Neoadjuvant Dato-DXd, Durvalumab Response Rates Vary in Breast Cancer

Guiding treatment via response predictive subtype could be beneficial for identifying patients with high-risk breast cancer who may respond to Dato-DXd plus durvalumab.

Datopotamab deruxtecan (Dato-DXd) plus durvalumab (Imfinzi) elicited a pathologic complete response (pCR) rate of 50% in patients with stage II/III high-risk HER2-negative breast cancer, according to data from the phase 2 adaptive I-SPY 2.2 trial (NCT01042379).

The study findings, which were presented at the 2024 ESMO Congress, highlighted the importance of evaluating treatment response per response predictive subtype (RPS).¹

“The I-SPY 2.2 Dato-DXd plus durvalumab treatment strategy resulted in an overall observed pCR rate of 50%. Further investigation in the randomized controlled trial setting in the immune-positive and hormone receptor [HR]–negative/DNA damage repair deficiency [DRD]–negative subtypes is warranted,” Meghna S. Trivedi, MD, MS, lead study author and assistant professor of medicine at Columbia University Irving Medical Center in New York, New York, said in a presentation.

The rationale for use of the combination in the early stage setting stems from the “promising” results from the phase 1b/2 BEGONIA trial (NCT03742102) built on preclinical data showing enhanced antitumor immune response when topoisomerase-1 inhibitors are combined with PD-L1 therapy. Findings from the trial demonstrated that the combination led to a confirmed objective response rate, median progression-free survival, and median duration of response of 79% (95% CI, 66.8%-88.3%), 13.8 months, and 15.5 months, respectively, as frontline therapy in patients with metastatic triple-negative breast cancer.²

“[The present] study is enabled by the unique I-SPY 2.2 trial design which utilizes sequential treatment blocks assigned based on a unique set of biomarkers called RPS,” Trivedi said. Per the study design patients received experimental treatment in block A, RPS-guided therapy in block B, and salvage chemotherapy in block C. Patients could receive early treatment escalation in blocks A and B if needed. Alternatively, patients in blocks A and B could proceed directly to surgery, foregoing subsequent therapy if de-escalation was deemed appropriate.¹

“The goal is to identify novel agents and to individualize neoadjuvant breast cancer treatment [in order] to achieve a pCR,” Trivedi said. “The RPS examines immunotherapy benefit, DRD, HR status, and HER2 status over the course of treatment. Each patient is evaluated for response to therapy with breast MRI and core biopsy as part of the predicted RCB or pre-RCB assessment. The pre-RCB guides decision-making for de-escalation and early escalation of therapy [although] the treatment decisions are ultimately at the discretion of the treating physician.”

Within the trial there were 5 RPS categories that received the following treatments in blocks B and C, respectively, based on RPS:

1. HR-positive/HER2-negative/immune-negative/DRD-negative;
   1. Paclitaxel; doxorubicin and cyclophosphamide (AC)
2. HR-negative/HER2-negative/immune-negative/DRD-negative;
   1. Paclitaxel plus carboplatin and pembrolizumab (Keytruda); AC plus pembrolizumab
3. HER2-negative/immune-positive;
   1. Paclitaxel plus carboplatin and pembrolizumab; AC plus pembrolizumab
4. HER2-negative/immune-negative/DRD-positive; and
   1. Paclitaxel plus carboplatin and pembrolizumab; AC plus pembrolizumab
5. HER2-negative/immune-negative/DRD-positive.
   1. Paclitaxel plus carboplatin; AC plus pembrolizumab

“In block B we used the RPS to optimize drug assignment based on the results from over 2000 patients previously treated in I-SPY with the goal to improve efficacy and minimize toxicity. The same patients are used as the subtype specific comparator arm in I-SPY 2.2 as the dynamic control,” Trivedi said.

To be eligible for enrollment in the Dato-DXd/durvalumab arm patients had to have anatomic stage II or III HER2-negative MammaPrint high-risk breast cancer. These patients were enrolled in block A and received 6 mg/kg of intravenous (IV) Dato-DXd plus 1120 mg of IV durvalumab on day 1 of each 3-week cycle for up to 4 cycles.

