Datopotamab-deruxtecan in early-stage breast cancer: the sequential multiple assignment randomized I-SPY2.2 phase 2...

Area of Science:

• Oncology
• Clinical Trials
• Pharmacology

Background:

• Patient-centric care aims for personalized treatments and reduced toxicity in cancer therapy.
• The I-SPY2.2 trial employs a novel neoadjuvant sequential therapy design for high-risk breast cancer.
• Datopotamab-deruxtecan (Dato-DXd) is an investigational agent tested within this adaptive trial framework.

Purpose of the Study:

• To evaluate the efficacy and safety of datopotamab-deruxtecan (Dato-DXd) as a neoadjuvant treatment for high-risk stage 2/3 breast cancer within the I-SPY2.2 trial.
• To assess Dato-DXd's performance across different breast cancer subtypes using a sequential, adaptive treatment strategy.
• To identify specific patient populations where Dato-DXd demonstrates significant pathological complete response (pCR).

Main Methods:

• The I-SPY2.2 trial utilizes a sequential multiple assignment randomization design with three blocks of neoadjuvant therapy.
• Patients with high-risk stage 2/3 breast cancer were randomized to receive investigational agents, including Dato-DXd, in block A.
• Treatment decisions were guided by imaging and biopsy data, with early surgical resection an option for predicted responders. Primary endpoint was pCR.

Main Results:

• Datopotamab-deruxtecan (Dato-DXd) did not meet the primary success threshold after block A in any breast cancer subtype.
• However, the overall treatment strategy incorporating Dato-DXd achieved success in the hormone receptor-negative, HER2-, Immune-, DNA repair deficiency- subtype, with a 41% pCR rate.
• Observed toxicities were generally low-grade, with stomatitis and ocular events being the most frequent, and no new safety concerns emerged.

Conclusions:

• Datopotamab-deruxtecan (Dato-DXd) demonstrated notable activity and was well-tolerated in a specific subtype of high-risk breast cancer within the I-SPY2.2 adaptive trial.
• The findings support further investigation of Dato-DXd in the hormone receptor-negative/HER2-/Immune-/DNA repair deficiency- breast cancer signature.
• The I-SPY2.2 trial's adaptive design effectively identified a subset of patients benefiting from Dato-DXd, aligning with personalized medicine goals.