KN026 Plus Docetaxel Demonstrates Efficacy in HER2+ Metastatic Breast Cancer

The frontline combination of KN026—a HER2-directed bispecific antibody—and docetaxel elicited durable responses and a manageable safety profile in patients with recurrent/metastatic HER2-positive breast cancer, according to findings from a phase 2 trial (NCT04165993), which were published in Cancer Communications.1

In the open-label, single-arm trial, among efficacy-evaluable patients (n = 55), the combination generated an objective response rate (ORR) of 76.4% (95% CI, 63.0%-86.8%), including 3 complete responses and 39 partial responses. The median duration of response (DOR) was not yet reached (NR; 95% CI, 20.7 months-NR). The 12-, 24-, and 30-month DOR rates were 85.2%, 59.3%, and 51.6%, respectively. Furthermore, the clinical benefit rate (CBR) was 85.5% (95% CI, 73.3%-93.5%). Subgroup analyses in patients stratified by location of baseline metastases, HER2 immunohistochemistry (IHC) status, clinical stage, and hormone receptor (HR) status showed ORRs that were mostly consistent with those of the overall population.

“[This ORR] demonstrates a noteworthy similarity with previous landmark studies,” lead study author Jianli Ma, PhD, of the Department of Radiotherapy at Cancer Hospital, Harbin Medical University in Heilongjiang, China, and coauthors, wrote in the paper.

According to the National Comprehensive Cancer Network Breast Cancer Clinical Practice Guidelines, the standard-of-care first-line regimen for patients with HER2-positive recurrent/metastatic breast cancer is pertuzumab (Perjeta) plus trastuzumab (Herceptin) and docetaxel. This combination was approved for this indication in 2012 based on findings from the phase 3 CLEOPATRA trial (NCT00567190), in which patients who received pertuzumab plus trastuzumab and docetaxel (n = 343) achieved an ORR of 80.2% vs 69.3% in those who received placebo plus trastuzumab and docetaxel (n = 336).2,3

KN026 is a recombinant humanized bispecific antibody that interacts with the HER2 protein at domains recognized by pertuzumab and trastuzumab.1 Preclinical and phase 1 data have shown the antitumor activity and safety profile of this agent in HER2-positive breast cancer.

“These promising results show that KN026 in combination with docetaxel may be a potential new frontline treatment option for HER2-positive recurrent/metastatic breast cancer,” the authors stated.

This phase 2 trial enrolled 57 patients at least 18 years of age with histologically proven HER2-positive locally recurrent or metastatic breast cancer across 19 centers in China between December 30, 2019, and May 27, 2021. HER2-positive breast cancer was defined as HER2 3+ by immunohistochemistry (IHC), HER2 gene amplification confirmed by in situ hybridization, or a HER2 copy gene number of at least 4 as detected by next-generation sequencing. Patients were not permitted to have received systemic antitumor therapy in the metastatic setting; however, they could have received a maximum of 2 prior lines of systemic endocrine therapy. Patients also needed to have at least 1 measurable lesion at baseline per RECIST 1.1 criteria, adequate organ function, and an ECOG performance status of 0 or 1.

Patients were excluded if they had untreated active brain or meningeal metastases; cardiotoxic events during prior HER2-targeted therapy; a history of other malignancies; uncontrolled comorbidities; a history of cardiac systolic dysfunction; or a history of drug allergies.

Patients received KN026 at 30 mg/kg plus docetaxel at 75 mg/m2 on day 1 of each 21-day cycle. Patients were treated until disease progression per RECIST 1.1 criteria, the initiation of a novel antitumor treatment, withdrawal of consent, loss to follow-up, or trial conclusion. Notably, no KN026 dose reductions were permitted, and the administration of this agent was suspended upon the development of a grade 3 or higher adverse effect (AE) associated with KN026 until the AE resolved to grade 1 or lower. Docetaxel dose reductions were allowed to 55 mg/m2 if docetaxel was intolerable at the protocol dose.

ORR and DOR served as the coprimary end points. Secondary end points included overall survival (OS), progression-free survival (PFS), CBR, and safety.

A total of 57 patients with HER2-positive, recurrent, metastatic breast cancer were enrolled onto the study from January 13, 2020, to May 27, 2021. By September 15, 2023, treatment was ongoing in 22 patients, and 35 patients discontinued treatment. All patients were women. The median age was 52 years, and most patients had stage IV disease (91.2%). Most patients had HER2 IHC 3+ disease (84.2%), and 45.6% of patients were HR positive. Furthermore, 59.6% of patients had visceral metastases.

