EA1211 – Interim FDG-PET/CT for Predicting Direct Response of HER2+ Breast Cancer to Neoadjuvant Therapy: DIRECT Trial

The study chair for this trial is Heather Jacene, MD (Dana-Farber/Harvard Cancer Center) and the study co-chair is Roisin Connolly, MD (Cork University Hospital).

Current standard-of-care neoadjuvant regimens for patients with HER2-positive breast cancer incorporate two to three chemotherapies alongside HER2-targeting drugs. These treatments are highly efficacious, with pathologic complete response (pCR) rates as high as 50% to 70% and excellent long-term survival. However, the regimens that yield the highest pCR rates are also associated with significant side effects, including gastrointestinal and bone marrow toxicity, febrile neutropenia, and hospital admission. Researchers are currently investigating if they can use less intensive regimens and still achieve pCR in patients with a low risk of recurrence (e.g., the EA1181/CompassHER2-pCR trial).

Due to this delicate balance of efficacy and toxicity in HER2-positive breast cancer, physicians monitor how well neoadjuvant treatment is working for patients with early-stage breast cancer through physical examination and various imaging techniques (FDG-PET CT, mammography, ultrasound, or breast MRI) before surgery. The goal is to deliver the appropriate therapy as tailored as possible to individual patient needs, to maintain efficacy but minimize side effects. Non-invasive imaging is a key tool for meeting this goal.

A growing body of evidence suggests that of all the imaging modalities, FDG-PET/CT scanning may provide the most reliable indication of patients with HER2-positive early breast cancer who will not have pCR in the neoadjuvant setting. The technique is routinely used in lymphoma for this purpose. The EA1211/DIRECT trial aims to validate FDG-PET/CT scanning as an interim imaging biomarker across several standard clinical neoadjuvant regimens for HER2-positive early breast cancer. If confirmed, the study would have significant clinical impact and, in the future, treatment could be more personalized for patients unlikely to achieve a pCR. For example, additions or changes could be made to neoadjuvant therapy to increase the likelihood of a pCR.

The DIRECT study will enroll 235 patients. All patients in the trial will have a baseline FDG-PET/CT scan. They will then start pertuzumab-based neoadjuvant chemotherapy per physician discretion (except anthracycline-based regimens, which are not permitted). Patients will have a second FDG-PET/CT scan between days 15 and 21, and then complete neoadjuvant chemotherapy, followed by surgery, and additional treatment after surgery per standard of care.

The study’s primary objective is to estimate the negative predictive value of this interim biomarker for predicting pCR, using delta maximum standardized uptake value corrected for lean body mass day 15 (deltaSULmaxD15), completed through central review, of the primary breast cancer at a threshold of 40%.

To be eligible for the trial, patients must have stage II to stage IIIc HER2-positive breast cancer. Their cancer may be either ER-positive or ER-negative. Tumor size must be larger than 2 cm and patients may have node-negative or node-positive disease.

Learn more about EA1211/DIRECT at ecog-acrin.org.