Transformative Treatments Take Hold Across Breast Cancer Settings

Lee S. Schwartzberg, MD

Treatment strategies in breast cancer have changed substantially over the last few years, said Lee S. Schwartzberg, MD, FACP, due in large part to the use of genomic profiling, CDK4/6 inhibitors, and immunotherapy.

“Most of the changes in early-stage, hormone receptor (HR)—positive breast cancer have been around treatment de-escalation. We’ve also seen a big change in the treatment landscape of metastatic HR–positive breast cancer with the widespread use of CDK4/6 inhibitors,” said Schwartzberg, chief and professor of medicine, Division of Hematology/Oncology, University of Tennessee Health Science Center. “Likewise, in triple-negative breast cancer (TNBC), we saw the breakthrough [approval] with immunotherapy this year.”

In an interview during the 2019 OncLive^® State of the Science Summit™ on Breast Cancer, Schwartzberg, who is also chief medical officer, OneOncology, medical director, West Clinic, and executive director, West Cancer Center, discussed paradigm shifts in HR-positive breast cancer and TNBC.

OncLive: How have treatment approaches recently changed in early-stage, HR-positive, HER2-negative breast cancer?

Schwartzberg: The reason we're able to de-escalate therapy and give less chemotherapy to our patients is due to the use of genomic expression profiling. These tests can help us decide which patients would benefit from chemotherapy. The seminal study that was reported in 2018 was the TAILORx trial; this was a prospective trial that randomized women who had a 21-gene recurrence score in the intermediate range to receive chemotherapy or not.

The results showed no difference in outcomes between patients who received chemotherapy and those who did not, proving that chemotherapy is not necessary in women with an intermediate recurrence score. Patients who had the lowest recurrence score only received endocrine therapy, and they had an excellent outcome at 9 years—only about 3% of patients relapsed. Patients with high recurrence scores received chemotherapy and endocrine therapy; these patients had worse outcomes and more relapses despite the fact that they received more aggressive therapy. The recurrence score is both prognostic and predictive of whether or not a patient with early-stage HR—positive disease needs chemotherapy in addition to endocrine therapy.

We have also examined whether patients need anthracyclines. Anthracyclines not only have acute toxicities, but occasionally, they can cause cardiac toxicities. In breast cancer, we're paying a lot more attention to cardiac toxicity—particularly long-term cardiac toxicity. Anything we can do to reduce that toxicity is important. Studies have shown fairly conclusively that patients with HR-positive breast cancer do not derive any benefit from an anthracycline, particularly if they have 0 to 3 positive lymph nodes. Therefore, these patients can be treated with a taxane-based regimen without [an anthracycline].

Could you shed light on research that has been done evaluating extended endocrine therapy?

This is a point of much discussion and debate because the benefit [of extended therapy] is modest, but some patients do benefit. We know that the risk of relapse in patients with HR-positive breast cancer continues after 5 and 10 years [of treatment], so the notion of reducing those late relapses is very attractive. One way to help us choose women who might benefit from extended endocrine therapy is to use genomic profiling. In the Trans-aTTom trial, the Breast Cancer Index (BCI) [was used to evaluate a patient’s risk of recurrence]. In the trial, patients received either 5 or 10 years of tamoxifen. Investigators reported a modest but real benefit in [recurrence-free interval] in the overall population of patients who received 10 years of tamoxifen versus 5 years.

In the node-positive group, patients who had a high BCI were much more likely to relapse than those with a low BCI. A low BCI score could be one indication that extended endocrine therapy [would not be needed]. Those data corroborate the previous data from the MA.17 trial, which evaluated the use of extended aromatase inhibition.

Could you discuss the work that is being done to bring CDK4/6 inhibitors into earlier settings?

There are a whole host of ongoing trials in HR-positive breast cancer. The trials that are going to be the most impactful in the near [future] are examining the addition of CDK4/6 inhibitors to current therapy. Specifically, these trials are investigating the addition of a CDK4/6 inhibitor to standard endocrine therapy for 1 to 2 years in the adjuvant setting. Some of these studies have already completed accrual, while others are ongoing and accruing now. In the next few years, we'll know whether there’s a benefit to adding a CDK4/6 inhibitor to standard therapy in early-stage, HR-positive breast cancer, particularly in those who are at higher clinical risk.

