CORRECTED December 10, 2018 // SAN ANTONIO — For patients with HER2-positive, early stage breast cancer who receive chemotherapy and trastuzumab before surgery and disappointingly have residual disease upon excision, there is now a new standard for the next step in treatment, suggest results from a major trial.
Typically, these early stage patients, who have a worse prognosis than their counterparts who clear the disease, would go on to receive more trastuzumab in the adjuvant setting.
But according to new results from the phase 3 KATHERINE trial, use of adjuvant ado-trastuzumab emtansine (T-DM1; Kadcyla, Roche) in this residual disease group cuts the risk of recurrence of breast cancer or death by 50% versus trastuzumab alone.
T-DM1 is an antibody–drug conjugate of trastuzumab and the cytotoxic agent emtansine and is approved by the US Food and Drug Administration for HER2-positive metastatic breast cancer.
The new data were presented here today at the 2018 San Antonio Breast Cancer Symposium and simultaneously published online in the New England Journal of Medicine.
In an interim analysis of the trial, invasive disease or death occurred in 91 patients in the 743-patient T-DM1 group (12.2%) and 165 patients in the 743-patient trastuzumab group (22.2%).
The estimated percentage of patients free of invasive disease at 3 years was 88.3% in the T-DM1 group and 77.0% in the trastuzumab group.
This 11.3% difference constituted a "large and substantial absolute improvement," said lead author Charles Geyer, MD, of the Virginia Commonwealth University Massey Cancer Center in Richmond, at a meeting press conference.
The KATHERINE results create "the foundation of a new standard of care in this population," he proclaimed.
"I believe these results will be practice changing," Geyer added in a press statement.
Meeting discussant Eric Winer, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, agreed: "In my view, the standard of care has actually changed."
"T-DM1 should be recommended to the vast majority of patients with residual disease," he said, referring to this setting.
"TDM-1 represents a big benefit over the standard trastuzumab and is a new standard of care for these poor prognosis patients," said Charles Shapiro, MD, of the Icahn School of Medicine at Mount Sinai in New York City, who was asked for comment.
Notably, Geyer reported that there was a "striking consistency" of benefit across all of the "key" subgroups including patients who had hormone receptor-positive and -negative tumors; differing amounts of residual disease at surgery; and single or dual HER2-targeted therapy in the neoadjuvant regimen that preceded the study's adjuvant treatment.
Also importantly, distant recurrence (metastatic disease) as the first invasive-disease event occurred in 78 patients who received T-DM1 (10.5%) and 118 patients who received trastuzumab (15.9%). However, as Winer pointed out, there was no impact on brain metastases.
Longer follow-up is needed to determine overall survival benefit. Currently, the median duration of follow-up was about 41 months. At this point, there were 42 deaths in the T-DM1 group and 56 deaths in the trastuzumab group.
T-DM1 Is More Toxic But Well Tolerated
Geyer said the adverse events data were "consistent with the known toxicities of T-DM1" and "temporary for the most part."
However, T-DM1 was more toxic with regard to completing treatment. The study's 14 cycles of assigned therapy were completed in 81.0% of patients who received trastuzumab but in only 71.4% of patients who received T-DM1.
Also, adverse events leading to discontinuation occurred in 133 patients in the T-DM1 group (18.0%) and 15 patients in the trastuzumab group (2.1%).
Furthermore, T-DM1 consistently had higher rates of grade 1, 2, and ≥ 3 adverse events compared with trastuzumab across a spectrum of side effects.
Geyer highlighted a number of the adverse events including sensory neuropathy, which occurred in 19% of the T-DM1 group versus 7% of the trastuzumab group. However, he emphasized that only 5% of the 19% was a high-grade adverse event.
T-DM1 appears to be a "tolerable and manageable regimen," Geyer summarized. Dana-Farber's Winer said the same: "It is a treatment that is well tolerated by most of our patients."
Study Design and Some Words About Pertuzumab
An open-label, randomized trial, KATHERINE is a multinational collaborative effort involving US and German clinical trial groups (National Surgical Adjuvant Breast and Bowel Project and German Breast Group) and Roche, the makers of T-DM1.
All patients had HER2-positive early breast cancer at presentation (clinical tumor stage T1 to T4, nodal stage N0 to N3, and metastasis stage M0 excluding clinical stage T1aN0 or T1bN0). All also had residual invasive disease in the breast or axilla at surgery after receiving and completing neoadjuvant therapy including a taxane (with or without anthracycline) and a minimum of 9 weeks of trastuzumab.
Importantly, the patients were stratified by a number of variables because of the heterogeneity of the population. Factors included operable versus inoperable disease, hormone receptor status, preoperative therapy (trastuzumab versus trastuzumab plus a second HER2-targeted therapy), and lymph node status.
A minority of KATHERINE patients (20%) received pertuzumab (Perjeta, Roche) in the neoadjuvant setting (before the start of the new study). Should such patients switch to T-DM1 in clinical practice? Yes, Winer answered, explaining that if such patients do not have a pathologic complete response on pertuzumab, it is "unlikely" they will benefit from ongoing pertuzumab. "I would not continue pertuzumab with T-DM1," he added.
Winer concluded that KATHERINE is a "big boost" for T-DM1 and anticipated pertuzumab will be used less in the adjuvant setting going forward.
The KATHERINE study was supported by Roche. One study author, Hannah Douthwaite, MSc, is an employee of Roche. Other study authors, including Geyer, have financial ties to Roche.
San Antonio Breast Cancer Symposium 2018. Presented December 5. Abstract GS1-10.
N Engl J Med. Published online December 5, 2018. Full text
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Editor's note: This article has been corrected to provide the correct proportion of study patients who received neoadjuvant pertuzumab. It was 20% and not 2% as initially reported.
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