Genentech has completed its FDA submission of a supplemental Biologics License Application for ado-trastuzumab emtansine as an adjuvant treatment for patients with HER2-positive early breast cancer who had residual disease following neoadjuvant therapy.
Sandra Horning, MD
Genentech (Roche) has completed its FDA submission of a supplemental Biologics License Application (sBLA) for ado-trastuzumab emtansine (T-DM1; Kadcyla) as an adjuvant treatment for patients with HER2-positive early breast cancer who had residual disease following neoadjuvant therapy.
The sBLA is based on data from the phase III KATHERINE study, in which T-DM1 reduced the risk of invasive disease recurrence or death by 50% compared with trastuzumab (Herceptin) in this setting. The 3-year invasive disease-free survival (iDFS) rate was 88.3% with T-DM1 versus 77.0% with trastuzumab. The iDFS benefit with T-DM1 was upheld across key patient subgroups, according to results presented at the 2018 San Antonio Breast Cancer Symposium and simultaneously published in the New England Journal of Medicine.1,2
“Kadcyla was granted breakthrough therapy designation and is also the first Genentech medicine to be reviewed under the FDA’s Real-Time Oncology Review pilot program; both FDA initiatives aim to expedite reviews and bring medicines to patients sooner,” Sandra Horning, MD, chief medical officer and head of Global Product Development at Roche, said in a statement. “We are working closely with the FDA to bring Kadcyla to people with HER2-positive early breast cancer who have residual disease after neoadjuvant therapy as early as possible.”
The open-label KATHERINE trial included 1486 patients with centrally confirmed HER2-positive, nonmetastatic, invasive primary breast cancer who were found to have residual invasive tumor in the breast or axillary nodes at surgery after completing neoadjuvant chemotherapy. Neoadjuvant chemotherapy had to consist of ≥6 cycles of chemotherapy containing a taxane (with or without anthracycline) and ≥9 weeks of trastuzumab.
Patient characteristics were well balanced between the 2 study arms. Across the study population, the median age was 49, three-fourths of patients were white, and 75% of patients had operable breast cancer at presentation. Three-fourths of patients in both arms were ER-positive, PR-positive, or both.
Over seventy-six percent of patients had prior anthracycline use. Across both arms, neoadjuvant HER2-targeted therapy consisted of trastuzumab alone for approximately 80% of patients, trastuzumab plus pertuzumab (Perjeta) for 19%, and trastuzumab plus other HER2-targeted therapy (neratinib, dacomitinib, afatinib, and lapatinib) for 1%.
Patients were randomized within 12 weeks of surgery to either T-DM1 at 3.6 mg/kg IV (n = 743) or trastuzumab at 6 mg/kg IV (n = 743). Both agents were administered every 3 weeks for 14 cycles.
The consistent iDFS benefit with T-DM1 was shown across several key subgroups: operable disease at presentation (HR, 0.47), inoperable disease at presentation (HR, 0.54), negative hormone receptor status (HR, 0.50), positive hormone receptor status (HR, 0.48), trastuzumab as only anti-HER2 agent in neoadjuvant setting (HR, 0.49), trastuzumab plus ≥1 anti-HER2 agent in neoadjuvant setting (HR, 0.54), node-positive disease after neoadjuvant treatment (HR, 0.52), and node-negative disease after neoadjuvant treatment (HR, 0.44).
“One of the remarkable findings [of this study] is there really is a striking homogeneity of consistency in terms of the efficacy in all these various subgroups,” said Geyer.
Regarding toxicity, Geyer said, “Safety data were consistent with the known toxicities of T-DM1, with expected increases in manageable adverse events associated with T-DM1 compared to trastuzumab.”
The safety analysis included 740 patients in the T-DM1 arm and 720 patients in the trastuzumab arm. “The majority of adverse events were grad 1/2—milder symptoms,” said Geyer.
The rate of grade ≥3 adverse events (AEs) was 25.7% versus 15.4%, and the rate of serious AEs was 12.7% versus 8.1%, respectively. AE-related discontinuations occurred in 18% of the T-DM1 arm versus 2.1% in the trastuzumab arm.
The most common grade ≥3 AEs across the overall population included decreased platelet count (5.7% with T-DM1 vs 0.3% with trastuzumab), hypertension (2.0% vs 1.2%, respectively), peripheral sensory neuropathy (1.4% vs 0), decreased neutrophil count (1.2% vs 0.7%), hypokalemia (1.2% vs 0.1%), fatigue (1.1% vs 0.1%), and anemia (1.1% vs 0.1%).
In a discussion session following his data presentation, Geyer addressed a question on whether trastuzumab alone is the current standard for this high-risk patient population, or whether it is trastuzumab plus pertuzumab.
“That would be variable globally. Pertuzumab is becoming used more frequently. If you’ve used the 2 antibodies preoperatively, they tend to be carried postoperatively. But [given] the fact that [T-DM1] has a 50% reduction in hazard versus trastuzumab, [it] is just very unlikely that pertuzumab could have that much benefit in this patient population,” explained Geyer.
T-DM1 is currently approved by the FDA for the treatment of patients with metastatic HER2-positive breast cancer who previously received trastuzumab and a taxane, either alone or in combination.