In the neoadjuvant I-SPY2.2 trial, a treatment strategy including the antibody-drug conjugate datopotamab deruxtecan (Dato-DXd), partnered with the PD-L1 inhibitor durvalumab, yielded a high pathologic complete response rate, especially in immune-positive and “all-negative” subtypes.¹

“Dato-DXd/durvalumab is a promising therapy combination that may eliminate standard chemotherapy in many patients,” the authors wrote in an article in Nature Medicine,² which coincided with a presentation at the European Society for Medical Oncology (ESMO) Congress 2024.

Meghna S. Trivedi, MD, MS

I-SPY2.2 is incorporating novel therapies into the neoadjuvant treatment of high-risk stage II/III breast cancer using a sequential design. The results, which were presented by Meghna S. Trivedi, MD, MS, the Herbert Irving Assistant Professor of Medicine at Columbia University Irving Medical Center, New York, focused on Dato-DXd plus durvalumab.

As Dr. Trivedi noted, preclinical data have shown that topoisomerase I inhibitors such as Dato-DXd can enhance antitumor immune response and improve the efficacy of anti–PD-L1 therapy. In the phase Ib/II BEGONIA trial, in which Dato-DXd plus durvalumab was given in the first-line setting in metastatic triple-negative breast cancer, the response rate was 79%, and median progression-free survival approached 14 months.³

About I-SPY2.2

I-SPY2.2 is a phase II neoadjuvant sequential, multiple-assignment randomization trial for high-risk stage II/III breast cancer. The trial includes three blocks of treatment, with initial randomization to different experimental agent(s) (block A), followed (when further escalation is needed) by a taxane-based regimen tailored to tumor subtype (block B), followed (when further escalation is needed) by anthracycline/cyclophosphamide (block C). The treatment assignment/randomization was based on a unique set of biomarkers called “response-predictive subtypes”; they are defined by hormone receptor status, HER2 status, predicted benefit derived from immunotherapy, DNA damage repair deficiency (DRD), and luminal signaling.

Each patient was evaluated for response to therapy with breast magnetic resonance imaging (MRI) and core biopsies as part of the predicted residual cancer burden (pre-RCB) assessment. These results guided the decision-making for de-escalation or early escalation of therapy.

Dato-DXd Plus Durvalumab Cohort

In total, 106 patients began treatment with Dato-DXd plus durvalumab in block A. This doublet proved to be beneficial, especially in certain subsets.

“The Dato-DXd plus durvalumab treatment strategy was highly effective, with an overall observed pathologic complete response rate of 50%,” Dr. Trivedi announced. It was most effective in the immune-positive subtype, where after block A, it exceeded the prespecified threshold for success—in other words, it “graduated.”

“At the 2024 ASCO Annual Meeting, we showed that Dato-DXd plus durvalumab met graduation criteria for block A alone in the immune-positive subtype.⁴ In the 2024 ESMO Congress presentation of the entire treatment strategy (blocks A + B + C), although the immune-positive subtype demonstrated the highest rate of pathologic complete response (79%), the rate in the dynamic control was also high (78%). For this reason, the entire treatment strategy did not graduate in the immune-positive subtype.

“However, it is important to highlight the timing of these responses,” Dr. Trivedi added. “In keeping with the graduation in block A, the exciting finding for the immune-positive subtype was that in patients who achieved a pathologic complete response, 54% were achieved after block A, and 92% were achieved after block B…. Nearly all pathologic complete responses were achieved by the end of block B, avoiding anthracycline/cyclophosphamide.”

In addition, in the hormone receptor–negative/immune-negative/DRD-negative (all-negative) subtype, the full treatment strategy (blocks A + B + C) also graduated. Although the rate of pathologic complete response was lower—44% in the intent-to-treat population (56% in the pre-RCB–met population)—“it far exceeded the rate of 16% in the dynamic control,” thus meeting the graduation strategy in this subset of patients, she explained. “The numbers in this subtype are small, but it shows how meaningful it can be to find a new and better solution for a traditionally hard-to-treat subtype.”

Based on the I-SPY2.2 findings, Dr. Trivedi concluded: “Further investigation in the randomized controlled trial setting is warranted in the immune-positive and hormone receptor–negative/immune-negative/DRD-negative subtypes.”

