In contemporary breast cancer clinical practice, the correlation between achieving a pathologic complete response after neoadjuvant chemotherapy and significantly improved outcomes after chemotherapy has been well established. However, in a discussion at the 2019 Lynn Sage Breast Cancer Symposium, William J. Gradishar, MD, cautioned colleagues that there is more to the story when one looks at long-term data in these patients.
William J. Gradishar, MD
In contemporary breast cancer clinical practice, the correlation between achieving a pathologic complete response (pCR) after neoadjuvant chemotherapy and significantly improved outcomes after chemotherapy has been well established. However, in a discussion at the 2019 Lynn Sage Breast Cancer Symposium, William J. Gradishar, MD, cautioned colleagues that there is more to the story when one looks at long-term data in these patients.
Different Modalities Boost pCR
Gradishar, chief of the Division of Hematology and Oncology in the Department of Medicine and Betsy Bramsen Professor of Breast Oncology at Northwestern University Feinberg School of Medicine, began his discussion by summarizing the improvements different modalities have brought to pCR rates in recent years.
First, the anthracyclines brought the pCR rate to 10% to 15%, he said, followed by the addition of taxanes to anthracyclines, which increased pCR rates to 25% to 30%. pCR rates approached 50% with the addition of trastuzumab (Herceptin) to the HER2-positive arsenal, and they have now reached up to 60% with combined chemotherapy plus dual anti-HER2 therapy. Additionally, that same regimen has also achieved a decrease in the rates of axillary positivity of 50% or more.
Additionally, pCR data from two randomized trials that tested PD-1/PD-L1 targeted agents as neoadjuvant therapy in triple-negative breast cancer are expected soon. Gradishar, who has chaired the Lynn Sage Breast Cancer Symposium since its inception in 1998, told colleagues that the IMpassion-031 trial, which is testing nab-paclitaxel followed by adjuvant chemotherapy with or without atezolizumab has completed accrual with 204 patients and should be reporting soon.
Gradishar also discussed data from the KEYNOTE-522 trial. Findings from the trial presented at the 2019 ESMO Congress showed that neoadjuvant treatment with the combination of pembrolizumab (Keytruda) and chemotherapy extended pCR rates by 13.6 percentage points (CI, 5.4-21.8) compared with chemotherapy alone for patients with early triple-negative breast cancer (TNBC).2 The pCR rate was 64.8% with pembrolizumab plus chemotherapy compared with 51.2% for chemotherapy alone.
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).
After discussing the findings from KEYNOTE-522, Gradishar said he was reminded of data from MD Anderson researchers that showed a significant drop-off over several years among patients with TNBC post-adjuvant chemotherapy who had achieved pCR but then developed residual disease later. “What can we do to improve survival among these patients?” he asked.
How Can Outcomes Be Improved?
In response to his rhetorical question, Gradishar emphasized the importance of the CREATE-X trial that tested adjuvant capecitabine following preoperative chemotherapy.3 In this trial, 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 DFS (HR, 0.7; 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 triple-negative cohort were notable: the HR for recurrence was 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 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 two ongoing large, randomized trials in TNBC. The EA1131 trial is accruing 750 TNBC patients with residual disease of 1 cm or greater. They will be randomized to adjuvant capecitabine versus carboplatin or cisplatin for 4 cycles. The S1418 trial is accruing 1000 TNBC patients with residual disease of 1 cm or greater who have completed capecitabine or therapy on EA1131. These patients will be randomized to receive adjuvant pembrolizumab or observation for 1 year. “Importantly, patients can participate in one or both of these trials simultaneously,” he said.
Gradishar also focused on the results of the phase III KATHERINE trial, which studied 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.4 In this trial, patients had centrally confirmed cT1-4/N0-3/M0 HER2-positive disease at presentation. Neoadjuvant therapy must have consisted of a minimum of 6 cycles of chemotherapy and a minimum of 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.
With 743 patients in each arm, 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 only 91 iDFS events (12.2%) in the T-DM1 arm (Unstratified HR, 0.50; 95% CI, 0.39-0.64; P <.0001). The 3-year iDFS rate was 77.0% in the trastuzumab group and 88.3% in the T-DM1 group.
“The standard of care has changed,” said Gradishar. “T-DM1 should be recommended to the vast majority of patients with residual disease after a taxane-based neoadjuvant regimen.”
Thus, not only can response to neoadjuvant chemotherapy be used to tailor subsequent systemic therapies, but the post-neoadjuvant chemotherapy residual disease setting is ideal for evaluating novel drugs and combinations, Gradishar said: “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.”