SAN ANTONIO – Patients with HER2-positive early breast cancer with residual invasive disease following neoadjuvant therapy had a 50% reduction in risk for invasive breast cancer recurrence or death when they were treated with the antibody-drug conjugate trastuzumab emtansine (T-DM1; Kadcyla), results of the KATHERINE trial showed.
Among 743 patients randomized to adjuvant therapy with T-DM1, the 3-year invasive disease-free survival (IDFS) rate was 88.3%, compared with 77.0% for patients assigned to adjuvant trastuzumab (Herceptin).
The hazard ratio for IDFS – a composite endpoint of freedom from ipsilateral invasive breast tumor recurrence, ipsilateral locoregional invasive breast cancer recurrence, contralateral invasive breast cancer, distant recurrence, or death from any cause – was 0.50 (P less than .001), reported, from Virginia Commonwealth University, Richmond.
“While additional follow-up will be necessary to evaluate the effect of T-DM1 on overall survival, the compelling and consistent efficacy seen on the IDFS endpoint with the safety profile will likely form the foundation of a new standard of care in the KATHERINE patient population,” he said at the San Antonio Breast Cancer Symposium.
Results from KATHERINE were published online into coincide with its presentation in a briefing and in a general session.
KATHERINE was an open-label, phase 3 trial pitting T-DM1 against trastuzumab as adjuvant therapy in patients with early HER2-positive breast cancer with residual invasive disease in the breast or axilla at surgery following neoadjuvant therapy with a taxane (with or without an anthracycline) and trastuzumab. After stratification for clinical presentation (operable vs. inoperable), hormone receptor status, type of preoperative therapy, and pathological nodal status after neoadjuvant, patients were randomized to 14 cycles of either T-DM1 or trastuzumab.
The primary endpoint, IDFS, was as noted before. The trial was stopped after the results were found to cross the efficacy stopping boundary (HR less than 0.732) at the prespecified interim IDFS analysis in July 2018.
The efficacy of T-DM1 was supported by the finding that distant recurrence as the first invasive-disease event occurred in 10.5% of patients assigned to T-DM1, compared with 15.9% of those assigned to trastuzumab. The benefit of T-DM1 was consistent across all key subgroups, including all of the aforementioned stratification factors plus age, group, and race.
The safety analysis included data on 740 patients treated with T-DM1 and 720 treated with trastuzumab. The most common grade 3 or greater adverse events in the T-DM1 group included decreased platelet count in 5.7% and hypertension in 2.0%. The most common grade 3 or greater events in the trastuzumab group were hypertension in 1.2% and radiation-related skin injury in 1.0%.
Serious adverse events were more common in the T-DM1 arm, occurring in 12.7% of patients, compared with 8.1% in the trastuzumab arm. Adverse events leading to discontinuation of the trial drug occurred in 18.0% versus 2.1%, in the T-DM1 arm versus trastuzumab arm respectively.
Dr. Geyer said that, in general, adverse events in the T-DM1 arm were consistent with those seen in other studies, with manageable toxicities and no new safety signals.
“At the present time, the role of T-DM1 in the adjuvant and neoadjuvant setting is limited,” commented invited discussant, from the Dana-Farber Cancer Institute in Boston. “It’s confined to patients who have residual disease after neoadjuvant therapy, but I predict this will change dramatically over time. Given how well tolerated T-DM1 is, how effective it was in this study, the answer that one comes to is why not consider using it more broadly and in an earlier-stage setting?”
, from Massachusetts General Hospital in Boston, who was not involved in KATHERINE, agreed that the trial results are practice changing.
“I anticipate we would be using T-DM1 in the future for patients who would otherwise have been eligible for KATHERINE,” he said in an interview.
It’s still unclear, however, whether patients who receive pertuzumab (Perjeta) in the neoadjuvant setting and have residual lymph-node positive or estrogen receptor–negative might benefit with adjuvant therapy with T-DM1 instead of trastuzumab, he said.
“The second question that’s unclear at this time is patients who get 1 year of T-DM1, should they then receive neratinib [Nerlynx], because we have data from the ExteNET trial which showed that patients who complete 1 year of anti-HER2 therapy, if they receive 1 year of neratinib, there’s also reduced risk of recurrence, and that’s an unknown question at this time,” Dr. Bardia said.
The trial was funded by Hoffman–La Roche/Genentech. Dr. Geyer reported travel support from Roche and AstraZeneca, medical writing support from AbbVie and Roche, and honoraria from Celgene. Dr. Winer reported receiving grants for clinical research from and has served as an adviser or consultant to Genentech, AstraZeneca, Pfizer, and GlaxoSmithKline. Dr. Bardia reported relationships with Genentech and Novartis.
SOURCE: Geyer CE et al. N Engl J Med. 2018 Dec 5. doi: 10.1056/NEJMoa1814017.