Patients with high-risk, hormone receptor (HR)-positive, HER2-negative breast cancer treated with presurgical patritumab deruxtecan (HER3-DXd) with or without Femara (letrozole) experienced similar responses, including pathologic complete response (pCR) and objective response rate (ORR) compared to multiagent chemotherapy, but with a lower occurrence of severe or worse treatment-related side effects, study results have shown.
Primary results from the phase 2 SOLTI VALENTINE trial presented during the 2024 San Antonio Breast Cancer Symposium showed that the antibody-drug conjugate (ADC; 50 patients) elicited a pCR rate of 4% and an ORR of 70%. When paired with Femara (48 patients), the pCR rate was 2.1% and the ORR was 81.3%; one patient experienced progressive disease (PD). With standard multiagent chemotherapy (24 patients), the pCR rate was 4.2% and the ORR was 70.8%; one patient had PD. In the total population of 122 patients, the pCR rate was 3.3%, and the ORR was 74.6%; two patients had PD.
Moreover, patritumab deruxtecan demonstrated biological evidence of antitumor activity, with a drop in Ki67, a switch to less proliferative PAM50 subtypes, and a decrease in risk of recurrence (ROR). The ADC also led to an increase in CelTIL score that correlated with treatment response.
“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,” Dr. Mafalda Oliveira of Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology, and of the SOLTI Cancer Research Group, both in Barcelona, Spain, said in a presentation of the data.
It is known that multiagent chemotherapy regimens boost survival outcomes for this population, but a need remains for not only effective, but tolerable, therapeutic approaches. The first-in-class, HER3-directed ADC patritumab deruxtecan has demonstrated activity in several subtypes of breast cancer.
Based on these observations, investigators hypothesized that patritumab deruxtecan monotherapy or in combination with Femara would be a safe and effective neoadjuvant option for treatment-naive patients with high-risk, HR-positive, HER2-negative early breast cancer.
To test this, they launched the parallel, randomized, noncomparative, open-label, phase 2 SOLTI VALENTINE trial, which sought to enroll 120 pre- and postmenopausal patients with primary operable breast cancer of 1 centimeter or larger by MRI. To be eligible, patients needed to have HR-positive, HER2-negative disease, as well as a Ki67 expression of 20% or higher and/or high genomic risk. They could not have previously received treatment for their current breast cancer. They also needed to have pretreatment formalin-fixed paraffin-embedded core-needle biopsy.
Patients were randomly assigned to receive patritumab deruxtecan at 5.6 milligrams per kilogram (mg/kg) every 21 days for six cycles; patritumab deruxtecan at the same dose plus Femara at 2.6 mg once daily with or without ovarian function suppression; or standard multiagent chemotherapy in the form of epirubicin at 90 mg/per square meter plus cyclophosphamide at 600 mg/ per square meter or doxorubicin at 60 mg/m2 plus cyclophosphamide at 600 mg/per square meter for four cycles followed by weekly paclitaxel at 80 mg/ per square meter for 12 weeks. Patients were stratified by axillary nodal status. Patients then went on to surgery and will be followed for five years.
Patients were recruited between November 2022 and September 2023. A total of 154 patients were assessed for eligibility, and 32 were excluded due to withdrawn consent (eight patients), metastatic disease (nine patients), no pretreatment biopsy (two patients) and other (13 patients). A total of 122 patients were included in the analysis; 50 received the ADC alone, 48 received the doublet and 24 received chemotherapy; 49, 48 and 23 patients, respectively, went on to surgery. The data cutoff date for the analysis shared during the meeting was April 22, 2024.
In the overall population, the median age was 51 years, and 99.2% were female. About half (52.9%) were premenopausal, and most had lymph node positivity (76.2%). More than half of patients had stage 2 disease (64.0%) and grade 1 or 2 disease (78.4%).
Regarding safety, any-grade treatment-related side effects occurred in 96% of those in the ADC-alone arm (50 patients), 97.9% of those in the ADC/Femara arm (48 patients) and 95.8% of those in the chemotherapy arm (24 patients); they were grade 3 or higher in 14%, 14.6% and 45.8% of patients, respectively. In the ADC-alone arm, dose reduction and interruption were needed for 6% and 12% of patients, respectively. No patients in this arm experienced treatment-related side effects that led to treatment discontinuation. In the ADC/Femara arm, dose reduction, interruption and treatment discontinuation was needed for 8.3%, 4.2% and 4.2% of patients, respectively; in the chemotherapy arm, these respective rates were 37.5%, 50% and 8.3%.
No cases of interstitial lung disease were reported, and no treatment-related deaths occurred. However, one non-related death occurred in the ADC arm due to a cerebrovascular accident.
The most common non-hematologic treatment-related side effects reported in 20% or more of patients in the ADC-alone, ADC/Femara and chemotherapy arms included fatigue (50%; 68.8%; 79.2%), nausea (56%; 72.9%; 58.3%), alopecia (52%; 68.8%; 45.8%), diarrhea (42%; 54.2%; 8.3%), stomatitis (14%; 18.8%; 41.7%), increased transaminase levels (14%; 37.5%; 20.8%), neurotoxicity (0%; 0%; 33.3%), abdominal pain (16%; 29.2%; 8.3%), constipation (20%; 29.2%; 8.3%) and vomiting (22%; 22.9%; 8.3%).
The most common hematologic treatment-related side effects in the respective arms included neutropenia (26%; 18.8%; 41.7%), anemia (12%; 14.6%; 33.3%), lymphopenia (2%; 4.2%; 8.3%), thrombocytopenia (2%; 4.2%, 12.5%), leukopenia (4%; 0%; 8.3%), and febrile neutropenia (0%; 0%; 4.2%).
Reference
“Neoadjuvant HER3-DXd alone or in combination with letrozole for high-risk HR+/HER2- early EBC: Primary results of the randomized phase II SOLTI VALENTINE trial” by Dr. Mafalda Oliveira et al., presented at: 2024 San Antonio Breast Cancer Symposium; December 10-13, 2024; San Antonio, Texas.
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