Exploratory Analyses of KATHERINE Trial Inform Adjuvant T-DM1 Use in HER2+ Breast Cancer

Maria Hafez, MD

After demonstrating the efficacy of adjuvant ado-trastuzumab emtansine (Kadcyla; T-DM1) vs trastuzumab (Herceptin) in patients with HER2-positive breast cancer, updated efficacy, safety, and biomarker analyses from the phase 3 KATHERINE trial (NCT01772472) continue to influence how to navigate the selection of adjuvant therapy for patients in this high-risk subgroup, according to Maria Hafez, MD.

Primary findings from the KATHERINE trial showed that patients treated with T-DM1 experienced a 3-year invasive disease-free survival (IDFS) rate of 88.3% vs 77.0% in those treated with trastuzumab (HR, 0.50; 95% CI, 0.39-0.64; P < .001). Moreover, this IDFS benefit was observed across key patient subgroups. Distant recurrence as the first invasive disease event was observed in 10.5% and 15.9% of patients in the T-DM1 and trastuzumab arms, respectively. Notably, more toxicities were observed with T-DM1 than with trastuzumab alone, although these data were consistent with the known safety profile of T-DM1.¹

“[Updated exploratory analyses of KATHERINE showed that] even patients who became HER2-negative following surgery or neoadjuvant chemotherapy still benefited from T-DM1,” Hafez said following her participation in an OncLive^® State of the Science Summit™ on breast cancer.

In an interview with OncLive, Hafez spotlighted the KATHERINE trial in HER2-positive breast cancer, expanding on the respective toxicity profiles of T-DM1 and trastuzumab that were identified in an exploratory safety analysis of the trial; updated outcomes with T-DM1 in patients with residual invasive disease following neoadjuvant treatment and surgery; and the relationship between biomarker expression and survival outcomes in patients with residual disease.

Hafez is an assistant professor at Sidney Kimmel Medical College, a breast and sarcoma medical oncologist, and the director of Breast Cancer Clinical Research at Sidney Kimmel Cancer Center at Thomas Jefferson University in Philadelphia, Pennsylvania.

OncLive: What was the primary objective and design of the KATHERINE trial?

Hafez: The KATHERINE trial was considered practice changing when it came out in 2019. This was a phase 3 trial evaluating T-DM1 vs standard-of-care trastuzumab in the adjuvant setting in patients with HER2-positive breast cancer who had residual disease following neoadjuvant chemotherapy and surgery. The primary end point was IDFS, and the secondary end points included disease-free survival and overall survival. The study met its primary end point with a 50% decrease in recurrence or death with T-DM1 compared with trastuzumab.

Could you expand on the safety profile of these agents according to data from the exploratory analysis of the KATHERINE trial?²

An exploratory safety and efficacy subgroup analysis from the KATHERINE trial was presented at the 2021 ESMO Congress. It [included] the incidence and resolution of peripheral neuropathy, thrombocytopenia, and central nervous system [CNS] disease.

There was more peripheral neuropathy with T-DM1 compared with trastuzumab. However, [this neuropathy] was resolved within 300 days of the treatment in 82% of patients. The average [duration of peripheral neuropathy] was between 105 and 109 days. The patients who received platinum chemotherapy in the neoadjuvant setting and T-DM1 in the adjuvant setting had more grade 3/4 thrombocytopenia, [and most experienced] resolution within 30 days after the treatment. There was no grade 3 or higher hemorrhage in those patients. Interestingly, the incidence of peripheral neuropathy was similar regardless of whether patients received paclitaxel or docetaxel.

CNS recurrence was not better with T-DM1 than with trastuzumab. CNS recurrence was higher in the T-DM1 arm compared with the trastuzumab arm because T-DM1 has better control of peripheral distant metastases [than trastuzumab]. We still have more research to do to better control CNS recurrence in this population.

What additional efficacy data were reported from this analysis?

[Updated data] from the KATHERINE trial showed that patients with residual disease of 1 cm or smaller still benefit from T-DM1 compared with trastuzumab. Another update from the trial showed that some patients [with HER2-positive disease at baseline] who received neoadjuvant chemotherapy [displayed] HER2-negative disease after surgery.³ Approximately 70 patients had HER2-negative [residual] disease compared with the 775 patients [who had] HER2-positive [disease after surgery]. [Notably,] we’re not encouraging [oncologists] to check HER2 status again after surgery.

What differences in biomarker expression before and after neoadjuvant therapy were identified in the biomarker analysis of the KATHERINE trial that was published in April 2023?⁴

The latest update from an analysis of the KATHERINE trial [includes] biomarker data from [patients with HER2-positive breast cancer with] residual invasive disease after neoadjuvant therapy. This analysis aimed to identify biomarkers of response and differences in biomarker expression before and after neoadjuvant chemotherapy. That exploratory analysis investigated the relationship between iDFS and HER2 protein expression or gene amplification; PIK3CA hotspot mutations; and expression of PD-L1, CD8, predefined immune signatures, and Prediction Analysis of Microarray 50 intrinsic molecular subtypes, as classified by Absolute Intrinsic Molecular Subtyping.

The results showed that T-DM1 improved IDFS vs trastuzumab across most biomarkers. High HER2gene expression in residual disease was associated with worse outcomes with trastuzumab vs low expression, with an HR of 2.02. However, IDFS with T-DM1 was independent of HER2 expression level, with an HR of 1.01. [Findings] also showed that low PD-L1 gene expression in residual disease was associated with worse outcomes with trastuzumab, with an HR of 0.66, but not with T-DM1, with an HR of 1.05. PIK3CA mutations were not prognostic, and increased variability in HER2 expression was observed in post-neoadjuvant samples vs paired pre-neoadjuvant samples.

References

1. von Minckwitz G, Huang CS, Mano MS, et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med. 2019;380(7):617-628. doi:10.1056/NEJMoa1814017
2. Mamounas EP, Untch M, Mano MS, et al. Adjuvant T-DM1 versus trastuzumab in patients with residual invasive disease after neoadjuvant therapy for HER2-positive breast cancer: subgroup analyses from KATHERINE. Ann Oncol. 2021;21(8):1005-1014. doi:10.1016/j.annonc.2021.04.011
3. Loibl S, Huang CS, Mano MS, et al. Adjuvant trastuzumab emtansine in HER2-positive breast cancer patients with HER2-negative residual invasive disease in KATHERINE. NPJ Breast Cancer. 2022;8(1):106. doi:10.1038/s41523-022-00477-z
4. Denkert C, Lambertini C, Fasching PA, et al. Biomarker data from the phase III KATHERINE study of adjuvant T-DM1 versus trastuzumab for residual invasive disease after neoadjuvant therapy for HER2-positive breast cancer. Clin Cancer Res. 2023;29(8):1569-1581. doi:10.1158/1078-0432.CCR-22-1989