Editor's Note: With advancements in medical research and technology, new therapies for complex diseases like breast cancer are continually emerging. Dato-DXd, a novel antibody-drug conjugate (ADC), shows potential in the treatment of breast cancer. The I-SPY2.2 trial, presented at ASCO 2024, utilizes an innovative trial design to demonstrate the efficacy of Dato-DXd as a monotherapy in HR-HER2-negative breast cancer, particularly in TNBC patients and those with positive immune markers. Oncology Frontier interviewed Professor Jane Lowe Meisel from Emory University's Winship Cancer Institute to delve into the innovative I-SPY 2.2 trial and its implications for personalized neoadjuvant therapy in high-risk breast cancer patients.I-SPY2.2: TROP-2 ADC Dato-DXd as Neoadjuvant Therapy in High-Risk Breast Cancer
Study Design
I-SPY2.2 is a multicenter, phase II platform trial using a sequential multiple assignment randomized trial (SMART) design to evaluate novel experimental treatments in the neoadjuvant breast cancer setting. The innovative therapy is administered initially in one sequence (Block A), followed by standard chemotherapy/targeted therapy as needed (Block B/C). The goal is to identify drugs that lead to pathological complete response (pCR) through either novel targeted drugs alone or optimal therapy sequences predicted by tumor response subtype (RPS).
Subtype Classification
RPS categorizes patients based on expression-based immune markers, DNA repair deficiency (DRD), luminal markers, hormone receptor (HR), and HER2 status:
- S1: HR+HER2- immune-DRD-
- S2: HR-HER2- immune-DRD-
- S3: HER2- immune+
- S4: HER2- immune-DRD+
- S5: HER2+/non-Luminal
- S6: HER2+/Luminal
Treatment Protocol
Eligible RPS S1, S2, S3, and S4 subtypes were assigned to Dato-DXd in Block A. Patients were monitored via MRI during treatment (weeks 3, 6, and 12 of Block A and B). Those showing treatment response by MRI or biopsy could opt for early surgery; otherwise, they proceeded to the next treatment block (B +/- C). Block B included specific taxane-based regimens tailored to RPS:
- S1: Taxol
- S2 and S3: Taxol + Carboplatin + Pemetrexed
- S4: Taxol + Carboplatin vs. Taxol + Carboplatin + Pemetrexed
Block C (AC or AC + Pemetrexed if HR-HER2-) was continued for non-surgical patients post-Block B. The primary endpoint was pCR, evaluated within each RPS and HR+HER2- and HR-HER2- markers.
Data Analysis
A Bayesian covariate-adjusted model was used to estimate pCR rates, comparing posterior distributions against fixed thresholds specific to each subtype. The model utilized available pCR data, substituting MRI data where pCR data was unavailable. Bayesian modeling estimated pCR rates considering the timing of pCR occurrence in the multi-decision treatment scheme, comparing posterior probabilities to dynamic controls based on historical I-SPY data.
Results
From August 2022 to June 2023, 103 patients were randomized to the Dato-DXd group. All patients completed Block A; 33 patients underwent surgery with Dato-DXd monotherapy. Dato-DXd efficacy results as a monotherapy are summarized in Figure 2. As of April 24, 2024, no subtype met the “graduation threshold” (an 85% probability of phase III success). TNBC and immune marker-positive subtypes showed a higher likelihood of achieving pCR.
Conclusion
Dato-DXd monotherapy demonstrated effectiveness, particularly in HR-HER2-negative breast cancer, but did not meet the predetermined efficacy threshold in the I-SPY 2.2 trial. Further studies are warranted.
Clinical Trial Information: NCT01042379.
Oncology Frontier: Dr. Miesel, could you provide an overview of the recent findings from the I-SPY 2.2 trial?
Dr. Jane Miesel: Certainly. The I-SPY 2.2 trial is a continuation of the original I-SPY 2 trial, which started in 2010 with the goal of personalizing neoadjuvant therapy for high-risk breast cancer patients. This trial design is quite unique, as it aims to provide more targeted and better-tolerated treatments with the goal of curing breast cancer more effectively.
Oncology Frontier: Can you elaborate on the structure of the I-SPY 2.2 trial?
Dr. Jane Miesel: The I-SPY 2.2 trial is structured into three blocks. In the first block, patients receive experimental therapies only. For this arm of the trial, we used Datapodimab durextacan. If patients meet specific criteria after this first block, they can proceed directly to surgery, bypassing further systemic therapy. If not, they move on to a more personalized taxane-based therapy in block B, which may include immunotherapy or carboplatin depending on their specific subtype. Finally, if criteria are still not met, traditional AC therapy is administered before surgery.
Oncology Frontier: What were the key outcomes of this trial so far?
Dr. Jane Miesel: We observed that 32% of the enrolled patients went to surgery after the first block of therapy, with high PCR rates in those who met the criteria for a low predicted residual cancer burden. The therapy was well-tolerated, with no new safety signals and no treatment discontinuations due to toxicity. This is promising as it supports the goal of the I-SPY 2.2 trial to find better-targeted and better-tolerated drugs for breast cancer treatment.
Oncology Frontier: What are the next steps for Datapodimab durextacan in this context?
Dr. Jane Miesel: While the single-agent Datapodimab durextacan did not meet criteria to be studied on its own, there is considerable excitement about combination therapies, particularly with immunotherapy. Ongoing trials are exploring longer durations of treatment and combination therapies, which could enhance the effectiveness of this drug. There are also promising studies in the metastatic setting and for patients with residual disease after neoadjuvant therapy.
Oncology Frontier: How do you see the future of personalized neoadjuvant therapy evolving?
Dr. Jane Miesel: The future looks promising, especially with the ongoing trials. Personalized therapy has the potential to significantly improve outcomes for high-risk breast cancer patients. The I-SPY 2.2 trial is paving the way for more tailored and effective treatments, which could eventually lead to better survival rates and improved quality of life for these patients.
