'Remarkable' New Benefit in HER2+ Breast Cancer

KATHERINE and T-DM1 Change Practice

Nick Mulcahy

February 13, 2019

The treatment of HER2-positive, early stage breast cancer has taken "one more step toward personalized medicine and reduced mortality" thanks to the results of the KATHERINE trial, according to Daniel Hayes, MD, a medical oncologist at the University of Michigan Rogel Cancer Center in Ann Arbor.

He says the trial is a "game changer" for patients who have residual disease after initial drug treatment and surgery, in an editorial published online February 13 in the New England Journal of Medicine.

The editorial accompanies publication of the trial results, which were first presented at the San Antonio Breast Cancer Symposium in December 2018, as reported by Medscape Medical News.

The trial enrolled patients with stage I to III HER2-positive disease who were found to have residual disease upon excision after standard neoadjuvant treatment (chemotherapy plus a HER2-targeted drug).

The trialists randomized these patients to post-surgery ado-trastuzumab emtansine (T-DM1; Kadcyla, Roche) or the current adjuvant standard — trastuzumab — for 14 cycles.

T-DM1 is an antibody–drug conjugate of trastuzumab and the cytotoxic agent emtansine (DM1) approved for use in patients with HER2-positive metastatic breast cancer.

The intent of the trial was to see whether T-DM1 could improve outcomes in this residual disease population. These early stage patients who have lingering disease after pre-surgery drug treatment have a higher risk of disease recurrence or death than those who have a pathological complete response (ie, no residual disease), previous studies have shown.

The intent was met, suggested Hayes. The results amount to a "remarkable benefit" and are "impressive and clinically meaningful," he says.

Specifically, among 1486 randomly assigned patients (743 in the T-DM1 arm and 743 in the trastuzumab arm), invasive disease or death, which was the primary endpoint, had occurred in 91 patients in the T-DM1 group (12.2%) and 165 patients in the trastuzumab group (22.2%).

The estimated percentage of patients who were free of invasive disease at 3 years was 88.3% in the T-DM1 group and 77.0% in the trastuzumab group — an absolute difference of 11.3%.

"T-DM1 offers a major opportunity to improve long-term outcomes," Hayes summarizes.

There is a price, however, for the improved efficacy, he adds. "Caveat emptor: doctors and patients need to be aware that the side effects of this regimen are more common than with trastuzumab alone, and occasional severe toxic effects need to be considered," Hayes writes.

Hayes stresses that the neoadjuvant standard of care remains chemotherapy plus HER2-targeted therapy for patients with newly diagnosed HER2-positive breast cancer.

If patients do not have a pathological complete response with such a regimen, then postoperative or adjuvant treatment with T-DM1 is now the new standard, he writes.

However, Hayes believes this new adjuvant standard is fitting for stage II and III HER2-positive disease but not stage I. These [stage I] patients have a "very favorable outcome with adjuvant paclitaxel and trastuzumab alone," he observes, citing other research (N Engl J Med. 2015;372:134-141).

Medscape Medical News asked senior study author Charles Geyer, MD, of the Massey Cancer Center, Virginia Commonwealth University, in Richmond, and lead author Gunter von Minckwitz, MD, PhD, of the German Breast Group Research Institute in Neu-Isenburg, about Hayes' recommendation that T-DM1 be limited to stage II and III patients with residual disease.

"The bottom line is that all of the post neoadjuvant size groups benefited from T-DM1," said Geyer, explaining that tumor size dictates stage I, II, and III.

von Minckwitz emphasized that whatever their stage, all of the patients in the trial are at considerable risk of recurrence. "We were selecting patients with resistance to intense chemo-antibody therapy, so despite early stage these patients are at significant risk of relapse," he commented.

Hayes' comments about T-DM1 as the new standard of care in this setting were akin to those of the San Antonio meeting discussant Eric Winer, MD, of the Dana Farber Cancer Institute in Boston, Massachusetts.

"In my view, the standard of care has actually changed," Winer told the meeting audience.

"T-DM1 should be recommended to the vast majority of patients with residual disease," he said.

However, Winer did not sound any cautionary notes about toxicity or stage appropriateness. "It is a treatment that is well tolerated by most of our patients," he said at the time.

However, notably, adverse events leading to drug discontinuation occurred in 133 patients in the T-DM1 group (18.0%) but only 15 patients in the trastuzumab group (2.1%).

More on Trial Results

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 [NSABP] and German Breast Group) and Roche, the makers of T-DM1.

Patients were eligible for the trial if they had histologically confirmed, HER2-positive, nonmetastatic, invasive primary breast cancer (clinical tumor stage T1 to T4, nodal stage N0 to N3, and metastasis stage M0).

In other efficacy data from the trial, 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, there was no impact on brain metastases.

A total of 98 deaths were reported (42 in the T-DM1 group and 56 in the trastuzumab group), but additional follow-up is needed to establish overall survival.

All 14 cycles of assigned therapy were completed in 71.4% of T-DM1 patients and 81.0% of trastuzumab patients.

Serious adverse events occurred in 94 T-DM1 patients (12.7%) and 58 trastuzumab patients (8.1%).

The most prominent adverse events included peripheral sensory neuropathy (of any grade), which was reported in 138 patients who received T-DM1 (18.6%) and 50 patients who received trastuzumab (6.9%). However, the investigators said 103 of the 138 cases of sensory neuropathy in the T-DM1 group (74.6%) were resolved at the data cutoff point.

The KATHERINE study was funded by Roche and designed by a steering committee comprised of members from the German Breast Group, NSABP Foundation, independent investigators, and the sponsor. One study author is an employee of Roche. Other study authors have financial ties to Roche. Hayes has financial ties to multiple pharmaceutical companies but reports none with Roche.

N Engl J Med. 2019;380:617-628. Abstract, Editorial

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