Recent results from one of the UCSF I-SPY 2.2 study arms, published September 14, 2024 in Nature Medicine, 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. Importantly, for the patients with the immune positive subtype who achieved a complete response, over 50% achieved this without any standard chemotherapy, and over 90% did not need doxorubicin-cytoxin (AC), one of the standard treatments that is particularly toxic.
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.
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.
Another intriguing finding from the trial is that 35% of patients with luminal B breast cancer, a subtype that shows particularly low rates of response to chemotherapy, showed no or minimal residual disease after going through the treatment strategy.
