Heather Han, MD, research director, Department of Breast Oncology, Moffitt Cancer Center, discusses initial safety and efficacy results from the phase 2 NATASHA trial (NCT05325632) in patients with early-stage HER2-positive breast cancer.

The phase 1/2 neoadjuvant study aimed to optimize the efficacy of neoadjuvant therapy by adding a HER2-directed intratumoral dendritic cell (IT-DC1) therapy to the combination of paclitaxel, trastuzumab (Herceptin), and pertuzumab (Perjeta) in patients with HER2-positive breast cancer. Administration of a dendritic cell vaccine prior to treatment with an IgG1 antibody-mediating agent was hypothesized to drive tumor regression and improve immune stimulation without increasing toxicity, Han explains.

Twelve patients were enrolled onto the initial safety lead-in portion of the trial, Han continues. Patients were given DC1 plus trastuzumab and pertuzumab for 6 weeks, followed by 12 weeks of paclitaxel, trastuzumab, and pertuzumab, Han describes. DC1 was administered at doses of either 5.0 x 107 or 10.0 x 107 cells, she notes, adding that patients underwent blood collection at baseline and after the 6 weeks of vaccine administration. MRIs were also performed at baseline, prior to immunotherapy administration, and after chemotherapy administration, Han adds.

Results from the phase 1 portion of the study showed that both DC1 dose level cohorts demonstrated robust radiologic tumor responses, Han reports. Notably, the higher DC1 dose level led to a consistent decrease in peripherally circulating anti-HER2 T-cell response at week 6 vs the lower dose level, Han says. However, this could be attributed to increased T-cell trafficking at the tumor site, she explains.

Additionally, 7 patients who completed surgery (n = 11) experienced a pathologic complete response (pCR), Han details. Of the remaining 4 patients, 1 patient displayed a residual cancer burden (RCB) score of 1, 2 had a score of 2,and 1 had a score of 3. Assessment of radiologic responses per a breast MRI showed that 3 patients experienced a complete response, 8 had a partial response, and 1 achieved stable disease.

Dr Han reports grants from/contracts with AbbVie, GSK, G1 Therapeutics, Quantum Leap Healthcare Collaborative, Pfizer, Zymeworks, Department of Defense, Arvinas, Celcuity, and Marker; consulting fees from Eli Lilly; institutional research funding from Mersana Therapeutics; and data safety monitoring board/advisory board roles with Novartis, AstraZeneca, and Gilead.

Videos

Heather Han, MD, discusses initial safety and efficacy results from the phase 2 NATASHA trial in patients with early-stage HER2-positive breast cancer.

Dr Han on the Investigation of Neoadjuvant Therapy Plus a Dendritic Cell Vaccine in HER2+ Breast Cancer

Heather Han, MD, research director, Department of Breast Oncology, Moffitt Cancer Center, discusses prior research with gedatolisib that provided the rationale for the phase 3 VIKTORIA-1 trial (NCT05501886) in patients with hormone receptor (HR)–positive, HER2-negative metastatic breast cancer.

Patients with HR-positive, HER2-negative, metastatic breast cancer have effective frontline treatment options, including endocrine therapy combined with a CDK4/6 inhibitor, Han says. However, these patients often progress on or after their first-line treatment because of acquired resistance to endocrine therapy or CDK4/6 inhibitors, prompting investigations of more effective first- or second-line treatments that may overcome these resistance issues, Han explains.

Previously, a phase 1b study (NCT02684032) explored the clinical activity of gedatolisib, a dual small molecule inhibitor of PI3K and mTOR, in combination with the CDK4/6 inhibitor palbociclib (Ibrance) and the endocrine therapy fulvestrant (Faslodex), in patients with HR-positive, HER2-negative, advanced breast cancer with prior exposure to a CDK4/6 inhibitor. This triplet combination led to a median progression-free survival of 12.9 months in the second-line setting and an overall response rate of 63% in this population, regardless of 

Additionally, the combination was well tolerated, with 1 patient discontinuing treatment at the phase 3 dosing schedule because of treatment-related adverse effects (AEs). The incidence of grade 3/4 AEs typically associated with PI3K/mTOR inhibitors was low. In total, 7%, 6%, and 4% of patients experienced grade 3/4 hyperglycemia, diarrhea, and aspartate aminotransferase/alanine transaminase increase, respectively.

Based on the response rates and safety profile seen in this phase 1b trial, the registrational VIKTORIA-1 trial was designed, Han emphasizes. In this multinational trial, patients with HR-positive, HER2-negative, advanced breast cancer with prior exposure to a CDK4/6 inhibitor plus a non-steroidal aromatase inhibitor will be stratified by 

mutations will be randomized to receive gedatolisib plus palbociclib and fulvestrant; alpelisib (Piqray) plus fulvestrant; or gedatolisib plus fulvestrant. Patients without 

 mutations will be randomized to receive gedatolisib plus palbociclib and fulvestrant; gedatolisib plus fulvestrant; or fulvestrant alone.

Heather Han, MD, discusses prior research with gedatolisib that provided the rationale for the phase 3 VIKTORIA-1 trial (NCT05501886) in patients with hormone receptor (HR)–positive, HER2-negative metastatic breast cancer.

Dr Han on the Investigation of Gedatolisib in HR+/HER2– Metastatic Breast Cancer

Heather Han, MD, research director, medical oncologist, Department of Breast Oncology, Moffitt Cancer Center, discusses breakthrough data from the phase 3 DESTINY-Breast04 trial (NCT03734029).

This trial, which investigated fam-trastuzumab deruxtecan-nxki (Enhertu) vs physician’s choice of chemotherapy in HER2-low metastatic breast cancer, defined HER2-low as a new subset of breast cancer, creating new options for patients with an immunohistochemistry score of 1+ or 2+, who were historically considered HER2-negative, Han says. Trastuzumab deruxtecan showed improved progression-free survival (PFS) and overall survival (OS) in this patient population, Han explained. The median PFS was 9.9 months in all patients treated with trastuzumab deruxtecan vs 5.1 months with physician’s choice of chemotherapy, and the median OS was 23.4 months in all patients treated with trastuzumab deruxtecan vs 16.8 months with physician’s choice of chemotherapy.

In defining HER2-low as a new breast cancer subset, almost half of patients with metastatic breast cancer, including those with hormone receptor–positive or triple-negative disease, now have a more effective treatment, Han notes. Trastuzumab deruxtecan will help many patients with newly defined HER2-low disease live longer, Han concludes.

Heather Han, MD, discusses breakthrough data from the phase 3 DESTINY-Breast04 trial.

Heather Han, MD

Articles

Dr Han on the Investigation of Neoadjuvant Therapy Plus a Dendritic Cell Vaccine in HER2+ Breast Cancer

Dr Han on the Investigation of Gedatolisib in HR+/HER2– Metastatic Breast Cancer

Dr Han on the Significance of Trastuzumab Deruxtecan in HER2-Low Breast Cancer