Lisa A. Carey, MD, ScM, FASCO

Using the Data from ESMO Congress 2019 in Practice: Breast Cancer

Question

What were some novel approaches to managing breast cancer discussed at the European Society of Medical Oncology (ESMO) Congress 2019?

Answer

There were several studies to note. The KEYNOTE 522 trial examined pembrolizumab added to conventional neoadjuvant chemotherapy (paclitaxel + carboplatin followed by AC or EC) and then given in the adjuvant setting for nonmetastatic triple negative breast cancer. In this trial, adding the immune checkpoint inhibitor augmented pathologic complete response (pCR) by about 14%.¹ Whether this will help with relapse and survival is not yet known, but it is promising. There were also significantly increased immune-related adverse events, as expected, with 14% with grade 3 or greater toxicity. Given that many add capecitabine in residual disease triple negative breast cancer, if approved, we will need to come up with a new strategy.

What did not work was pembrolizumab instead of chemotherapy in previously treated metastatic triple negative breast cancer, which was tested in KEYNOTE 119.² As has been suggested in smaller trials, immune checkpoint inhibitors in general, particularly if given alone, seem to work better in first-line (untreated) metastatic disease than those who have previously received chemotherapy.

Another trial, BROCADE3, examined the PARP inhibitor veliparib added to carboplatin plus paclitaxel in patients with germline BRCA1/2 mutations and metastatic breast cancer. Veliparib is unusual in that it can be combined with chemotherapy, where most others have too much toxicity. Adding veliparib augmented progression-free survival significantly. Per investigators, the difference was about 2 months; per independent review, the difference was about 5 months.³

This has several implications. The first is a beneficial effect of adding PARP inhibitor to chemotherapy rather than substituting it for chemotherapy, which is only possible with veliparib. There was some toxicity but fewer than 10% of patients discontinued treatment prematurely due to toxicity. The second is that this is added to not only standard first-line drugs, but specifically including a platinum.

One of the problems with the other PARP inhibitor trials is that they compared the inhibitor to second-line drugs, and excluded platinums to which PARP inhibitors may be cross-resistant. How this strategy would compare with a substitution strategy in this setting is unknown.

Question

In your view, what new approaches may have the greatest impact on breast cancer treatment?

Answer

Several studies presented at ESMO 2019 either cemented current practice or opened up new options. Two CDK 4/6 inhibitor trials, MONARCH-2 and MONALEESA-3, reported improved overall survival with the addition of a CDK4/6 inhibitor (abemaciclib and ribociclib, respectively) to endocrine therapy (fulvestrant) in patients with metastatic disease who had progressed on a prior endocrine regimen.^4,5

These 2 trials help clarify that the benefit of these drugs is long-lasting and impactful. What is not clear is when they should be included. The trials using them in the first-line setting have not yet reported a benefit on survival, but patients are living so much longer that that may take some time to determine.

However, the greatest promise is that the trials testing this class of drugs in the nonmetastatic setting will demonstrate improved cure rates. Given the positive results presented at ESMO 2019, this is becoming more likely. Similarly, if the neoadjuvant pembrolizumab trial mentioned above, and other immune checkpoint inhibitor trials that are ongoing, improve relapse rates in addition to pCR, then combining these drugs with chemotherapy will become standard of care for nonmetastatic triple negative disease.

Question

In what ways is the management of triple negative breast cancer (TNBC) evolving?

Answer

Last year, we found that adding the immune checkpoint inhibitor atezolizumab to chemotherapy with nab paclitaxel improves progression-free and overall survival in patients with first-line metastatic triple negative breast cancer and evidence of immune activation. This is now standard of care for “PDL1-positive” breast cancer. However, the quotation marks are because it is currently unclear how best to test for immune activation. This will be the topic of much research in the near future.

Separately, the KEYNOTE 522 neoadjuvant/adjuvant trial found improvement in pCR rates in triple negative disease regardless of PDL1 status. It is possible that prior evidence of immune activation may not be necessary if the chemotherapy itself is immunogenic. It is also clear, as highlighted by the negative KEYNOTE 119 trial, that while immune checkpoint inhibitors are becoming part of the armamentarium for treating triple negative breast cancer, we have a long way to go before we have real transformation of this disease outcome.

Trilaciclib is a CDK4/6 inhibitor that unlike the other CDK4/6 inhibitors discussed above was tested to see if it could spare the bone marrow from toxicity during chemotherapy for triple negative disease. Interestingly, in a small randomized trial, trilaciclib seemed to have less impact on toxicity, but improved survival.⁶ The trial randomized patients with metastatic triple negative disease to receive gemcitabine plus carboplatin plus trilaciclib or chemotherapy alone. This was intriguing, some preclinical studies suggest that these drugs may themselves have an immune or other effect in triple negative disease, but it is way too early to say whether this approach will work.

One of the real challenges of nonmetastatic triple negative disease is that we are dependent on chemotherapy to reduce relapse rates, but we do not have a way to identify those who will do well without chemotherapy. Patients with chemotherapy-treated triple negative disease that has tumor infiltrating lymphocytes (TILs) do better than those without TILs. A small study looked at a group of TNBC patients who for one reason or another, usually age or comorbid conditions, did not receive chemotherapy. In those patients, the tumors with TILs did better than those without TILs. The future is that we may be able to identify through tumor size, negative nodes, and presence of TILs, a real subset of patients who will do well without chemotherapy.⁷

Question

What effects, if any, are concerns regarding cardiotoxicity having on breast cancer treatment decisions?

Answer

Cardiotoxicity is of course a significant toxicity of many cancer therapies. The good news is that modern therapies are often designed to minimize this toxicity, which is now relatively uncommon. Several abstracts centered on this topic. One from the EORTC, a European cooperative group, examined ways in which radiation-induced cardiac toxicity might be predicted based on a variety of clinical and radiation variables.

Another, the SAFE trial, looked at adding cardio-protecting drugs to anthracycline (eg, doxorubicin)-based therapy. It found at interim analysis that subclinical early effects might be minimized by beta-blockers.⁸

The last examined a biomarker, NT-ProBNP, as a predictor of trastuzumab cardiotoxicity, finding that it might help predict cardiac toxicity in patients with diabetes.9 However, it is also true that much of the cardiac “damage” measured in these trials is based on radiographic findings and of unclear clinical significance. The more impactful approaches are likely to be the continued efforts to tailor both radiation and medical therapy to minimize the use of cardio-toxic drugs and the risk of cardiac damage.

Question

Were there any overriding themes or improvements in care that stood out this year?

Answer

The overriding themes this year were: Better defining the targetability of the microenvironment through immunotherapy, clarifying the clinically meaningful impact of CDK 4/6 inhibition in metastatic ER-positive disease, and patient-centered care through attention to minimizing toxicity and overtreatment.