Emerging Therapies Show Promise in Treating Metastatic Breast Cancer

Although metastatic breast cancer remains incurable, several novel therapies have been approved by the Food and Drug Administration (FDA) and have been shown to improve outcomes, including immunotherapy, antibody drug conjugates and poly (ADP)-ribose polymerase (PARP) inhibitors.

In a presentation at CURE®’s Educated Patient® Breast Cancer Summit, Dr. Neelima Vidula, breast oncologist at Massachusetts General Hospital and Harvard Medical School, detailed the available drugs for each of these novel therapies, how they can benefit patients with metastatic breast cancer and what side effects to be aware of. CURE® also spoke with Vidula to learn more about the development and FDA approval of these treatments over the past several years and what implications they may have for patients.

CURE®: What are some of the major takeaways from your presentation?

A: There are many promising new directions for the treatment of metastatic breast cancer. Immunotherapy is a form of therapy that blocks the interaction of the program cell death 1 (or PD-1) receptor with program death ligand 1 (or PD-L1) increasing antitumor immunity. At the present time, we have two immunotherapy agents that have now been FDA approved in combination with chemotherapy for patients who have metastatic triple negative breast cancer that is PD-L1 positive.

This was based on two studies. The first is the IMpassion130 study, in which patients with advanced triple negative disease were randomized to treatment with Tecentriq (atezolizumab), a form of immunotherapy, and Abraxane (nab-paclitaxel), a form of chemotherapy, or Abraxane chemotherapy alone. The takeaway message from this study was that in patients whose tumors were PD-L1 positive, there was an improvement in overall survival with the addition of Tecentriq to the standard chemotherapy backbone. That's what led to the FDA approval of this combination of Tecentriq and Abraxane.

The second study is the KEYNOTE-355 study, which had a similar design, enrolling patients with advanced triple negative disease and randomizing them to treatment with Keytruda (pembrolizumab) and chemotherapy or chemotherapy alone. What we saw from the study was that there was an improvement in progression-free survival with the addition of Keytruda to chemotherapy in PD-L1 positive tumors. This led to the FDA approval of Keytruda and chemotherapy for patients whose tumors are PD-L1 positive and have triple negative breast cancer.

Antibody drug conjugates are a novel approach to treating breast cancer. Recently, we saw the approval of Trodelvy (sacituzumab govitecan). The ASCENT trial was a phase 3 study that has demonstrated the efficacy of Trodelvy. In the study, patients who had metastatic triple negative breast cancer and had received at least two prior lines of chemotherapy were randomized to treatment with Trodelvy or treatment of physician’s choice. And what this study showed was that there was an improvement in progression-free survival and overall survival with Trodelvy compared to chemotherapy of physician’s choice. So, these findings lent support to a prior phase 1-2 study that had led to the breakthrough drug designation of Trodelvy. This is an option for patients who have advanced triple negative disease and have received at least two prior lines of chemotherapy.

Another antibody drug conjugate actually in the HER2 space that has been approved is Enhertu (trastuzumab deruxtecan). In a phase 2 study, this drug was shown to be very effective in patients who had heavily pretreated disease. This is also an exciting new drug. I think we're seeing that there are a couple of antibody drug conjugates now that are approved and are options for patients.

PARP inhibitors are really exciting because these are oral-targeted therapies that target the DNA damage repair pathway. They're exciting because they're oral drugs that can be taken at home and tend to have less side effects than standard chemotherapy.

There have been two studies of two PARP inhibitors — Lynparza (olaparib) and Talzenna (talazoparib) —for patients who have advanced triple negative breast cancer or hormone receptor positive, HER2 negative disease and express a germline BRCA mutation. Both these drugs, Lynparza and Talzenna, in their respective phase 3 studies have shown an improvement in progression-free survival compared to chemotherapy for these populations of patients, and that's what led to their approval.

Q: In addition to PARP inhibitors and the other treatments you mentioned, how is it determined that a patient might be better suited for a particular treatment?

A: For patients who have metastatic breast cancer, I think that the first most important step is to have biopsy confirmation of the disease. In this day and age, it's really important, if there's an accessible tumor lesion, to be able to biopsy a metastatic site because in about 10% to 15% of cases, sometimes the type of breast cancer can actually change from the primary tumor to a recurrence. In standard practice, if it's feasible to obtain a tumor biopsy of a metastatic site, that is important for a patient's care to confirm, No. 1, the diagnosis, and No. 2, to confirm the type of breast cancer.

In terms of triaging treatments for metastatic disease, that's dependent on the type of metastatic disease. For patients who have triple negative breast cancer, I certainly do think it's very important to be able to understand the PD-L1 status of the tumor because we have two immunotherapy agents that are now approved for patients who have PD-L1 positive disease. That should be considered a standard of care and should be done on a tumor biopsy, whether it's a primary lesion or a metastatic specimen because it might give patients an option to receive immunotherapy in addition to chemotherapy.

