have metastatic TNBC and PD-L1 expression improved survival by about 10 months. That may not seem like a lot, but in this field, it is a significant amount. It’s also the first time we’ve seen such an effect. That's a very practical study that will impact practice soon. Having the general understanding and framework of what the different subtypes are may allow us to personalize therapy a little bit better beyond chemotherapy, which is very important.TNBC is not a single disease; it's not one entity. It is a very heterogeneous disease that has multiple subtypes. We're just starting to understand what those subtypes are. I would envision that in the future we are going to see a management strategy that may mirror lung cancer, where we will identify subsets of the disease that will get diverted to individual types of therapy rather than treating everybody the same way.

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.