T-DM1 Plus Palbociclib Displays Activity in HER2+ Metastatic Breast Cancer

Breast Cancer

| Image Credit: © Sebastian Kaulitzki – stock.adobe.com

Ado-trastuzumab emtansine (T-DM1; Kadcyla) in combination with palbociclib (Ibrance) showed signs of efficacy in patients with HER2-positive metastatic breast cancer, according to data from a phase 2 trial (NCT03530696) presented during the 2025 ESMO Breast Cancer Congress.1

Patients who received the combination (n = 36) achieved a median progression-free survival (PFS) of 16.9 months (95% CI, 8.3-not evaluable). Those who received T-DM1 monotherapy (n = 11) had a PFS of 8.3 months (95% CI, 2.7-8.8). Notably, the median PFS in patients with estrogen receptor (ER)–positive (n = 25) and -negative (n = 13) disease who received the combination was 16.9 months and 17.1 months, respectively.

“Given the limitation of the sample size, we [believe] the combination of T-DM1 and palbociclib warrants further investigation as our data suggest that the efficacy of palbociclib in [patients with] HER2-positive tumors might not be dependent on ER status,” lead study author Pavani Chalasani, MD, MPH, said during the presentation.

Chalasani is the division director of the George Washington Cancer Center in Washington, DC.

Unpacking the Study Design

The multicenter, single-arm study enrolled patients with HER2-positive recurrent or metastatic breast cancer who received 2 or fewer lines of prior therapy in the metastatic setting.1,2 In order to be eligible for the trial, patients also needed to have an adequate cardiac reserve, an ECOG performance status of 0 to 2, and adequate bone marrow function.2 Prior pertuzumab (Perjeta) exposure was also required.1

Patients received intravenous T-DM1 at a dose of 3.6 mg/kg every 21 days and 125 mg of oral palbociclib on days 5 through 18 every 3 weeks. Treatment in both arms continued until disease progression or unacceptable toxicity. Prior to a design amendment, the study also included a T-DM1 monotherapy arm.

“Our first site was activated in October 2018, [and] the last site was activated in May 2020,” Chalasani noted. “In the interim, we [saw] an approval for fam-trastuzumab deruxtecan-nxki [T-DXd; Enhertu] and tucatinib [Tukysa], and then the COVID-19 pandemic, which affected study enrollment significantly. This led to a change in the study design to a single-arm [trial] of T-DM1 plus palbociclib.”

The primary end point was PFS. Secondary end points included overall response rate (ORR) and overall survival.

At baseline, patients who received the combination had a mean age of 56.5 years (SD ± 12.6). Most patients were non-Hispanic White (66.7%) and postmenopausal (73.7%). Most patients also had ER-positive disease (65.8%), progesterone receptor–positive disease (52.6%), and did not have central nervous system (CNS) metastases (81.1%).

In the monotherapy cohort, the mean age was 57.8 years (SD ± 11.4). Most patients were non-Hispanic White (76.9%) and postmenopausal (92.9%). No patients in the monotherapy group had CNS metastases; most patients also had ER-positive disease (64.3%). Progesterone receptor–negative disease was present in 64.3% of patients.

Additional Efficacy Data and Safety

Additional findings showed that the ORR in the combination group (n = 38) was 42.9%, including a complete response (CR) rate of 8.6%. The disease control rate (DCR) was 85.7%. In the monotherapy cohort, the ORR was 18.2%; no patients achieved a CR. The DCR was 63.6%.

“The adverse effects noted with the combination treatment were as expected for each individual drug. There were no new safety findings,” Chalasani said. “The [median] PFS of T-DM1 and palbociclib was longer than single-agent T-DM1, but this was not statistically compared.”

Disclosures: Chalasanireports receiving research support from Pfizer, Vaxiion Therapeutics, Immutep, Personalis, and Stemline. She is also an advisory board member/consultant for Medscape, ReachMD, Health Advances, Expert Connect, and Pfizer (Oncology Breast Cancer Lecture Series).

References

1. Chalasani P, Gandhi S, Wertheim B, et al. Phase II trial of TDM-1 and palbociclib in metastatic HER2 positive breast cancer. Presented at: 2025 ESMO Breast Congress; May 14-17, 2025; Munich, Germany. Abstract 305MO.
2. T-DM1 and palbociclib for metastatic HER2 breast cancer (T-DM1). ClinicalTrials.gov. Updated August 13, 2024. Accessed May 16, 2025. https://clinicaltrials.gov/study/NCT03530696