EXPERT POINT OF VIEW

Fatima Cardoso, MD

I-SPY2.2’s invited discussant, Fatima Cardoso, MD, Director of the Breast Unit at the Champalimaud Clinical Center in Lisbon, and President of the ABC Global Alliance, said this trial offered some interesting observations for the treatment of various breast subtypes but provokes some questions.

Most notably, Dr. Cardoso said, a treatment regimen of datopotamab deruxtecan (Dato-DXd) and durvalumab plus chemotherapy was found to be effective in the subtype “that is quite hard to treat,” which is hormone receptor–negative, HER2-negative, immune-negative, and DNA damage repair–deficient patients. In that group, the full three-block regimen of Dato-DXd and durvalumab plus taxane plus anthracycline/cyclophosphamide outperformed the dynamic control, with pathologic complete response rates of 44% and 16%, respectively, therefore “graduating” to further evaluation.

In immune-positive patients, this three-block regimen resulted in the highest rate of pathologic complete response among all cohorts—79%. However, the rate in the dynamic control group was 78%; therefore, it was not considered more beneficial and did not graduate in this subtype.

“The decision to move forward in the development of a new therapeutic strategy must always be a balance between efficacy and toxicity,” Dr. Cardoso continued. “Dato-DXd plus durvalumab plus taxane-based and anthracycline-based chemotherapy (blocks A, B, and C) was associated with high toxicity, including a toxic death. We are always very careful when we see toxic deaths in such a small number of patients.”

Dr. Cardoso continued: “We also need to remember that the magnitude of difference we see in pathologic complete response often does not translate into long-term benefit. That is why we need to evaluate these initial results in a phase III trial.”

Remaining Questions

Dr. Cardoso posed the following questions still to be answered:

• How can we identify the characteristics of the tumors that achieve pathologic complete response after block A alone and thus can avoid an “add-on” treatment strategy?
• With the achievement of a pathologic complete response with less treatment, can we be sure additional treatments are not worthwhile, especially since there were low numbers of patients in each subtype?
• For patients achieving a pathologic complete response only after blocks A, B, and C, how can the individual benefit of each component be ascertained?
• How can I-SPY2.2 results help to define the best design for a phase III trial for drugs that graduate?

 “We tend to go for the easiest design, which is to add an experimental drug to what we are already giving,” Dr. Cardoso explained. “I-SPY2.2 clearly shows this is probably not the best strategy for all new treatments being developed, and a sequential strategy may be better—it would allow us to escalate and de-escalate for the individual patient.”

DISCLOSURE: Dr. Trivedi has received institutional research funding from AstraZeneca, Gilead Sciences, Lilly, Merck, Novartis, Phoenix Molecular Designs, and Regeneron. Dr. Cardoso disclosed financial relationships with Amgen, Astellas/Medivation, AstraZeneca, Bayer, Celgene, Daiichi Sankyo, Eisai, GE Oncology, Genentech, Gilead Sciences, GlaxoSmithKline, Iqvia, MacroGenics, Medscape, Merck Sharp, Merus BV, Mylan, Mundipharma, Novartis, Pfizer, Pierre-Fabre, prIME Oncology, Roche, Sanofi, Samsung Bioepis, Seagen, Teva, and TouchIME.

REFERENCES

1. Trivedi MS, Shatsky RA, Nanda R, et al: Rates of pathologic complete response after datopotamab deruxtecan plus durvalumab treatment strategy in the neoadjuvant setting: Results from the I-SPY2.2 trial. ESMO Congress 2024. Abstract LBA15. Presented September 14, 2024.

2. Shatsky RA, Trivedi MS, Yau C, et al: Datopotamab–deruxtecan plus durvalumab in early-stage breast cancer: The sequential multiple assignment randomized I-SPY2.2 phase 2 trial. Nat Med. September 14, 2024 (early release online).

3. Schmid P, Wysocki P, Ma C, et al: Datopotamab deruxtecan + durvalumab as first-line treatment for unresectable locally advanced/metastatic triple-negative breast cancer: Updated results from BEGONIA, a phase 1b/2 study. Ann Oncol 34(suppl 2):S337, 2023.

4. Shatsky RA, Trivedi MS, Omene CO, et al: Rates of pathologic complete response after datopotamab deruxtecan plus durvalumab in the neoadjuvant setting: Results from the I-SPY2.2 trial. 2024 ASCO Annual Meeting. Abstract LBA501.