In total, 37 patients had previously undergone surgical treatment; among these, 56.1% had curative surgery, 3.5% had palliative surgery, and 21.1% had other types of surgery. Among the 12 patients who had previously received radiotherapy, 5.3% had undergone intensity-modulated radiation therapy, and 3.5% had received 3-dimensional conformal radiotherapy. Overall, 52.6% and 8.8% of patients had received prior adjuvant and neoadjuvant therapy, respectively. Prior chemotherapy, endocrine therapy, and targeted therapy had been administered in 54.4%, 12.1%, and 7.0% of patients, respectively. The most common chemotherapy agents patients had previously received were cyclophosphamide (50.9%), docetaxel (40.4%), and epirubicin (24.6%).

The median time of exposure to the study drugs was 674 days (range, 21-1171), and the median duration of treatment was 28 weeks (range, 1-52). Eighty-six percent of patients in the safety-evaluable population (n = 57) received more than 6 cycles of therapy.

At a median follow-up of 31.1 months (range, 0.8-41.4), among the safety-evaluable population, the median PFS was 27.7 months (95% CI, 18.0-NR); the 6-, 12-, 24-, and 30-month PFS rates were 87.4% (95% CI, 75.4%-93.8%), 76.3% (95% CI, 62.6%-85.5%), 54.2% (95% CI, 39.7%-66.6%), and 45.2% (95% CI, 30.9%-58.4%), respectively.

The median OS was NR; the 6-, 12-, 24-, and 30-month OS rates were 98.2% (95% CI, 88.2%-99.8%), 93.0% (95% CI, 82.4%-97.3%), 84.1% (95% CI, 71.7%-91.4%), and 78.5% (95% CI, 65.2%-87.2%), respectively.

All patients experienced treatment-emergent AEs (TEAEs), and grade 3 or higher TEAEs were reported in 63.2% of patients. Serious AEs were seen in 21.1% of patients, and 17.5% of patients had a grade 3 or higher serious AE.

Eleven patients died because of disease progression; no deaths in the study population were associated with KN026 or docetaxel. One patient who received 1 dose of KN026 had a fatal AE of unknown cause; this patient had grade 3 allergic reactions after 12 minutes of KN026 administration, which resolved on the same day at discharge. This patient was withdrawn from the study without receiving docetaxel and developed grade 4 sepsis 10 days later. The patient died more than 23 days after receiving KN026, and this death was not considered related to either study drug.

The most common TEAEs were decreased white blood cell counts (63.2%), decreased neutrophil counts (61.4%), and diarrhea (36.8%). The most frequently observed grade 2 or higher TEAEs were decreased neutrophil counts (40.4%), decreased white blood cell counts (28.1%), and hypokalemia (8.8%).

TEAEs led to KN026 dose interruption and permanent discontinuation in 26.3% and 5.3% of patients, respectively. This included 1 case each of grade 3 type I KN026-related hypersensitivity, 1 case of grade 3 KN026-related hypersensitivity, and 1 case of grade 3 pericardial effusion that was not deemed related to KN026 and was possibly related to disease progression. Moreover, TEAEs leading to docetaxel dose interruption and permanent discontinuation were observed in 15.8% and 3.5% of patients, respectively.

Five patients had AEs of special interest, including grade 2 pneumonitis (n = 3) and grade 2 left ventricular ejection fraction (LVEF) decrease of at least 15% from the baseline absolute value (n = 2). No patients had symptomatic left ventricular systolic dysfunction or an LVEF reduction of at least 10% from the baseline absolute value and an LVEF of less than 50.

“The safety profile of KN026 combined with docetaxel in this study was good and manageable, without novel safety concerns. This finding suggests that KN026 provides a safety advantage, particularly in terms of cardiac toxicity,” the authors explained.

Limitations of this research included its small sample size, which may limit the generalizability of the findings; the lack of a control arm, which eliminates the possibility of making direct comparisons with standard therapies; and the absence of long-term follow-up. To address these limitations and build upon these preliminary data, the investigators are planning a randomized, controlled phase 3 trial (NCT05838066) investigating the efficacy and safety of first-line KN026 plus HB1801 in patients with HER2-positive recurrent or metastatic breast cancer.4

“These findings demonstrate the potential of KN026 plus docetaxel as a new therapeutic option for patients with HER2-positive recurrent-metastatic breast cancer. Subsequent large, randomized controlled studies are warranted to validate the clinical benefits of KN026 plus docetaxel,” the authors concluded.1

References

1. Ma J, Wang J, Xu T, et al. Efficacy and safety of KN026 and docetaxel for HER2-positive breast cancer: a phase II clinical trial. Cancer Commun (Lond). Published online January 18, 2025. doi:10.1002/cac2.12662
2. Drug approval package. Perjeta (pertuzumab) injection. FDA. Accessed February 6, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/125409Orig1s000TOC.cfm
3. Baselga J, Cortés J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366(2):109-19. doi:10.1056/NEJMoa1113216
4. Efficacy and safety of KN02 in combination with HB1801 in the first-line treatment of subjects with HER2-positive recurrent or metastatic breast cancer. ClinicalTrials.gov. Updated May 1, 2023. Accessed February 6, 2025. https://clinicaltrials.gov/study/NCT05838066