Heather Han, MD A neoadjuvant treatment regimen consisting of HER2-directed conventional dendritic cell (DC1) intratumoral therapy plus paclitaxel, trastuzumab (Herceptin), and pertuzumab (Perjeta) elicited pathologic complete responses (pCRs) in patients with stage I to III HER2 positive breast cancer, according to data from the ongoing phase 2 NATASHA trial (NCT05325632) presented at the 2023 ASCO Annual Meeting. Between October 2021 and October 2022, 12 patients enrolled onto the NATASHA trial and completed neoadjuvant therapy.
Among 11 patients who completed surgery, 7 experienced a pCR with a residual cancer burden (RCB) of 0; the remaining 4 patients had an RCB of 1 (n = 1), 2 (n = 2), or 3 (n = 1). Moreover, by measuring radiologic response via MRI before and after vaccine therapy, 3 patients achieved a complete response, 8 had a partial response, and 1 patient had stable disease.
Notably, all patients with estrogen receptor (ER)–negative or –low disease experienced a pCR. “Optimizing neoadjuvant therapy with improved toxicity is critical in this patient population. We thought to evaluate the addition of HER2 DC1 vaccine followed by escalated chemotherapy with weekly paclitaxel [plus] trastuzumab and pertuzumab to see how patients’ tumors would respond,” lead study author Heather Han, MD, research director in the Department of Breast Oncology at Moffitt Cancer Center, in Tampa, Florida, said in an interview with OncLive®. Intranodal DC1 vaccines are associated with anti-HER2 CD4 Th1 responses.
Preclinical and clinical studies have demonstrated that the vaccine led to primary tumor control and a decrease in anti-HER2 CD4 Th1 in peripheral blood. NATASHA is a phase 2, non-randomized, open-label study enrolling patients with HER2-positive stage I to III breast cancer whose tumors are at least 1 cm.
Following a lead-in phase where 2 dose levels of DC1 were examined in 6 patients each, an expansion phase of the study will evaluate patients with either ER-positive (n = 24) or ER-negative (n = 23) disease. During the lead-in phase, patients received intratumoral DC1 at 50 x 106 or 100 x 106 cells once per week for 6 weeks plus intravenous (IV) trastuzumab and IV pertuzumab once every 3 weeks for a total of 2 doses each.
Trastuzumab was given as an 8 mg/kg loading dose, followed by 6 mg/m2. Pertuzumab was given as an 840 mg loading dose, then 420 mg. After receiving an MRI following the completion of DC1, patients then received 80 mg/m2 of IV paclitaxel once per week for 12 weeks plus trastuzumab and pertuzumab once every 3 weeks for 4 cycles. Advertisement The primary end point of the study is pCR rate, and secondary end points include safety, MRI response, immunogenicity, and recurrence-free survival at 3 years.
An MRI was performed at baseline, post-DC1, and post-chemotherapy. Among patients enrolled in the lead-in portion of the study, the median age was 57 years. Nine patients were Caucasian, 2 were Black, and 1 was listed as other. Four patients had stage I disease, 6 had stage II, and 2 had stage III.
Notably, 75% of patients had hormone receptor (HR)–positive disease. Regarding histology, 10 patients had invasive ductal disease, 1 had invasive lobular disease, and 1 had invasive mammary disease. Furthermore, 33% of patients were node positive. Regarding HER2 status, 11 patients were immunohistochemistry (IHC) 3+, and 1 patient was IHC 2+/fluorescence in situ hybridization amplified. Regarding safety, the most common adverse effects observed during the first 6 weeks of treatment with DC1, trastuzumab, and pertuzumab included chills (50%), diarrhea (42%), nausea (42%), and fatigue (42%).
When patients were treated with paclitaxel, trastuzumab, and pertuzumab, the most frequent toxicities included diarrhea (67%), peripheral neuropathy (67%), fatigue (58%), and rash (58%). “We have not seen any new safety signals in this study, other than injection site discomfort and some flu-like symptoms, [which were] similar to what we have observed in prior studies,” Han said. Findings also showed that in patients treated with DC1 at 100 x 106 cells, there was a decrease in peripherally circulating anti-HER2 T-cell response at week 6, which study authors attributed to a likely increase in T-cell trafficking to the tumor site. “We decided that we will expand further [on the] second dose level of 100 x 106 cells.
Forty-one additional patients will be enrolled in the phase 2 study in 2 subgroups of ER-negative and ER-positive [disease]. We are looking to evaluate pCR, other radiologic responses, and biomarkers. This trial is still ongoing in phase 2,” Han concluded. Reference Han HS, Costa RL, Armaghani AJ, et al.
Neoadjuvant therapy of HER2 directed conventional dendritic cell (DC1) intratumoral (IT) therapy plus weekly paclitaxel, trastuzumab, and pertuzumab in patients with HER-2 positive breast cancer: NATASHA trial. J Clin Oncol. 2023;41(suppl 16):596. doi:10.1200/JCO.2023.41.16_suppl.596