Patritumab deruxtecan (HER3-DXd), administered with or without letrozole, has demonstrated efficacy comparable to multiagent chemotherapy in patients with high-risk, hormone receptor (HR)-positive, HER2-negative breast cancer. The phase 2 SOLTI VALENTINE trial (NCT05569811) revealed similar pathologic complete response (pCR) and objective response rate (ORR) estimates with a lower incidence of grade 3 or higher treatment-related adverse effects (TRAEs).
The data, presented at the 2024 San Antonio Breast Cancer Symposium, highlighted that patritumab deruxtecan as a single agent (n = 50) achieved a pCR rate of 4.0% (95% CI, 0.5%-13.7%) and an ORR of 70.0% (95% CI, 55.4%-82.1%). The combination of patritumab deruxtecan and letrozole (n = 48) resulted in a pCR rate of 2.1% (95% CI, 0.1%-11.1%) and an ORR of 81.3% (95% CI, 67.4%-91.1%), with one patient experiencing progressive disease (PD). In comparison, standard multiagent chemotherapy (n = 24) yielded a pCR rate of 4.2% (95% CI, 0.1%-21.1%) and an ORR of 70.8% (95% CI, 48.9%-87.4%), also with one patient experiencing PD. Across the entire study population of 122 patients, the pCR rate was 3.3% (95% CI, 0.9%-8.2%), and the ORR was 74.6% (95% CI, 65.9%-82.0%).
Biological Evidence of Antitumor Activity
Beyond response rates, patritumab deruxtecan showed biological evidence of antitumor activity, including a reduction in Ki67 expression, a shift to less proliferative PAM50 subtypes, and a decrease in the risk of recurrence (ROR). The antibody-drug conjugate (ADC) also increased the CelTIL score, correlating with treatment response.
According to Dr. Mafalda Oliveira, MD, PhD, of Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology, and the SOLTI Cancer Research Group in Barcelona, Spain, “SOLTI VALENTINE supports the effectiveness of [patritumab deruxtecan] in early breast cancer and its potential incorporation in the treatment of high-risk HR-positive/HER2-negative breast cancer.”
The Need for Tolerable Therapies
While multiagent chemotherapy regimens are known to improve survival outcomes in this patient population, there remains a need for effective yet tolerable therapeutic approaches. Patritumab deruxtecan, a first-in-class, HER3-directed ADC, has previously demonstrated activity in various breast cancer subtypes. Prior research, including the early phase 1 SOLTI TOT-HER3 study (NCT04610528), indicated that a single dose of the agent increased CelTIL score and enhanced clinical response.
Based on these findings, investigators hypothesized that patritumab deruxtecan, either as monotherapy or in combination with letrozole, could serve as a safe and effective neoadjuvant treatment option for treatment-naive patients with high-risk, HR-positive/HER2-negative early breast cancer.
Study Design and Patient Population
The SOLTI VALENTINE trial was designed as a parallel, randomized, noncomparative, open-label, phase 2 study. It enrolled 120 pre- and postmenopausal patients with primary operable breast cancer of 1 cm or larger, as determined by MRI. Eligible patients had to have HR-positive/HER2-negative disease, a Ki67 expression of 20% or higher, and/or high genomic risk. Prior treatment for the current breast cancer was not allowed, and pretreatment formalin-fixed paraffin-embedded core-needle biopsies were required.
Patients were randomized in a 2:2:1 ratio to receive either patritumab deruxtecan at 5.6 mg/kg every 21 days for six cycles; patritumab deruxtecan at the same dose plus letrozole at 2.6 mg once daily with or without ovarian function suppression; or standard multiagent chemotherapy consisting of epirubicin at 90 mg/m2 plus cyclophosphamide at 600 mg/m2, or doxorubicin at 60 mg/m2 plus cyclophosphamide at 600 mg/m2 for four cycles, followed by weekly paclitaxel at 80 mg/m2 for 12 weeks. Patients were stratified by axillary nodal status and underwent surgery after treatment, with a follow-up period of five years.
The primary endpoint of the study was the pCR rate (ypT0/is ypN0) at surgery. Secondary endpoints included ORR, CelTIL score change, Ki67 drop, PAM50, ROR, and safety.
Safety Profile
Regarding safety, any-grade TRAEs occurred in 96.0% of patients in the ADC-alone arm (n = 50), 97.9% in the ADC/letrozole arm (n = 48), and 95.8% in the chemotherapy arm (n = 24). Grade 3 or higher TRAEs were less frequent in the ADC arms, occurring in 14.0%, 14.6%, and 45.8% of patients, respectively. No cases of interstitial lung disease were reported, and no treatment-related deaths occurred, though one non-related death occurred in the ADC arm due to a cerebrovascular accident.
The most common non-hematologic TRAEs reported in 20% or more of patients across the ADC-alone, ADC/letrozole, and chemotherapy arms included fatigue, nausea, alopecia, and diarrhea. The most common hematologic TRAEs included neutropenia and anemia. Dose reductions and interruptions were less frequent in the ADC arms compared to the chemotherapy arm.
