Strategies Emerge for Treating Residual TNBC Post Chemo

William Gradishar, MD

Despite known correlations between achieving pathologic complete response (pCR) after neoadjuvant chemotherapy and improved outcomes, there may be more to long-term outcomes in these patients, according to William J. Gradishar, MD.

Gradishar, chief of the Division of Hematology and Oncology in the Department of Medicine and the Betsy Bramsen Professor of Breast Oncology at Northwestern University Feinberg School of Medicine in Chicago, Illinois, began his discussion at the 2019 Lynn Sage Breast Cancer Symposium by summarizing the improvements different modalities have brought to pCR rates in recent years.¹

Different Modalities Boost pCR

First, the use of anthracyclines brought pCR rates to 10% to 15%, he said; and then the addition of taxanes raised pCR rates to 25% to 30%. Adding trastuzumab (Herceptin) to the HER2-positive arsenal helped bring pCR levels to roughly 50%. With combined chemotherapy plus dual anti-HER2 therapy strategies, levels elevated further to around 60%, with the same regimen also resulting in decreased rates of axillary positivity of 50% or more.

Additionally, pCR data from 2 randomized trials that tested PD-1/PD-L1 targeted agents as neoadjuvant therapy in triple-negative breast cancer (TNBC) are expected soon. Gradishar, who has chaired the Lynn Sage Breast Cancer Symposium since its inception in 1998, told colleagues that the IMpassion031 trial (NCT03197935), which is testing nab-paclitaxel (Abraxane) followed by adjuvant chemotherapy with or without atezolizumab (Tecentriq), has completed accrual with 204 patients and should be reporting soon.

Gradishar also discussed data from the KEYNOTE-522 trial. Findings presented at the European Society for Medical Oncology 2019 Congress showed that neoadjuvant treatment with the combination of pembrolizumab (Keytruda) and chemotherapy extended pCR rates by 13.6 percentage points (95% CI, 5.4-21.8) compared with chemotherapy alone for patients with early TNBC. The pCR rate was 64.8% with pembrolizumab plus chemotherapy compared with 51.2% for chemotherapy alone.²

After a median of 15.2 months of follow-up, the event-free survival rate with pembrolizumab was 91.3% compared with 85.3% for placebo; however, this benefit was not yet statistically significant (HR, 0.63; 95% CI, 0.43-0.93).²

Gradishar also referred to data from investigators at The University of Texas MD Anderson Cancer Center in Houston that showed a significant drop-off over several years among patients with TNBC who received postadjuvant chemotherapy and had achieved pCR but developed residual disease later.³“What can we do to improve survival among these patients?” he asked.

How Can Outcomes Be Improved?

Answering his own question, Gradishar emphasized the importance of the CREATE-X trial that tested adjuvant capecitabine following preoperative chemotherapy.⁴In that study, patients with HER2-negative breast cancer who were either node positive or did not achieve pCR following surgery were randomized to receive standard therapy with or without the addition of capecitabine.

Capecitabine improved both disease-free survival (DFS; HR, 0.70; 95% CI, 0.53-0.92;P= .01) and overall survival (OS; HR, 0.59; 95% CI, 0.39-0.90;P= .01). When stratified by receptor status, the DFS results in the TNBC cohort were notable, with an HR for recurrence of 0.58 (95% CI, 0.39-0.87). The OS results were similar, with an HR for death of 0.52 (95% CI, 0.30-0.90).

Is this dramatic OS effect plausible? Gradishar says he believes that it is. “Several randomized adjuvant trials failed to demonstrate improvement in recurrence-free survival with the addition of capecitabine to a third-generation regimen, but most of these studies included both estrogen receptor [ER]—positive and ER-negative patients, and there was no enrichment for cases with pCR or poor prognosis,” he said. “For these reasons, these trials are noninformative rather than contradictory to the CREATE-X results.”

Gradishar urged colleagues to refer patients to 2 ongoing large, randomized trials in TNBC. EA1131 has an accrual goal of 750 patients with TNBC and residual disease of 1 cm or greater (NCT02445391). Patients will be randomized to adjuvant capecitabine versus carboplatin or cisplatin for 4 cycles. S1418 will accrue close to 1000 patients with TNBC and residual disease of 1 cm or greater who have completed capecitabine or therapy on EA1131 (NCT02954874). These patients will be randomized to receive adjuvant pembrolizumab or observation for 1 year. “Importantly, patients can participate in 1 or both of these trials simultaneously,” he said.

Gradishar also focused on the results of the phase III KATHERINE trial, which investigated ado-trastuzumab emtansine (T-DM1; Kadcyla) versus trastuzumab as adjuvant therapy in patients with HER2-positive early breast cancer with residual invasive disease following neoadjuvant chemotherapy and HER2-targeted therapy.⁵Enrolled patients had centrally confirmed cT1-4/N0-3/M0 HER2-positive disease at presentation. Neoadjuvant therapy must have consisted of at least 6 cycles of chemotherapy and at least 9 weeks of taxane. Anthracyclines and alkylating agents were allowed, and all chemotherapy must have been given preoperatively. Patients received at least 9 weeks of trastuzumab, and a second HER2- targeted agent was allowed. Randomization must have occurred within 12 weeks of surgery.

Each arm contained 743 patients, and the invasive disease-free survival (iDFS) curves favored the T-DM1 arm. There were 165 iDFS events (22.2%) in the trastuzumab arm compared with just 91 (12.2%) in the T-DM1 arm (unstratified HR, 0.50; 95% CI, 0.39-0.64; P <.001). The 3-year iDFS rate was 77.0% in the trastuzumab group and 88.3% in the T-DM1 group.

&ldquo;The standard of care has changed,&rdquo; Gradishar said. &ldquo;T-DM1 should be recommended to the vast majority of patients with residual disease after a taxane-based neoadjuvant regimen.&rdquo;

Thus, not only can response to neoadjuvant chemotherapy be used to tailor subsequent systemic therapies, but the postneoadjuvant chemotherapy residual disease setting also is ideal for evaluating novel drugs and combinations, Gradishar said: &ldquo;In addition to the important CREATE-X and KATHERINE trials, several ongoing trials are evaluating promising novel targeted therapies for patients who have residual disease following neoadjuvant chemotherapy.&rdquo;

References:

1. Gradishar WJ. Optimal approach to residual disease after NAC. Presented at: Lynn Sage Breast Cancer Symposium; October 3-6, 2019; Chicago, IL.
2. Schmid P, Cortes J, Dent R, et al. KEYNOTE-522: Phase 3 study of pembrolizumab + chemotherapy vs placebo + chemotherapy as neoadjuvant treatment, followed by pembrolizumab vs placebo as adjuvant treatment for early-stage high-risk triple-negative breast cancer. Presented at: European Society for Medical Oncology 2019 Congress; September 27-October 1, 2019; Barcelona, Spain. Abstract LBA8_PR.
3. Leidtke C, Mazouni C, Hess KR, et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer.J Clin Oncol. 2008;26(8):1275-1281. doi: 10.1200/JCO.2007.14.4147.
4. Masuda N, Lee S-J, Ohtani S, et al. Adjuvant capecitabine for breast cancer after preoperative chemotherapy.N Engl J Med.2017;376(22):2147-2159. doi: 10.1056/NEJMoa1612645.
5. von Minckwitz G, Huang CS, Mano MS, et al; KATHERINE Investigators. Trastuzumab emtansine for residual invasive HER2-positive breast cancer.N Engl J Med. 2019;380(7):617-628. doi: 10.1056/NEJMoa1814017.