Baseline characteristics of the overall population (n = 106) indicated that the median age at screening was 50.5 years (range, 25.0-77.0) and most patients were not Hispanic/Latino (76.4%) and were White (59.4%). Within the HR-positive, HER2-negative population (n = 42) patients were balanced between the HR-positive/HER2-negative/immune-negative/DRD-negative (n = 25) and HR-negative/HER2-negative/immune-negative/DRD-negative populations (n = 23). Within the HR-negative, HER2-negative population (n = 64) most patients had HER2-negative/immune-positive disease (n = 47) vs HER2-negative/immune-negative/DRD-positive disease (n = 11).

Of the 106 patients who were treated in block A, 64 went on to receive treatment in block B, and 25 in block C.

“Neither the HR-positive/immune-negative/DRD-negative, nor the immune-negative/DRD-positive subtypes outperformed the dynamic control,” Trivedi said. In the former population the pCR rate was 14% (95% CI, 0%-28%) vs 15% in the dynamic control population (95% CI, 6%-24%; P > .41). In the latter population (n = 10) the pCR rate was 50% (95% CI, 25%-70%) vs 72% (95% CI, 52%-92%) in the dynamic control population (P > .10). Moreover, the HER2-negative/immune-positive population (n = 47) fell short of exceeding the model rate of pCR, with a rate of 77% (95% CI, 65%-89%) vs 78% (95% CI, 66%-90%) in the dynamic control population (P >.46).

However, the HR-negative/HER2-negative/immune-negative/DRD-negative population (n = 23) which “historically has low rates of response,” saw a pCR rate of 44% (95% CI, 24%-64%) vs 16% (95% CI, 6%-26%) with the dynamic control (P > .99), meeting graduation criteria, according to Trivedi.

“What is important to highlight is the timing of when the pCRs occurred. The overall rate of observed pCR [with] the treatment strategy was 50%. In the immune-positive and triple-negative subtypes, greater than 50% of the observed pCRs were achieved by the end of block A, avoiding all standard chemotherapy and nearly all pCRs were achieved by the end of block B, avoiding AC,” Trivedi said.

Among all patients (n = 106) the cumulative percentages of observed pCR rates by the end of blocks A, B, and C were 47% (n = 25/53), 89% (n = 47/53), and 100% (n = 53/53), respectively. In the HER2-negative/immune-positive population (n = 47) these rates were 54% (n = 20/37), 92% (n = 34/37), and 100% (n = 37/37), respectively, for a total pCR rate of 79%. In the HR-negative/HER2-negative population (n = 63), excluding 1 patient who did not receive pembrolizumab in block B, the respective rates were 54% (n = 21/39), 92% (n = 36/39), and 100% (n = 39/39), for a total pCR rate of 62%.

“The reported toxicity profile of this combination was consistent with prior studies,” Trivedi said. “There were a variety of other adverse effects [AEs] associated with cytotoxic chemotherapy that can be avoided if a pCR is achieved in block A. There was one participant, a 70-year-old with history of hypertension, who experienced a grade 5 cardiac arrest in block B. The immune-related AEs across all blocks were also consistent with previous findings. To date, there are no reports of adrenal insufficiency in patients who exited after block A.”

Disclosures: Dr Trivedi reported institutional research funding from AstraZeneca, Gilead Sciences, Lilly, Merck, Novartis, Phoenix Molecular Designs, and Regeneron.

References

1. Trivedi M, Shatsky RA, Nanda R, et al. Rates of pathologic complete response (pCR) after datopotamab deruxtecan (dato) plus durvalumab (durva) treatment strategy in the neoadjuvant setting. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Presentation LBA15.

2. Schmid P, Wysocki PJ, Ma CX, et al. Datopotamab deruxtecan (Dato-DXd) + durvalumab (D) as first-line (1L) treatment for unresectable locally advanced/metastatic triple-negative breast cancer (a/mTNBC): updated results from BEGONIA, a phase Ib/II study. Ann Oncol. 2023;34(suppl 2):S337. doi:10.1016/j.annonc.2023.09.556