There is a continued need to improve treatment strategies and therapies that not only improve patient survival, and also reduce long-term treatment-related toxicities.
This is particularly true for aggressive breast cancer subtypes in which many patients are cured of their disease, but at the expense of long-lasting, serious complications, including peripheral neuropathy, adrenal insufficiency, therapy-related leukemia, and long-term heart damage.
For over a decade, the UCSF-led I-SPY trial consortium has worked to accelerate the development of new therapeutics for early-stage breast cancer, focusing on rapid identification of targeted treatment regimens for Phase III trials.
I-SPY2 has focused on patients with stage II and III molecularly high-risk breast cancer, with the early endpoint of pathologic complete response (pCR) – the elimination of cancer all signs of cancer in response to treatment – which correlates strongly with fewer complications and prediction of good long-term outcomes.
Like its predecessor trial, I-SPY2, the I-SPY 2.2 trial evaluates multiple agents in parallel, using an adaptive randomization algorithm that preferentially assigned patients to study arms that exhibited efficacy in the same breast cancer subtype.
By using a Sequential Multiple Assignment Randomized Trial (SMART) design, the trial has enabled the testing of drugs in sequence and a personalized approach to therapy, using early end points to optimize therapies based on individual patient responses.
Recent results from one of the I-SPY 2.2 study arms, published September 14, 2024 in Nature Medicine and presented simultaneously at European Society for Medical Oncology’s (ESMO) annual meeting, showed that neoadjuvant treatment with the antibody-drug conjugate datopotamab–deruxtecan (Dato-DXd) in combination with the immune checkpoint inhibitor, durvalumab (Imfinzi), produced high rates of pCR in patients who have an immune breast cancer subtype as well as a subtype of triple negative cancer that would ordinarily have a high risk of recurrence.
Among 106 patients with HER2-negative breast cancer, 50% of the patients overall had a complete response.
The smart trial design included three neoadjuvant treatment blocks (across six prespecified HER2-negative subtypes), with patients initially randomized to different experimental agents (block A), followed by a taxane-based chemotherapy regimen tailored to the patient’s specific tumor subtype (block B), followed by combination chemotherapy regimen doxorubicin–cyclophosphamide or AC (block C).
The clinical goal is to get each patient to pCR with the minimum required amount of therapy, limiting exposure to potential toxicities.
Subtype-specific algorithms based on MRI volume change and core biopsy guided treatment redirection after each block, including the option of early surgery in patients who were predicted to have a high likelihood of pCR.
In the immune-positive subtype, Dato-DXd/Imfinzi combination exceeded the expected threshold for success after block A, and across all blocks had a complete response rate of 79%.
This pCR rate was equivalent to the rate expected for the standard of care (neoadjuvant treatment with chemotherapy), but 54% achieved that result after Dato-DXd/Imfinzi alone (block A) and 92% without doxorubicin–cyclophosphamide (after blocks A + B).
For patients in hormone-negative/ immune-negative subtypes, treatment with Dato-DXd and Imfinzi led to a pCR rate of 46% across all three blocks of treatment, exceeding the threshold for success.
It is pretty exciting to see this pace of release of important results. Dato-DXd/durvalumab is a promising therapy combination that can eliminate standard chemotherapy in many patients, particularly the immune-positive subtype.
Laura Esserman, MD, MBA, Director of the UCSF Breast Care Center
There were no new toxicities from the treatments observed in the study arm. While common side effects of nausea, fatigue stomatitis and rash were observed in block A, they were almost entirely low grade and resolved after treatment. No patients receiving block A treatment alone had adrenal insufficiency.
Side effects like neuropathy and cytopenia in block B and C were consistent with treatment with taxanes and chemotherapy. The smart design of the trials showed the benefit of being able to evaluate neoadjuvant therapies like Dato-DXd/Imfinzi alone to minimize side-effects.
The trial is ongoing, and the researchers are making adjustments based on specific patient’s experiences and treatment outcomes. They hope to continue investigation of Dato-DXd/Imfinzi treatment combination in the immune-positive and HR−immune−DRD subtypes, which appear to be the most likely to benefit from this combination.
Newswise/AJ
