Neoadjuvant Studies Identifying Optimal Strategies for TNBC

Angela DeMichele, MD

A better understanding of how patients with triple-negative breast cancer (TNBC) respond to neoadjuvant therapy regimens is helping to further individualize therapy for patients while also informing treatment decisions in the adjuvant setting, explained Angela DeMichele, MD, MSCE, at the 2016 International Congress on the Future of Breast Cancer.

DeMichele, professor of Medicine & Epidemiology and co-leader of the Breast Cancer Program at the Abramson Cancer Center, University of Pennsylvania, reviewed recent research findings that may shed light on some of the key questions in treating early TNBC, with the caveat that the promising pathologic complete response (pCR) rates observed with some agents in these recent studies do not necessarily translate into improved survival.

Although knowledge of the many categories of TNBC has advanced, the standard of care in this setting remains anthracycline-based chemotherapy, DeMichele noted. Additionally, she added, nab-paclitaxel is a reasonable alternative for patients who are allergic to paclitaxel, and there is no clear role for bevacizumab. The remaining challenge for clinicians is how to best treat patients who often have a difficult and poor prognosis.

“We do know that a subset of patients with triple-negative breast cancer is actually exquisitely sensitive to chemotherapy,” DeMichele explained. “Yet, our ability to predict who is going to respond is quite limited.”

Role of Platinum-Based Therapy

Long-term outcomes from two neoadjuvant trials evaluating the addition of carboplatin—CALGB 40603 and GeparSixto—were reported at the 2015 San Antonio Breast Cancer Symposium.^1,2In the randomized phase II CALGB 40603 study, patients received weekly paclitaxel followed by dose-dense doxorubicin/cyclophosphamide plus either bevacizumab or carboplatin or a combination of the two. In GeparSixto, paclitaxel remained the backbone, but notably, said DeMichele, it was administered concurrently with nonpegylated liposomal doxorubicin and carboplatin in the experimental arm—all of the drugs given concurrently and all the patients receiving bevacizumab.

These differences in the two trials led to some significant differences in outcomes, she said. Three-year event-free survival in the GeparSixto trial was 85.8% compared with 76.5% in the CALGB 40603 arm, suggesting a better overall prognosis and larger incremental carboplatin effect. However, “when we tease out these data,” said DeMichele, “we could have seen pharmacologic synergy by giving all of these drugs simultaneously [in GeparSixto].”

And, she added, “in both trials, we saw significant toxicity, and this is something we encounter every day in our patients when we try to add carboplatin to these regimens.” Although both trial results suggest benefit, currently not enough data exist to be conclusive, the chemo backbone and carboplatin dose/schedule may be critical to optimal efficacy, and long-term effects of added toxicity are not known, DeMichele said. “We really need to individualize who we’re going to give carboplatin to in the triple-negative setting.”

PARP Inhibitors

DeMichele said there is much excitement about PARP inhibitors in the neoadjuvant and adjuvant setting, particularly in patients who have an underlying alteration in DNA repair, either due to aBRCAmutation or some other abnormality.

She is one of the investigators on the I-SPY2 trial,³and she noted recently published pCR findings from the TNBC cohort of this trial that indicated the addition of veliparib to carboplatin in the neoadjuvant setting has the potential to be highly successful in a subsequent phase III randomized trial.

In this portion of the I-SPY2 trial, the estimated rates of pCR rate for those with TNBC with veliparib and carboplatin were 51% compared with 26% for a standard neoadjuvant therapy. Adverse events were higher in the veliparib group. Overall, these findings suggest an 88% probably of success for veliparib and carboplatin in a phase III study.

Role of Anthracyclines and Taxanes

Data from a prospective registry study reported at the 2016 ASCO Annual Meeting may shed light on the need for anthracyclines in the neoadjuvant setting. In the PROGECT trial,⁴77 patients received neoadjuvant carboplatin (AUC 6) + docetaxel (75 mg/m²) every 21 days for a total of 4 to 6 cycles.

“Patients achieving pCR with this anthracycline-free regimen demonstrated excellent relapse-free survival (96% at 2.3 years) without adjuvant anthracycline chemotherapy,” DeMichele reported, suggesting that a “significant proportion of TNBC patients achieve pCR with neoadjuvant carboplatin-docetaxel (CbD) and can be spared anthracycline exposure.”