Aside from that, patients certainly have options in terms of standard chemotherapy. The trophoblast antigen 2 antibody drug conjugate Trodelvy is certainly an exciting option. It's currently approved for patients who have received at least two prior therapies, so that certainly is a great option for patients since it was associated with a survival benefit.

However, I would also recommend for patients who have triple negative breast cancer to discuss with their providers about obtaining tumor genotyping. This can be done either on a metastatic specimen itself, a tumor biopsy, or it can be done using a blood-based assay such as cell-free DNA. The identification of actionable mutations may help guide a patient to appropriate clinical trials of targeted agents.

In terms of HER2 positive disease, at this point, the accepted first-line standard of care regimen is Herceptin (trastuzumab), Perjeta (pertuzumab) and a taxane based on the results of the CLEOPATRA study demonstrating excellent outcomes. Then I think in the second-line setting, often, providers will use T-DM1 (Kadcyla, ado-trastuzumab emtansine) which is a form of antibody drug conjugate. That being said, if you had a patient who unfortunately developed brain metastases, we now have the approval of Tukysa (tucatinib) in combination with Xeloda (capecitabine) and Herceptin, which can also be considered in that setting, and Enhertu for more heavily pretreated disease.

And lastly, for ER positive, HER2 negative disease, the first-line accepted standard of care regimen is a CDK 4/6 inhibitor in combination with hormone therapy. Having cell-free DNA sent is also beneficial in this setting because if a patient were to have a PIK3CA mutation found either in the tumor or in the blood, they might be a candidate for Piqray (alpelisib), which is a PIK3 inhibitor, in combination with Faslodex (fulvestrant). Certainly, there are lots of ongoing trials and new hormonal therapies, but patients also have the option of receiving Faslodex, (selective estrogen receptor degraders, or SERDs), and then on progression after hormone therapy, there’s certainly a whole host of chemotherapy options.

In summary, depending on the type of breast cancer, there are certainly multiple different therapy options that are available. In terms of how to triage treatments and what's the best option for a patient, certainly working with your physician is beneficial because an oncologist will know how to best walk you through these options, and triage them to maximize benefit and maintain quality of life.

Q: Despite all of these benefits, are there any side effects associated with either PARP inhibitors, antibody drug conjugates or immunotherapy, and are they easily managed?

A:All treatments — chemotherapy included — unfortunately do come with some side effects. PARP inhibitors are actually relatively well tolerated, especially in contrast to chemotherapy. That being said, in the studies that have led to the approval of Lynparza and Talzenna, they have demonstrated that patients will often experience neutropenia or low white blood cell counts, anemia or low blood counts, fatigue, nausea, sometimes low platelets, hair loss and diarrhea. It's important to work with a physician because many of these side effects can be easily managed by either holding the drug, dose reduction or supportive care. I think that usually we can get patients through (the side effects), but it's just important to work with one's physician.

In terms of the antibody drug conjugates, these are, again, combining both an antibody and chemotherapy, so some of the side effects that we see are actually similar to what you would expect from chemotherapy. With Trodelvy, the typical side effects that a patient may experience include neutropenia or low white cells counts, anemia or low blood counts, nausea, diarrhea and fatigue. The other antibody drug conjugate that I had mentioned for HER2 positive disease, Enhertu, was commonly associated with nausea, some hair loss, low blood counts and diarrhea. In the study that was done with this agent, some patients developed interstitial lung disease, which is a form of lung inflammation. It's really important for physicians and patients to be cognizant of any changes in breathing patterns, any development of a new cough and so forth, and certainly to be vigilant about reporting those symptoms so that they can be managed.

The two immunotherapy agents that have been approved, Tecentriq and Keytruda, had been approved in conjunction with chemotherapy. So again, many of the side effects that you see are similar to what you would expect with chemotherapy alone. This can include hair loss, nausea, neuropathy or numbness and tingling, low blood counts, fever, anemia or low hemoglobin, neutropenia or low white cell counts and so forth. That being said, in some patients, immunotherapy can actually also trigger autoimmune events because of increased activity of the immune system. What has often been seen in trials that have been looking at immunotherapy agents is that patients may sometimes develop thyroid issues, either a hypoactive thyroid or hypothyroidism, or an overactive thyroid or hyperthyroidism. And also, sometimes there can be inflammation of other organs, for example, hepatitis or inflammation of the liver, adrenal insufficiency, colitis or inflammation of the colon causing diarrhea, dermatitis or skin reactions and pneumonitis, which is a form of inflammation of the lungs. These are really important side-effects for providers and patients to be mindful of, so careful monitoring of patients is needed with these agents. They can often be managed by holding the drug and adding a little bit of a steroid to dampen down any immune response that's causing those side effects.

This interview has been edited for clarity and conciseness.

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