How would you define the benefit of CDK4/6 inhibitors in the metastatic HR-positive setting?

We know that all 3 drugs—palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio)—improve progression-free survival (PFS) in the first- or second-line settings. Although the studies had slightly different designs, we saw about a 10-month improvement in PFS with the addition of a CDK4/6 inhibitor. At the 2019 ESMO Congress, we saw long-term data that showed an overall survival (OS) advantage with both ribociclib and abemaciclib [in their respective trials]. I was surprised by the extent of the benefit that we saw, and the fact that PFS2 was not impacted.

We also saw an improvement in the time to chemotherapy. Most women with metastatic breast cancer who are trying to manage quality of life with quantify of life don’t want chemotherapy. [CDK4/6 inhibitors] enable patients to stay on endocrine therapy longer—in some cases 3 to 4 years—before they receive chemotherapy in the metastatic setting; it’s really transformative.

We also saw data with trilaciclib at the 2019 ESMO Congress. Could you shed light on those data?

Trilaciclib is a new CDK4/6 inhibitor that was evaluated in a randomized phase II study. The trial didn't meet its primary endpoint of reducing neutropenia, and interestingly, it didn't improve PFS; however, OS was increased, which is intriguing. Sometimes we see [an improvement in OS] in phase II trials that doesn’t translate to phase III trials. However, it’s certainly a strong signal that should be investigated in a phase III trial. One could conjecture that the mechanism of action could have an immune effect. There are some preclinical data to suggest that this drug could improve immune response and perhaps impact OS. We’ll have to see the phase III data.

You also gave a presentation on TNBC at the State of the Science Summit™. Could you discuss the key advances in that space?

TNBC remains the most difficult subgroup of breast cancer to treat. With standard therapies, the median survival in the metastatic setting is only about 1.5 years. The breast cancer community has been waiting for immunotherapy to take hold, and now we can use atezolizumab (Tecentriq) in combination with nab-paclitaxel (Abraxane) in the first-line setting for PD-L1—positive patients with TNBC. That’s important to stress, because not every breast cancer is a “hot” tumor. We have to define these patients dichotomously. PD-L1–positive patients experienced a benefit with atezolizumab [in the IMpassion130 trial]; PD-L1–negative patients really didn’t derive any benefit from atezolizumab at all. Approximately 40% of patients with TNBC are PD-L1 positive, and now, we have an FDA-approved immunotherapy regimen for them. Therefore, I recommend testing all patients with metastatic TNBC for PD-L1.

At the 2019 ESMO Congress, we saw data on what antibody to use, as there are other antibodies that are companion diagnostics for some of the other checkpoint inhibitors. In the [IMpassion130 trial], the [Ventana PD-L1] SP142 assay was used. To summarize, …we should stick with the SP142 assay, per the label, to determine which patients are eligible for the. Combination of atezolizumab and nab-paclitaxel.

We also saw data from the phase III KEYNOTE-522 trial with pembrolizumab (Keytruda) and chemotherapy at the 2019 ESMO Congress. Could you discuss those findings?

The data were very interesting. KEYNOTE-522 evaluated the addition of pembrolizumab to standard chemotherapy in the neoadjuvant setting and for 1 year in the adjuvant setting. The primary endpoint was pathologic complete response (pCR), which is a well-established surrogate marker for long-term outcome.

The long-term outcome needs to show an event-free survival (EFS) advantage. The pCR rate was increased in the intent-to-treat population by about 14%, meeting the primary endpoint of the trial. We also saw an early hint of EFS, which I was a little surprised by. After 2 to 3 years of follow-up, we’re already seeing the curves starting to separate; however, no formal analysis was done because it was too soon to evaluate.

Interestingly, both PD-L1—positive and PD-L1–negative subgroups benefitted by about 15% in terms of the improvement in the pCR rate. That's very different [from what we saw in the IMpassion130 trial]. One could conjecture that patients with nonmetastatic disease have a more intact immune system. We have to wait for the publication to get more details, but it's very encouraging. The regimen could be registered with the FDA based on that surrogate endpoint; it has been done before. We'll have to wait and see what happens.