Second Line T-DM1 Worsens Outcomes for HER2+ Breast Cancer in Real-World Study

Trastuzumab emtansine as a second-line treatment led to shorter median treatment duration and time to treatment failure in patients with HER2-positive metastatic breast cancer who progressed on pertuzumab and trastuzumab–based regimens.

Trastuzumab emtansine (T-DM1; Kadcyla) as a second-line treatment led to shorter median treatment duration and time to treatment failure in patients with HER2-positive metastatic breast cancer who progressed on pertuzumab (Perjeta) and trastuzumab (Herceptin)–based regimens, according to data from a real-world study of patients in the United States presented at the 39th Annual Miami Breast Cancer Conference®.1

Investigators identified 222 patients collected in IQVIA Oncology Electronic Medical Records database who initiated second-line treatment after receiving a pertuzumab and trastuzumab–based regimen in the first line. Notably, 71.6% of those patients were administered T-DM1 in the second line.

An analysis of these records showed that the median time to second-line T-DM1 discontinuation was 5.7 months (95% CI, 4.7-7.8) and the median time to T-DM1 treatment failure was 7.9 months (95% CI, 6.5-10.0). For all second-line treatment regimens, the median time to discontinuation was 5.9 months (95% CI, 5.0-8.7). The median time to second-line treatment failure was 8.6 months (95% CI, 7.3-11.5).

Additionally, the median overall survival (OS) for all second-line treatment initiation was 25.4 months (95% CI, 19.5-35.6) compared with 24.4 months (95% CI, 18.9-31.8) for T-DM1 (Figure).

“This study suggests high rates of treatment discontinuation and treatment failure associated with existing second-line therapies, including T-DM1, highlighting the unmet needs for more effective treatments among patients with HER2-positive metastatic breast cancer after failing [on a] first-line pertuzumab and trastuzumab–based regimen,” wrote lead study author Sandhya Mehta, PhD, director, HEOR, Oncology at Daiichi Sankyo Inc., and colleagues.

Investigators have previously observed efficacy for T-DM1 and other anti-HER2 therapies following pertuzumab and trastuzumab–based regimens. For example, T-DM1 elicited a higher median progression-free survival (PFS) and OS (9.6 months and 30.9 months, respectively), compared with lapatinib (Tykerb) plus capecitabine (6.4 months and 25.1 months, respectively), according to data from the phase 3 EMILIA trial (NCT00829166).2

However, there has been limited real-world data on these strategies in the broader United States population. This real-world study used the IQVIA Oncology Electronic Medical Records database to identify adult patients with HER2-positive metastatic breast cancer who initiated pertuzumab and trastuzumab–based first-line therapy from January 1, 2015, to September 30, 2019, and had at least 60 days of follow-up following the start of first-line treatment.

Investigators defined a new line of therapy as the use of a different anti-HER2 agent, a switch to a different class of chemotherapy, or a resumption of the same regimen after a gap of 365 days or more. An anti-HER2–based regimen could include hormonal therapy and/or chemotherapy, and the time window for identifying combination therapies was 14 days for intravenous drugs or 30 days for oral drugs. Treatment discontinuation was defined as a gap of 1 year or more, initiation of a new line of therapy, or death.

The study evaluated clinical outcomes including time to treatment discontinuation, time to treatment failure, and OS. All 3 were analyzed for second-line regimens using Kaplan-Meier analyses.

The database identified 710 patients with a median age of 57.0 years (interquartile range, 48.0-65.0) who were treated with a pertuzumab and trastuzumab–based regimen in the first-line. Median follow-up was 20.3 months. Overall, 47.3% of patients were hormone receptor (HR)–positive, 26.5% were HR-negative, and 26.2% had an unknown HR status.

Ninety-two percent of patients received first-line pertuzumab and trastuzumab in combination with other metastatic breast cancer treatment, including a taxane (80%). The median time to first-line treatment discontinuation was 15.3 months (95% CI, 13.4-17.6).

Investigators found that 68.7% of patients did not initiate second-line treatment (n = 488). As of the last day of follow-up, 83.6% of that group remained on first-line treatment, 7.4% died, and 9.0% discontinued treatment but did not initiate second-line therapy.

Of the 222 patients who begin second-line treatment, 71.6% received T-DM1 only. Other common second-line treatment regimens included lapatinib alone (5.9%), immunotherapy or other targeted therapies (1.8%), trastuzumab alone (1.4%), trastuzumab plus pertuzumab (1.4%), trastuzumab plus lapatinib (1.4%), chemotherapy with or without hormonal therapy (0.9%), and hormonal therapy alone (0.9%).

The study authors noted the lines of therapy that were defined using algorithms might not match actual treatment history, putting a limitation on this real-world study. Additionally, more than half of the patients were lost to follow-up on first- or second-line treatments before actual treatment discontinuation or death could be observed. This resulted in smaller populations for some second-line treatment groups.

Investigators did not analyze comorbidities or perform adjusted analyses. Finally, since date of death was inferred used the last encounter in EMR data as a proxy, OS results need to be confirmed by future studies.

Finally, study authors pointed to emerging therapies that are expected to improve patient outcomes and provide alternative to T-DM1 and other current second-line treatment options. In the phase 3 DESTINY-Breast03 trial (NCT03529110), for instance, trastuzumab deruxtecan demonstrated significant improvement in PFS vs T-DM1 in patients previously treated with trastuzumab and a taxane.3


  1. Mehta S, Pavilack M, Xie J, et al. Treatment patterns following first-line pertuzumab + trastuzumab in patients with HER2+ metastatic breast cancer in the United States. Presented at: 39th Annual Miami Breast Cancer Conference®. March 3-6, 2022; Miami Beach, FL.
  2. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367(19):1783-91. doi:10.1056/NEJMoa1209124
  3. Hurvitz SA, Kim SB, Chung WP, et al. Trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients with HER2+ metastatic breast cancer: subgroup analyses from the randomized phase 3 study DESTINY-Breast03. Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021. San Antonio, TX. Abstract GS3-01.