FDA Approval Sought for Adjuvant T-DM1 in High-Risk HER2+ Breast Cancer

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.

References

1. Geyer Jr CE, Huang C-S, Mano MS, et al. Phase III Study of Trastuzumab Emtansine(T-DM1) vs Trastuzumab as Adjuvant Therapy in Patients with HER2-Positive Early Breast Cancer with Residual Invasive Disease after Neoadjuvant Chemotherapy and HER2-Targeted Therapy Including Trastuzumab: Primary Results from KATHERINE (NSABP B-50-I, GBG 77 and Roche BO27938). Presented at: 2018 San Antonio Breast Cancer Symposium; December 4-8, 2018; San Antonio, TX. Abstract GS1-10.
2. von Minckwitz G, Huang C-S, Mano MS, et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer [published online December 5, 2018]. New Engl J Med. doi: 10.1056/NEJMoa1814017.