HER3+ CTC Count May Affect Responses to Patritumab Deruxtecan in Pretreated Advanced Breast Cancer

Barbara Pistilli, MD

Higher baseline HER3-positive circulating tumor cell (CTC) count at baseline and reduction following treatment initiation was associated with a higher likelihood of deriving an early response with patritumab deruxtecan (HER3-DXd) in patients with hormone receptor (HR)–positive or HER2-low advanced breast cancer, according to findings from an exploratory biomarker analysis of the phase 2 ICARUS-Breast01 trial (NCT04965766) that were presented at the 2023 ESMO Breast Cancer Annual Congress.

A total of 31 of 56 enrolled patients had evaluable CTC samples. CTC counts by CellSearch demonstrated that the median CTC count at baseline, day 3, and day 19 of cycle 1; day 3 of cycle 2; and end of treatment was 2, 4, 0, and 1, respectively. HER3-positive CTCs by FACS showed marked reduction from baseline to day 1 of cycle 2 and end of treatment, at 8, 1, and 6, respectively. Notably, patritumab deruxtecan had no significant effect on HER3-negative CTC count from baseline to end of treatment, irrespective of response.

“Total and HER3-positive CTCs count decreased after the first cycle of HER3-DXd; although not statistically significant, patients with higher HER3-positive CTCs count at baseline and patients with greater HER3-positive CTCs decrease were more likely to have an early treatment response,” lead study author Barbara Pistilli, of Gustave Roussy in Paris, France, said in a presentation on the data.

The prospective, multicenter, single-arm study enrolled patients with unresectable, locally advanced or metastatic HR-positive, HER2-negative or HER2-low breast cancer following progression on a CDK4/6 inhibitor, endocrine therapy, and at least 1 line of chemotherapy for advanced disease. Prior PI3K/AKT/mTOR inhibition was permitted, whereas prior treatment with fam-trastuzumab deruxtecan-nxki (Enhertu) was prohibited.

Per a protocol amendment made on April 21, 2022, HER3 expression prescreening requiring 75% of membrane positivity was lifted.

Eligible patients received 5.6 mg/kg of patritumab deruxtecan every 3 weeks until progressive disease or unacceptable toxicity. Patients underwent mandatory tumor biopsy at baseline, day 3 or 19 of cycle 1, day 3 of cycle 2, and after treatment completion.

Investigator-assessed objective response rate served as the primary end point of the trial. Secondary end points included duration of response, progression-free survival, clinical benefit rate, overall survival, safety, and tolerability. Predictors of response and resistance were evaluated as exploratory end points.

Previously, patritumab deruxtecan demonstrated encouraging antitumor activity in patients with heavily pretreated HER3-expressing advanced breast cancer in the phase 1/2 U3-1402-J101 trial (NCT02980341). Activity was observed in patients with HR-positive, triple-negative, and HER2-positive breast cancer, irrespective of HER3 expression level. Despite this, biomarkers of response and resistance to patritumab deruxtecan are not well understood.

Those included in the current analysis had a median age of 56 years (range, 28-82). Most patients had HER2-low disease (immunohistochemistry [IHC] 0, 62.5%; IHC 1+, 14.3%); 1.8% and 21.4% of patients were estrogen receptor and progesterone receptor negative, respectively. Given the protocol amendment, 48.2% of patients had unknown HER3 expression and 51.8% met the threshold previously required for enrollment.

Most patients had received prior neoadjuvant or adjuvant therapy (64.8%), most commonly capecitabine (Xeloda; 52.0%) or paclitaxel (26.0%), and 32.1% received prior PI3K/AKT/mTOR inhibition with everolimus (Afinitor). The median number of prior lines of therapy received for advanced disease was 2 (range, 1-4), and the median duration of treatment with a prior CDK4/6 inhibitor was 12.2 months (range, 1.9-43.5).

As of the data cutoff date of February 15, 2023, 57.1% of patients had discontinued treatment. Reasons for discontinuation included disease progression (41.1%), adverse effects (7.1%), investigator decision (3.6%), patient withdrawal (3.6%), or other (1.7%). The median number of treatment cycles was 8 (range, 1-20), and 37.5% of patients required dose reduction.

Three months from treatment initiation, 28.6% of patients achieved a partial response; 53.6% of patients had stable disease and 17.8% had progressive disease.

Regarding HER3-positive CTC dynamics and treatment response, patients with higher HER3-positive CTC count at baseline (odds ratio, 1.07; 95% CI, 0.92-1.26; P = .335) or greater HER3-positive CTC reduction after the first cycle of treatment (odds ratio, 0.78; 95% CI, 0.54-1.02; P = .102) were more likely to have an early treatment response with patritumab deruxtecan. However, the association was not significant.

Whole-exome sequencing was also performed on frozen samples from 18 patients. Seventeen samples were collected at baseline and 5 samples were collected at the time of progression, and they showed activity with patritumab deruxtecan regardless of common breast cancer genomic alterations.

Transcriptomic response to treatment in early responders was also evaluated by conducting RNA sequencing from 24 frozen patient samples (baseline, n = 24; matched on-treatment, n = 14). After mapping a volcano plot, investigators were able to show differentially expressed genes in early responders (n = 7) vs non-responders (n = 17; adjusted P value < .05).

Safety data were evaluated through November 4, 2022. All patients experienced a treatment-emergent adverse effect (TEAE); grade 3 or greater events occurred in 48.2% of patients. TEAEs that occurred in at least 25% of patients included fatigue (89.3%), nausea (75.0%), diarrhea (46.4%), alopecia (44.6%), and constipation (26.8%).

All grade neutropenia was reported in 14.0% of patients, and this was grade 3 or higher in 10.0% of patients. Moreover, all grade thrombocytopenia occurred in 8.0% of patients, with 4.0% of patients experiencing events that were grade 3 or higher in severity.

Grade 3 or greater events leading to treatment discontinuation, interruption, dose reduction, or death occurred in 12.5%, 16.0%, 23.2%, and 0% of patients, respectively. Adjudicated treatment-related, grade 1 interstitial lung disease occurred in 1 patient.

“HER3-DXd showed a manageable safety profile and early signs of clinical activity in patients who progressed on CDK4/6 inhibitors and further lines of endocrine therapy [with or without] targeted therapies; these data are consistent with prior results of HER3-DXd in advanced breast cancer,” Pistilli said.

Further analysis will be performed to examine the link between HER3-positive CTCs count and dynamics and main treatment outcomes to determine whether HER3-positive CTCs can help to better select patients who can derive benefit from the agent, Pistilli concluded.

Disclosures: Dr Pistilli disclosed that institutional consulting fees were received from AstraZeneca, Seagen, Gilead, Novartis, Lily, and MSD, and personal consulting fees were received from Pierre Fabre. Institutional and personal consulting fees were received from Daiichi Sankyo. Research funding to Dr Pistilli’s institution was granted by AstraZeneca, Daiichi-Sankyo, Gilead, Seagen, and MSD. Travel support was provided by AstraZeneca, Pierre Fabre, MSD, and Daiichi Sankyo.

Reference

B Pistilli, N Ibrahimi, Lacroix-Triki M, et al. 189O A phase II study of patritumab deruxtecan (HER3-DXd) in patients (pts) with advanced breast cancer (ABC), with biomarker analysis to characterize response to therapy (ICARUS-BREAST01). ESMO Open. 2023;8(suppl 4):101378. doi:10.1016/j.esmoop.2023.101378