She cautioned, however, that this is an observational study and there is no comparator arm and no randomization. Nevertheless, “this regimen did behave in the way that other regimens behave in the neoadjuvant setting … and certainly this data is quite compelling.” She said that while anthracyclines remain the standard of care, researchers are anxiously awaiting results from an ongoing randomized phase II neoadjuvant study comparing the CbD regimen to carboplatin/paclitaxel (NCT02413320).

To address the issue of optimal taxane dosing, DeMichele noted results from the ETNA trial were also reported at ASCO this year.⁵In this neoadjuvant trial, weekly paclitaxel dosed at 90 mg/m²was compared with weekly 125 mg/m²nab-paclitaxel (nab-P). Both regimens were administered for 3 weeks with 1 week of rest over 4 cycles and followed by 4 cycles of an anthracycline regimen selected by the investigator. In the paclitaxel arm, 110 of 349 patients had triple-negative disease, and this was true for 109 of 346 patients in the nab-P cohort.

There was an improvement in pCR rate with nab-P overall but it did not reach the 10% threshold set for difference in pCR rates. In the subgroup analysis of TNBC patients, no statistically significant benefit was seen with one taxane over the other, and nab-P was more toxic, with more grade 3 myelosuppression as well as fatigue and vomiting, said DeMichele.

“At this point, we don’t have enough evidence to convince us that nab-paclitaxel is superior, but I think we also do now have the benefit of knowing that it’s not inferior. For those patients who have allergic reactions to paclitaxel, nab-paclitaxel could be a very good alternative.”

Bevacizumab and Capecitabine

DeMichele noted that results are mixed, following numerous trials with bevacizumab. In an update of findings from the phase III ARTemis trial reported at ASCO this year, a very small pCR difference was seen between the control chemotherapy arm versus the group where bevacizumab was added, and in the TNBC subgroup, no difference was seen in disease-free or overall survival.

Despite a lack of defined benefit currently, DeMichele said, “Neoadjuvant therapy can give us a very nice way of starting to sort out biomarkers, and hopefully with these neoadjuvant trials, we can start to tease out, ‘is there a group of patients who will benefit with bevacizumab, because right now, we don’t know who they are.”

Additionally, neither adjuvant nor neoadjuvant data are compelling enough in her view to add capecitabine to these regimens for all patients. “However, I do think for patients who are at very high risk, with substantial residual disease after neoadjuvant therapy, it’s something I am considering.”

DeMichele is optimistic about the role of post-neoadjuvant trials as a way to improve treatment decision making. “This is a great model, because what it allows us to do is to give additional therapy to patients who aren’t responding to standard therapy. Rather than continuing to add more and more therapy to every patient—many of whom don’t need it—we can really focus on those patients who aren’t getting the benefit from our standard therapies and give them something else.

“This trial model allows us to answer that type of question with many fewer patients than would be required in a large adjuvant setting. I think you’re going to see more and more of these kinds of trials.”

References

1. Sikov WM, Berry DA, Perou CM, et al. Event-free and overall survival following neoadjuvant weekly paclitaxel and dose-dense AC +/- carboplatin and/or bevacizumab in triple-negative breast cancer: outcomes from CALGB 40603 (Alliance). Presented at: 2015 San Antonio Breast Cancer Symposium; San Antonio, TX; December 8-12, 2015. Abstract: S2-05.
2. von Minckwitz G, Loibl S, Schneeweiss A, et al. Early survival analysis of the randomized phase II trial investigating the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive early breast cancer (GeparSixto). Presented at the 2015 San Antonio Breast Cancer Symposium; San Antonio, Texas, December 8-12, 2015. Abstract S2-04.
3. Rugo H, Olopade OI, DeMichele A, et al. Adaptive randomization of veliparib-carboplatin treatment in breast cancer.N Engl J Med.2016;375(1):23-34.
4. Sharma P, Kimler BF, Ward C. Prognosis of triple negative breast cancer patients who attain pathological complete response with neoadjuvant carboplatin/docetaxel and do not receive adjuvant anthracycline chemotherapy.J Clin Oncol.2016; 34 (suppl; abstr 1015).
5. Gianni L, Mansutti M, Anton A, et al. ETNA (Evaluating Treatment with Neoadjuvant Abraxane) randomized phase III study comparing neoadjuvant nab-paclitaxel (nab-P) versus paclitaxel (P) both followed by anthracycline regimens in women with HER2-negative high-risk breast cancer: A MICHELANGO study.J Clin Oncol.2016; 34 (suppl; abstr 502).