Adjuvant ado-trastuzumab emtansine provides ‘transformative’ benefit for certain patients with HER2-positive breast cancer
SAN ANTONIO — Adjuvant ado-trastuzumab emtansine reduced risk for invasive recurrence by 50% compared with trastuzumab among patients with HER2-positive early breast cancer who still had residual invasive disease after neoadjuvant chemotherapy and HER2-targeted therapy, according to results of the KATHERINE trial presented at San Antonio Breast Cancer Symposium.
The findings show how less-than-optimal response to standard neoadjuvant therapy can identify patients at increased risk for recurrence who may benefit to switching to ado-trastuzumab emtansine (Kadcyla, Genentech), according to researcher Charles E. Geyer Jr., MD, professor of medicine at Virginia Commonwealth University School of Medicine, associate director for clinical research and chair in cancer research at Massey Cancer Center in Richmond, Virginia.
“These results really are going to be transformative,” Geyer told HemOnc Today. “One of the concerns we always had with giving patients neoadjuvant therapy was that ... patients who still had residual disease were at higher risk for recurrence but we had nothing to offer them except finishing standard treatment. ...
“Now, we see that switching these patients to a different agent clearly is a good thing to do,” Geyer added. “I think it will have a substantial impact and address an unmet medical need.”
Patients with HER2-positive breast cancer who present with larger tumors or tumors that have spread to axillary lymph nodes typically undergo neoadjuvant chemotherapy, plus HER2-targeted therapy with trastuzumab (Herceptin, Genentech) alone or in combination with pertuzumab (Perjeta, Genentech).
Patients who have no residual disease at the time of surgery generally have favorable prognosis and low recurrence risk. However, patients who have residual invasive disease at surgery have a higher recurrence risk and need more effective therapies, according to study background.
In the randomized phase 3 KATHERINE trial, researchers evaluated whether treating patients with invasive residual breast cancer at surgery with adjuvant ado-trastuzumab emtansine instead of standard trastuzumab would reduce recurrence risk without increasing toxicity.
Ado-trastuzumab emtansine is approved in the United States to treat patients with metastatic HER2-positive breast cancer who underwent prior treatment with trastuzumab and taxane chemotherapy.
The open-label KATHERINE study included 1,486 patients with HER2-positive early-stage breast cancer who completed neoadjuvant chemotherapy that consisted of a minimum six cycles of chemotherapy plus a minimum 9 weeks of trastuzumab. Patients who received a second HER2-targeted agent were eligible.
All patients had invasive disease in the breast or axillary lymph nodes at the time of surgery. Adjuvant treatment began within 12 weeks of surgery.
Researchers randomly assigned half of the patients to ado-trastuzumab emtansine dosed at 3.6 mg/kg via IV ever 3 weeks. The other half received trastuzumab 6 mg/kg via IV every 3 weeks for 14 cycles.
Stratification factors included clinical presentation (operable vs. inoperable), hormone receptor status, preoperative therapy (trastuzumab alone or with a second HER2-targeted agent), and pathological nodal status after neoadjuvant therapy.
Invasive DFS — defined as disease recurrence events or death without recurrence — served as the primary endpoint.
Results showed ado-trastuzumab emtansine reduced the risk for invasive recurrence or death by half (HR = 0.5; 95% CI, 0.39-0.64). Three-year DFS rates were 88.3% in the ado-trastuzumab emtansine group and 77% in the trastuzumab group.
The benefit persisted across all key patient subgroups and also appeared consistent regardless of baseline characteristics, such as age, race and menopausal status.
Ado-trastuzumab emtansine also conferred benefit for DFS and distant recurrence-free interval, both of which served as secondary efficacy endpoints.
OS data are immature and likely will not be available for several years, Geyer said.
Adverse events observed with ado-trastuzumab emtansine in the KATHERINE study appeared consistent with those previously observed when the agent had been used to treat patients with metastatic disease, Geyer said.
Adverse events that occurred at higher rates among ado-trastuzumab emtansine-treated patients than trastuzumab-treated patients included fatigue (50% vs. 34%), nausea (42% vs. 13%), decreased platelet counts (29% vs. 2%), increased aspartate aminotransferase levels (28% vs. 6%), headache (28% vs. 17%), arthralgia (26% vs. 21%), increased alanine aminotransferase levels (23% vs. 6%) and sensory neuropathy (19% vs. 7%).
However, the majority of these toxicities were grade 1 or grade 2, and they resolved after ado-trastuzumab emtansine dose reductions or discontinuation.
The study may be limited by the fact central confirmation of positive HER2 status was performed on the pretreatment core biopsy instead of the residual tumor, Geyer said.
Researchers have collected paired specimens from more than two-thirds of patients in the KATHERINE trial.
Those samples will be analyzed to determine the rate of HER2 loss in postsurgical specimens, as well as the activity of ado-trastuzumab emtansine among those patients, Geyer said. They also will be used to explore potential resistance mechanisms to neoadjuvant chemotherapy plus trastuzumab, as well as adjuvant ado-trastuzumab emtansine.
The results to date, though, are practice changing, Geyer told HemOnc Today.
“Standards of care are a process, and this gives a foundation for that discussion,” he said. “My opinion is this should be accepted as a standard of care. Of course, that will be driven by whether regulators and third-party payers agree, but these are very compelling data and it is hard to imagine how you would not make this available.” – by Mark Leiser
Geyer JR CE, et al. Abstract GS1-10. Presented at: San Antonio Breast Cancer Symposium; Dec. 4-8, 2018; San Antonio.
F. Hoffmann La Roche/Genentech sponsored this study. Geyer reports travel support from AstraZeneca and Roche; medical writing support from AbbVie and Roche; and honoraria from Celgene. Please see the abstract for all other authors’ relevant financial disclosures.